EPA/600/R-02/050

September 2003

Human Health Research Strategy

Office of Research and Development

U.S. Environmental Protection Agency

Washington, DC 20460
 

Disclaimer

This document has been subjected to review by the National Health and Environmental

Effects Research Laboratory and the Science Advisory Board and has been approved for

publication. It does not constitute an EPA position or policy concerning human health risk

assessment research. Any mention of trade names does not constitute EPA endorsement.

iv

TABLE OF CONTENTS

Page

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

LIST OF FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi

AUTHORS, CONTRIBUTORS, AND REVIEWERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

PEER REVIEW HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

ABBREVIATIONS AND ACRONYMS .......................................... ix

GLOSSARY ............................................................... ..x

EXECUTIVE SUMMARY ................................................... . E-1

1. INTRODUCTION ........................................................ 1-1

1.1 PURPOSE OF THE STRATEGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-1

1.2 CURRENT RESEARCH PROGRAM ON HUMAN HEALTH ................ 1-2

1.3 FUTURE RESEARCH PRIORITIES ..................................... 1-4

1.3.1 Framework for an Integrated Research Program in ORD ............... 1-4

1.3.2 Research Themes ............................................ . .1-8

1.4 STRATEGIC PRINCIPLES ........................................... . 1-9

2. RESEARCH TO IMPROVE THE SCIENTIFIC FOUNDATION OF HUMAN HEALTH

RISK ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-1

2.1 RESEARCH ON HARMONIZING RISK ASSESSMENT APPROACHES . . . . . 2-1

2.1.1. Scientific Uncertainties .......................................... 2-1

2.1.2 Research Objectives ............................................. 2-2

2.1.3 Research Approach ............................................. 2-2

2.2 RESEARCH ON AGGREGATE AND CUMULATIVE RISK ................ 2-6

2.2.1 Scientific Uncertainties .................................. . ....... 2-6

2.2.2 Research Objectives ............................................ . 2-7

2.2.3 Research Approach ............................................ . 2-7

2.3 RESEARCH ON SUSCEPTIBLE AND HIGHLY-EXPOSED

SUBPOPULATIONS ............................................... 2-12

2.3.1 Scientific Uncertainties ......................................... 2-13

2.3.2 Research Objectives ........................................... 2-14

2.3.3 Research Approach ............................................ 2-14

3. RESEARCH TO ENABLE EVALUATION OF PUBLIC HEALTH OUTCOMES FROM

RISK MANAGEMENT ACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3-1

3.1 SCOPE AND DEFINITIONS ........................................... 3-2

3.2 SCIENTIFIC UNCERTAINTIES ....................................... 3-4

3.3 SCIENTIFIC OBJECTIVES ........................................... 3-5
v

 3.4 RESEARCH APPROACH ............................................. 3-6

3.5 RESEARCH IMPLEMENTATION ..................................... . 3-7

4. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-1

APPENDICES

APPENDIX A- ORD Research Plans and Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-1

APPENDIX B- EPA’s Office of Research and Development-Organizational Chart . . . . A-3

APPENDIX C- Examples of Mechanistic Data Used in Risk Assessment . . . . . . . . . . . . A-4

 APPENDIX D- Agencies Having Research Programs Complementary to ORD . . . . . . . A-5

APPENDIX E- Examples of Health and Environmental Databases to Evaluate Public Health 

Outcomes From Risk Management Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-7
vi

 LIST OF FIGURES

Figure Page

1-1 Relationship Between Core and Problem-Driven Research ................... 1-1

1-2 The Risk Assessment-Risk Management Paradigm ......................... 1-2

1-3 The Exposure-Dose-Effect Continuum .................................... 1-5

1-4 ORD’s Approach to Solving Agency Problems ............................. 1-6

1-5 ORD’s Integrated Research Program ..................................... 1-7

1-6 Integrated ORD Research Program on Molds and Asthma in Children ......... . 1-8

1-7 Role of Research in Assessment of Health Outcomes ....................... . 1-9

in the Risk Assessment and Risk Management Process

3-1 Role of Analysis of Health Outcomes in the Risk Management Process .......... 3-3
vii

 AUTHORS, CONTRIBUTORS, AND REVIEWERS

Executive Lead

Harold Zenick, National Health and Environmental Effects Research Laboratory (NHEERL),

Office of Research and Development (ORD), U.S. Environmental Protection Agency (EPA)

Authors

Hugh Barton, ORD/NHEERL

Jerry Blancato, ORD/National Exposure Research Laboratory (NERL)

Michael Callahan, formerly with ORD/National Center for Environmental Assessment 

(NCEA)

Larry Cupitt, ORD/NERL

Judith Graham, formerly with ORD/NERL

Karen Hammerstrom, ORD/NCEA

Jonathan Herrmann, ORD/National Risk Management Research Laboratory (NRMRL)

Robert Kavlock, ORD/NHEERL

Gary Kimmel, ORD/NCEA

Hugh McKinnon, ORD/NRMRL

Hugh Tilson, ORD/NHEERL

Vanessa Vu, formerly with ORD/NCEA

Jennifer Orme-Zavaleta, ORD/NHEERL

Contributors

Linda Birnbaum, ORD/NHEERL

Rebecca Calderon, ORD/NHEERL

Robert Chapman, formerly with 

 ORD/NCEA

Gary Foureman, ORD/NCEA

Herman Gibb, ORD/NCEA

Annie Jarabek, ORD/NCEA

Carole Kimmel, ORD/NCEA

Suzanne McMaster, ORD/NHEERL

Patricia Murphy, ORD/NCEA

Dale Pahl, ORD/NERL

Julian Preston, ORD/NHEERL

Chris Saint, ORD/National Center for 

Environmental Research (NCER)

John Schaum, ORD/NCEA

Linda Sheldon, ORD/NERL

William Steen, formerly with ORD/NERL

Michel Stevens, ORD/NCEA

Reviewers

Tom Barnwell, ORD/NERL Steven Hedtke, ORD/NHEERL

William Farland, ORD/NCEA Robert Menzer, formerly of ORD/NCER

Elaine Francis, ORD/NCER Lee Mulkey, ORD/NRMRL

Fred Hauchman, ORD/NHEERL Kevin Teichman, ORD/Office of Science Policy 

 (OSP)
viii

PEER REVIEW 

Peer review is an important component of research strategy development. The peer review

history for this research strategy follows:

ORD Science Council: March 21, 2001, Elaine Francis and Kevin Teichman, Lead Reviewers

External Peer Review: Science Advisory Board/Human Health Research Strategy (HHRS)

Review Panel, November 20-21, 2002

External Peer Review Panel Members:

Dr. James Klaunig, Panel Chair, Professor of Toxicology and Director of Toxicology,

Department of Pharmacology and Toxicology, Indiana University School of Medicine,

Indianapolis, IN

Dr. Paul Blanc, Professor of Medicine and Endowed Chair in Occupational and Environmental

Medicine, University of California-San Francisco, San Francisco, CA 

Dr. James Gibson, Research Professor of Pharmacology and Toxicology, The Brody School of

Medicine, East Carolina University, Greenville, NC

Dr. Michael Jayjock, Senior Research Fellow, Rohm and Haas Co., Springhouse, PA

Dr. George Lambert, Associate Professor of Pediatrics and Associate Director of the Clinical

Research Center, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson

Medical School, Piscataway, NJ

Dr. Joseph Landolph, Associate Professor of Molecular Pharmacology and Toxicology, School

of Pharmacy, University of Southern California in Los Angeles, Los Angeles, CA

Dr. Steve Lewis, Distinguished Scientific Associate, Exxon Mobil Biomedical Sciences, Inc., 

Annandale, NJ

Dr. Randy Maddalena, Indoor Environment Department Lawrence Berkeley National

Laboratories, Berkeley, CA

Dr. Maria Morandi, Assistant Professor, University of Texas Houston Health Sciences Center,

School of Public Health, Houston, TX

Dr. Beate Ritz, Associate Professor, Department of Epidemiology and Center for Occupational

and Environmental Health, School of Public Health, University of California in Los Angeles,

Los Angeles, CA

Dr. Herbert Rosenkrantz, Professor, Environmental and Occupational Health and Pharmacology,

University of Pittsburgh, Pittsburgh, PA

Dr. Robert Spengler, Associate Administrator, Agency for Toxic Substances and Disease

Registry, Atlanta, GA

Dr. Bernard Weiss, Professor, Environmental Medicine and Pediatrics, University of Rochester

School of Medicine and Dentistry, Rochester, NY

Peer Review Coordinator:

Dr. Sue Shallal, Designated Federal Officer, Environmental Health Committee EPA Science

Advisory Board, Environmental Protection Agency, Washington, DC
ix

ABBREVIATIONS AND ACRONYMS

Ah Arylhydrocarbon

ATSDR Agency for Toxic Substance and Disease Registry

BBDR Biologically Based Dose Response Modeling

CCL Contaminants Candidate List

CDC Centers for Disease Control and Prevention

EPA U.S. Environmental Protection Agency

FFDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act

GPRA Government Performance and Results Act

HUD Housing and Urban Development

IPCS International Programme on Chemical Safety

MOE Margin of Exposure

NAS National Academy of Science

NCEA National Center for Environmental Assessment (EPA/ORD)

NCEH National Center for Environmental Health

NCER National Center for Environmental Research (EPA/ORD)

NCHS National Center for Health Statistics

NCI National Cancer Institute

NCT National Center for Toxicogenomics

NCTR National Center for Toxicological Research

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

NIAID National Institute of Allergy and Infectious Diseases

NICHD National Institute of Child Health and Human Development

NIEHS National Institute of Environmental Health Sciences

NOAEL No-Observed-Adverse-Effect Level

NRC National Research Council (NAS) 

NRMRL National Risk Management Research Laboratory (EPA/ORD)

NTP National Toxicology Program

OPP Office of Pesticide Programs

ORD Office of Research and Development (EPA)

OSP Office of Science Policy

PBPK Physiologically Based Pharmacokinetic Modeling

PK Pharmacokinetic

QSAR Quantitative Structure-Activity Relationship

RfC Reference Concentration

RfD Reference Dose

SAB EPA’s Science Advisory Board

STAR EPA/ORD Science to Achieve Results Extramural Grants Program

TSCA Toxic Substances Control Act 

TEF Toxicity Equivalent Factor

UF Uncertainty Factor
x

GLOSSARY

Aggregate Exposure: The combined exposure of an individual or defined population to a

specific agent or stressor via relevant routes, pathways, and sources (working definition

developed by EPA Science Policy Council).

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

(working definition developed by EPA Science Policy Council).

Biological Markers or Biomarkers: Indicator 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.

Biologically-Based Dose Response (BBDR) Model: A model that describes biological

processes at the cellular and molecular level linking the target organ dose to the adverse effect.

Childhood: Nominally, the period from birth through the onset of puberty. However, the

Human Health Research Strategy addresses adverse effects on the developing organism that may

result from exposure to environmental agents, starting with preconception exposures of the

parents and continuing through gestation and postnatally up to the time of maturation of all

organ systems. 

Cumulative Risk: The combined risks from aggregate exposures to multiple agents or stressors

(working definition developed by EPA Science Policy Council).

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 of a substance presented to an absorption barrier and available for absorption (although

not necessarily having 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 pollutant available for interaction by any particular organ or cell is termed the

biologically effective dose for that organ or cell.

Effectiveness: The improvement in health outcome that a prevention strategy can produce in

typical community-based settings.
xi

GLOSSARY (Continued)

Efficacy: The improvement in health outcome that a prevention strategy can produce in expert

hands under ideal circumstances

Exposure: Contact of a pollutant, 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.

Margin of Exposure: The ratio of the critical NOAEL to the expected human exposure level.

Mechanism of Action: The complete sequence of biological events that must occur to produce

a toxic effect.

Mode of Action: 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.

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.

No-Observed-Adverse-Effect Level (NOAEL): The highest exposure level at which there are

no statistically or biologically significant increases in the frequency or severity of adverse effects

between the exposed population and its appropriate control.

Outcome Measure: The final health consequence (e.g., cases prevented, quality-adjusted life

years) resulting from an intervention. 

Pharmacodynamics: The determination and quantification 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 quantification of the time course of absorption,

distribution, biotransformation, and excretion of pollutants (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

between target organs and tissues, metabolism, and excretion.

Program Office: An EPA organizational unit that administers a major EPA program (i.e., Air

and Radiation; Water; Prevention, Pesticides, and Toxic Substances; and Solid Waste and

Emergency Response).

Reference Concentration (RfC): An estimate (with uncertainty spanning perhaps an order of

magnitude) of a continuous inhalation exposure of the human population (including sensitive

subpopulations) that is likely to be without an appreciable risk of deleterious noncancer effects

during a lifetime.
xii

GLOSSARY (continued)

Reference Dose (RfD): An estimate (with uncertainty spanning perhaps an order of magnitude)

of a daily exposure of the human population (including sensitive subpopulations) that is likely to

be without an appreciable risk of deleterious noncancer effects during a lifetime. 

Susceptibility: Increased likelihood of an adverse effect related to intrinsic (i.e., life stage,

genetic predisposition) or extrinsic determinants (i.e., preexisting disease) unique to the

organism. 

Threshold Effect: An effect for which there is some dose below which the probability of an

individual’s responding is zero.

Uncertainty Factor (UF): One of several factors used in calculating an exposure level that will

not cause toxicity from experimental data. For example, UF’s are used to account for the

variation in susceptibility among humans, the uncertainty in extrapolating from experimental

animal data to humans, and the uncertainty in extrapolating data from studies in which agents are

given for less than a lifetime.

Vulnerability: Synonymous with susceptibility
E-1

EXECUTIVE SUMMARY

The mission of the U.S. Environmental

Protection Agency (EPA) is to protect

public health and safeguard the natural

environment. Risk assessment is an integral

part of this mission in that it identifies and

characterizes environmentally related

human health problems. The Human Health

Research Strategy document presents a

conceptual framework for future human

health research by EPA’s Office of Research

and Development (ORD). This research

strategy outlines ORD’s core research effort

to provide broader, more fundamental

information that will improve understanding

of problem-driven health risk issues

encountered by the EPA’s Program and

Regional Offices. The scope of this

research document is strategic in that it

discusses broad themes and general

approaches. Implementation of an integrated research program on human health is

described in greater detail in ORD’s

Multiyear Plan on Human Health Research. 

The Multiyear Plan identifies specific

performance goals and the measures needed

to achieve those goals over a 5- to 10-year

period. Each Laboratory and Center in

ORD is also developing an approach linking

research at the project level to the goals and

measures in the Multiyear Plan and the

general themes outlined in this research

strategy document.

Based on the needs of the EPA’s

Program and Regional offices, recommendations made by external advisory groups,

and goals established by EPA in response to

the Government Performance and Result

Act (GPRA) under Sound Science (Goal 8),

ORD has identified two strategic research

directions that will be pursued over the next

5 to 10 years (see text box).

Research in these strategic areas will

improve the scientific foundation for EPA’s 

risk assessments and lead to principles that

can be used to evaluate the effectiveness of

risk management actions aimed at improving environmental public health. Chapter 1

of the Human Health Research Strategy

document provides background information

regarding the regulatory and scientific basis

for a core research program on human health

risk assessment. Chapter 1 also develops

the need for a multidisciplinary, integrated

research program and describes how ORD

will formulate problems and approaches to

study complex questions related to human

health. Chapter 2 describes the scientific

uncertainties, objectives, and approaches

that ORD will use to harmonize risk assessments, assess aggregate and cumulative risk,

and determine risk to susceptible subpopulations. Chapter 3 describes ORD’s public

health outcomes research program that will

work toward providing more scientifically

defensible assessments of actual reduction

in risk. 

Strategic Research Directions

‘ Research to Improve the Scientific

Foundation of Human Health Risk

Assessment, including: 

C Harmonizing Cancer and

Noncancer Risk Assessments

C Assessing Aggregate and 

Cumulative Risk

C Determining Risk to Susceptible

Human Subpopulations

‘ Research to Enable Evaluation of

Public Health Outcomes from Risk 

Management Decisions.
E-2

ORD will focus on developing a 

multidisciplinary, integrated program that

will build linkages between exposure, dose,

effect, and risk assessment methods to provide the scientific basis for harmonizing risk

assessment approaches, predicting aggregate

and cumulative risk, and protecting susceptible subpopulations. In addition, ORD will

develop an integrated research program

utilizing its intramural scientific capacity in

conjunction with extramural grants, cooperative agreements, and interagency agreements. Efforts have been and will continue

to be made to identify and foster collaboration with other Federal and State agencies,

as well as academic and private organizations having research programs that

complement ORD’s research efforts.

