EPA/600/R-05/093A 

 March 2006 

External Review Draft 

 

 

A Framework for Assessing Health Risks of Environmental 

Exposures to Children 

NOTICE 

 THIS DOCUMENT IS AN EXTERNAL REVIEW DRAFT. It has not been formally 

released by the U.S. Environmental Protection Agency and should not at this stage be 

construed to represent Agency policy. It is being circulated for comment on its technical 

policy implications. 

National Center for Environmental Assessment 

Office of Research and Development 

U.S. Environmental Protection Agency 

Washington, DC 20460 
This document is a draft for review purposes only and does not constitute Agency policy. 

03/01/06 ii DRAFT—DO NOT CITE OR QUOTE 

DISCLAIMER 

This document is a draft for review purposes only and does not constitute Agency policy. 

Mention of trade names or commercial products does not constitute endorsement or 

recommendation for use. 

Preferred Citation: 

U.S. Environmental Protection Agency (EPA). (2006) A framework for assessing health risks of 

environmental exposures to children. National Center for Environmental Assessment, 

Washington, DC; EPA/600/R-05/093A. Available from National Technical Information Service, 

Springfield, VA, and online at http://www.epa.gov/ncea. 
This document is a draft for review purposes only and does not constitute Agency policy. 

03/01/06 iii DRAFT—DO NOT CITE OR QUOTE 

CONTENTS 

LIST OF TABLES........................................................................................................................ vi 

LIST OF FIGURES ..................................................................................................................... vii 

LIST OF ABBREVIATIONS AND ACRONYMS ...................................................................viii 

PREFACE..................................................................................................................................... ix 

AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................................................... xii

1. EXECUTIVE SUMMARY ...................................................................................................... 1 

2. INTRODUCTION, PURPOSE, AND SCOPE......................................................................... 3 

3. PROBLEM FORMULATION.................................................................................................. 9 

3.1. PLANNING AND SCOPING ......................................................................................... 9 

3.2. CONCEPTUAL MODEL.............................................................................................. 13 

3.2.1. Exposure Considerations.................................................................................... 13 

3.2.2. Outcome Considerations .................................................................................... 15 

3.2.3. Integration of Exposure Considerations and Biological Effects 

Considerations................................................................................................... 15 

3.3. ANALYSIS PLAN ........................................................................................................ 15 

4. LIFE STAGE-SPECIFIC ANALYSIS................................................................................... 17 

4.1. HAZARD CHARACTERIZATION ............................................................................. 17 

4.1.1. Introduction ........................................................................................................ 17 

4.1.2. Scoping of Hazard Characterization................................................................... 21 

4.1.3. Qualitative Evaluation of Individual Studies ..................................................... 21 

4.1.3.1. Study Purpose...................................................................................... 22 

4.1.3.2. Study Design ....................................................................................... 22 

4.1.3.3. Exposures ............................................................................................ 23 

4.1.3.4. Outcomes............................................................................................. 23 

4.1.3.5. Toxicokinetic (TK) Data ..................................................................... 24 

4.1.3.6. Toxicodynamic (TD) Data .................................................................. 24 

4.1.3.7. Mode of Action (MOA) Information .................................................. 25 

4.1.3.8. Detailed Qualitative Evaluation of the Dose-Response Data 

Profile.................................................................................................. 25 

4.1.3.9. Variability Analyses............................................................................ 25 

4.1.3.10. Uncertainty Analyses......................................................................... 26 

4.1.4. Evaluation of the Hazard Database .................................................................... 27 

4.1.4.1. Summarizing the Hazard Database ..................................................... 27 

4.1.4.2. Description of the Weight of Evidence (WOE) .................................. 29

4.1.4.2.1. Modifiers and Interactions................................................ 29 

4.1.4.2.2. Intra- and Interspecies Comparisons of Outcomes........... 30

4.1.4.2.3. Toxicokinetics (TK) and Toxicodynamics (TD) .............. 31 

4.1.4.2.4. Variabilities, Data Gaps, and Uncertainties in the 

Database........................................................................... 31

4.1.4.2.5. Extent of the Database ...................................................... 33 
This document is a draft for review purposes only and does not constitute Agency policy. 

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4.1.4.2.6. Relevance of Animal Data to Humans.............................. 34 

4.1.5. Life Stage-Specific Hazard Characterization Narrative ..................................... 34 

4.2. DOSE-RESPONSE ASSESSMENT ............................................................................. 36 

4.2.1. Introduction ........................................................................................................ 36 

4.2.1.1. Scoping of the Dose-Response Assessment........................................ 36 

4.2.1.2. Extent of Assessment .......................................................................... 36 

4.2.1.3. Regulatory Needs and Considerations................................................. 38 

4.2.2. Mode of Action (MOA) Conceptualization ....................................................... 39 

4.2.2.1. Summarizing the Available Dose-Response Relationships ................ 39 

4.2.2.2. Mechanistic Data and Mode of Action................................................ 41 

4.2.2.3. Selection of Dose Metric ..................................................................... 42 

4.2.3. Analysis in the Range of Observation ................................................................ 44 

4.2.3.1. Dose-Response Models....................................................................... 44 

4.2.4. Extrapolations and Risk Derivation from a Life Stage Approach...................... 49 

4.2.4.1. Duration and Route Adjustments ........................................................ 49 

4.2.4.2. Interspecies and Intraspecies Adjustments.......................................... 50 

4.2.4.3. Low-dose Extrapolation ...................................................................... 53 

4.2.4.4. Model Uncertainty, Sensitivity, and Variability.................................. 54 

4.2.4.5. Risk Value Derivation and Application of Uncertainty Factors 

(Including Age-Dependent Adjustment Factors)................................ 55 

4.2.5. Life Stage-Specific Dose-Response Characterization Narrative........................ 56 

4.3. EXPOSURE ASSESSMENT ........................................................................................ 57 

4.3.1. Introduction ........................................................................................................ 57 

4.3.2. Scoping of Exposure Assessment....................................................................... 59 

4.3.2.1. Sources ................................................................................................ 59 

4.3.2.2. Pathways.............................................................................................. 59 

4.3.2.3. Scenarios.............................................................................................. 60 

4.3.3. Refinement of the Conceptual Model................................................................. 61 

4.3.4. Review of the Available Exposure Data ............................................................ 63 

4.3.4.1. Chemical Properties, Fate, and Transport ........................................... 63 

4.3.4.2. Media Concentrations.......................................................................... 64 

4.3.4.3. Life Stage-Specific Population Characteristics................................... 65 

4.3.4.4. Life Stage-Specific Activity Data ....................................................... 67 

4.3.4.5. Iteration of the Review of Data with Hazard and Dose-Response 

Characterization .................................................................................. 67 

4.3.5. Life Stage-Specific Exposure Analysis.............................................................. 69 

4.3.5.1. Exposure Measurement and Estimation Approach ............................. 69 

4.3.5.2. Analysis Level or Tier......................................................................... 70

4.3.5.2.1. Screening Assessment....................................................... 71 

4.3.5.2.2. Refined Assessment.......................................................... 73 

4.3.5.2.3. Supplemental Data Collection .......................................... 74 

4.3.6. Life Stage-Specific Exposure Characterization Narrative ................................. 75 

4.3.6.1. Variability Analyses............................................................................ 75 

4.3.6.2. Uncertainty Analyses........................................................................... 76 

4.3.6.3. Sensitivity Analyses ............................................................................ 77 

4.4. SUMMARY OF ANALYSIS PHASE .......................................................................... 77 
This document is a draft for review purposes only and does not constitute Agency policy. 

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5. LIFE STAGE-SPECIFIC RISK CHARACTERIZATION .................................................... 78 

5.1. SUMMARY OF THE MAJOR CONCLUSIONS IN LIFE STAGE-SPECIFIC 

RISK CHARACTERIZATION..................................................................................... 78 

5.1.1. Hazard Characterization ..................................................................................... 79 

5.1.2. Dose-Response Characterization........................................................................ 79 

5.1.3. Exposure Characterization.................................................................................. 79 

5.2. SUMMARY OF ALL THE VARIABILITY AND UNCERTAINTY 

ANALYSES .................................................................................................................. 84 

5.3. RISK CONTEXT........................................................................................................... 85 

6. SUMMARY AND IDENTIFICATION OF GAPS IN GUIDANCE FOR 

CHILDREN’S HEALTH RISK ASSESSMENT............................................................. 87 

GLOSSARY ................................................................................................................................ 89 

REFERENCES ............................................................................................................................ 98 

APPENDIX 1. Hazard Characterization – Example Questions for the Data Evaluation of 

Individual Studies........................................................................................................... 110 
This document is a draft for review purposes only and does not constitute Agency policy. 

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LIST OF TABLES 

4-1. Developmental life stages and age groups for exposure assessments.................................. 66 

5-1. Issues Addressed in Hazard Characterization (Section 4.1.)................................................ 80 

5-2. Issues Addressed in Dose-Response Characterization (Section 4.2.) .................................. 82 

5-3. Issues Addressed in Exposure Characterization (Section 4.3.) ............................................ 83 

5-4. Issues Addressed in Variability and Uncertainty Analyses.................................................. 85 

5-5. Types Of Issues To Be Considered to Illustrate The Risk Context...................................... 86 
This document is a draft for review purposes only and does not constitute Agency policy. 

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LIST OF FIGURES 

2-1. General health risk assessment framework ........................................................................ 4

2-2. Children’s health risk assessment framework. ................................................................... 5 

2-3. Life stages of outcomes after developmental exposure...................................................... 6 

3-1. Flow diagram for life stage-specific problem formulation .............................................. 10 

3-2. Conceptual Model for Problem........................................................................................ 14 

3-3. Life stage-specific database inventory sheet.................................................................... 16 

4-1. Framework for life stage-specific analysis with animal and human data ........................ 19 

4-2. Flow diagram for life stage specific hazard characterization........................................... 20 

4-3. Hazard characterization Step 1: Evaluate individual studies with exposures during 

developmental life stages (including preconception)....................................................... 22 

4-4. Hazard characterization Step 2: Evaluate the database as a whole for potential 

hazards to children from environmental exposures during different life stages .............. 28 

4-5. Conceptual view of a weight of evidence (WOE) assessment......................................... 30 

4-6. Hazard characterization, Step 3: Describe and determine life stage-relevant 

outcomes........................................................................................................................... 35 

4-7. Flow diagram for life stage-specific dose-response assessment ...................................... 37 

4-8. Generalized biologically based dose-response (BBDR) model ....................................... 48 

4-9. Flow diagram for life stage-specific exposure assessment .............................................. 58 

4-10. Exposure routes during developmental life stages........................................................... 62 
This document is a draft for review purposes only and does not constitute Agency policy. 

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LIST OF ABBREVIATIONS AND ACRONYMS 

ADAF Age-Dependent Adjustment Factors 

ADME Absorption, distribution, metabolism, and elimination 

ARE Acute reference exposure 

AUC Area under the curve 

BBDR Biologically based dose-response 

BMD Benchmark dose 

BMDL Benchmark dose lower confidence level 

Cmax Maximum concentration 

CatReg Categorical regression 

CSF Cancer slope factor 

CYP Cytochrome P450 

DAF Dosimetric adjustment factor 

EHC Environmental health criteria 

EPA U. S. Environmental Protection Agency 

FQPA Food Quality Protection Act 

GFR Glomerular filtration rate 

HA Health advisory 

HEC Human equivalent concentration 

HED Human equivalent dose 

LOAEL Lowest-observed-adverse-effect level 

MOA Mode of action 

MRL Minimal risk level 

NOAEL No-observed-adverse-effect level 

PBTK Physiologically based toxicokinetics 

POD Point of departure 

RfC Reference concentration 

RfD Reference dose 

RfV Reference value 

SAR Structure-activity relationships 

TD Toxicodynamics 

TK Toxicokinetics 

UF Uncertainty factor 

Vmax Maximum velocity 

WOE Weight of evidence 
This document is a draft for review purposes only and does not constitute Agency policy. 

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PREFACE 

The mission of the U. S. Environmental Protection Agency (EPA) is to protect human 

health and the environment. In the early 1990s the National Academy of Science released a 

watershed report on Pesticides in the diets of infants and children regarding evaluation of risk to 

environmental exposures (NRC, 1993). In addition to this report and in response to it, increased 

emphasis on protecting children from environmental exposures has evolved due to mounting 

scientific evidence to support the vulnerability of the developing fetus and child as well as 

legislative and administrative mandates. In 1995, the EPA Administrator issued Policy on 

Evaluating Health Risks to Children (U.S. EPA, 1995a), which states that EPA will consider 

risks to infants and children consistently and explicitly as a part of risk assessments generated 

during its decision-making process, including the setting of standards to protect public health and 

the environment. Subsequent provisions in the Food Quality Protection Act (FQPA) (U.S. 104th

Congress, 1996a) and the Safe Drinking Water Act (SDWA) Amendments (U.S. 104th Congress, 

1996b) underscored this policy by requiring a focus on the evaluation of children’s exposures 

and toxicities in the context of risk assessment. In 1997, Presidential Executive Order 13045, 

Protection of Children from Environmental Health Risks and Safety Risks (April, 1997), gave 

further emphasis to the need for establishing potential risks from childhood environmental 

exposures. Strategy for Research on Environmental Risks to Children was published by EPA in 

2000 (U.S. EPA, 2000d). 

EPA risk assessment guidelines relevant to children’s health issues had been published 

(U.S. EPA, 1991,1996; 1998b), and other guidelines (U.S. EPA, 2005b, 2005c), policies, and 

recommendations were under development (U.S. EPA, 2002a; U.S. EPA, 2002b; U.S. EPA, 

2003b). Implementation of the FQPA and SDWA amendments required additional development 

of guidance and policy for protecting children’s health, particularly the application of the FQPA 

10-fold safety factor (U.S. EPA, 2002c). Thus, there are a number of guidelines and policies 

related to children’s health, but there is no single comprehensive document that can serve as a 

resource of information on children’s health risk assessment. 

In 1999, a draft report that collected information on current EPA guidance and practices 

was developed for the Office of Children’s Health Protection (ICF Consulting, 1999). This 

report was a compendium of information on child-related risk assessment policy and 

methodology guidance, but much has happened since the draft was completed. This framework 
This document is a draft for review purposes only and does not constitute Agency policy. 

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document builds on that report and other drivers referred to above by updating the information 

and linking to reference documents and other published information that can be used as a 

resource for those interested in children’s health risk assessment. 

Another major effort sponsored by EPA and others that serves as background for this 

document was a workshop organized by the International Life Sciences Institute Risk Science 

Institute and held in Stowe, VT, July 30–August 2, 2001. The report of that workshop (ILSI, 

2003) and subsequent publications (Olin & Sonawane, 2003; Daston et al. 2004; Landrigan et al., 

2004; Ginsberg et al., 2004c; Morford et al., 2004) proposed a framework for children’s health 

risk assessment and laid out a number of issues of concern. The current framework builds on the 

dedicated efforts of the experts and participants at that workshop. 

Parallel activities have been or are being developed at other agencies such as the U.S. 

Food and Drug Administration (FDA), which regulates pharmaceuticals, medical devices, 

biologics, food, animal feed and drugs, cosmetics, radiation-emitting devices, and combination 

products. For example, under the Best Pharmaceuticals for Children Act (U.S. FDA, 2002), an 

amendment to Section 11 of the Food and Drug Modernization Act (U.S. FDA, 1997), FDA’s 

Office of Pediatric Therapeutics coordinates and facilitates all activities affecting the pediatric 

population or practice of pediatrics or involving pediatric issues within the FDA. Assessment of 

risks and benefits to children is conducted in compliance with the Pediatric Research Equity Act 

(U.S. FDA, 2003b), which requires that all applications for new active ingredients indications, 

dosage forms, dosing regimens, and routes of administration contain a pediatric assessment 

unless a waiver or deferral has been granted. Although the guidance documents may apply 

specifically to pharmaceutical testing and regulation, there can be significant overlap with 

assessments conducted to determine risk to children from environmental exposures. For 

example, Guidance to Industry – Nonclinical Safety Evaluation of Pediatric Drug Products (U.S. 

FDA, 2003a), addresses considerations on the evaluation of pharmaceuticals in juveniles, one of 

the life stages discussed in this Framework. 

Additionally, the International Programme for Chemical Safety of the World Health 

Organization is in the process of developing an Environmental Health Criteria (EHC) document 

entitled Principles for Evaluating Health Risks Associated with Chemical Exposures to Children. 

When completed, the EHC document will serve as useful background information for utilizing 

this framework. 
This document is a draft for review purposes only and does not constitute Agency policy. 