Research to Improve the Scientific

Foundation of Human Health Risk

Assessment

ORD’s human health risk assessment

program is based on the assumption that

major uncertainties in risk assessment can

be reduced by understanding and elucidating

the fundamental determinants of exposure

and dose and the basic biological changes

that follow exposure to pollutants leading to

a toxic response. Research in this area will

provide the scientific knowledge and principles to improve the risk assessment of all

human health endpoints, aggregate and

cumulative risk, and susceptible and highly

exposed subpopulations.

Harmonizing Risk Assessment Approaches

ORD’s research in this area will address

the disparate approach for the risk assessment of cancer and noncancer endpoints. 

Research on harmonizing risk assessment

approaches will lead to a common set of

principles and guidelines for drawing

inferences about risk based on mechanistic

information. The overall goal of this

research is that Program and Regional

Office risk assessors will use mechanistic

data in a harmonized manner for risk

assessments for all health endpoints. 

Specific research objectives include the

following:

‘ Develop emerging technologies or

methods to study mode or mechanism of

action;

‘ Develop the biological basis for

understanding mode or mechanism of

action;

‘ Develop a basis for comparing risk

across all health endpoints using

mechanistic information;

‘ Develop principles for the use of

mechanistic data to select the most

appropriate risk assessment model; and

‘ Develop principles for the use of

mechanistic data to reduce or replace

uncertainty factors in risk assessments,

especially for inter- and intraspecies

extrapolation, including approaches for

linking dosimetry models, such as

pharmacokinetic models, with empirical

or pharmacodynamic models for effects

of pollutants with similar or different

modes of action.

 Aggregate and Cumulative Risk

ORD’s research program on aggregate

and cumulative risk will address the fact that

humans are exposed to mixtures of pollutants from multiple sources. Research will

provide the scientific support for decisions

concerning exposure to a pollutant by

multiple routes of exposure or to multiple

pollutants having a similar mode of action. 

ORD will also develop approaches to study

how people and communities are affected

following exposure to multiple pollutants

that may interact with other environmental

stressors. Specific research objectives

include the following:
E-3

‘ Determine the best and most costeffective ways to measure human

exposures in all relevant media, including pathway-specific measures of multimedia human exposures to environmental contaminants across a variety of

relevant microenvironments, exposure

durations, and conditions; 

‘ Develop exposure models and methods

suitable for EPA and the public to assess

aggregate and cumulative risk, including

mathematical and statistical relationships among sources of environmental

contaminants, their environmental fate,

and pathway-specific concentrations;

models linking dose and exposure from

biomarker data; and approaches to assess

population-based cumulative risk,

including those involving exposure to

stressors other than pollutants; and

‘ Provide the scientific basis to predict the

interactive effects of pollutants in mixtures and the most appropriate

approaches for combining effects and

risks from pollutant mixtures. 

Susceptible and Highly-Exposed

Subpopulations

ORD research on susceptible subpopulations will focus on developing a scientific

understanding of the biological basis for

differing responsiveness of subpopulations

within the general population, including

factors associated with their differential

exposure. Research on biological susceptibility will focus on the role of intrinsic

factors, such as life stage and genetic

background, and extrinsic factors, such as

preexisting disease, on responsiveness to

environmental pollutants. Specific research

objectives include the following: 

‘ Identify the key factors that contribute to

variability in human exposure, including

the distribution of human exposures and

behavior associated with exposure to 

pollutants; 

‘ Improve the accuracy of dose estimation

in the general population;

‘ Identify the biological basis underlying

differential responsiveness of sensitive 

subpopulations of humans to pollutant

exposure; and

‘ Determine how exposure, dose and

effect information can be incorporated

into risk assessment methods to account

for interindividual variability.

Research to Enable Evaluation of Public

Health Outcomes from Risk Management

Actions

Generally, EPA has not prepared retrospective evaluations to determine if the

intended benefits in protecting public health

were realized once an EPA decision had

been in place for a period of time. With the

advent of GPRA and calls for EPA to stress

and demonstrate outcome-oriented goals and

measures of success, research is needed to

enable evaluation of actual public health

outcomes from risk management actions. 

Estimating public health benefits of EPA

regulatory decisions and rule making or, in a

more general sense evaluating public health

outcomes from risk management actions

will be a challenging undertaking. It will

involve a number of disciplines grounded in

both the physical and social sciences and

increasingly must take into account the

economic and behavioral aspects of human

decision-making.

The long-term goal of ORD’s research

on public health outcomes will be to provide

the scientific understanding and tools to

EPA and others for use in evaluating the

effectiveness of public health outcomes

resulting from risk management actions. 

Research will focus on identifying, discovering, or developing the most effective

methods and models; determining how they

can be integrated into a decision-making

framework to assist Federal, State, and local

decision-makers in evaluating changes in
E-4

public health as a result of risk management

actions; and developing a framework to

quantify such changes accurately. Specific

research objectives include the following: 

‘ Establish the linkage between sources,

environmental concentrations, exposure, 

adverse effects or disease, and effectiveness such that a change in a human

health outcome consequent to a risk

management action can be determined

by measuring or modeling any one of

these linked steps; and

‘ Improve methods and models by which

others can measure or model changes in 

public health outcomes following

various risk management actions.

Because of the novelty of the long- term

goal and research objectives and the requirement for an unusually high degree of

interdisciplinary coordination, ORD will

develop a multiyear implementation plan for

the public health outcomes research

program. This plan will provide

considerable details on the development,

investigation, and delivery phases of the

research. 
1-1

Human Health

Research Program

Disinfectant

By-Products

Arsenic

Particulate

Matter

Air 

Toxics

Mercury Endocrine

Disruptors

Safe

Water

FQPA

Ozone

Figure 1-1 Relationship Between Core and 

Problem-Driven Research 

1. INTRODUCTION

 The mission of the U.S. Environmental

Protection Agency (EPA) is to protect

public health and safeguard the natural

environment (i.e., air, water, and land) upon

which life depends. Risk assessment is an

integral part of this mission in that it identifies and characterizes environmentally

related health problems. EPA’s Office of

Research and Development (ORD) conducts

research that contributes to the scientific

foundation for risk assessment and risk

management decisions in EPA’s regulatory

programs. Since 1996, ORD has used a

risk-based strategic planning process in

consultation with EPA’s Program and

Regional Offices and the external scientific

community to set research priorities. From

this process, research to improve human

health risk assessment was identified as one

of six priority research areas in the 1997

Update to ORD’s Strategic Plan (U.S. EPA,

1997a) and ORD Strategic Plan (U.S. EPA,

2001b). As such, fundamental human health

research is also part of the ORD Sound

Science Program under Goal 8, which is one

of EPA’s 10 strategic environmental goals

in accordance with the requirements of

GPRA (see text box).

1.1 PURPOSE OF THE STRATEGY

The Human Health Research Strategy

presents a conceptual framework of ORD’s

future research directions in human health

risk assessment and risk management. This

strategy identifies the broad, overarching

questions that will guide ORD’s core human

health research program over the next 5 to10

years. Core research aims to provide broad,

fundamental scientific information that will

improve understanding of problem-driven

human health issues arising from risk

assessment in EPA’s Program and Regional

Offices. Core research consists of understanding the fundamental processes that

underlie environmentally related health

problems; the development of broadly applicable research and risk assessment tools and

approaches; and the design, implementation,

and maintenance of appropriate measures of

environmental exposure (NRC, 1997). 

Approximately 40% of ORD’s research

program has been defined as core research. 

Problem-driven human health issues

associated with specific contaminants,

media, or issues (e.g., particulate matter,

arsenic in drinking water, disinfection

byproducts, endocrine disruptors) are

addressed in separate ORD Research

Strategies and Plans (see Appendix A). 

Fundamental research issues that cut across

those research strategies must often be

addressed before more problem-driven

Goal 8: Sound Science, Improved

Understanding of Environmental Risk,

and Greater Innovation to Address

Environmental Problems - EPA will

develop and apply the best available

science for addressing current and future

environmental hazards as well as new

approaches toward improving

environmental protection.
1-2

Figure 1-2 The Risk Assessment-Risk Management Paradigm

Formulate the Problem

Define Risk Management

Objectives

Identify/Evaluate Risk

Management Options

Risk Management Decision

Hazard ID

Dose-Response

Assessment

 Risk

Characterization

Exposure

Assessment

Risk Assessment

Risk Management

Problem Identification

Develop Compliance

Assurance Models

and Methods

Implement Option(s)

Develop Measures of

Environmental and Public

Health Improvement

Monitor Environmental

and Public Health

Improvement

Reduced Environmental

and/or Public Health Risk

-Public Health and

Legal

Considerations

-Social and

Economic Factors

-Political

Considerations

questions can be studied. There will

be a constant need to integrate

problem-driven and core research as

illustrated in Figure 1-1. For

example, problem-driven research is

being conducted to study the

interaction of pesticides in mixtures

because the Food Quality Protection

Act (FQPA, 1996) indicates that

EPA should consider the risk

associated with cumulative

exposures of pesticides having a

common mechanism. However,

core or basic research on the mode

or mechanism of action of these

pollutants will have to be done

before addressing more problemdriven questions concerning the

interaction of pesticides based on

their mechanism or mode of action.

The Human Health Research

Strategy is not intended to be a

technical document. The target audience

includes EPA and other federal agency

scientists, managers, and policymakers, as

well as the scientific community at large. It

describes the scientific uncertainties,

objectives and general approaches that will

be taken by ORD’s core research program

on human health. ORD has developed a

Multiyear Plan for Human Health Research

that describes anticipated goals and

measures over a 5- to 10-year period. In

addition, each Laboratory and Center within

ORD is developing its own approach to link

specific projects and tasks to the ORD

Multiyear Plan and the themes described in

this research strategy document.

1.2 CURRENT RESEARCH PROGRAM

ON HUMAN HEALTH

Human health risk assessment provides a

qualitative and quantitative characterization

of the relationship between environmental

exposures and effects observed in exposed

individuals. In 1983, the National Research

Council (NRC) described four primary steps

in the process of risk assessment, i.e., hazard

identification, dose-response assessment,

exposure assessment, and risk characterization (Figure 1-2). Risk assessment is the

primary scientific input to the risk management process, which involves the recognition of a potential new risk and development, selection and implementation of EPA

actions to address the risk. Risk management often considers a wide variety of other

factors. The overall process of risk assessment and risk management is often called

the Risk Assessment-Risk Management

Paradigm. 

Over the last several years, ORD has

aligned its organizational structure and

research program to be consistent with the 

Risk Assessment-Risk Management

Paradigm (Appendix B)(see text box on next

page). ORD is organized into three national

Laboratories and two Centers. The National

Exposure Research Laboratory (NERL)

focuses on measuring exposures and 
1-3

 Laboratories and Centers in ORD

Major Focus Lab/Center

Exposure and Dose NERL

Dose and Effects NHEERL

Risk Assessment NCEA

Risk Management NRMRL

Extramural Research NCER 

producing scientifically defensible exposure

models that reduce the gaps in scientific

knowledge related to actual human exposure

to pollutants. In 1995, EPA’s Science

Advisory Board (SAB) (U.S. EPA, 1995)

reviewed the state of exposure assessment

science and reported that this area was

hampered by a variety of technical

limitations, including lack of exposure

measurement techniques, a paucity of

exposure databases and other exposurerelevant data, and reliance on numerous

default assumptions with little justification

for their selection. The SAB also found that

available exposure models had rarely been

evaluated against actual human exposure

measurements. In addition, there were no

comprehensive human exposure models that

could describe the complex relationships

between pollutant sources, environmental

concentrations, exposure pathways, actual

human exposures, and the dose that results

from exposure to pollutants by multiple

pathways. The SAB also found that the

methods available for both human exposure

measurements and exposure modeling were

too intrusive or costly to implement

routinely. Much of the work conducted by

NERL over the last several years has been

directed at these data and methodological

gaps. 

In the Risk Assessment-Risk Management paradigm, dose-response assessment is

the process for determining the likelihood of

an adverse effect at a particular exposure or

dose. A primary concern for dose-response

assessment is an understanding of the dose

of the pollutant that reaches its target organ,

tissue, cell, or biomolecule. Research on

issues related to dose is largely conducted at

NERL and the National Health and Environmental Effects Research Laboratory

(NHEERL). Research at NERL focuses on

pharmacokinetic (PK) modeling to estimate

internal dose metrics for multiroute aggregate exposure. Research at NHEERL

focuses on determining the basis for metabolic differences between species. This

information is crucial for extrapolating

toxicological data from animals to humans

in risk assessment and determining the

biologically effective dose of the parent

compound or metabolite(s) of the pollutant.

The goal of hazard identification is to

describe and ultimately predict in humans

the toxicological effects of pollutants that

might occur due to exposure to environmental agents. Research related to hazard

identification is largely conducted at

NHEERL and focuses on test methods

development and characterization of hazard

potential in animal models. Clinical or

epidemiological studies are also used to

identify potential risks in the human

population and generate testable hypothesis

for future studies in animal or in vitro

models. Risk assessment is often confounded by a number of uncertainties related to

the risk assessment methodology, including

extrapolation across species, extrapolation

from short-term to lifetime exposures, and

variability of response within the human

population. A significant component of

research at NHEERL focuses on reducing or

eliminating uncertainties in the risk assessment process. Research at NHEERL also

seeks to understand the cascade of events

between the presence of a pollutant at a

target site and the ultimate manifestation of

toxicity. Knowledge of the sequence of

biological events that must occur to produce

an adverse effect [i.e., the mechanism of

action, or an understanding of some, but not
1-4

all, of the key biological steps leading to

toxicity, i.e., the mode of action (U.S. EPA,

1996; U.S. EPA, 1999a; IPCS, 1999;

Schlosser and Bodganffy, 1999)] is being

used with increasing frequency in risk

assessment (see Appendix C). Procedures

for the use of mechanistic data are defined

in the EPA’s draft Guidelines for

Carcinogen Risk Assessment (U.S. EPA,

1999a).

The National Center for Environmental

Assessment (NCEA) performs complex risk

assessments of national interest and

develops risk assessment methods, databases, and tools based on results produced

by ORD and others. NCEA also serves an

integrating function within ORD, bringing

together results from hazard identification,

dose-response assessment, and exposure

assessment on issues related to the risk

assessment process. The risk assessment

program includes development of doseresponse and exposure models, factors,

databases, and guidance for conducting risk

assessment. Issues confronting the risk

assessment program include how to use

exposure, pharmacokinetic, and mechanistic

data in risk assessment; harmonizing cancer

and noncancer risk assessment methods, and

conducting cumulative risk assessments of

multiple pollutants.

The National Risk Management

Research Laboratory (NRMRL) focuses on

providing the most effective and useful risk

management options and improving the

linkage between risk assessment and risk

management efforts. 

Intramural research conducted by

NERL, NHEERL, NCEA, and NRMRL is

complemented by extramural research

sponsored by ORD’s National Center for

Environmental Research (NCER). Through

the Science to Achieve Results (STAR)

Program, NCER supports grants that focus

on specific research needs consistent with

the mission of the EPA. For example, the

STAR Program provides support to extramural scientists to develop statistical and

predictive approaches for assessing risks

from pollutant mixtures. Other examples of

STAR research include12 EPA/National

Institute of Environmental Health Sciences

(NIEHS)-supported Centers for Children’s

Health and Disease Prevention Research and

individual studies, such as the development

of biomarkers for risk assessment in

children. 