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Finally, EPA’s Risk Assessment Forum has been working for several years to harmonize 

approaches to risk assessment (U.S. EPA 1997c, 1998c). Efforts to develop a framework for a 

harmonized approach to human health risk assessment are underway, and the intent is for this 

framework on health risks from environmental exposures to children to be incorporated into the 

overall framework. 
This document is a draft for review purposes only and does not constitute Agency policy. 

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AUTHORS, CONTRIBUTORS, AND REVIEWERS 

AUTHORS 

Stan Barone Jr., National Center for Environmental Assessment, Office of Research and 

Development, U.S. Environmental Protection Agency, Washington, DC. (Formerly National 

Health and Environmental Effects Research Laboratory, Office of Research and Development, 

U.S. Environmental Protection Agency, Research Triangle Park, NC.). 

Rebecca C. Brown, National Center for Environmental Assessment, Office of Research and 

Development, Environmental Protection Agency, Washington, DC. (Formerly Association of 

Schools of Public Health Fellow, National Center for Environmental Assessment, Office of 

Research and Development, Environmental Protection Agency, Washington, DC.) 

Susan Y. Euling, National Center for Environmental Assessment, Office of Research and 

Development, U.S. Environmental Protection Agency, Washington, DC. 

Elaine Cohen Hubal, National Center for Computational Toxicology, Office of Research and 

Development, U.S. Environmental Protection Agency, Research Triangle Park, NC. (Formerly 

National Exposure Research Laboratory, Office of Research and Development, U.S. 

Environmental Protection Agency, Research Triangle Park, NC.) 

Carole A. Kimmel, formerly National Center for Environmental Assessment, Office of Research 

and Development, U.S. Environmental Protection Agency, Washington, DC. 

Susan Makris, National Center for Environmental Assessment, Office of Research and 

Development, U.S. Environmental Protection Agency, Washington, DC. (Formerly Office of 

Pesticide Programs, Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental 

Protection Agency, Washington, DC.) 

Hisham El-Masri, National Center for Environmental Assessment, Office of Research and 

Development, U.S. Environmental Protection Agency, Washington, DC. 

Jacqueline Moya, National Center for Environmental Assessment, Office of Research and 

Development, U.S. Environmental Protection Agency, Washington, DC. 

Sherry G. Selevan, National Center for Environmental Assessment, Office of Research and 

Development, U.S. Environmental Protection Agency, Washington, DC. 

Babasaheb R. Sonawane, National Center for Environmental Assessment, Office of Research 

and Development, U.S. Environmental Protection Agency, Washington, DC. 

Tracey Thomas, formerly American Association for the Advancement of Science Fellow, 

National Center for Environmental Assessment, Office of Research and Development, U.S. 

Environmental Protection Agency, Washington, DC. 
This document is a draft for review purposes only and does not constitute Agency policy. 

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Chad Thompson, National Center for Environmental Assessment, Office of Research and 

Development, U.S. Environmental Protection Agency, Washington, DC. (Formerly American 

Association for the Advancement of Science Fellow, National Center for Environmental 

Assessment, Office of Research and Development, U.S. Environmental Protection Agency, 

Washington, DC.) 

INVITED INTERNAL AGENCY PANEL REVIEWERS 

Framework for Children’s Health Risk Assessment (CHRA)

1 and Harmonization of Human 

Health Risk Assessment Colloquium, October 5-6, 2004, Arlington, VA 

Hugh Barton, ORD, NCCT (formerly NHEERL) 

Jerry Blancato, ORD, NCCT (formerly NERL, HEASD) 

Vicki Dellarco, OPPTS, OPP, HED 

Beth Doyle, OW, OST, HECD 

Brenda Foos Perkovich, OA, OCHP 

Greg Miller, OA, NCEE, OPEI 

Deirdre Murphy, OAR, OAQPS, ESD 

Marian Olsen, Region 2 

Jennifer Seed, OPPTS, OPPT, RAD 

Linda Sheldon, ORD, NERL, HEASD 

Daniel Stralka, Region 9 

Vanessa Vu, OA, SAB 

ADDITIONAL INTERNAL AGENCY REVIEWERS 

Ila Cote, ORD, NCEA 

Michael Firestone, OA, OCHP 

Matt Heberling, ORD, NCEA 

Sarah Levinson, Region 1 

Kelly Maguire, OA, NCEE, OPEI 

Lanelle Wiggins, OA, NCEE, OPEI 

Tracey Woodruff, OA, NCEE, OPEI 

William Wood, ORD, NCEA 

INTERNAL AGENCY REVIEW PROJECT OFFICER 

Marilyn Brower, RAF 

ACKNOWLEDGEMENT 

Jonathan Francis 

Emily Newell 

1 Framework for Children’s Health Risk Assessment was the previous title of this document. 
This document is a draft for review purposes only and does not constitute Agency policy. 

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1. EXECUTIVE SUMMARY 

The purpose of this document is to provide (1) a single resource for information on the 

assessment of health risks to children as a result of exposures of environmental agents, and (2) an 

overarching framework for a more complete assessment of health risks to children from 

exposures of environmental agents within EPA’s risk assessment paradigm, which examines the 

impact of potential exposures during all stages of development, while emphasizing the iterative 

nature of the analysis phase with a multidisciplinary team. In addition to outlining the risk 

assessment process, the document points to published sources for more detailed information. 

Guidance, policies, and other relevant materials are referenced in the document and linked 

electronically (when copyright allows) to the actual reference documents for easy access. 

The term “children” as used in this document includes the stages of development from 

conception to adulthood. The assessment of health risks to children from environmental 

exposure, or “children’s exposure” as used throughout this document, includes exposure before 

conception, as well as during the developmental life stages from conception through 

adolescence. Health risks may be detected during the same life stage as when the exposure 

occurred or they may not become apparent until much later in life. Life stages are defined in this 

document as temporal stages (or intervals) of life that have distinct anatomical, physiological, 

and behavioral or functional characteristics that contribute to potential differences in 

vulnerability to environmental exposures. A life stage approach to risk assessment considers the 

timeframe or life stage of exposure and outcome when evaluating the data. A life stage approach 

for evaluation of risks to children takes into account all relevant periods of exposure, and 

explicitly considers where data do and do not exist for both exposure and health outcomes. It 

focuses on considerations of early life stage exposure, and subsequent outcomes, which may not 

be expressed until later life stages. Information on mode(s) of action and pharmacokinetics that 

may inform life stages are another main emphasis of this approach. Risk assessment using a life 

stage approach is a shift in perspective from the current methodology that focuses primarily on 

adults, and then, secondarily, looks for information that may suggest greater susceptibility from 

exposures to children and other subpopulations. 

The added value of using a life stage approach to risk assessment is a more 

comprehensive evaluation of the potential for vulnerability of various populations at different life 
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stages. The approach outlined here encourages evaluation of the potential for toxicity during all 

developmental life stages, based on knowledge of external exposure, critical windows of 

development for different organ systems, modes of action (MOAs), anatomy, physiology, and 

behavior that can affect external exposure and internal dose metrics (units of measurement for 

dose). The use of MOA information is integral to this framework and is employed in a 

consistent manner to the EPA cancer guidelines (U.S. EPA, 2005b, 2005c) but is extended to the 

evaluation all outcomes. 

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It is important that one needs to consider whether anything is known about 

developmental life stages that would indicate particular vulnerability and incorporate that 

information in the assessment. This document also addresses the difficult issue of integrating 

toxicity data and exposure information, which is especially challenging when data are limited for 

particular time periods during pregnancy and early childhood development. 

The conceptual framework used in this document follows the basic framework developed 

for other areas of risk assessment and includes problem formulation, analysis, and risk 

characterization as the three major phases in the process. Within this structure, questions for 

consideration in the process of scoping the problem to be addressed, reviewing the toxicity and 

exposure data, and characterizing the risks are posed as a way of prompting and refining the 

assessment process. Gaps in guidance needed for various aspects of children’s health risk 

assessment are also discussed. In particular, guidance is lacking for life stage-specific evaluation 

of several system- and disease-specific areas, related biomarkers and outcomes, MOA(s), doseresponse assessment, and exposure assessment. Also, guidance on the use of specific 

developmental outcomes for application to risk assessments for various durations of exposure 

has not been defined, even though this issue is considered in many of the risk assessments 

currently being generated across EPA. 
This document is a draft for review purposes only and does not constitute Agency policy. 

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2. INTRODUCTION, PURPOSE, AND SCOPE 

The purpose of this document is to provide (1) a central resource of the information 

available for assessing risks as a result of environmental exposures to children, and (2) to provide 

an overarching framework for assessing health risks that examines the impact of potential 

environmental exposures during all stages of development. The term “children” as used in this 

document includes the stages of development from conception through adolescence to adulthood. 

The assessment of health risks to children from environmental exposure, or “children’s 

exposure,” includes exposure to either parent before conception as well as during the 

developmental life stages from conception through adolescence. Health risks may be detected 

during the same life stage as when the exposure occurred or they may not become apparent until 

later in life. 

The major question to be addressed by use of this document is: What is the risk of 

environmental exposure to children? This framework outlines the essential phases in making 

judgments about the risks of children’s exposure to environmental agents, singly or in 

combination. This information can be used in various situations, depending on the problem to be 

addressed. For example, if an overall assessment of health risks is needed, the information on 

risks from children’s exposures can be incorporated into the larger assessment. If, on the other 

hand, the major concern is about health risks to children as a result of environmental exposure, 

the information derived from this process could be used directly to assess risk, set standards and 

mitigate exposures. 

 In addition to outlining the process of assessing risks to children as a result of exposure, 

existing sources for more detailed information are referenced and linked to the actual reference 

documents (when copyright allows). These sources include guidelines, guidance documents, 

policies, and other relevant published materials that currently exist. 

The conceptual framework used in this document follows the basic framework developed 

27 for other areas of risk assessment (e.g., Guidance on Cumulative Risk Assessment, U.S. EPA, 

1997a; Guidelines for Ecological Risk Assessment, U.S. EPA, 1998a) and includes problem 

formulation, analysis, and risk characterization as the three major phases in the process. Figure 

2-1 shows this general health risk assessment framework. 

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Risk Communication/Management

Problem Formulation

Analysis

Risk Characterization

As Necessary, Collect Additional Data, Monitor 

Results; Iterative Process

Hazard 

Characterization

Dose-Response 

Assessment

Exposure 

Assessment

Develop Conceptual Model 

with Assessment Options

(Qualitative/Quantitative, 

Needs/Capabilities)

Risk Communication/Management

Problem Formulation

Analysis

Risk Characterization

As Necessary, Collect Additional Data, Monitor 

Results; Iterative Process

Hazard 

Characterization

Dose-Response 

Assessment

Exposure 

Assessment

Develop Conceptual Model 

with Assessment Options

(Qualitative/Quantitative, 

Needs/Capabilities)

Figure 2-1. General health risk assessment framework. This general health risk assessment 

framework is adapted from 

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Guidance on Cumulative Risk Assessment (U.S. EPA, 1997a) and 

includes three phases also identified in 

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3 Guidelines for Ecological Risk Assessment (U.S. EPA, 

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1998a): problem formulation, analysis, and risk characterization. 

The outline for this document adopts the general framework for health risk assessment 

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(2004), and, in each phase of the process raises questions to consider in assessing health risks to 

children from environmental exposure. This document incorporates information from relevant 

risk assessment guidelines and other reports while focusing on susceptibility, both inherent and 

acquired, at different life stages, as well as the potential for greater exposure of environmental 

agents to children than adults. 

This document is a draft for review purposes only and does not constitute Agency policy. 

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Life Stage-Specific Analyses

Life Stage-Specific 

Risk Characterization

• Characterize 

Life StageSpecific Risks

• Compare Risks Across 

Life Stages

• Summarize Uncertainty 

and Variability Analyses

Risk Communication/Management

Problem Formulation

Exposure Host Factors Outcomes

As Necessary, Collect Additional Data, Monitor 

Results; Iterative Process

Develop Conceptual Model 

with Assessment Options

(Qualitative/Quantitative, 

Needs/Capabilities)

Hazard 

Characterization

Exposure 

Assessment

Dose-Response 

Assessment

Life Stage-Specific Analyses

Life Stage-Specific 

Risk Characterization

• Characterize 

Life StageSpecific Risks

• Compare Risks Across 

Life Stages

• Summarize Uncertainty 

and Variability Analyses

Risk Communication/Management

Problem Formulation

Exposure Host Factors Outcomes

As Necessary, Collect Additional Data, Monitor 

Results; Iterative Process

Develop Conceptual Model 

with Assessment Options

(Qualitative/Quantitative, 

Needs/Capabilities)

Hazard 

Characterization

Exposure 

Assessment

Dose-Response 

Assessment

Figure 2-2. Children’s health risk assessment framework. This children's risk assessment 

framework diagram expands on the theme presented in Figure 2-1, with increased emphasis on life 

stage-specific evaluations during problem formulation, analysis, and risk characterization. 

(Source: Adapted from 

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4 Olin & Sonawane, 2003.) 

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Assessing health risks to children as a result of environmental exposure to children 

includes the consideration of risk from exposure before conception, during the prenatal period, 

and through childhood to adolescence (Figure 2-3). Life stages are defined in this document as 

periods of life with distinct anatomical, physiological, and behavioral or functional 

characteristics that contribute to potential differences in vulnerability to environmental 

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Figure 2-3. Life stages of outcomes after developmental exposure. This figure illustrates the 

different life stages during which developmental exposures may occur (before conception through 

adolescence). Exposure (shown on the left side of the figure) during a given life stage may result 

in outcomes observed during that same stage or later in life (shown on the right side of the figure). 

For illustrative purposes, the outcomes associated with exposure during two periods, prenatal and 

adolescence, correspond to the highlighted and hatched regions, respectively. Broad exposure 

intervals, e.g., “child,” are shown here for illustration; divisions between all life stages are not 

precise. There is some reproductive age overlap between the adolescent and the adult periods. 

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exposures.

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 The life stages from conception through adolescence comprise the period of 

development; outcomes may occur during that same life stage or later in life. Neither the 

outcomes nor the risks from these exposures will necessarily be the same. Rather, the outcomes 

will depend on the underlying developmental processes that determine susceptibility at the time 

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2 Preconception is any time before conception; the prenatal stage includes the embryonic and fetal stages from 

conception to birth; infancy is the period from birth through the first birthday; the toddler stage is from the first 

birthday through the third birthday; childhood encompasses all early life stages from birth through adolescence, 

approximately between 12 and 21 years of age, with difference between genders. The continuum between the 

reproductive- age adult and aged adult begins at approximately 21 years of age and reaches aged adulthood at 

approximately 65 years of age. Divisions between all life stages are not precise (U.S. EPA 2001c, U.S. EPA, 2002b, 

Table 3-1). 

Period Internal Dose Effective Dose Effects Function or Outcome or Adversity

Prenatal

Infant

Child

Adolescent

Reproductive

Age Adult

Aged Adult

Preconception

Infant Risk

Prenatal Risk

Adolescent 

Risk

Child Risk

ReproductiveAge Adult

Risk

Aged Adult

Risk

RISK: 

Prognostic 

Significance 

Clinical 

Manifestation 

Altered 

Structure or 

Precursor 

Events/Early 

Exposure Biologically Biological

-

Development 

Toxicokinetics Toxicodynamics 

RISK: 

Prognostic

Significance 

or Adversity 

Clinical 

Manifestation 

or Outcome 

Altered

Structure or

Precursor 

Prenatal 

Infant 

Child 

Adolescent 

ReproductiveFunction 

Events/Early

Biological

Effects 

Biologically

Internal Dose Effective Dose

Exposure

Period 

Age Adult 

Aged Adult 

Preconception 

Infant Risk 

Prenatal Risk 

Adolescent 

Risk 

Child Risk 

ReproductiveAge Adult 

Risk 

Aged Adult 

Risk 

Development

Toxicokinetics Toxicodynamics
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of exposure. A life stage approach for evaluation of risks to children is a hypothesis driven 

approach that takes into account all relevant periods of exposure explicitly considering where 

data do and do not exist for exposure and health outcomes. It focuses attention on considerations 

of early life exposure and potential outcomes which may be latent in their expression and is 

predicated on considerations of mode(s) of action considerations for all life stages of exposures. 

Risk assessments may require finer definition of exposure intervals than those shown in the 

figure because of rapid changes during development, even within a life stage. For example, 

gestational exposure is typically evaluated for each trimester; however, specific periods of 

vulnerability (also known as critical windows) for particular outcomes might be much shorter 

period of time as discussed in a series of publications that resulted from an EPA-sponsored 

11 workshop (Selevan, et al. 2000). 