1.3 FUTURE RESEARCH PRIORITIES

1.3.1 Framework for an Integrated

Research Program in ORD

 ORD will develop a multidisciplinary

research program that addresses linkages

lying along a continuum from the source of

an agent through exposure and dose to

adverse outcome such as disease (Figure 1-

3). One example of the need for an

integrated research program arises from the

opportunities and challenges associated with

data in recent reports by the Centers for

Disease Control and Prevention (CDC,

2001, 2003). The first publication, the

National Report on Human Exposure to

Environmental Chemicals, provided an

ongoing assessment of the U.S. population’s

exposure to environmental chemicals using

biomonitoring. This report contains blood

and urinary values on 27 pollutants collected

as part of the National Health and Nutrition

Examination Survey (NHANES). The

second report, which was released in

January 2003, presents biomonitoring

exposure data for 116 environmental chemicals for the U.S. population divided into age,

gender, and race/ethnicity groups. The

exposure information should help prioritize

research on the relation between exposure

and health effects and help identify population groups with unusually high exposure

for health effects evaluation. Efforts will be

made to link the biomonitoring data back to
1-5

pathway and source to guide risk management interventions.

ORD’s evolving integrated approach to

problem formulation and research planning

is illustrated in Figure 1-4. Risk assessment

issues arising from Regional or Program

Offices, through legislative or regulatory

mandates or ORD research results will be

evaluated to determine the scientific questions (Figure 1-4, Box A). This evaluation

will lead to the design of studies to address

those uncertainties (Box B). Results from

these studies (Box C) will be used to refine

additional studies and/or generate models

(Box D) to inform the development of better

risk assessment methods. Efforts to

construct modules or compartments of

models (Box D) will feed back onto the

design and execution of additional experiments. Ultimately, results from all experiments and models will be used to develop

risk assessment methods (Box F) and

develop an integrated framework (Box E)

that will form the scientific basis for risk

assessment guidance and risk management 

decisions. Consolidated information

resulting from the integrated framework

may also be used to iform or redefine the

original risk assessment issue.

A conceptual model illustrating a completely integrated research program is

illustrated in Figure 1-5. As this figure

shows, analysis of risk assessment issues

gives rise to scientific questions concerning

exposure, dose, effects, and risk assessment

methods. For example, risk assessment

questions related to exposure might require

studies involving the development of

analytic methods and the execution of pilotscale laboratory or field exposure research

followed by larger scale population or

epidemiological studies to gain important

Figure 1-3 The Exposure-Dose-Effect Continuum
1-6

Box A

Risk 

Assessment

Issues

Box B

Scientific

UncertaintiesStudy Design

Box C

Data

GenerationExperiments

Box D

Data

UtilizationModeling

Box F

Risk Assessment,

Data, Methods,

Guidance

Box E

Integrated

Framework

Figure 1-4 ORD’s Approach to Solving Agency Problems

Risk Management

exposure and/or exposure factor data. The

results of this research could be used to help

develop exposure assessment models. 

Research questions related to dose might

involve experiments to develop analytical

methods, obtain pharmacokinetic data, or

identify biomarkers. The results of these

experiments would be used to develop

physiologically based, pharmacokinetic

models for estimating internal dose. Effects

research may require the development of

sensitive and specific methods to help

understand the biological substrates underlying the mode or mechanism of action of

environmentally relevant pollutants. Epidemiological studies may provide the basis

for confirming possible health-related

adverse effects in the human population and

generate testable hypotheses for subsequent

confirmation in animal or in vitro models. 

The results of effects research would be

used to develop biologically based doseresponse models linking effects observed at

the cellular or molecular level to adverse

health effects. Assessment of data generated from exposure, dose and effects

research would be used to formulate better

risk assessment methods. All of the data

generated from research on exposure, dose,

effects, and risk assessment methods would

be used to help develop an integrated

framework for the development of guidance

for risk assessment and scientific support for

risk management options. 

Figure 1-5 also shows that results from

various experiments and models may feed

back at any time through an iterative process

to improve the design of future experiments. 

Results from experiments and outputs from

models in any area of analysis (i.e., exposure, dose, effect, risk assessment) may

influence the design of studies and the

generation of data in other areas. For

example, the results of field studies concerning exposure of children to pesticides might
1-7

Analyze data bases

Evaluate biological

data 

Analytic methods 

 Field and lab studies 

 Population studies 

 Epidemiological studies 

 

Exposure

models 

Analytic methods PK/PD measures 

Biomarkers 

 

PBPK 

models

BBDR

models

 

 Methods 

 Biological substrates 

Mechanistic studies 

Epidemiological studies

 

EffectsStudy 

Design

DoseStudy 

Design

ExposureStudy

Design

Risk Assessment

Methods-Study

Design

Guidance/

Risk Management

Risk

Assesment 

Issues

Figure 1-5 ORD’s Integrated Research Program

Integrated

framework

influence the choice of dose or concentration of pollutants for future research.

ORD ’s ongoing research on asthma and

exposure of children to fungi and molds

serves as a specific example of a multidisciplinary, integrated research program that

uses the scientific expertise and resources

from the various ORD Laboratories and

Centers to address a high priority research

issue (Figure 1-6). In 1998, a team of

researchers from NERL, NHEERL, NCEA

and NRMRL was organized to address the

effects of the S. chartarum fungus, a

common indoor contaminant, on children’s

health. The first objective of this program

was to determine, before and after remediation, the quantities of S. chartarum spores in

dust from homes of children with asthma or

pulmonary hemosiderosis and assess

specific antibodies to mold proteins in these

children. A second objective was to

establish a mouse model of allergic lung

disease to characterize IgE-inducing

proteins from three fungi, including S.

chartarum, immunologically, and identify

any common characteristics using advanced

proteomics. This research addresses the

hypothesis that differences in protein

constituents of mold

are associated with

allergenicity. The third

objective of this

research program is to

demonstrate parallels

between human and

rodent responses to the

mold in order to

facilitate interspecies

extrapolation. 

Epidemiological and

clinical studies evaluate

the exposures of

children to fungi that

might lead to asthma

using a cohort of

children to addresses

the hypothesis that

participants in the fungal-exposed cohort

will have significantly more asthma than

control participants. Other objectives of this

research are to test methods to reduce spore

release and growth of fungus and to begin to

develop a risk assessment model. The

ultimate goal is develop a model than can

be used to address risk assessment and risk

management approaches for indoor molds

associated with asthma and other health

conditions. 

Figure 1-6 illustrates the integrated

multidisciplinary approach that has been

developed to address this high priority need

of EPA. Exposure data from field studies

identify and characterize exposures to fungi

that might be associated with childhood

asthma. These studies also help define the

relationship between exposure and effects

and provide important exposure information

for the design of effects studies and risk

assessment approaches. Research on effects

focuses on developing animal models of

allergic lung disease that can be extrapolated

to humans and on studies providing a causal

link between the potential mode of action or

mechanism and allergic lung disease. 

Mechanistic effects research helps confirm
1-8

Assess spores in homes before

and after remediation

Develop animal model 

Test spores 

 Epidemiological studies 

EffectsStudy Design

ExposureStudy Design

Develop remediation

strategy for children

exposed to molds

Figure 1-6 Integrated ORD Research Program

on Molds and Asthma in Children

What is the Health Risk to 

Children following

Exposure to Molds? 

Risk Assessment

Study Design Develop risk assessment 

approaches to protect 

children exposed to molds

the associations observed in

the exposure assessment and

could lead to the identification

of specific fungi species

involved in producing allergic

lung disease. Epidemiological

studies in children provide

important information for the

design of risk assessment

approaches to protect children

exposed to fungi and help

shape the design of future

studies. Risk assessment

approaches are being

developed based on results

from the exposure assessment

and effects research, all of

which provide the scientific

basis for development of risk

management options and

remediation strategies, if

necessary. Once a remediation strategy has

been implemented, future studies will be

designed to evaluate the effectiveness of the

strategy. Depending on the outcome of

these studies, additional research on

exposure, effects, and risk assessment

models may be initiated to devise a more

effective risk assessment-risk management

approach. 

1.3.2 Research Themes

Based on input from Regional and Program

Office risk assessors and ORD scientists,

future ORD research will focus on two

strategic directions (see text box), including

research to improve the scientific foundation

of human health risk assessment and

research to enable evaluation of public

health outcomes from environmental risk

management decisions. Research to

improve human health risk

assessment will emphasize three

themes, i.e., harmonizing cancer and

noncancer risk assessments,

assessing aggregate and cumulative

risk, and evaluating risks for

susceptible and highly exposed

subpopulations. ORD has determined that there is a need to develop

the scientific basis for harmonizing

the use of mechanistic information in

cancer and noncancer risk

assessments. Research on assessing

aggregate and cumulative risk

addresses the need to develop risk assessment/risk management approaches to

Strategic Research Directions

‘ Research to Improve the Scientific Foundation of

Human Health Risk Assessment:

C Harmonizing Cancer and Noncancer Risk

Assessments

CAssessing Aggregate and Cumulative Risk

CEvaluating the Risk to Susceptible Human

Subpopulations
1-9

Figure 1-7 Role of Research in Assessment of Health Outcomes 

in the Risk Assessment and Risk Management Process

Assessing

Risk: 

 Exposure 

 Dose/Effects 

 Risk Assessment

Informing Risk

Management

Options:

Regulatory 

Risk Management

Assessing 

Effectiveness of

Decisions:

Health Indicators

Exposure Indicators

Research 

evaluate multichemical/multipathway

exposures to environmental agents, while

research on risks to susceptible and highly

exposed subpopulations focuses on understanding variability in human responses to

environmental agents. Susceptible subpopulations also include populations of people

that are differentially exposed to environmental agents. These themes are discussed

in greater detail in Chapter 2. 

 ORD will also initiate research to

enable the evaluation of public health

outcomes from risk management actions. 

This program will include new EPA efforts

to measure and monitor improvements in

environmental public health following risk

management actions as underscored by

requirements that EPA evaluate the success

of its environmental programs and decisions. Success will be measured by changes

in health outcomes and indicators resulting

from risk management decisions. EPA has

traditionally relied on “process” measures

(e.g., decreased emissions, number of sites

cleaned up) to measure public health benefit

indirectly. ORD’s future research program

will seek to identify and validate health

events that can serve as true public

health outcome measures (Figure 1-7). 

The regulatory and scientific bases for

this part of the research program are

described in greater detail in Chapter 3

of this document.

1.4 STRATEGIC PRINCIPLES

The following strategic principles

will be used in developing and implementing ORD’s research program on

human health:

Collaboration across ORD - As

described previously, the intramural

ORD program is organized around the Risk

Assessment-Risk Management Paradigm,

i.e., NERL, NHEERL, NCEA and NRMRL

(Figure 1-2). ORD’s future research

program will focus on more complex

environmental problems requiring

collaboration and synergy between the

various Laboratories and Centers in ORD.

Scientists in Program and Regional Offices

are viewed as collaborators as well as

clients, and collaborative relationships will

be established to design and conduct studies

related to human health risk assessment and

risk management. 

Focus and Broad Application - A

research strategy to improve human health

risk assessment and management must

emphasize selected high-priority issues with

outcomes expected to have a wide effect on

risk assessment. ORD will focus the core

human health research program on environmental pollutants, which is consistent with

the expertise and infrastructure ORD has

developed over the last several years. 

However, as knowledge gaps are identified

for other classes of environmental agents,

such as microbes and bioaerosols, research

will be initiated to address specific questions

related to those agents. 
1-10

Support EPA’s Mission - The research

must address knowledge gaps in risk assessment identified by Program and Regional

Offices or raised by specific regulatory or

legislative requirements. Results should

have tangible benefits to all groups interested in improved risk assessments (i.e., states,

local governments, industry, nongovernmental environmental organizations,

communities, international governments). 

ORD’s research will result in products and

information that have direct and practical

applications in risk assessment. ORD

scientists will also identify issues that may

be important to the future of risk assessment

that are not major concerns to programs and

regions at the present time. 

Outreach, Coordination, and Partnership with External Scientific Community - 

ORD will develop an integrated research

program utilizing its intramural scientific

capacity in conjunction with extramural

grants and cooperative and interagency

agreements. In addition, efforts have been

and will continue to be made to identify and

foster collaboration with other federal and

state agencies, as well as academic and

private organizations, that complement

ORD’s research efforts (see Appendix D).
2-1

2. RESEARCH TO IMPROVE THE SCIENTIFIC FOUNDATION 

OF HUMAN HEALTH RISK ASSESSMENT

ORD’s human health risk assessment

program is based on the assumption that

major uncertainties in risk assessment can

be reduced by understanding the fundamental principles of how, at what level, and

how often humans are exposed to pollutants;

how much of the toxic moiety arrives at the

target site; and the basic biological changes

that lead to a toxic or adverse health effect. 

Research questions related to harmonizing

risk assessment, assessing aggregate and

cumulative risk, and evaluating risk to

susceptible and highly exposed subpopulations will be framed to address knowledge

gaps and interrelationships of events along a

continuum from source through exposure

and dose to effect (Figure 1-3). The overall

objective of ORD’s human health research

program is to link exposure, dose, and effect

approaches along this continuum in order to

provide an integrated information base for

scientifically defensible risk assessment and

risk management decisions. 

2.1 Research on Harmonizing Risk

Assessment Approaches 

2.1.1 Scientific Uncertainties

 Assessment of health risk from exposures to environmental agents has traditionally been performed differently depending

upon whether the response is a cancer or a

noncancer health effect. This practice has

been based on a limited understanding of the

mode of action of toxic substances. Historically, cancer was thought to be largely the

consequence of the direct interaction of a

carcinogen with DNA to produce a heritable

change in a single cell that eventually produced a tumor. It was thought, therefore,

that the dose-response for such a mechanism

would not show a biological threshold but

would be linear at low doses. This led EPA

to employ a science policy that cancer risk

should be estimated by a linear, nonthreshold dose-response method.

 On the other hand, a threshold has been

generally assumed for noncancer effects

based on considerations of compensatory

homeostasis and adaptive mechanisms. The

threshold concept assumes that a range of

exposures can be tolerated up to some finite

level without adverse effects. This

threshold will vary from one individual to

another, so that there will be a distribution

of thresholds in the population. Except for

some pollutants, such as the criteria air

pollutants, evaluating human risks for

noncancer effects has generally involved the

determination of a level of daily exposure

that is likely to pose no appreciable risk of

deleterious effect during a lifetime. 

 The disparate approach for assessment

of cancer and noncancer endpoints has been

questioned (e.g., NRC, 1994). It now

appears that carcinogens can affect many

cellular targets and biochemical and biological processes that eventually lead to the

formation of tumors. Such targets may include DNA, which contains the genes that

control cell growth, or biochemical

processes involved in cell growth regulation,

cell signaling, and cell-to-cell communication. Other mechanisms may involve cell

toxicity and death, perturbation of hormonal

systems, and suppression of the immune

system. Many of these mechanisms may

have thresholds of response, as discussed in

the proposed new cancer risk assessment

guidelines (U.S. EPA, 1996, 1999a). It has

also been hypothesized that threshold

considerations may not be applicable to all

noncancer effects, e.g., lead-induced

cognitive deficits in children. Furthermore,

our emerging understanding of the

mechanisms of carcinogenesis and other

health effects suggests that the underlying
2-2

Biologically 

Effective

Dose 

Pharmacokinetic

Models

Absorbed Dose

Target Dose

Internal Dose

Exposure Scenario Interspecies

Differences

Early Biological

Effects

Precursor Effects

Mode or Mechanism

of Action

basis for certain noncancer and cancer

endpoints may have common precursors. 

For example, pollutant-induced toxicity can

cause altered biological function, cell death,

and tissue regeneration while surviving cells

compensate for that injury by increasing cell

proliferation which may result in tumor

formation if continued unchecked. Thus,

the primary precursor effect may be related

to both the cancer outcome and other types

of noncancer biological effects. 

Understanding an agent’s mechanism of

action will be crucial to a more accurate

prediction and characterization of hazard

and risk and will be the basis for developing

harmonized approaches for all health

endpoints. Harmonization in this context

refers to the development of a consistent set

of principles and guidelines for drawing

inferences from scientific information. It

does not mean that a single

methodology should be used for

the assessment of all toxicities and

pollutants. Instead, it emphasizes

the need for consistent application

of all pertinent information on

toxicity, dosimetry, mode of

action, and exposure in all risk

assessments regardless of the

nature of toxicities or pollutants. 

ORD will focus its research to

improve the foundation of these

risk assessment methods by

seeking to better understand the

mechanisms or modes of action

that are common to cancer and

noncancer health effects. One of the goals

of ORD’s research on harmonization is to

improve general understanding of mechanisms and modes of toxic action. 