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This report synthesizes the information currently available at EPA on assessing health 

risks as a result of children’s exposures and is based in part on existing risk assessment 

guidelines, guidance, and science policies. In addition, areas are identified where further 

guidance is needed, as are areas in need of research to support guidance. Within this structure, 

questions to be considered in the process of reviewing data are posed as a way of prompting the 

data evaluation. This framework document is not a guideline or science policy paper, but rather 

describes an overall vision of the structure, process, and the components considered important 

for assessing risks as a result of children’s exposure. This document intends to provide 

documentation of the state of the science for assessing risk to children. It is not intended to be 

proscriptive. The intended users of this approach are risk assessors involved in hazard 

characterization, dose response analysis, and exposure characterization who consider children’s 

risk to environmental exposures. The central focus of this framework is the developing embryo, 

24 fetus, and child, thus extending and expanding the approach in Guidelines for Developmental 

Toxicity Risk Assessment (U.S. EPA, 1991). The framework also takes a child-protective 

approach to assessing risk 

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(Landrigan et al., 2004) by putting the child, rather than an 

environmental agent at the focus of the evaluation. Because children are not a unique population 

but rather that all individuals pass through a series of life stages, this is considered a public 

health-oriented approach. 

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The added value of using a life stage approach to assess risks to children from 

environmental exposure is a comprehensive evaluation of the potential for vulnerability of 
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various populations at different life stages. In contrast, assessments often rely only on the 

available data, which can be limited to data for adults, and they do not necessarily account for 

the lack of data at other life stages. The approach outlined here encourages evaluation of the 

potential for toxicity during all developmental life stages, based on what is known about critical 

windows of development for different organ systems and differences in anatomy, physiology, 

and behavior that can impact external exposure and internal dose metrics. In the course of 

developing an assessment, the lack of data for certain life stages is not meant to imply greater 

uncertainty in the assessment of risk to children. Rather, the intent is to consider whether 

anything is known about life stages that would indicate particular vulnerability during that stage 

and incorporate that information into the assessment. This document also addresses the difficult 

issue of integrating animal toxicity or adverse health outcome data and exposure information for 

assessing risks. This integration is especially challenging because of data limitations for 

particular periods during pregnancy and early childhood development. A product of using this 

framework will be risk characterizations that are more transparent and scientifically justifiable 

with documentation of data gaps and data needs for children’s risk. 

The approach outlined here encourages evaluation of the potential for toxicity during all 

developmental life stages, based on what is known about critical windows of development for 

different organ systems, MOAs, anatomy, physiology, and behavior that can affect external 

exposure and internal dose metrics. MOA is defined in this framework as the[0] sequence of key 

events and processes, starting with interaction of a toxic agent with a cell, proceeding through 

functional and anatomical changes, and resulting in the adverse health outcomes. “A key event 

is an empirically observable precursor step that is itself a necessary element of the MOA or is a 

biologically based marker for such an element” (U.S. EPA, 2005b, 2005c). Both toxicodynamic 

and toxicokinetic steps are part of the mechanism and mode of action leading to the toxic 

response (

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Clewell et al., 2002a; Andersen et al., 2000). As stated in the latest cancer guidelines, 

“MOA is contrasted with mechanism of action, which implies a more detailed understanding and 

description of events, often at the molecular level” (

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Because of the complex issues that must be considered for assessing risks from children’s 

exposures, it is impossible for any one person to be an expert in all areas important to the 

process. Thus, consultation and iteration with appropriate experts in hazard, dose response and 

exposure assessment is recommended in all phases of the process. 
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3. PROBLEM FORMULATION 

Problem formulation is a systematic planning phase that defines the problem to be 

addressed in the assessment. The purpose of a problem formulation step is to aid in efficiency 

and transparency of the assessment. A general discussion of problem formulation can be found 

in the Framework for Cumulative Risk Assessment (U.S. EPA, 2003a). The major components 

of problem formulation are no different whether applied to assessment of any life stage of 

exposure (Figure 3-1). However, some of the specific considerations will be different in a risk 

assessment for childhood exposures. This section focuses primarily on the considerations for 

assessments of childhood exposures. 

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Problem formulation includes an initial characterization of exposures and outcomes 

during all developmental life stages, a planning and scoping phase, and the development of two 

products: a conceptual model and an analysis plan (Figure 3-1). 

3.1. PLANNING AND SCOPING 

In the planning and scoping phase, the assessment goals, breadth, and focus are 

established and regulatory and policy factors are identified. These steps include defining and 

identifying the purpose, scope, participants, approaches, resources, and relevant past assessments 

available. The extent of the risk assessments can be site specific, chemical specific, receptor 

based or broader in scope. In an assessment with a focused scope, potential outcomes for 

specific life stages thought to be at risk are analyzed; in the broader-scope assessment, each life 

stage is considered in the analysis steps of the assessment. Some of the questions that may need 

to be considered are: 

• Will the assessment consider, for example, exposure at all developmental periods 

(from preconception through adolescence into adulthood) in the general population 

and all possible sources, media, pathways and routes of exposure (aggregate and 

cumulative), or is it confined to specific scenarios such as children living near a 

specific Superfund site and potentially exposed via air, soil, and groundwater? 

• What other individual or community characteristics may be present that could put 

children at higher risk of exposure and thus more vulnerable (e.g., pre-existing 

diseases or disorders, belonging to a farm worker family, socio economic status 

(SES), poor nutrition, and sanitation conditions)? 
Planning and Scoping

(See Section 3.1.)

Consider:

• Purpose • Approach

• Scope • Resources

• Participants • Past Assessments

Conceptual Model

(See Section 3.2.)

Consider: 

Life Stage-Specific Analysis

(See Section 4)

Hazard 

Characterization

Dose-Response 

Assessment

Exposure 

Assessment

Discussion of possible outcomes of assessment 

with risk managers, risk assessment team, 

stakeholders and other interested parties

Life Stage-Specific 

Risk 

Characterization

(See Section 5)

• Exposures

• Individual 

Characteristics

• Outcomes

Analysis Plan

(See Section 3.3.)

Consider: 

•Methods •Data Gaps

•Models •Uncertainties and Variabilities

Planning and Scoping

(See Section 3.1.)

Consider:

• Purpose • Approach

• Scope • Resources

• Participants • Past Assessments

Conceptual Model

(See Section 3.2.)

Consider: 

Life Stage-Specific Analysis

(See Section 4)

Hazard 

Characterization

Dose-Response 

Assessment

Exposure 

Assessment

Discussion of possible outcomes of assessment 

with risk managers, risk assessment team, 

stakeholders and other interested parties

Life Stage-Specific 

Risk 

Characterization

(See Section 5)

• Exposures

• Individual 

Characteristics

• Outcomes

Analysis Plan

(See Section 3.3.)

Consider: 

•Methods •Data Gaps

•Models •Uncertainties and Variabilities

Figure 3-1. Flow diagram for life stage-specific problem formulation. This figure illustrates 

the flow of information and analysis that comprises problem formulation. The problem 

formulation phase establishes the context of the risk assessment and feeds into the life stagespecific analysis phase and ultimately to risk characterization (dotted line boxes). The problem 

formulation results in two products. First, a conceptual model is developed from both the 

planning and the scoping phases, and the consideration of exposures (e.g., sources, receptors, 

stressors, pathways, individual characteristics) and outcomes. Second, an analysis plan is 

developed, where preliminary consideration of study methods, dose-response models, data gaps, 

and uncertainty and variability is used to inform hazard characterization, dose-response 

assessment, and exposure assessment. Source: Adapted from 

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In this phase, a clear purpose of the assessment is defined in order to guide the risk 

assessment strategy. The scope sets the parameters of the assessment, allowing for decisions to 

include or exclude various elements. 

• Why is it being done? 

• How will it be used? 

• What is the public health concern? 

• What is (are) the risk question(s) being asked? 

• What is (are) the regulatory driver(s)? 

The participants who have information, expertise, or a stake in the assessment process 

and outcome(s) of the assessment are identified. Risk assessors, risk managers, and stakeholders 

13 (e.g., impacted community, non governmental organizations) are involved in the process (U.S. 

EPA, 2001b). Stakeholders are broadly defined as the interested parties who are concerned with 

the decisions made about how a risk may be avoided, mitigated, or eliminated, as well as those 

who may be affected by regulatory decisions. Those participating in the problem formulation 

will depend on the problem being addressed. Guidelines for stakeholder involvement are 

provided in 

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Framework for Cumulative Risk Assessment (U.S. EPA, 2003a, p. 21) and are based 

on the recommendations in 

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The approaches, such as methods and models, for developing a conceptual model and 

analysis plan are identified and selected. Identifying resources that will be required to achieve 

assessment goals within the timeframe of the assessment is necessary. Finally, identifying past 

assessments that relate to the purpose and scope of the assessment may assist the process with 

existing tools, methods, or models. 

Risk assessments are often conducted within the context of a regulatory requirement, a 

community need, a health concern, or some other driving force (U.S. EPA, 2003a) and require 

varying levels of scope or depth (

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U.S. EPA 2005b, Section 1.2.2). During planning and scoping, 

the risk assessment team (which includes the risk planning team; epidemiologists; public health 

specialists; toxicologists, including disciplinary specialist; chemists; and other technical experts) 

and the risk management team (which may include economists, policy analysts, engineers, and 

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public health specialists) work together, informed by stakeholder input, to develop the rationale, 

scope, and relevant outputs for the risk assessment and characterization. 

This phase of problem formulation involves a qualitative screening evaluation of existing 

information to scope the assessment and identifies whether children might have a greater 

potential for higher exposures or greater intrinsic susceptibility. The evaluation includes an 

examination of the quality and quantity of the available data on exposure and outcomes. More 

detailed evaluations may or may not be necessary or possible, depending on the available data. 

Where adequate data exist (particularly on potential critical windows of exposure, level of 

exposure, individual and community characteristics, optimum timing of outcome evaluation, and 

the magnitude of concern about the public health outcome), a more detailed approach can be 

employed to address essential questions needed for the exposure and health effects 

characterization. 

Children’s health risk assessment requires specialized expertise and understanding of 

critical windows of exposure and optimum timing for evaluation of outcomes. For example, 

experts in reproductive and developmental toxicology and epidemiology, neurotoxicology, 

pulmonary toxicology, children’s behavior, and exposure assessment may be needed, depending 

on the particular problem or agent(s) of concern. It is important that all risk assessors have a 

basic understanding of windows of exposure and timing for evaluation because these concepts 

can provide a common framework for both the exposure assessment and the hazard 

characterization components of the analysis phase. 

There may be regulatory requirements that have to be considered in this process. For 

example, there may be judicial and societal considerations that may influence the timing and 

breadth of the assessment. These factors may influence the risk management options, 

management goals, key participants, data sources, selection of assessment outcomes, or the 

schedule for developing the assessment. The risk management and assessment planning teams 

need to develop dialogue on the regulatory basis for the risk assessment and determine what kind 

of information is required to satisfy such requirements. 

Methods used for risk assessment of health outcomes can have an impact on the 

economic evaluation in benefits analysis (Griffiths et al., 2002; U.S. EPA, 2000e, 2003e, 2005f). 

Bringing economists into the discussion at the problem formulation stage will help clarify the 

approaches needed for data evaluation and quantification that may be most useful for assessing 

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benefits. Another key consideration here is the selection of outcomes for which economic 

valuation will be considered in the assessment, because this also requires dialogue between risk 

assessors and economists. 

3.2. CONCEPTUAL MODEL 

Within the conceptual model, the risk assessment team develops preliminary hypotheses 

about why adverse effects have occurred or may occur in the future. A conceptual model is 

developed keeping in mind the goal of identifying relevant stressors, sources, pathways 

(including exposure media and routes), receptors (exposed individual or population), and 

outcomes, along with the relationships among them. 

Problem formulation results in a qualitative characterization of hazard and exposure for 

specific life stages. The outcome is the accumulation of the information needed to develop a 

conceptual model (Figure 3-2) that aids the segue from the problem formulation stage to the 

analysis phase. The conceptual model forms the basis for the life stage-specific analysis. It can 

be presented as a diagram, a flow chart, or a narrative description of the predicted key 

relationships. 

These key relationships include the exposures, host factors, and the biological effects. 

They are informed by the initial identification of exposure scenarios, the life stage of exposure, 

the optimum times for evaluation of outcomes to be covered, and the identified characteristics 

and toxicological outcomes of the chemical(s) that may contribute to children’s risk. 

3.2.1. Exposure Considerations 

The approach is to perform a preliminary examination of the data to determine the life 

stages likely to be affected, given the properties of the environmental agent(s), possible sources 

and pathways of exposure, and the defined scope of the assessment. This involves a qualitative 

characterization of the sources, nature, magnitude, duration and pattern of exposures to parents 

or children, as appropriate, including the potential for dietary, drinking water, soil and air 

exposures, and other sources (e.g., pharmaceuticals) (U.S. EPA, 1992, 2002a). An important 

issue to consider is whether all life stages are at the same risk from exposure (e.g., from air 

toxicants, water contaminants), or whether a specific developmental life stage is more vulnerable 

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Source1

Route1

Dose1 absorbed

Media1

Source2

Route2

Dose2 absorbed

Media2

Individual Characteristics:

• Genetic Susceptibility

• Developmental Stage

• Behaviors

• Activities

• Locations

• Product use

• Diet

Community Characteristics

Outcomes

Child Exposure Exposure1 Exposure Exposure2

Life stage-specific dose (e.g., mg/kg/d)

Health assessment values (e.g., reference values for a specific duration)

Source1

Route1

Dose1 absorbed

Media1

Source2

Route2

Dose2 absorbed

Media2

Individual Characteristics:

• Genetic Susceptibility

• Developmental Stage

• Behaviors

• Activities

• Locations

• Product use

• Diet

Community Characteristics

Outcomes

Child

Individual Characteristics:

• Genetic Susceptibility

• Developmental Stage

• Behaviors

• Activities

• Locations

• Product use

• Diet

Community Characteristics

Outcomes

Individual Characteristics:

• Genetic Susceptibility

• Developmental Stage

• Behaviors

• Activities

• Locations

• Product use

• Diet

Community Characteristics

Outcomes

Child Exposure Exposure1 Exposure Exposure2

Life stage-specific dose (e.g., mg/kg/d)

Health assessment values (e.g., reference values for a specific duration)

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Figure 3-2. Conceptual Model for Problem. This figure shows an example of a conceptual 

model resulting from the problem formulation planning and scoping phase. Sources, media, 

routes, dose, pathways, individual characteristics, and outcomes are presented. The types of 

information to consider in developing a conceptual model include exposure, individual 

characteristics, and outcomes (Figure 3-1). The following three subsections provide an approach to 

a preliminary evaluation of the available data to help define the conceptual model and aid in the 

development of a problem-driven analysis plan. 

because of higher exposures or intrinsic susceptibility. A given product’s or compound’s 

properties, as well as its commercial uses and sources of exposure, provide qualitative 

information on where it is expected to be found in exposure media. 

 Information on exposure pathways and a qualitative understanding of activity patterns 

(patterns of exposure) can be used to identify potentially highly exposed life stages. Some 

considerations specific to children include 1) exposure media (e.g., breast milk, indoor air; see 

Section 4.3.4.2), 2) behaviors, activities, and locations that are a function of age/developmental 

stage (e.g., mouthing, crawling; see Section 4.3.4.4), 3) individual and community characteristics 

(e.g., SES, cultural practices; see Section 4.3.4.3), and 4) physical environment (e.g., climate; see 

Section 4.3.4.1). Qualitative information should be used to identify all potential sources, 

pathways (exposure media and routes), and scenarios (population, time frames, locations, and 

activities). 

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3.2.2. Outcome Considerations 

In this screening approach a preliminary identification of toxic effects is preformed, 

including kinetic and dynamic profiles. Some questions to consider are: 

• What do we know about the chemical being evaluated that may be important for 

considering age-specific risk? 

• Does the chemical cause known organ-specific toxicity? 

• Which organs are targeted, and how are these organs differentially susceptible 

during development? 

• What are the background rates for outcomes of concern in the general population? 

• What are the specific time periods of concern? 

• Are there toxicokinetic (e.g., metabolic activation/conjugation) or toxicodynamics 

considerations that may make the chemical more or less toxic during certain 

developmental life stages? 

3.2.3. Integration of Exposure Considerations and Biological Effects Considerations 

The concepts of timing and dosimetry are incorporated as unifying factors for both 

exposure and hazard components of the analysis. 

• How do sources, nature, magnitude, and patterns and pathways of exposure 

influence target outcomes? 