2.1.2 Research Objectives 

The following research objectives

provide the framework needed to develop an

integrated research program that will

harmonize risk assessment approaches:

‘ Develop, validate, and standardize

emerging technologies or methods to

study mode or mechanism of action;

‘ Develop the biological basis for understanding mode or mechanism of action;

‘ Develop a basis for comparing risk

across all health endpoints using

mechanistic information;

‘ Develop principles for the use of

mechanistic data to select the most

appropriate risk assessment models; and 

‘ Develop principles for the use of

mechanistic data to reduce or replace

uncertainty factors in risk assessments,

especially for inter- and intra-species

extrapolation, including approaches for

linking dosimetry models, such as pharmacokinetic models, with empirical or

pharmacodynamic models for effects of

pollutants with similar or different

modes of action.

2.1.3 Research Approach

Exposure Research. Specific exposure

issues have not been identified within the

 context of the harmonization of risk assessment approaches. Research to characterize

the various exposure pathways to relevant

pollutants is described in Section 2.2 under

the theme of Aggregate and Cumulative

Risk and includes a description of the

magnitude and nature of the pollutants to
2-3

Develop Sensitive

and Specific 

Methods 

Identify Cellular

Processes for 

Cancer and

Noncancer Effects

Identify Common

Precursors for

Cancer and 

Noncancer Effects

Compare DoseResponse Curves

for Prototypic

Compounds 

Develop BBDR 

Mechanistic Information PBPK Models

which people are exposed, as well as the

timing and sequence of those exposures. 

Research on differential exposure of

susceptible and highly exposed

subpopulations is described in Section 2.3.

Dose Research. It is hypothesized that

there may be common biological effects that

serve as precursors to various health effects. 

For example, some pollutants may cause

multiple effects, both cancer and noncancer,

through initially similar mechanisms, such

as adduction of DNA or binding to a

receptor. Subsequent events must differ in

order to produce different effects. Other

pollutants can cause multiple effects through

multiple mechanisms, often through the

formation of metabolites with different

biological activities. In either case,

knowing the biologically effective dose

of the active pollutant at the target site is

crucial for elucidating mechanisms and

modes of cancer and noncancer health

effects for risk assessment. Research on

dose will identify the biologically effective dose of parent compound or

metabolites in target tissue and attempt to

relate those levels to the presence of early

biological and precursor effects at the

molecular, biochemical, cellular, organ,

and organismal levels (see schematic on 

previous page). This information will, 

therefore, be crucial for studies attempting

to elucidate mode or mechanism of action. 

The development of pharmacokinetic

models to inform studies on mode or

mechanism of action must also take into

account variables such as the duration of

exposure and possible interspecies

differences in sensitivity.

Effects Research. Central to the question of harmonizing risk assessment

approaches is whether various modes or

mechanisms of action have a similar

necessary step (e.g., cell proliferation,

receptor interaction, response to injury or

stress, alterations in DNA repair mechanisms, apoptosis) leading to the adverse

effect. Virtually every toxic event in a

tissue or organism exposed to a pollutant is

modulated by a finite number of damageresponse pathways by which cells sense the

status of their internal environment. 

Through these sensors, critical processes

that activate specific genes or proteins to

cause the cell to migrate, proliferate,

differentiate, or die are made by a cell’s

biochemical machinery. Progress in this

area depends upon a clear understanding of

the changes in the biology of the cell

following delivery of the active chemical

moiety to target cells and the relationship of

responses with dose. Determining the presence of the active toxic moiety at specific

target sites will be crucial for these studies.

A significant first step in effects research

on harmonization will be the development

of sensitive and specific methods (see schematic above) to study mechanism or mode

of action based on the application of

emerging technologies, especially proteomics and genomics. Bioinformatic

approaches will also have to be developed to

help interpret the meaning of changes

coming from multigene, microarray assays

used in hazard identification and quantitative dose-response assessment. Effects
2-4

Computational Toxicology

The application of models from computational and systems biology and computational chemistry for prediction and

understanding mechanisms of action

research will initially focus on identifying

cellular processes (e.g., regeneration,

proliferation) that may be similar for cancer

and noncancer health effects. This research

will lead to studies that will identify

common biochemical or molecular

pathways associated with those cellular

processes. Research will then focus on

studies concerning the effects of environmentally relevant doses or concentrations of

prototypic pollutants with similar putative

modes or mechanisms of action or on

pollutants sharing similar structure-activity

relationships. If a common cellular target

can be identified for specific adverse

outcomes, physiologically based

pharmakokinetic (PBPK) models will

determine target tissue levels and the

influence of duration of exposure and

interspecies variation on adverse effects. 

One of the long-term goals of ORD’s

research is the development of models that

take into account the sequence of early

biological events leading to adversity (i.e.,

mechanisms or modes of action) for

multiple endpoints, the shape of the doseresponse curves at low doses, and the

influence of interspecies differences. ORD

research will study both high and low doses

in order to elucidate the likely shape of the

dose-response curve and to determine

whether different modes or mechanisms

may be operating at different doses. ORD

will also focus on developing animal models

that can be extrapolated directly to humans.

 Mechanistic effects research based on

emerging technologies such as proteomics, 

genomics, and bioinformatics will also feed

directly into ORD’s efforts to set mechanistically based priorities for pollutant risk

assessments and optimize in vivo and in

vitro testing requirements through the use of

computational methods and molecular

profiling, i.e., computational toxicology (see

text box). For example, computational

methods, such as quantitative structureactivity relationships (QSAR), could be used

to determine which set of chemicals out of a

larger population [e.g., Toxic Substances

Control Act (TSCA) inventory] might have

the potential to produce an adverse effect

(e.g., cancer or reproductive toxicity). This

information could be used to prioritize subsequent testing of this subset of chemicals

for potential human health or environmental

effects. Emerging technologies such as

genomics and proteomics could be used to

generate molecular profiles that would serve

as diagnostic tools to discriminate toxicological pathways leading to different

adverse effects. Diagnostic tools could be

used to design in vitro and in vivo tests to

confirm the toxicological pathway involved

in producing the adverse effects. This

information would then be used to guide the

selection of specific testing protocols for

risk assessment. ORD will initially

demonstrate the feasibility of this approach

by focusing on prioritization and screening

assays and models for endocrine disrupting

chemicals. This class of pollutants was

chosen because ORD has considerable

experience in determining environmental

exposure levels to these chemicals, as well

as developing in vivo and in vitro tests in

response to provisions of the Food Quality

Protection Act (FQPA). The primary focus

of these studies will be on endocrinemediated reproductive and developmental

effects following exposure to

environmentally relevant concentrations. 

Risk Assessment Methods. In developing harmonized approaches for the

assessment of risk to different health

endpoints, a key issue is to determine how

much information is needed to show that a
2-5

Improved Risk Assessment

Methods for All 

Risk Assessment

PBPK Data Base BBDR Data Base

Information

Required to Use

Mechanism or

Mode of Action Choice of Risk

Assessment

Model

Use of Uncertainty

Factors and Default

D/R Assessments and

Extrapolations

Evaluation of

Data from

Emerging

Technologies

particular toxic effect is mediated by a

specific mode of action and that the

pollutant or its metabolite is present in

sufficient quantities in the target tissue (see

schematic). 

For example, the proposed cancer risk

assessment guidelines (U.S. EPA, 1999a,

1996) provide for judging the plausibility

and adequacy of available evidence for a

postulated mode of action, identifying

susceptible subpopulations, and determining

the most appropriate approaches and

methods for low-dose extrapolation. ORD

research on risk assessment methods will

focus on how to incorporate mode-of-action

information for other health endpoints. 

Guidance will also be developed to

determine how different endpoints of

toxicity could develop through common

biological processes or modes of action. 

One high priority for ORD research on risk

assessment methods will be prototype

assessments for both data-rich and data-poor

pollutants to illustrate how mode of action,

PBPK, and biologically based dose response

(BBDR) models may be used in lieu of

default approaches. Risk assessment

research is also needed to develop principles

to evaluate the results of studies in which

the data have been generated using genomic

or proteomic methods. This “translational”

research will be a major challenge for EPA

as the onslaught of data generated by these

new approaches will far outpace the

research and guidance on interpretation and

application in risk assessment.

 Recent EPA guidance to

improve risk assessments has

emphasized the importance of

providing risk managers with a

fuller characterization of risk. 

Current default approaches to

express risk for health effects

presumed to be mediated by

threshold or nonlinear modes of

action include the use of reference

toxicity values [e.g., chronic oral

Reference Dose (RfD), inhalation

Reference Concentration (RfC), or

the concept of the margin of

exposure (MOE)], i.e., the ratio of

the critical NOAEL to the expected human exposure level. Although these

risk assessment models consider all the

available data, they do not provide an

explicit estimate of variability and

uncertainty or provide information on the

consequences of exposures that exceed the

reference values or have a small MOE. 

 An important focus of ORD’s risk

assessment research on harmonization will

be the development of approaches to characterize variability and uncertainty in reference toxicity values and to provide a probabilistic framework for estimating risks associated with exposures above reference toxicity values. This research will examine

data underlying the various uncertainty factors commonly applied in setting reference

values, including factors for inter-species

and intra-species extrapolation (including

pharmacokinetic and pharmacodynamic

variability) and variability in responses due

to changes in exposure duration. As an

example, this research would explore the use

of probability distributions that can be com-
2-6

Working Definitions Developed by EPA

Science Policy Council

Aggregate Exposure: The combined

exposure of an individual or defined

population to a specific agent or stressor via

relevant routes, pathways, and sources.

Aggregate Risk: The risk resulting from

aggregate exposure to a single agent or

stressor.

Cumulative Risk: The combined risks

from aggregate exposures to multiple agents

or stressors.

bined to characterize the variability and

uncertainty around the reference values for

health effects. Various statistical

approaches will be explored as a means for

estimating risks above the reference toxicity

values for informing risk management

decisions and supporting economic benefits

analyses. Risk assessment methods on risk

predictive models for cancer and noncancer

effects will also be investigated.

2.2 Research on Aggregate and

Cumulative Risk

2.2.1 Scientific Uncertainties

The development of risk assessment

methodology during the 1970s and early

1980s closely followed EPA’s strategy for

pollution control. Historically, EPA evaluated the risks of a single pollutant in a single

exposure medium, such as lead in outdoor

air or drinking water. In reality, people are

constantly exposed to mixtures of pollutants. 

Furthermore, exposure to the same pollutant

may occur from a variety of routes, including the air, water, and food. In addition, the

composition and concentration of pollutants

in the environment is constantly changing,

depending on people’s activities and geographical location. It is now fully understood that environmental exposure to pollutants occurs via multiple exposure routes

and pathways, including inhalation, ingestion, and uptake through the skin. Research

on aggregate and cumulative risk will focus

on defining the multitude of ways in which

people are exposed to pollutants and characterizing the subsequent effects and risks. 

The FQPA directed EPA to include in its

assessment of pesticide safety the risk associated with the cumulative effects of chemicals that have a common mechanism of

toxicity and to consider aggregate dietary

and non-occupational sources of pesticide

exposure. However, EPA’s efforts to assess

aggregate and cumulative risk go far beyond

the FQPA and pesticides. For example, the

Office of Water must assess risks from mixtures of disinfectants and their byproducts

and must balance those risks against the

risks of toxic microbes in the drinking water

supply. The Air Program Office needs

methods to assess risks from mixtures of

criteria air pollutants and sources containing

a mixture of hazardous air pollutants. The

Waste Program Office deals with mixtures

of many different chemical classes found

together in the soil, water, and air of waste

sites and their surroundings. In addition,

EPA’s Program and Regional Offices deal

with communities that may be more highly

exposed than average and subject to a

variety of other stressors such as poverty,

lack of access to medical care, inadequate

nutrition, and stresses associated with living

near landfills, incinerators, and/or heavy

industry. To encompass all these concerns,

this document defines aggregate exposure

and cumulative risk broadly in accordance

with the working definitions developed by

EPA’s Science Policy Council (see text

box).
2-7

The traditional approach to assessing

aggregate and cumulative risk is to focus

primarily on individual pollutants and their

sources. The pollutants are initially traced

through the environment, and the concentrations and doses of each chemical are estimated separately. The toxicity and risks from

the multiple stressors are added or combined

using the basic methods in EPA’s Chemical

Mixtures Guidelines (U.S. EPA, 1986,

2000c) to determine risk. This pollutantbased approach has most often been applied

for estimating exposures and risks for

specific locations or scenarios (e.g., risks

associated with a hazardous waste site). 

The objective of ORD’s research program on aggregate and cumulative risk is to

provide methods, models, data, and guidance for assessing human health risk so that

EPA can protect the health of the public and

environment more effectively. ORD’s

research program on aggregate and cumulative risk will take two approaches: 

chemical-focused and population-based. 

The chemical-focused approach may be

better suited to address the likely effects of a

specific source or a pollution control

strategy when the key variables associated

with that source can be well characterized

for specified human exposure scenarios. A

population-based approach may be better at

revealing total exposures and identifying

when important sources or important pathways of exposure may not have been identified. A population-based approach may also

be useful in assessing public health outcomes because the objective of any control

policy is to decrease public exposure and

risk. ORD research will build on these two

approaches to develop scientifically robust

aggregate and cumulative risk assessment

methods, including how to identify important stressors to a population, combine risk

over several stressors, define risks that

accumulate over time, and assess the interaction between stressors. The research

program for aggregate and cumulative

research consists of several interrelated

research efforts, all of which add critical

components to the overall aggregate/cumulative risk assessment effort.

2.2.2 Research Objectives 

The following research objectives provide the framework to develop an integrated

research program on aggregate and cumulative risk:

‘ Determine the best and most costeffective ways to measure human

exposures in all relevant media,

including pathway-specific measures of

multimedia human exposures to

environmental contaminants across a

variety of relevant microenvironments

and exposure durations and conditions; 

‘ Develop exposure models and methods

suitable for EPA and the public to assess

aggregate and cumulative risk, including

mathematical and statistical

relationships among sources of

environmental contaminants, their

environmental fate, and pathwayspecific concentrations; models linking

dose and exposure from biomarker data;

and approaches to assess populationbased cumulative risk, including those

involving exposure to stressors other

than pollutants; and

‘ Provide the scientific basis to predict the

interactive effects of pollutants in mixtures and the most appropriate

approaches for combining effects and

risks from pollutant mixtures.

2.2.3 Research Approach 

Exposure Research. One goal of ORD’s

research program is to develop methods and

approaches for measuring exposures and

identify exposure factors accounting for

aggregate and cumulative exposure. In

assessing aggregate and cumulative risk, the

focus will be on measuring exposure and
2-8

Identify Major Factors

that Contribute to 

Variability in

Human Exposures

Determine Distributions

of Aggregate and

Cumulative 

Exposure in Population

Develop Probabilistic

Exposure Models

Test Models in Lab and 

Field Measurement Studies

Integrated Modeling

Framework 

Source Models

Fate and

Transport

Models

Dose-Effects

Models

estimating biologically relevant doses in

exposed individuals. Considerable progress

has been made over the past two decades

toward developing personal measurementbased methodologies for assessing human

exposures in either a population of concern,

or in the population at large. The Total

Exposure Assessment Methodology

program and the National Human Exposure

Assessment Survey (U.S. EPA, 1999b) have

demonstrated the techniques and values of

measuring personal exposures. In addition,

the CDC continues to improve their methods

for measuring pollutants and their metabolites in blood and urine and have recently

begun reporting exposure data for a representative sample of the U.S. population. 

These measurement-based methods add to

our arsenal of approaches to address

aggregate and cumulative risk. 

Exposure research on cumulative and

aggregate risk will build upon the problemdriven research being conducted under other

research strategies (see Appendix A) and

focus principally on describing how people

come into contact with pollutants. As a

result of this emphasis, important components of this research will be to: (1) identify

and characterize major factors, including

time-activity patterns, that contribute to

human variability in aggregate and

cumulative exposure, and (2) to conduct

studies to determine distributions of

aggregate and cumulative exposure for the

general population and for specific

susceptible or targeted subpopulations

(see schematic). Exposure research will

integrate an understanding of exposure

pathways and human contact with

pollutants into probabilistic human

exposure models that account for both

aggregate and cumulative exposures. 

These exposure models will then be tested

against the exposure and exposure factor

data generated through targeted laboratory

and field measurement studies, including

population and epidemiological studies. 