• How does dosimetry impact the temporal resolution required for exposure 

assessment? 

• Based on the fate of the product or compound being evaluated, are we assessing 

hazard of the compound(s) to which children are actually exposed? 

• What MOAs are being considered for relevant child health outcomes? 

• What dose metrics (e.g., AUC or Cmax) are being considered for child related 

assessments? 

3.3. ANALYSIS PLAN 

The analysis plan should identify the methods, models, critical data gaps, major 

uncertainties, and key assumptions that need to be considered as the problem-driven 

assessment moves forward to more in-depth analyses. The analysis plan is a working 
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outline that provides the rationale for the expertise, time, and resources required to 

complete the assessment. 

 A database inventory may be useful for identifying data gaps (Figure 3-3). 

Negotiation of consensus among the relevant risk managers may be needed on the 

conceptual model and analysis plan, including the possible outputs of the assessment. 

This exercise can facilitate identification of strengths and weaknesses in the database, 

especially with regard to life stage assessment. 

Planning and scoping, the conceptual model, and the analysis plan are then used in the 

life stage-specific analysis, which comprises hazard characterization, dose-response assessment, 

and exposure assessment. Further scoping may be considered in each of the three analysis 

phases, thus leading to a further refinement of the conceptual model and analysis plan. 

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Figure 3-3. Life stage-specific database inventory sheet. This table presents an example of a 

database inventory method. Types of information are described in the left-hand column, and life 

stages of exposure are shown in the top row. After assessing the available information on life 

stages of exposure, the assessor can note whether there are the different types of information for 

each life stage. For example, are there human studies assessing outcomes after in utero exposure? 

Hazard Characterization

Exposure Assessment Dose-Response

Life-stage of 

exposure 

Preconception In Utero Infant Child Adolescent Adult 

Human 

studies 

Animal 

studies 

Toxicokinetic 

data 

Toxicodynamic 

data 

Mode of 

Action 

Source 

characteristics 

Chemical 

properties 

Population 

characteristics 

Exposure 

Factor data 
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4. LIFE STAGE-SPECIFIC ANALYSIS 

The life stage-specific analysis includes hazard characterization, dose-response 

assessment, and exposure assessment phases. In these phases, data are analyzed, both 

qualitatively and quantitatively. Iterations among all three components are necessary for 

communication among the team members and stakeholders, as well as to refine the focus on the 

key assessment questions identified in the problem formulation phase (Figure 3-1). For 

children’s health risk assessment, data on outcomes after exposure during life stages of greatest 

susceptibility (critical windows) are key to the evaluation of hazard, dose, and exposure. 

Assessing the data by life stage of exposure and outcome is necessary. This includes the 

identification of data gaps for particular life stages of exposure and, data that may identify 

critical windows of exposure. Mode of action information based on toxicokinetic and 

toxicodynamic data may inform the life stage specific analysis (Figure 4-1). The next three 

sections discuss the factors important in each part of the analysis phase and provide information 

to guide the assessor through the process. 

Dose-response assessment for health risk assessment of children’s exposures must 

consider both timing and dosimetry; and links the characterization of the exposure with potential 

health effects. In order to link exposures and outcomes appropriately, an iterative process 

comparing duration of exposure and dosimetry by life stage of development is recommended. 

Integrating hazard and exposure data is important for a robust risk characterization, the final 

phase in the risk assessment process. The integration process is discussed further in Section 

4.3.4. 

4.1. HAZARD CHARACTERIZATION 

4.1.1. Introduction 

Hazard characterization is the risk assessment phase in which the data are evaluated for 

potential adverse health effects. It includes the identification of any outcomes associated with 

exposure and dose. The primary purpose of hazard characterization for children’s health risk 

assessment is the evaluation of the potential for life stage-specific health outcomes after 

exposure during preconception or developmental stages, taking into consideration toxicokinetic 

(TK), toxicodynamic (TD), and dose-response information. Information derived from both 

human data and animal toxicology studies are evaluated in this analysis phase. Additionally, 
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information about differences and similarities in experimental animal models versus humans 

regarding life stage-specific TK and TD should be considered in the evaluation. More specific 

information on hazard characterization for developmental life stage exposures can be found in 

the existing risk assessment guidelines for developmental toxicity (U.S. EPA, 1991), 

reproductive toxicity 

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5 (U.S. EPA, 1996), neurotoxicity (U.S. EPA, 1998b), and cancer (U.S. EPA, 

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Figure 4-2 illustrates a detailed approach to characterizing hazard to children from 

environmental exposures. This framework is based on the use of a life stage approach (Figure 2-

3), which evaluates data according to the life stage for exposure, outcome, and all intervening 

steps (e.g., TK, TD). This approach focuses on exposures prior to conception and during 

development (i.e., conception to young adulthood), but outcomes at any life stage up to and 

including adulthood are considered (i.e., conception to aged adult). It provides a temporal 

context within which to evaluate data for risk assessment. Thus, the initial evaluation of data for 

a chemical or mixture considers what information is available (and not available, i.e., data gaps) 

for different life stages and what the data indicate in terms of life stage-specific susceptibilities. 

Figure 4-2 presents a flow diagram for life stage-specific hazard characterization. In the 

scoping step of hazard characterization, information on life stage differences in exposure and 

susceptibility is described, assembled by life stage, and synthesized in the hazard 

characterization segment of the assessment (Section 4.1.2). Following the scoping step, there are 

three major steps in the data evaluation process. In the first step, a detailed qualitative evaluation 

of each study is developed (Section 4.1.3). In the second step, the database is synthesized from 

the individual study evaluations, and the quality and quantity (i.e., the comprehensiveness) are 

characterized (Section 4.1.4). This step utilizes a weight of evidence (WOE) approach. In the 

final step (Section 4.1.5), the life stage-specific hazard characterization is summarized. A 

scientific rationale for the selection of relevant outcomes and susceptible life stages is developed 

based upon the data. The selected outcomes and susceptible life stages are further evaluated 

subsequently in the dose-response assessment phase. Finally, a comprehensive life stagespecific risk characterization is developed that requires iterative input among the dose-response, 

exposure, and hazard characterization assessment teams. 
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Figure 4-1. Framework for life stage-specific analysis with animal and human data. 

Qualitative Organization and Analysis represents the overall structure of the analysis phase of risk 

assessment, whereby observable responses are related to an exposure dose in which the 

intervening processes are known or unknown. Qualitative and Quantitative Analysis of sufficient 

data can predict response from exposure, informed by data on tissue dosimetry toxicokinetics (TK) 

and toxicity process toxicodynamics (TD). In instances where there is no mechanistic information 

(far right-hand side), animal dose-response data can be utilized and traditional default methods 

applied. Although much of the intervening information is often absent in humans, data from 

animal species can be used in a parallelogram approach to predict the various portions of the 

Qualitative and Quantitative Analysis. With TK data, dose metrics can be used to predict the overt 

response, or in data-rich settings the dose metric can be used to predict a TD event that can 

subsequently predict the overt response. As depicted in this figure, life stage-specific data in 

animals and humans is preferable, although in its absence, adult animal and human data may be 

useful as long as appropriate intraspecies life stage considerations and extrapolations are made. 

With certain analytical tools (e.g., physiologically based toxicokinetic models), tissue dosimetry 

information can be used to estimate the exposure or applied dose. In such instances, exposure 

analysis can inform selection of the most appropriate dose-response model(s) by providing 

information on to the relevant exposure levels at various life stages. 

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Response ResponseResponse Response ResponseResponse

Toxicity Process ToxicityToxicity Process TD

Tissue Dosimetry Tissue Dosimetry sue Dosimetry TK

ExposureExposureExposure Life Stage-Life Stage-Life StageResponse ResponseResponse

TD

TK

Life Stage-Life Stage-Life StageSpecificSpecificSpecific

ExposureExposureExposure

(human)

limited

informationinformationformation 

default

Mode of Action Mode of Action

SpecificSpecificSpecific

ExposureExposure

(animal)(animal) Qualitative QualitativeQualitative 

Organization OrganizatOrganization

and Analysis

Qualitative and Quantitative Qualitative and Quantitative

Analysis Analysis
Characterization of the Hazard Database

(See Section 4.1.4.)

• Summarize the database

• Conduct weight of evidence (WOE) assessment: 

• Control of confounders, effect modifiers

• Interspecies comparisons of outcomes

• Toxicokinetic & toxicodynamic information

• Variabilities, data gaps, and uncertainties 

• Extent of the database

• Relevance of animal data to humans

Scoping of Hazard Characterization

(See Section 4.1.2.)