The resulting data will be used to improve

our understanding of human exposure and

refine the exposure models. The ultimate

objective of this research will be to

assemble and integrate a knowledge of

human exposures into models that describe

those exposures and to combine the source

models, the transport and fate models, and

the probabilistic exposure models into an

integrated modeling framework that can be

linked and effectively employed by the risk

assessor. The framework is designed to link

a variety of source, exposure, exposuredose, and dose-effect modules into a

comprehensive source-to-effects modeling

framework characterizing and assessing

user-specified aggregate and cumulative

exposures and risks. The resulting tools,

models, and framework will then be

disseminated to scientists and risk assessors

as they work to solve specific programmatic

problems as outlined in ORD’s research

strategies (see Appendix A).

Exposure to Dose Research. When

exposures to an agent occur via multiple

routes, they must be converted to a common

basis, usually some measure of dose, to

evaluate the risk of aggregate and

cumulative exposure. Ideally, the common
2-9

Risk Assessment for

Aggregate and Cumulative

Exposures

Biologically

Effective Dose

Dosimetry

Models

Route

Activity Patterns

Multiple Pollutants

Humans -----------

Biomarkers

 -Exposure

-Effect

Mechanistic Data

Exposure Data

Statistical Models

Analytical

Methods

metric would be the biologically effective

dose, that is, the dose to the target organ,

tissue, cell, or molecule that causes the toxic

or adverse health effect (see schematic). 

The biologically effective dose may be the

pollutant itself or one or more metabolites

and may be affected by many factors. For

example, contemporaneous exposure of a

single pollutant by more than one route can

result in different proportions of parent

compound or metabolites than would be

predicted from one route alone. The route

of exposure may also modulate the internal

dose of systemic toxicants at the target

tissue due to alterations in physiological

parameters (e.g., breathing rate due to an

irritant) or pharmacokinetic parameters

(e.g., induction of enzymes). Human

activity patterns may also affect the

biologically effective dose. A pesticide, for

example, may contact the body through

inhalation of dust from contaminated

surfaces, the diet, and as a result of hand-tomouth activity. People may be exposed

occupationally as well as incidently away

from their place of work. People may also

be exposed to low background levels and

also, by virtue of special intermittent

activities, to bursts of higher exposure. 

Finally, the biologically effective dose may

be affected by exposure to more than one

pollutant. Multiple pollutant exposures

might change the metabolic transformation

of the pollutants in the mixture, resulting in

different biologically effective

doses than seen after exposure

to the pollutants in isolation. 

Ingestion of otherwise

innocuous substances, because

of enzyme induction, might

also increase the rate of

formation of a toxicologically

relevant metabolite of a pollutant of environmental concern. 

Knowledge of the biologically

effective dose provides the

basis for developing dosimetry

models that can be used in

assessing risk of aggregate and

cumulative exposures.

Measuring the biologically

effective dose in humans, however, is not

easily accomplished and is therefore not

usually attempted. More often, a surrogate

for the biologically effective dose, such as

the absorbed dose (the amount of substance

crossing an absorption barrier such as the

skin, the lining of the lung, or the lining of

the gastrointestinal tract) or the level of

pollutant in human blood, urine, or other

biological tissue is measured or estimated

and used in the aggregate assessment as the

common metric. In some notable cases

(e.g., concentration of lead in the blood,

carboxyhemoglobin), the human biomarker

can also be used as a quantitative predictor

of effects. An exposure biomarker is an

exogenous substance or its metabolite(s)

measured in a compartment within an

organism, whereas an effects biomarker is a

measurable change within an organism that

can be recognized as an established or

potential health impairment. Exposure

biomarkers are actual evidence of internal

dose. However, only a few biomarkers,

such as urinary metabolites, are relatively

easy to measure in exposure field studies. 
2-10

With proper research, such biomarkers can

be used with pharmacokinetic models to

estimate, via a “back calculation,” the

biologically effective dose and even the

exposure that occurred. Thus here, the

exposure-to-dose continuum is actually used

in reverse for “dose-to-exposure”

estimations. 

Identification and characterization of

biomarkers and development of methods to

use them will be a high priority for ORD’s

research on aggregate and cumulative risk.

Development of analytic methods to

measure biomarkers and methods for their

analysis and interpretation will be necessary

for exposure and dose assessment. This will

require contributions from ORD’s research

on effects to provide the scientific basis for

the development of sensitive and specific

biomarkers based on mechanistic studies.

Combined with proper modeling techniques

and some knowledge of possible exposure

patterns and measurements, biomarker data

can be used to estimate dose and exposure.

Research in this area will also focus on the

development and/or implementation of

advanced statistical methods to help formulate and use dosimetry models for estimating

exposure from biomarkers. This is especially important as more and more

biomarker measurements are taken and their

results are made available. For example,

CDC is publishing on the internet the results

of such measurements taken in the

population. Those data, often representing

“snap-shots in time” will have to be

interpreted using a variety of modeling and

statistical tools to determine the meaning of

these data with respect to exposure and

dose.

Initially, ORD’s dose research will focus

on the development of a suite of routespecific models for use in dose-response

assessment of cumulative and aggregate

exposures. This will build upon the

dosimetry-based approach in the current risk

assessment guidelines, extend it to oral and

dermal exposures, and use it to evaluate

aggregate exposures. As the program

progresses, dose models will be expanded to

describe and predict chemical disposition

within the body resulting from aggregate

and cumulative exposures. ORD’s

dosimetry models will enable users to

estimate biologically relevant doses

resulting from exposure to multiple

pollutants and multiple pathways of

exposure. The most immediate phases of

this research will concentrate on aggregate

exposures. In addressing cumulative risk,

models will be first developed for those

cases involving exposure to multiple

compounds with common modes of action. 

The next phase will begin to address those

cases in which compounds may act with

different modes of action. 

ORD realizes that there must be significant integration between research on exposures, dose, and effects to study the problem

of aggregate and cumulative risk adequately. 

ORD has already implemented plans to

facilitate a multidisciplinary approach to this

problem. For example, scientists from

NERL, NHEERL and NCEA, as well as

scientists from the Office of Pesticide

Programs (OPP), are working on a

collaborative research project to develop

methods and models for assessing the

exposure, dose, and aggregate and cumulative risk of pyrethroid mixtures. In addition,

NERL and NHEERL sponsored an

Exposure to Dose Modeling Workshop in

July 2001 to begin linking quantitative

modeling in a Human Health Risk

Assessment context. This meeting

examined a number of issues related to

source, exposure pathways, doses in

toxicology and epidemiological studies,

pharmacokinetic modeling of mode of

action, effects, and dose-response modeling. 

Presentations at the meeting were followed

by a discussion of research directions and

options for linking models. Significant
2-11

Principles of Chemical 

Interaction 

Studies on Complex M ixtures

Dose-Response Assessment

of Prototypic Agents to Test 

Principle of Additivity

Identify Precursor or

Adverse Effects for

Assessment

Information on M echanism

or M ode of Action

Single vs Combined

Different Ratios

Different Order

opportunities for collaboration and modelsharing between principal investigators in

both laboratories were identified. Projects

have been initiated to integrate to a greater

extent the modeling efforts of the two

laboratories. Interactions between the

exposure, dose, and effects research

programs and the risk assessment methods

are also being developed.

Effects Research. The FQPA indicates

that EPA must consider the cumulative

effects of pesticides and other chemicals

having a common mode or mechanism of

toxicity. Understanding cumulative risk

requires knowledge about mechanisms or

modes of action and an understanding of

how chemicals will interact in mixtures. 

The principal effects issue for cumulative

risk is the possibility that chemicals in

mixtures may interact in a nonadditive

manner. There is evidence that the

assumption of dose additivity may not hold

for all mixtures of pollutants. For example,

research has indicated that antagonism can

occur at high concentrations of some

mixtures of pollutants; whereas synergistic

interactions have been noted at the low end

of the dose-response curve for other

mixtures. Understanding the conditions

under which nonadditive interactions will

occur between pollutants is needed to

support risk assessment approaches for

cumulative exposures.

ORD’s effects research program on

mixtures will test various assumptions

concerning the behavior of pollutants in

defined mixtures containing major or key

known constituents at concentration ratios

resembling real-world mixtures. To develop

quantitative models, it is crucial in these

studies to understand dose-response

behavior and the pharmacokinetic characteristics of each pollutant. Much of this

information can be derived from projected

work on the development of methods and

mechanistically based dose-response

models. It is likely that a systematic

approach to the study of mixtures will

require the development of new

investigative tools such as genomics and

proteomics so that effects of multiple pollutant interactions can be studied in rapid

fashion.

The overall approach of ORD’s effects

research on chemical mixtures will be to

identify key biological processes (see

schematic) that could be used in testing for

various health endpoints and in determining

effects of pollutants based on their mechanism or mode of action and environmental

relevance. Initial studies will focus on doseresponse curves for pollutants in isolation,

and then pollutants will be tested for evidence of antagonism, potentiation, or synergism with other pollutants in the mixture. 

Two key questions are where on the doseresponse curve interactions occur and

whether interactions vary with the ratio of

the pollutants in the mixture. Additionally,

fit will be important to determine the

influence of the order of presentation of

pollutants in the mixture. Studies on

interactions between pollutants in mixtures
2-12

will be used to develop principles for the

assessment of real-world mixtures.

Risk Assessment Methods. Human

populations are most frequently exposed to

multiple environmental pollutants (e.g.,

particulate matter, pesticides, microbes,

climatic stressors). Exposure to multiple

stressors could change health risks through

combining effects arising from similar

modes of action or through interactions

between nonchemical stressors that increase

or decrease the potency of environmental

agents. Research will be designed and

conducted to evaluate population-based

approaches to assess effects of total

exposures in the environment and the

interaction of chemicals with nonchemical

stressors. Because this is an emerging area,

case studies will be conducted and a conceptual framework will be developed incorporating results from ORD aggregate/cumulative research and addressing issues of

aggregate and cumulative exposure,

mechanisms of action, and PBPK and doseresponse modeling. The objective of this

research is to develop guidance and EPA

guidelines for population-based cumulative

risk that will incorporate cumulative and

aggregate exposure to multiple stressors. 

2.3 Research on Susceptible and Highly

Exposed Subpopulations

The goal of ORD’s program on

susceptible and highly exposed

subpopulations is to understand why some

people and groups are more susceptible or

highly exposed than others. Observed

variability in human responses to

environmental agents reflects differences in

biological susceptibility and exposure. 

Variation in biological susceptibility

depends on intrinsic factors (e.g., life stage,

gender, genetic factors) and acquired factors

(e.g., preexisting disease, nutrition, stress,

licit and illicit drug use, cigarette smoking,

alcohol use). Variation in exposure and

dose can be influenced by many of the same

factors. In addition, factors such as occupation, location of residence, and activity

patterns that place individuals in contact

with environmental agents can cause variation in exposure. Information is needed on

how various susceptibility and exposure

factors alter responses to chemical exposures. ORD research on susceptible and

highly exposed subpopulations will focus on

three factors (i.e., life stage, genetic factors,

and preexisting disease) that have been

identified by a program office and the

scientific community as having a high

priority for risk assessment. 

In addition to examining the role of each

of the three factors separately, ORD will

examine the interactions among these

factors that may result in susceptibility

greater than that caused by the presence of

only one factor. For example, a child with

autism or developmental delay might mouth

hands and toys to a greater degree than the

average child. The condition of autism

might make the child a highly exposed

individual within a group that is already

prone to higher exposures. An early

exposure might also affect the development

of the immune system, which in turn, could

make the individual more susceptible to

development of cancer later in life. Genetic

predisposition, such as lack of an enzyme

that detoxifies a particular chemical, can

make individual members of an already

susceptible life stage even more susceptible. 

 

 While life stage, genetic predisposition,

and preexisting disease provide a focus for

the strategy, there are many complex interactions among risk factors that must be

considered in any research program on

susceptible and highly exposed subpopulations. Gender is not highlighted as a factor

in this research strategy, but it is recognized

that any study of the effect of life stage,

genetic factors, or disease on response to

environmental agents must understand how
2-13

differences between the sexes influence

response to exposures. ORD recognizes that

stressors associated with the physical and

social environment of an individual can also

increase susceptibility to environmental

agents. In addition, factors such as socioeconomic status of individuals and

communities, access to health care,

nutrition, drug and alcohol use, and

exposure to environmental tobacco smoke

can alter the sensitivity to environmental

agents. The influence of these factors on

susceptibility and exposures associated with

life stage, genetic predisposition, and

disease will be considered in future

implementation of the strategy. 

ORD will identify and study those that

are susceptible to disease that can be

induced or exacerbated by environmental

exposures. Disease endpoints that are

included within the strategy include cancer;

neurotoxicity; immune system effects;

asthma and other respiratory effects; reproductive effects; and birth defects including

death, malformation, and growth alteration. 

While the strategic focus is on life stage,

genetic factors, and the effects of disease on

responses to exposure, the interaction of

these factors with intrinsic factors including

gender and stressors in the physical and

social environment will be an important

consideration.

Other ORD research strategies which

address susceptible and highly exposed

subpopulations are the Strategy for Research

on Environmental Risks to Children (U. S.

EPA, 2000a) and the Asthma Research

Strategy (U.S. EPA, 2001a). The influence

of life stage on responsiveness to endocrine

disruptors is also described in the Research

Plan for Endocrine Disruptors (U.S. EPA,

1998). 

2.3.1 Scientific Uncertainties

Life Stage. There are specific periods or

windows of vulnerability during development, particularly during early gestation but

also throughout pregnancy and early childhood through adolescence and old age, when

toxicants might permanently alter the morphology and/or function of a system

(Rodier, 1980; Bellinger, et al., 1987). 

Many specific adverse effects ranging from

functional impairment to anatomical birth

defects depend on an exposure at a specific

stage of development. Children may also be

more vulnerable to specific environmental

pollutants because of differences in absorption, metabolism, and excretion (NRC,

1993). In addition, children’s exposures to

environmental pollutants are often different

from those of adults because of different

diets and different activities (e.g., 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 (NRC, 1993). 

These health threats to children are often

difficult to recognize and assess because of

a limited understanding of when and why

children’s exposures and responses are

different from those of adults. 

The effect of aging on response to

environmental exposures is another area of

uncertainty based on life stage. The elderly

may respond to environmental exposures

differently than younger adults. There may

be an increased risk of cancer and degenerative diseases as a function of age. The

prominence of these concerns is rapidly

elevating with the largest birth cohort in the

US, namely the “baby boomers,” now

becoming senior citizens. Many of these
2-14

individuals are living longer and the effect

of previous exposures may be markedly

magnified with aging. In 2002, EPA

launched an Aging Initiative designed to

study and prioritize the environmental

health risks aging citizens face. As part of

that initiative, EPA is in the process of

creating a National Agenda on the

Environment and the Aging. The intent of

this agenda is to help identify research gaps

and develop strategies that will help

scientists better understand the environmental hazards affecting the health of older

Americans. EPA has held listening sessions

to solicit input from the public concerning

the development of a research program on

aging. 

Genetic factors. There are a number of

genetic factors that could predispose human

subpopulations to adverse effects from

exposure to pollutants, including genetic

polymorphisms for metabolizing enzymes,

differing rates of DNA repair, and different

rates of compensation following toxic insult. 

The main scientific question for this

research is whether such genetic differences

significantly influence risk at realistic, lowdose exposures. Information on genepollutant interactions as a result of longterm exposure to environmentally relevant

concentrations of pollutants is needed. 

Health status. Preexisting diseases may

influence an individual’s response to

environmental toxicants by altering

xenobiotic metabolism or otherwise altering

the host’s response in a synergistic, additive,

or antagonistic manner. ORD research has

shown, for example, that mice challenged

with influenza have increased mortality

from exposure to several environmental

agents including dioxin, ozone, and

ultraviolet radiation. Research is needed to

develop animal models of diseases having a

high incidence in the human population and

to determine the effects of the disease on the

dose-response curves for high priority

environmental agents (e.g., air pollutants,

pesticides). 

2.3.2 Research Objectives 

The Human Health Research Strategy

provides a broad framework for ORD

research in human variability. Issues

specifically related to children’s risk are also

covered in more detail in the Strategy for

Research on Environmental Risks to

Children (U.S. EPA, 2000a), the Strategic

Plan for Endocrine Disruptors (U.S. EPA,

1998) and the Asthma Research Strategy

(U.S. EPA, 2001a). The following research

objectives provide the framework for an

integrated research program on variability in

the human population:

‘ Identify the key factors that contribute to

variability in human exposure, including

the distribution of human exposures

and behavior associated with exposure to

pollutants; 

‘ Improve the accuracy of dose estimation

in the general population;

‘ Identify the biological basis underlying

differential responsiveness of sensitive

subpopulations of humans to pollutant

exposure; and

‘ Determine how exposure, dose and

effect information can be incorporated

into risk assessment methods to account

for interindividual variability.

2.3.3 Research Approach

Exposure Research. Although an

average person may not be exposed to an

environmental agent at a level that would

cause a health concern, a small percentage

of the population may have significantly

higher exposures because proximity to

sources or activities increase likelihood of

exposure. Therefore, exposure assessments

should include distributions of exposures to

allow identification and assessment of

groups of people at risk from high-end
2-15

M odel Estim ating C hildren’s 

E xposure to Pollutants

Probabilistic Total-Exposure

M odel

PB PK M odels on

C hildren

C ollect D ata on E xposures in 

C hildren

Identify Factors Increasing

Exposure of C hildren

M o d e ls to E stim a te D o se o r 

C o n c e n tra tio n in T a rg e t T issu e fo r 

S u sc e p tib le S u b p o p u la tio n s

D e te rm in a n ts o f V a ria b ility

P ro b a b ilistic 

E x p o su re 

M o d e ls

P h a rm a c o k in e tic

 M o d e ls

C h ild re n

G e n e tic P o ly m o rp h ism s

P re e x istin g D ise a se

exposures. Exposure assessments should

also account for the exposures of people

who may be especially susceptible. 

 Initially, ORD’s exposure research will

focus primarily on children. The overall

objective is to develop a broadly applicable

probabilistic total-exposure model capable

of linking to a PBPK model to estimate

children’s exposure (see schematic). 

ORD will collect data on children’s

exposures and factors that influence

exposure. These data will provide input to

the development of a probabilistic model. 

Status and trends in children’s exposure to

environmental agents will also be characterized. Highly exposed subpopulations of

children will be identified, and important

sources and pathways of children’s

exposures will be delineated. Residential

exposure factors for children will be

characterized by age and gender for the

national population, regional populations,

highly exposed groups, and susceptible

groups. Factors that will be characterized

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

pollutant residues on surfaces. Future

research will include the aging population.

 Dose Research. Dose research in the

area of susceptible subpopulations will

focus on developing probabilistic exposure

and pharmacokinetic models which estimate

doses in susceptible subpopulations,

including children and those with genetic

polymorphisms or preexisting disease (see

schematic below). This research will

provide crucial information on the

likelihood that a pollutant or its

metabolites will be present at the

target site, the concentrations in target

tissues, and whether and how the dose

varies between members of the

general population and susceptible

individuals. Measuring and modeling

the effect of susceptibility factors on

dose will help ORD design and

conduct studies of the biological

mechanisms on the cellular and

molecular levels that lead to adverse

effects. This will lead to a better

understanding of the biological bases

for differential sensitivity of

susceptible subpopulations.
2-16

Biological Models Describing Differential 

Responsiveness of Susceptible Subpopulations

Biological Basis for Differential

Sensitivity to Specific Chemicals and 

Interspecies Extrapolation 

Pharmacodynamic Studies on 

Differential Sensitivity in Animals

-Life Span

-Genetics 

-Disease 

Data from Clinical and Epidemiological

Studies

Mechanism or

Mode of Action

For the near term, ORD will continue its

focus on children. Broadly applicable

PBPK models and methods will be produced

that allow better quantitative

characterizations of dose to target tissue in

developing organisms to replace default

assumptions in children’s risk assessments. 

Over the next two to three years, research on

the influence of aging on pharmacokinetic

parameters will increase. 

The development and linkage of

probabilistic exposure and pharmacokinetic

models will provide valuable tools for

analyzing and utilizing data describing

variations in subpopulations for risk

assessment. A key step will be to establish

methods and approaches that can be applied

to both animals and humans to aid in

extrapolating from dose-response data

collected in animals to humans.

Effects Research. The main hypothesis

of the effects research on susceptible

subpopulations is that differences among

individuals (inter-individual) as well as the

variability in an individual’s responses over

time (intra-individual) are due to biological

variability. ORD’s effects research on

susceptible subpopulations will focus on

developing biological models that describe

the differential sensitivity of various

subpopulations for risk assessment,

especially the influence of life stage, genetic

factors and preexisting disease on

toxicological outcome or adverse health

effect (see schematic). 

Life Stage. There is now evidence that

differential sensitivity of very young (early

postnatal, children) and elderly individuals

to certain pollutants may be related to pharmacokinetic factors. In conjunction with

ORD’s dose research program, the effects

research program will develop longitudinal

pharmacokinetic information for prototypic

environmental agents from the prenatal and

early postnatal period to senescence in

laboratory animals to determine how

specific xenobiotic metabolizing enzymes

change as a function of lifestage. Research

will also determine how biological changes

specific to some life stages (e.g., proliferative phase during development) can increase

the risk of certain pollutants. Identification

of such pharmacodynamic factors is crucial

for the protection of susceptible subpopulations at different stages of development. 

As in the case of research on exposure, the

initial emphasis will be on children. 

Research in this area will begin to focus on

the elderly following the development of a

national research agenda on aging. An

objective of ORD’s effects research will be

to link life stage-related effects at the tissue,

organ, and system levels with the underlying

effects at the cellular and molecular levels

and to develop the first-generation of

biologically based predictive models. 

Information from dose-response,

pharmacokinetic, and mode-of-action

studies in animals will be incorporated into

models that more accurately predict

children’s risks. 
2-17

Effects research currently focuses on the

effects of pollutants on early stages of

development. These endpoints include birth

defects, reproductive, neurodevelopmental,

immunological and endocrine disorders. As

more is known about the effects of pollutants on infants and children, research

efforts will begin to examine the influence

of early exposure to pollutants on health

status later in life. Multidisciplinary

approaches will be developed in animal

models to examine the effect of environmental pollutants on the aging process and

to develop predictive models that can be

incorporated into the risk assessment

process. 

 While animal studies are useful in

understanding mechanisms of toxicity and

are frequently used to predict adverse effects

in humans in the absence of human data,

animals may not always be appropriate

models for humans or for particular life

stages. Extrapolation between animals and

humans can be uncertain. Coordinating the

development of animal models in ORD will

be closely coordinated with human research.

Epidemiological studies will be crucial

to understanding whether certain groups are

more susceptible to environmental contaminants than others, and such studies will be

conducted by all Laboratories and Centers in

ORD. Hypothesis-based human epidemiological and clinical studies will be necessary

to identify and confirm that adverse effects

occur in humans, to identify risk factors, to

develop dose-response relationships in

humans, and to improve extrapolations from

animal data to humans. Human studies will

be conducted as needed for high-priority

environmental agents and to assist in model

development and validation. 

In the Children’s Health Act of 2000,

Congress directed the National Institute of

Child Health and Human Development to

establish a consortium of federal agencies,

including EPA and the CDC, to design and

implement a National Children’s Study. 

This study will follow a cohort of children

from as early in pregnancy as possible to

adulthood to evaluate the effects of chronic

and intermittent exposure on child health

and human development. The goal is to

enroll at least 100,000 children in the study. 

Exposure information will be collected for

preconception exposures, at several times

during pregnancy, and at several ages after

birth; and outcome data will be collected

during pregnancy, infancy, childhood, and

beyond, perhaps focusing on developmental

milestones of potential susceptibility in each

of several age ranges. Biological specimens

from the parents and children will be

collected. Children will be followed at least

through their primary school years and,

preferably, into adulthood. ORD is

participating in the planning and design of

the study and developing and testing

methods for data collection.

Genetic Differences. ORD’s effects

research on genetic influences will address

the hypothesis that individuals harboring

genetic polymorphisms in metabolic genes

may have increased vulnerability to health

effects following exposure to some pollutants. ORD research has shown, for

example, that people who are phenotypic for

rapid acetylation have higher levels of

urinary mutagens following exposure to

heterocyclic amines in food. The main

scientific question for this research is

whether such genetic differences significantly influence risk. This research will

focus on the influence of genetic factors on

long-term exposure to low levels of pollutants. The role of other genetic factors in

susceptibility, such as differing rates of

DNA repair and compensatory responses to

toxic insult, will also be investigated.

Genotype can alter exposure and pharmacokinetic and pharmacodynamic factors. 

If individuals are genetically predisposed to
2-18

Improved Methods, Models, Tools 

and Databases for Risk Assessment

of Susceptible and Highly 

Exposed Subpopulations

PBPK Models on 

Susceptible 

Subpopulations

Biological Models on 

Phamacodynamic

Differences

Exposure Variables 

autism and if autism results in higher

mouthing of objects and hands, then genetic

factors could lead to higher exposures. 

Genotype can also alter transport proteins,

clearance, metabolic profiles, and target

organ sensitivity. Therefore, research will

be conducted with the goals to develop

exposure and pharmacokinetic and pharmacodynamic data and models with which to

estimate dose and response in individuals

with genetic polymorphisms. The use of

these data in dose-response assessment will

be similar to that described in the discussion

of life stage. 

Disease. Preexisting diseases may

influence the response to environmental

toxicants by altering xenobiotic metabolism

or otherwise altering the host’s response in a

synergistic, additive, or antagonistic

manner. Preexisting dysfunction of a target

organ may alter the type or severity of a

chemically induced adverse effect on end

organ function, such as the effect of air

pollutants on lung function in individuals

with asthma or the effect of exposure to a

neurotoxicant on children with

neurobehavioral dysfunction. In the near

term, research will focus on the

development of animal models of diseases

having a high occurrence in the human

population (e.g., asthma, bronchitis, hypertension) and on determining the effects of

the disease on the dose-response curves of

high priority environmental agents (e.g., air

pollutants, pesticides). Mechanistic research

will establish animal models that employ

specific host traits that are characteristic of

the disease and represent “risk factors” for

increased sensitivity to chemicals. Once

effects have been established using these

animal models, studies will be conducted to

extrapolate from animal data to human

effects and across levels of biologic organization. Epidemiological studies will also be

used to identify possible associations

between exposure to a specific pollutant and

manifestation of a disease. Such associations will then be tested in in vitro or in vivo

animal models. Data derived from these

studies can be used to assess the possible

increased risk to pollutant exposure in

individuals with preexisting disease. 

Research on health status will continue to

focus on asthma and other respiratory

diseases and air pollution; studies on other

diseases and pollutant classes will be

conducted as time and resources allow.

Effects research will be conducted with

a goal to develop pharmacokinetic and pharmacodynamic data and models with which

to estimate dose and response in individuals

with a preexisting disease. ORD will

examine the physiological and biological

changes associated with common diseases

and how these changes influence the pharmacokinetics and pharmacodynamics of

environmental agents. This information will

lead to improved models and methods for

accounting for the effects of disease on

individuals’ responses to environmental

agents.

Risk Assessment Methods Research.

The results of ORD’s research in exposure,

dose, and effects, along with research

supported by other government agencies and

nongovernmental sponsors, will be used to

develop improved methods, models, tools

and databases for risk assessments of

susceptible and highly exposed subpopulations (see schematic). 
2-19

ORD will use pharmacodynamic data and

PBPK models from research on effect and

dose to develop better dose-response

methodologies to account for susceptibilities

of various life stages and to evaluate the

adequacy of the current default uncertainty

factor of 10 in accounting for human

variability for noncancer health effects. 

ORD risk assessment methods research will

also analyze data on exposure factors,

human activity patterns, and environmental

concentrations, including those generated by

the exposure research program on pesticides

and air pollutants, to quantify the important

factors used in exposure assessment and to

evaluate representativeness of the data based

on factors such as life stage, genetics, and

pre-existing disease. Databases on

physiological and pharmacokinetic factors

for various life stages will be developed to

aid in development and implementation of

PBPK models. Dose-response

methodologies for specific life stages,

accounting for differences between children

and adults, will be developed. Distributions

of exposure factors measured in ORD

studies will be incorporated into the

Exposure Factors Handbook (U.S. EPA,

1997b, 2000b). Finally, ORD will develop

guidance for performing risk assessments

for children, the elderly, and those with

preexisting diseases and for taking into

account genetic variation in risk assessment.
3-1

3. RESEARCH TO ENABLE EVALUATION OF PUBLIC 

HEALTH OUTCOMES FROM RISK MANAGEMENT ACTIONS

ORD’s current Human Health Core

Research Program began a new effort to

evaluate the public health outcomes of EPA

policies in 2001. The issue of “accountability,” i.e., making sure that our research

and pollution control programs produce

measurable benefits in public health, is an

important one. In order to better protect the

country’s air, water, and land resources,

EPA must go beyond its current reliance on

process indicators such as decreased emissions or discharges and measure actual

changes in the status of ecological condition

and human health. This issue is fundamental to the first goal of ORD’s Strategic

Plan, i.e., to support EPA’s mission “to

protect human health and to safeguard the

natural environment–air, water, and

land–upon which life depends.” With the

advent of the GPRA and calls for EPA to

stress and demonstrate outcome-oriented

goals and measures of success, research is

needed to enable evaluation of actual public

health outcomes from risk management

(emission or exposure control) actions.

Furthermore, in 2001, EPA announced an

“Environmental Indicators Initiative” to

improve the EPA’s ability to report on the

status of and trends in environmental conditions and their effect on human health and

the nation’s resources. ORD will work with

the Office of Environmental Information to

develop and publish a “State of the Environment Report” using available national level

data and indicators to describe human health

environmental conditions and human health

concerns. Part of that report will identify

data gaps and research needs and discuss

opportunities for partnering with other

research organizations in filling those gaps.

Estimating public health benefits of EPA

regulatory decisions and rule-making or, in

a more general sense, evaluating public

health outcomes from risk management

actions will be a challenge. It will involve a

number of disciplines grounded in both the

physical and social sciences and

increasingly must take into account the

economic and behavioral aspects of human

decision-making. The remainder of this

chapter outlines the basic conceptual

strategy of an emerging research program to

evaluate the environmental public health

consequences of EPA regulations,

regulatory or non-regulatory programs, or

other risk management activities. Both the

precise methods to be used and the

outcomes that will be studied have not yet

been chosen.

Evaluating public health outcomes from

risk management actions is clearly linked to

assessing human health risks. EPA risk

assessors and risk managers must consider

the uncertainties associated with the risk

assessment process, including the upper as

well as the lower bounds of such uncertainty. Coupled with these uncertainties is

the fact that EPA very often estimates the

future benefits of public health outcomes in

a politically charged environment. Depending on the desired human health protection

endpoint, final decisions often rest with

national and state policy makers and decision officials. These officials take scientific

findings into account along with a number

of other considerations that assist them in

making more informed public policy

decisions. 

Generally, EPA has not prepared retrospective evaluations examining whether the

intended benefits in protecting public health

were realized once an EPA decision had

been in place for a period of time. One

exception to this was the decision to ban

lead in gasoline and other products, the

subsequent tracking of reduced blood-lead

levels in children as a result of the ban, and
3-2

the epidemiological studies to confirm the

linkage between elevated blood level levels

and reduced cognitive development in

children. The confounding influences of

various factors (e.g., age of exposure, duration of exposure, exposure to other pollutants alone or in complex mixtures) offer

challenges at every turn in evaluating public

health outcomes. As EPA develops and

implements a research program advancing

the evaluation of public health outcomes,

either prospective or retrospective, participants and observers must recognize that the

program will take years or perhaps decades

to develop and fully implement. It will

involve a number of organizations both

within and outside of EPA working in

partnership to collect and analyze data and

then to use that data in methodologies and

tools to objectively determine the effectiveness of risk management decisions on public

health outcomes. 

The Presidential Commission on Risk

Assessment and Risk Management (1997)

has supported the need for EPA to measure

the effectiveness of public health interventions (see text box).

The National Research Council (1997) also

noted a lack of consensus concerning

appropriate indicators of health status that

could be used to measure the performance of

environmental health programs. This led

the Council of State and Territorial

Epidemiologists, the CDC, the Agency for

Toxic Substances and Disease Registry, and

EPA to begin developing a set of public

health indicators to track adverse health

events related to the environment. The Pew

Environmental Health Commission (Pew,

2000) has also recommended a nationwide

tracking of priority chronic diseases such as

asthma and respiratory diseases and of

exposures to environmental pollutants such

as polychlorinated biphenyls, metals, and

pesticides.

Chapter 2 of the Human Health

Research Strategy sets forth priorities for

improving the science of human health risk

assessment. These improvements will result

in more effective and longer lasting risk

management actions and will contribute to

public health outcomes that can be achieved. 

Chapter 3 describes research enabling more

informative and reliable evaluations of

public health outcomes (e.g., improved

estimates of actual reductions in risks to

public health via exposure and effects

data) from risk management actions. 

These two chapters taken together will

provide the foundation for successful

implementation of the Human Health

Research Strategy in the years to come.

3.1 SCOPE AND DEFINITIONS

As discussed in Chapter 1, there are

great similarities in information needs for

risk assessment and risk management. 

This is because understanding the

efficacy of an EPA decision requires a

comparative analysis of risks before and

after implementation of risk management

actions (see Figure 3-1). At the same

time, various risk management actions

The Presidential Commission on Risk Assessment

and Risk Management points out the need for

progress in several scientific areas “...if we are to

improve our ability to implement and measure the

effectiveness of public health interventions. 

Specifically, we need to: 

(1) Link studies of exposure and studies of adverse

health or ecological outcomes; 

(2) Determine regional differences in disease

prevalence and disease incidence trends and risk

factors; 

(3) Develop good baseline and surveillance

information about incidence rates of diseases

specifically linked to environmental causes; and 

(4) Identify the most important environmental

causes of diseases.” (page 47, Vol. 1)
3-3

Definitions of Key Terms (Haddix et al., 1998)

Effectiveness: The improvement in health outcome that a

prevention strategy can produce in typical community-based

settings (p.146).

Efficacy: The improvement in health outcome that a

prevention strategy can produce in expert hands under ideal

circumstances (p.146).

Outcome Measure: The final health consequence (e.g.,

cases prevented) on an intervention (p.149)

must be applied within the framework of

maximum achievable risk reduction that is

efficient, cost-effective, and long-lasting. 

Important issues need to be addressed that

require research targeted at the most robust

possible evaluation of public health

outcomes from risk management actions.

This chapter stresses the identification

of existing information and the creation of

new information that can be used in

evaluating public health outcomes from

risk management decisions. Reflecting

the close relationship between risk

assessment and risk management, this

public-health-outcomes research program

is included in the Human Health Research

Strategy for two reasons: (1) the need to

link more closely risk assessment and risk

management so as to improve human

health risk assessments and (2) the need to

improve the scientific basis for evaluating

public health outcomes from risk

management actions. 

It is essential for the research described

in this chapter to be based upon a common

set of definitions. Haddix and others in their

Prevention Effectiveness: A Guide to

Decision Analysis and Economic Evaluation

(1998) offer a set of useful definitions

adopted for this research strategy (see text

box).

Figure 3-1. Role of analysis of health outcomes in the risk management decision process.
3-4

Long-Term Goal: Provide the scientific

understanding and tools to assist EPAand others

for use in evaluating the effectiveness of public

health interventions from risk management

actions.

Key Scientific Questions: How can the most

effective tools, systems, methods, and models be

identified, discovered, or developed and

integrated into a decision-making framework, to

assist federal, state and local decision-makers in

evaluating changes in public health as a result of

risk management actions? What is the ability of

this framework to quantify such changes

accurately?

The remainder of this chapter discusses the

scientific uncertainties underlying the

evaluation of public health outcomes from

risk management actions and describes the

research approach used to meet the

objectives of ORD’s public-health-outcomes

research program.

3.2 SCIENTIFIC UNCERTAINTIES

The basic philosophy behind the EPA’s

public health policies is that regulatory or

other risk management actions are taken

with the intent of preventing or reducing

releases of pollutants of concern. This

philosophy assumes that exposure prevention or reduction will lead to measurable

reductions in specific human health effects. 

However, actual reductions in health effects

will depend on the proportional relationships between the pollutant releases and

health risks from a given source as well as

whether the health risks are influenced by

other sources and factors not being considered. The degree of certainty and

directness of the links between source,

exposure, and effect influence the validity of

this assumption. Behavior of individuals

and communities in reducing risk are additional important variables.

Unfortunately, in most cases, this linkage has a very poor quantitative scientific

foundation; and health-protective default

assumptions are generally used in cases of

uncertainty or lack of information. If this

linkage were better forged scientifically, the

predictability of risk management action

effectiveness would be more accurate. Even

so, actual effects will need to be measured

to evaluate whether the predictions (or the

prediction approach) are correct. The

optimal approach is to compare a health risk

assessment before and after the risk management action has been employed. This is,

however, a very complex and challenging

undertaking because a systematic evaluation

framework does not always exist given the

unethical nature of randomized controlled

clinical trials in humans with toxic agents. 

Prospective assessments of risk often use

multiple approaches with varying degrees of

sensitivity, uncertainty, and reliability. 

Furthermore, even if prospective assessments were reliable, they may not be

suitable for a retrospective analysis. For

example, an epidemiological study with

sufficient sensitivity for prospective risk

assessment may not have the statistical

power to detect the expected risk reductions

in the size of the community affected. In

addition, if the expected public health outcome is the lessening of a chronic effect

(e.g., cancer), it may take many years to be

detected with current risk assessment

approaches that use cancer incidence as the

outcome. Finally, some risk management

actions create multiple and perhaps

disparate benefits and possibly unintended

consequences. This causes great difficulty

in the analysis of management actions

because the unintended effect has to be

identified and evaluated.
3-5

3.3 SCIENTIFIC OBJECTIVES 

Two research objectives were developed

based on the three research issues described

below. The research questions were

developed in accordance with the LongTerm Goal and Key Scientific Questions

described in the text box on the previous page.

The research questions serve as the foundation

upon which to develop a coherent

framework for an integrated research

program and include the following: 

G The kinds of policies, regulations, or

actions that should be evaluated to

determine the efficacy of risk

management actions; 

G The approaches available to address the

effectiveness of risk management

actions on public health; and

G The improvements needed to the

approaches and the development of a

useful framework for evaluating public

health outcomes.

Admittedly, achieving the long-term

goal and answering the key scientific and

associated research questions will take

considerable time and effort. ORD’s three

national Laboratories and two national

Centers have agreed to work on this publichealth-outcomes research program together;

however, neither ORD nor EPA proposes to

undertake this research alone. The research

program described here will be a daunting

undertaking and one that must rely on the

contributions and collaboration with a

number of different organizations. It will

require feedback loops, engagement, and

partnering with other organizations both

within and outside EPA if it is to succeed.

In close collaboration with research

partners, ORD’s research will provide the

scientific understanding and tools to assist

EPAand others in evaluating public-healthoutcomes resulting from risk management

actions. The new public health outcomes

research program is designed to address the

long-term goals and key scientific questions

in a stepwise fashion from reductions in

release, through reductions in exposure, to

improvements in public health. It is not

designed to be an expansion of the EPA’s

epidemiological research program; but will

rely on collaborations with, and data and

information from, other federal, state, and

public health organizations. Ultimately, the

tools, systems, methods, models, and the

framework within which they operate should

measure or reliably estimate changes in

human health risks with a known level of

precision and accuracy. This precision and

accuracy should be sufficient to allow EPA

to determine how its regulatory decisions

and risk management actions contributed to

those changes. Two specific objectives of

ORD’s research program emerge:

G Establish linkages between sources,

environmental concentrations, exposure,

effects, and effectiveness such that a

change in a public health outcome

consequent to a risk management action

can be determined by measuring or

modeling any one of these linked steps;

and

G Improve tools, systems, methods, and

models by which EPA and others can

measure or predict changes in public

health outcomes following risk

management actions.

 It should be noted that a substantial part

of the research on the complex relationship

between sources and environmental quality

(i.e., fate, transport, and transformation) is

contained within problem-driven research

programs (e.g., particulate matter, air toxics,

hazardous waste; see Appendix A). 

Research on the effectiveness of public

health outcomes will provide the linkages to

these other related research programs.

General precedents indicate the feasibility and utility of meeting these two
3-6

objectives. For example, effectiveness

evaluations have been conducted for diverse

risk management actions (e.g., for pharmacologic therapy, vaccine efficacy, and

smoking cessation). These evaluations are

becoming more commonplace, and several

groups have attempted to provide guidance

for the conduct of such studies (Gold et al.,

1995; Graham et al., 1998; Haddix et al.,

1998).

3.4 RESEARCH APPROACH

In developing research program priorities and a deeper understanding of the

relationships between risk management

actions and public health outcomes, it will

be necessary to select cases to study based

on the suite of risk management actions that

might be employed by the EPA. A decision

on the appropriate number and scope of the

case studies will be made after further deliberations in workshops and other fora both

internal and external to EPA. Particular

emphasis will be placed on policies, regulations, or actions attendant to risk management that EPA has developed, is developing,

or may need to develop within the next 10

years. This type of approach will require

close collaboration with EPA’s Program and

Regional Offices. Study sites and the

selection of appropriate research approaches

will vary depending upon the environmental

exposures and effects of interest. 

To ensure full coverage of the possible

risk management alternatives, classes of risk

management actions will be identified as the

first step in the case study process. These

classes of action include, but are not limited

to, those that reduce exposure to pollutants

currently in the environment, dispose of or

redistribute substances currently in the

environment, and those that license (or

allow) new substances into the environment

or allow levels of substances already in the

environment to be increased. Coupled with

these classes of risk management actions

will be an identification of their implications

for evaluating public health outcomes. 

Efforts to ascertain the effectiveness of

risk management actions will depend on the

selection of pertinent research approaches

and appropriate indices of public health

exposure and effects outcomes. An

evaluation of the public health outcome of a

risk management decision should answer

two questions:

G Did the risk management action actually

prevent, reduce, eliminate, or modify

exposure to the pollutants of concern? 

G Did this prevention, reduction,

elimination, or modification result in

disease prevention and improved public

health?

Four approaches might be used to assess

public health outcomes, including health

outcome/effect studies, population exposure

studies, field sampling of environmental

media, and measuring changes in source

emissions. Coupled with this will be the

need to investigate and evaluate the

performance of models used to estimate

outcomes when measurement data may be

inaccessible or too costly to collect except

as a representative sample. These

approaches are ordered in terms of their

ability to determine human exposures and to

link them with public health outcomes;

however, this ordering does not mean that

an approach listed before another approach

is necessarily more feasible. Using these

approaches effectively in evaluating public

health outcomes from risk management

actions will require linking them in the

development of a framework or model. 

Each of these areas can be improved, in

some cases as a result of the risk assessment

research program discussed in Chapter 2. 

However, there are some special needs for

evaluating regulatory efficacy for public

health protection. Thus, a careful analysis

and prioritization of the approaches vis-a-vis
3-7

the risk management action classes

described above are essential. 

Although the above approaches are

listed discretely, perhaps the greatest

challenge of the public-health-outcomes

research program will be to elucidate the

linkages among them. Ultimately, this will

vastly increase the feasibility and accuracy

of both prospective and retrospective risk

assessments. Given the immense number of

scenarios to be evaluated, models of this

process are needed. Such models are under

development as part of the core research

program described in Chapter 2, but

additional models are likely to be required

that incorporate the special needs of an

retrospective assessment and more

thoroughly link the approaches under

consideration.

To assess the strengths and weaknesses

of evaluations of public health outcomes

from risk management actions, a logical first

step will be to use existing approaches and

to evaluate available databases that compile

pollutant release information and environmental concentrations, health endpoints, or

both. Appendix E lists some databases and

other sources that contain information that

could be used to correlate health endpoints

with concentrations of pollutants. Such an

exercise will likely identify priorities for

future research. Better ways to measure

changes in effects (or in indicators of

effects, exposure, indicators of exposure,

environmental concentrations, or source

strength) are needed, together with programs

to measure the effects before and after

implementation of the EPA’s decisions. 

Risk management tools are needed that

express the EPA’s understanding of the

cost-effectiveness and long-lasting nature of

risk management actions and that convey

that understanding to other regulatory

offices, the regulated community, and the

public. Finally, a framework to link models

all the way from source to human health

effects provides more confidence in

exposure-dose-response relationships

through a thorough understanding of the

critical processes within, and linkages

between, each component of the human

exposure-dose-response sequence. 

3.5 RESEARCH IMPLEMENTATION

 The ultimate goal of ORD’s new publichealth-outcomes research program is to

provide a set of fully developed frameworks

and a suite of technical tools, systems,

methods, and models that assist EPA and

others in evaluating public health outcomes

from risk management actions. The overall

intention is to quantify environmental public

health outcome trends that could (or should)

change in response to risk management

decisions (e.g., regulations, implementing

emission control technologies) that affect

the environmental exposures that are the

primary risk factors in the causality of the

outcome. The research program will require

the full participation and active engagement

of stakeholders at all levels, both internal

and external to the EPA. It must leverage

the research program with other public- and

private-sector organizations involved in

similar or compatible efforts since that is the

only way it will succeed. The long-term

goal to provide the scientific understanding

and tools to assist EPA and others in

evaluating the effectiveness of public health

outcomes resulting from risk management

actions is extremely ambitious and research

in this area will proceed in a step-wise and

incremental fashion as described below. 

Developmental phase. This phase will

provide a comprehensive state-of-thescience evaluation of currently available

domestic and international tools, systems,

and methods, along with frameworks that

are being, or could be, used in evaluating

public health outcomes from a variety of

risk management actions. It will of

necessity partner with EPA Program and
3-8

Regional Offices and will seek to engage

organizations outside EPA that are

positioned to engage in a public health

outcomes research program.

Investigation phase. This phase will

implement a detailed multiyear research

plan for improving various tools, systems,

and methods (existing and new) to evaluate

public health outcomes from risk management actions. A preliminary compendium

of tools, systems, and methods, along with

selected framework(s), will be developed for

the multiyear plan. Pilot investigations and

studies on evaluations of health and exposure information will also be conducted,

leading to further refinements of the

frameworks.

Delivery phase. This phase will provide

a set of fully developed frameworks and a

suite of technical tools, systems, and

methods for use by various stakeholders. 

This compendium will be closely coupled

with illustrations and training on its use,

along with case studies targeting decisionmakers at multiple levels. As discussed

above, a near-term objective of this research

is to develop a framework and a multiyear

plan for undertaking research on evaluating

public health outcomes from risk

management actions. Recommended next

steps include the following:

G Conduct workshops, in consultation with

federal, regional, state, and local

decision-makers and other interested

parties, to develop a comprehensive

state-of-the-science evaluation and to

identify the elements of a possible

framework(s) for evaluating public

health outcomes from risk management

actions;

G Describe a set of specific cases/situations that are potential targets for case

studies (including rationale) for

evaluating public health outcomes from

risk management actions;

G Through ORD’s STAR program, issue a

request for assistance for the development of statistical techniques using

environmental and human health data in

evaluating public health outcomes and

conduct case studies to test these

techniques;

G Assess state-of-the-science approaches

for evaluating how human health is

impacted by risk management actions; 

G Identify the policies and regulations that

would most likely benefit from the use

of a framework and set of tools that

evaluate public health outcomes from

risk management actions; 

G Understand how various decisionmakers at the national, regional, state,

and local levels currently use, or might

use in the future, various frameworks

and tools for evaluating public health

outcomes from risk management

actions; and

G Identify a set of environmental health

indicators that can be used to evaluate

the effectiveness of risk management

actions on public health.

Components of the research program

must address such factors as the likelihood

for case studies to be informative and useful

and the composition of research designs to

achieve the desired long-term goals of the

research program. It will be critical that

pilot studies fill evidence gaps that provide

cause and effect linkages between toxicants

and environmental public health outcomes. 

Clearly, this new research program on the

evaluation of public health outcomes of risk

management activities is an undertaking too

broad for EPA alone. While both the precise methods to be used and the outcomes

which will be studied have not been

decided, we expect much of the data,

particularly on the public health side, will

have to come from collaborations with our

sister agencies such as the CDC. A multidisciplinary approach to tying emissions,

fate, transports of toxins; environmental
3-9

exposures; biomarkers of exposure; and

early indicators of disease, as well as

morbidity and mortality, requires the

unification of many scientific disciplines. 

We expect broad teams of researchers, from

several ORD laboratories and partners from

other federal agencies will work together to

carry our this research on an case-by-case

basis.
4-1

4. REFERENCES

Bearer C. 1995. How are children different from

adults? Environ Health Perspect 103 (Suppl. 6):

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Bellinger D, Leviton A, Waternaux C, Needleman

H, Rabinowitz M.. 1987. Longitudinal analysis of

prenatal and postnatal lead exposure and early

cognitive development. New Eng J Med 316:

1037-1043.

Centers for Disease Control and Prevention (CDC).

2001. National Report on Human Exposure to

Environmental Chemicals. National Center for

Environmental Health, CDC, Atlanta, GA 

Centers for Disease Control and Prevention (CDC).

2003. Second National Report on Human Exposure

to Environmental Chemicals. National Center for

Environmental Health, CDC, Atlanta, GA 

Food Quality Protection Act (FQPA). 1996. Federal

Insecticide, Fungicide and Rodenticide (FIFRA) and

Federal Food, Drug and Cosmetic Act (FFDCA) As

Amended by the Food Quality Protection Act

(FQPA) of August 31, 1996; U.S. EPA, OPP,

document #730L97001, March 1997.

Gold MR, Siegel JE, Russel LB, Weinstein MC.

1995. Cost Effectiveness in Health and Medicine.

New York: Oxford University Press.

Graham JD, Corso PS, Morris JM, Segui-Gomez M,

Weinstein MC. 1998. Evaluating the costeffectiveness of clinical and public health measures.

Ann Rev Public Health 19: 125-152.

Haddix AC, Teutsch SM, Shaffer PA. 1998. 

Prevention Effectiveness: A Guide to Decision

Analysis and Economic Evaluation. New York:

Oxford University Press.

International Programme on Chemical Safety (IPCS).

1999. IPCS Workshop on Developing a Conceptual

Framework for Cancer Risk Assessment. 16-18

February, Lyon, France.

National Research Council (NRC). 1983. Risk

Assessment in the Federal Government: Managing

the Process. Washington, DC: National Academy

Press. 

National Research Council (NRC). 1993. Pesticides

in the Diets of Infants and Children. Washington,

DC: National Academy Press.

National Research Council (NRC). 1994. Science and

Judgment in Risk Assessment. Washington, DC:

National Academy Press.

National Research Council (NRC). 1997. Building a

Foundation for Sound Environmental Decisions.

Washington, DC: National Academy Press.

Pew Environmental Health Commission. 2000.

America’s Environmental Health Gap: Why the

Country Needs a Nationwide Health Tracking

Network. Baltimore, MD.

Presidential Commission on Risk Assessment and

Risk Management. 1997. Volume 1: Framework for

Environmental Health Risk Management. Volume 2: 

Risk Assessment and Risk Management in Regulatory

Decision-Making.

Rodier PM. 1980. Chronology of neuron

development: animal studies and their clinical

implications. Dev Med Child Neurol 22:525-545.

Schlosser PM, Bogdanffy MS. 1999. Determining

modes of action for biologically based risk

assessments. Regul Toxicol Pharmacol 30:75-79.

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

1986. Guidelines for health risk assessment of

chemical mixtures. Federal Register 51:34014.

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

1995. Science Advisory Board, Committee on Indoor

Air Quality and Total Human Exposure. Human

Exposure Assessment: A Guide to Risk Ranking,

Risk Reduction, and Research Planning. U.S.

EPA-SAB-IAQC-95-005.

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

1996. Proposed guidelines for carcinogen risk

assessment. Federal Register 61:56274-56322.

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

1997a. Update to ORD’s Strategic Plan. Office of

Research and Development. Washington, DC. 

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

1997b Exposure Factors Handbook. Office of

Research

and Development. Washington, DC. EPA/600/P95/002Fa.

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

1998. Strategic Research Plan for Endocrine
4-2

Disruptors. Office of Research and Development.

Washington, DC. EPA/600/R-98-087.

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

1999a. Guidelines for Carcinogen Risk Assessment.

Risk Assessment Forum. U.S. EPA, NCEA-F-0644.

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

1999b. National Human Exposure Assessment

Survey. National Exposure Research Laboratory,

National Center for Environmental Assessment,

Office of Research and Development. Research

Triangle Park, NC.

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

2000a. Strategy for Research on Environmental Risks

to Children. Office of Research and Development. 

Washington, DC. EPA/600/R-00/068.

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

2000b. Child-Specific Exposure Factors Handbook. 

External Review Draft. Office of Research and

Development. NCEA-W-0853

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

2000c Supplementary Guidance for Conducting

Human Health Risk Assessment of Chemical

Mixtures. Risk Assessment Forum. EPA/630/R00/002.

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

2001a. Asthma Research Strategy. Draft. Office of

Research and Development. Research Triangle Park,

NC.

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

2001b. Strategic Plan for the Office of Research and

Development. Washington, DC.
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APPENDIX A

ORD Research Plans and Strategies

Final Research Plan for Microbial Pathogens

and Disinfection By-Products in Drinking

Water (U.S. EPA, 1997) 

This research plan describes ORD’s research to

support EPA’s drinking water regulations

concerning disinfectants, disinfection byproducts,

and microbial pathogens. The research plan

identifies key scientific and technical information

gaps and provides guidance to both intramural

and extramural research programs regarding

priorities and sequencing of research. 

Research Plan for Arsenic in Drinking Water

(U.S. EPA, 1998a)

This research plan provides guidance to improve

the scientific understanding of health risks

associated with arsenic in drinking water and to

support improved control technologies for water

treatment. 

Strategic Research Plan for Endocrine Disruptors (U.S. EPA, 1998b)This research plan addresses research needs of

biological effects for human health and wildlife

and exposure assessment of endocrine disruptors.

Integration of effects and exposure research is

emphasized to provide a complete analysis of risk.

Airborne Particulate Matter Research Strategy (U.S. EPA, 1999)This research strategy describes health, exposure,

risk assessment, and management research on

particulate matter to support EPA’s review and

implementation of the National Ambient Air

Quality Standards. 

Strategy for Research on Environmental Risks

to Children (U.S. EPA, 2000a)

This research strategy describes future directions

and priorities of ORD’s program to reduce

uncertainties in EPA risk assessments for

children, leading to effective measures to prevent

and/or reduce risk.

Mercury Research Strategy (U.S. EPA, 2000b) This strategy presents the scientific questions and

research goals and priorities for EPA’s research

program on mercury.

Asthma Research Strategy (U.S. EPA, 2000c) This strategy describes the research directions and

priorities to improve the scientific understanding

of environmental factors underlying increased risk

for asthma and to develop more effective risk

management control technologies to reduce and

prevent asthma cases.

Air Toxics Research Strategy (U.S. EPA,

2000d)

This strategy presents research approaches and

objectives to improve the scientific and technical

knowledge base for the assessment and management of health risks from hazardous air pollutants.
A-2

Drinking Water Contaminants Candidate List

(CCL) Research Plan (U.S. EPA, 2000e)

This plan describes the research approach and

process to provide improved scientific and

technical bases for the assessment and

management of drinking water contaminants that

are on the CCL.

U.S. Environmental Protection Agency (U.S. EPA). 1997. Final Research Plan for Microbial Pathogens and Disinfection ByProducts in Drinking Water. Office of Research and Development. Washington, DC.

U.S. Environmental Protection Agency (U.S. EPA). 1998a. Research Plan for Arsenic in Drinking Water. Office of Research

and Development. Washington, DC. EPA/600/R-98/042.

U.S. Environmental Protection Agency (U.S. EPA). 1998b. Strategic Research Plan for Endocrine Disruptors. Office of

Research and Development. Research Triangle Park, NC.

U.S. Environmental Protection Agency (U.S. EPA). 1999. Airborne Particulate Matter Research Strategy. Office of Research

and Development. Research Triangle Park, NC.

U.S. Environmental Protection Agency (U.S. EPA). 2000a. Strategy for Research on Environmental Risks to Children. Office of

Research and Development. Washington, DC.

U.S. Environmental Protection Agency (U.S. EPA). 2000b. Mercury Research Strategy. Office of Research and Development.

Washington, DC. EPA/600/R-00/073.

U.S. Environmental Protection Agency (U.S. EPA). 2000c. Asthma Research Strategy. Draft. Office of Research and

Development. Research Triangle Park, NC.

U.S. Environmental Protection Agency (U.S. EPA). 2000d. Air Toxics Research Strategy. Draft. Office of Research and

Development. Research Triangle Park, NC.

U.S. Environmental Protection Agency (U.S. EPA). 2000e. Drinking Water Contaminants Candidate List (CCL) Research 

Plan. Draft. Office of Research and Development. Research Triangle Park, NC.
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APPENDIX B

Organizational Chart

 EPA’s Office of Research and Development
A-4

APPENDIX C

Examples of Mechanistic Data Used in Risk Assessment

 

Pollutant Supporting Research

Aflatoxin

B1

Mechanistic studies showed that this compound forms DNA adducts and

protein adducts, causing specific mutations in the p53 tumor suppressor gene. 

Because of this mechanistic information, formation of DNA adducts is now

being used to assess cancer risk in human populations.

Dioxin The understanding that essentially all the effects of dioxin are mediated via

binding to the arylhydrocarbon (Ah) receptor provides the underpinning for the

species extrapolation in the risk assessment of dioxin. The Ah receptor is

highly conserved, present, and functional in nearly all vertebrates. The current

consensus that dioxin is a known human carcinogen is based on clear animal

data, limited human data, and the presence of a common mechanism of action.

Dioxin The importance of PBPK models for risk assessment is illustrated by the

identification of an inducible hepatic binding protein by dioxin, which results

in dose-dependent sequestration of dioxin in multiple mammalian species,

including humans. This information has allowed for a better understanding of

the dose-dependent differences in the disposition of dioxin, which has led to

the conclusion that body burden is the best dose metric for risk assessment of

dioxin and related compounds. This approach allows for a direct comparison

of animal and human data, which reduces the animal-to-human uncertainty in

risk assessment.

dLimonene

A number of chemicals (e.g., d-limonene) and chemical mixtures (e.g.,

unleaded gasoline) induce kidney tumors in male rats in cancer bioassays. 

Mechanistic studies have shown that kidney tumors in male rats are associated

with an increase in the level of a specific protein, "2:-globulin. Because this

protein is not present in human male kidneys, risk assessors could predict that

the cancer risk in humans for chemicals acting via an "2:-globulin-mediated

process will be low.

Atrazine Research from ORD showed that the effects of atrazine on mammary gland

and prostate development are associated with alterations in the hormone

prolactin. This mechanistic information is currently being used to reevaluate

the risk assessment for atrazine.
A-5

APPENDIX D

Agencies Having Research Programs Complementary to ORD

The National Institute of Environmental

Health Sciences (NIEHS) achieves its

mission through multidisciplinary biomedical research programs; prevention and

intervention efforts; and communication

strategies that encompass training, education, technology transfer, and community

outreach. For example, the NIEHS program

includes a trans-NIH effort to study effects

of chemicals, including pesticides and other

toxics, in children. EPA has collaborated

with NIEHS in establishing Centers for

Children’s Environmental Health and

Disease Prevention to define the environmental influences on asthma and other

respiratory diseases, childhood learning, and

growth and development. NIEHS and the

National Institute of Allergy and Infectious

Diseases (NIAID) are conducting the InnerCity Asthma Study, which is a prevention

trial to develop an intervention strategy to

reduce asthma morbidity in inner-city

children and adolescents. The National

Allergen Study, being conducted by NIEHS

in collaboration with the Department of

Housing and Urban Development (HUD),

examines the relationship between allergens

and lead and how allergen exposures differ

as a function of geographic region, socioeconomic status, housing type, and ethnicity. NIEHS and the National Toxicology

Program (NTP) are developing new technologies for high-throughput toxicity testing,

and these agencies are responsible for onethird of all toxicity testing performed

worldwide. Long-term collaborative efforts

with NTP, particularly in the areas of

carcinogenesis, reproductive/developmental

toxicity, and neurotoxicity, are well

established. NIEHS has established the

National Center for Toxicogenomics (NCT)

to coordinate an international research effort

to develop the field of toxicogenomics. The

NCT will provide a unified strategy, a

public database, and will develop the

bioinformatics infrastructure to promote the

development of the field of toxicogenomics. 

NIEHS will pay special attention to

toxicogenomics as applied to the prevention

of environmentally related diseases. 

The National Cancer Institute (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,

or inhibition of cancer and on the biological

and health effects of exposure to radiation. 

The Centers for Disease Control and

Prevention (CDC), through the National

Center for Environmental Health (NCEH),

studies health problems associated with

human exposure to lead, radiation, air

pollution, and other toxicants, as well as to

hazards resulting from technological or

natural disasters. These are mainly

surveillance and epidemiological studies. 

NCEH is particularly interested in studies

that benefit children, the elderly, and

persons with disabilities. The National

Center for Health Statistics (NCHS) of CDC

is conducting the National Health and

Nutrition Examination Survey (NHANES). 

NHANES is a national population-based

survey and includes data on potentially

sensitive subpopulations such as children

and the elderly. EPA is participating in this

survey with NCHS to collect information on

children’s exposure to pesticides and other

environmental contaminants. CDC’s

National Report on Human Exposure to

Environmental Chemicals provides an

ongoing assessment of the exposure of the

U.S. population to environmental chemicals

using biomonitoring data collected through

NHANES. The first national report

provides information about levels of 27
A-6

chemicals, while the second report presents

biomonitoring exposure data for 116

environmental chemicals for the U.S.

population divided into age, gender, and

race/ethnicity groups. 

The National Institute of Child Health

and Human Development (NICHD)

supports laboratory, clinical, and epidemiological research on the reproductive,

neurobiological, developmental, and

behavioral processes that determine and

maintain the health of children and adults. 

ORD is collaborating with NICHD, CDC,

and other Federal agencies in the design and

implementation of a National Children’s

Study of 100,000 children who will be

enrolled during the mother’s pregnancy and

followed throughout childhood and

adolescence. The Children’s Health Act of

2000 mandated this study of environmental

influences on children’s health and

development. 

 

The National Center for Toxicological

Research (NCTR) supports fundamental

research on the effects of chemicals

regulated by the Food and Drug

Administration. Although some of the

models used by NCTR may be similar to

those used by EPA, the chemicals and

regulatory context vary significantly. 

Historically, NCTR has been a leader in

developing models and principles for risk

assessment, which has led to collaborations

between EPA and NCTR scientists.
A-7

APPENDIX E

Examples of Health and Environmental Databases to Evaluate 

Public Health Outcomes From Risk Management Actions

Environmental Databases

Source Database Name Contents

EPA/ORD NHEXAS Exposure data for Arizona, EPA Region V, and

Baltimore

EPA SDWIS/FED Regulated pollutant concentration in drinking

water

EPA STORET Surface water quality/biological monitoring

EPA/OAQPS AIRS Air pollutant concentrations at 4,000 sites;

9,000 point sources

EPA ETS Emissions from electric utilities

EPA Center for

Environmental

Information and

Statistics

Central source of environmental data/trends

EPA/OPPTS TRI Toxic compounds release inventory

EPA CERCIS Hazardous waste sites, assessment, and status

EPA BASINS Watershed pollutants (point and area source)

and locations
A-8

Health Effects Databases

EPA/ORD IRIS Hazard characterization and risk numbers for

cancer and noncancer endpoints

NCI SEER Cancer incidence/prevalence by type and

location

CDC Behavioral Risk Factor

Survey

Incidence of contagious diseases

Veterans

Administration

VA databases Major disease incidence and prevalence by

location

National Center for

Health Statistics 

National Health

Interview Survey

Prevalence and incidence data in populations

State Health

Departments

Various Disease incidence by location and time

Insurance

Companies

Various Disease and death incidence by location, time,

and population

Health and Environmental Databases

EPA, Region 3 Green Communities

Initiative

Environmental health, economic, and societal

indicators of impact of environmental

regulation

ATSDR Registries 

Hazardous Substances

Emergency Event

Surveillance System

Follow-up individual health outcomes on

communities and populations exposed to

specific environmental contaminants

Collects information on releases and victims