Consider:

• Available studies

• Life stage-specific exposures, assessments, and 

outcomes

Qualitative Evaluation of Individual Studies 

(See Section 4.1.3.)

• Consider:

• Study purpose and design

• Exposures and outcomes

• Toxicokinetic & toxicodynamic information

• Qualitative dose-response relationships for adverse 

outcomes

• Variability and uncertainty analyses

Life Stage-Specific Hazard Characterization 

(See Section 4.1.5.)

Consider:

• Life stage-specific outcomes

• Susceptibility

• Variability analyses

• Uncertainty analyses

Problem

Formulation

(See Section 3)

Dose- Response

Assessment

(See Section 4.2.)

Life StageSpecific Risk

Characterization

(See Section 5)

Identify Studies 

and Issues

Exposure

Assessment

(See Section 4.3.) Characterization of the Hazard Database

(See Section 4.1.4.)

• Summarize the database

• Conduct weight of evidence (WOE) assessment: 

• Control of confounders, effect modifiers

• Interspecies comparisons of outcomes

• Toxicokinetic & toxicodynamic information

• Variabilities, data gaps, and uncertainties 

• Extent of the database

• Relevance of animal data to humans

Scoping of Hazard Characterization

(See Section 4.1.2.)

Consider:

• Available studies

• Life stage-specific exposures, assessments, and 

outcomes

Qualitative Evaluation of Individual Studies 

(See Section 4.1.3.)

• Consider:

• Study purpose and design

• Exposures and outcomes

• Toxicokinetic & toxicodynamic information

• Qualitative dose-response relationships for adverse 

outcomes

• Variability and uncertainty analyses

Life Stage-Specific Hazard Characterization 

(See Section 4.1.5.)

Consider:

• Life stage-specific outcomes

• Susceptibility

• Variability analyses

• Uncertainty analyses

Problem

Formulation

(See Section 3)

Dose- Response

Assessment

(See Section 4.2.)

Life StageSpecific Risk

Characterization

(See Section 5)

Life StageSpecific Risk

Characterization

(See Section 5)

Identify Studies 

and Issues

Exposure

Assessment

(See Section 4.3.)

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Figure 4-2. Flow diagram for life stage specific hazard characterization. This figure 

illustrates the flow of information and analysis that make up hazard characterization. Problem 

formulation establishes the context of the risk assessment and feeds into a hazard scoping process 

to identify the information that will be relevant for the hazard characterization phase. The three 

major steps in hazard characterization include the evaluation of individual studies, a weight of 

evidence assessment of the hazard database, and a full characterization of the hazard. For the 

assessment of risks to children, each phase of the process focuses on life stage-specific 

considerations. During the evaluation of hazard, repeated iterations (illustrated by dashed arrows) 

represent points when information is exchanged with other phases and may identify the need to 

collect more data or conduct more detailed analyses. Further refinement of the problem 

formulation or approach may also occur at these steps. As illustrated by the solid arrows, hazard 

characterization, dose-response assessment, and exposure assessment contribute to the risk 

characterization. 
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During each step, it is important to consider whether the information and conclusions 

address the overall goals of the assessment that were defined in the problem formulation phase. 

Each of these steps is described in subsequent sections, and questions that can help guide the life 

stage-specific hazard characterization process are presented in Appendix 1. The questions in 

Appendix 1 cover considerations for both human data and animal studies. 

4.1.2. Scoping of Hazard Characterization 

The refinement of the conceptual model during the hazard characterization focuses on the 

identification and evaluation of all human and animal toxicology data on outcomes resulting 

from preconception or developmental life stage exposures. The scoping exercise includes 

identifying studies for evaluation and determining the types of data available. The evaluation 

process considers life stage-specific information (pertaining to both the time of exposures and 

outcomes) and issues within the overall context of the risk assessment in order to focus on risks 

to children’s health. Primary to this process is the identification of studies that assess outcomes 

after exposures within specific life stages, including preconception. The objectives and scope of 

the risk assessment, as identified in the problem formulation phase, provide structure and focus 

for this scoping step of hazard characterization. The culmination of hazard scoping is the 

identification of individual studies and issues to evaluate in greater detail. 

4.1.3. Qualitative Evaluation of Individual Studies 

The basis of the hazard evaluation process is a thorough examination of all published 

human and animal studies identified in the scoping phase. A thorough qualitative evaluation of 

each human and animal study includes, to the greatest extent possible, a complete description, an 

assessment of the data quality, and a determination of sufficiency of data for hazard 

characterization (Figure 4-3). To assess study quality, the adequacy of the methods and results 

must be fully characterized. In addition, it is be helpful to establish a basis or criteria for 

confidence in the evaluation and interpretation of the study findings. This phase, as implemented 

for each individual study, will contribute to the overall determination of the adequacy, strength, 

and completeness of the database for the characterization of hazard across life stages. After 

qualitative evaluation, the assessor should be able to identify the major strengths and weaknesses 

of the human and experimental animal database. 
Evaluation of Individual Studies

(See Section 4.1.3.)

Outcomes

Exposures

Study Design

Study Purpose

Data Gaps & 

Uncertainties

Variabilities

Dose-Response 

Data

Toxicokinetic & 

Toxicodynamic data An evaluation of study

quality and data 

gaps for

assessing potential

risks to children.

(See Section 4.1.4.)

Evaluation of Individual Studies

(See Section 4.1.3.)

Outcomes

Exposures

Study Design

Study Purpose

Data Gaps & 

Uncertainties

Variabilities

Dose-Response 

Data

Toxicokinetic & 

Toxicodynamic data An evaluation of study

quality and data 

gaps for

assessing potential

risks to children.

(See Section 4.1.4.)

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Figure 4-3. Hazard characterization Step 1: Evaluate individual studies with exposures 

during developmental life stages (including preconception). Following identification of studies 

with preconception or developmental life stage exposures and developmental or adult outcomes 

(i.e., hazard scoping), the first step in the analysis of hazard is an evaluation of each individual 

study, focusing on the details of study conduct, content, and outcomes. This step of the life stagespecific hazard characterization emphasizes a description of the timing of exposure and outcome. 

The resulting evaluation of study quality and data adequacy for assessing potential risks to 

children provides a firm basis for the life stage-specific hazard characterization process. 

4.1.3.1. Study Purpose 

Characterizing the intent or purpose of each study is necessary to focus the evaluation of 

the study and to assess the adequacy of the study to address issues by life stages. For example, 

the study may be conducted in response to general risk evaluation issues or as a result of a 

specific public health concern. The purpose of the study can range from hypothesis generation to 

hypothesis testing. 

4.1.3.2. Study Design 

A clear, concise description and evaluation of the study design is critical. Important aspects of 

study design include the number of subjects in each exposure group, descriptions of the study 

members, gender, route and duration of exposure, and outcomes assessed (including the timing 

of assessment in relation to exposure and life stage). It is helpful to highlight strengths and 

weaknesses in the study design, particularly in relation to life stage-specific assessments and how 

they influence issues identified in the problem formulation stage. 

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4.1.3.3. Exposures 

An evaluation of the exposures to the study individuals (including exposure to humans or 

dosing/treatment to test animals) is particularly important for determining the adequacy of the 

study, interpreting the results and conclusions, and assessing the relevance and application of the 

findings to children’s health risk assessment. It is important to characterize the manner in which 

exposures have occurred across the life stages of the study individuals. It is during this 

assessment that a determination can be made regarding whether the study has addressed the 

timing of exposure (e.g., exposure during preconception and critical windows of pre- or postnatal 

development). For example, in laboratory animal studies, if the toxicological evaluation 

characterizes adverse outcomes following exposures throughout childhood and to the time of 

adolescence, then study exposure methods may need to incorporate direct dosing techniques in 

juvenile animals (Zoetis & Walls, 2003). Additionally, the timing and the duration of exposure 

to test substance in animal studies could be informed by data on the critical windows of 

development of organ systems. A useful source of information is the proceedings of a workshop 

on critical windows of exposure for children (

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Selevan et al., 2000) which addresses the 

respiratory and immune systems (

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16 Pinkerton & Joad, 2000; Holladay & Smialowicz, 2000; Peden, 

2000; Dietert et al., 2000), the reproductive system (Pryor, 2000; Lemasters et al., 2000), the 

nervous system (

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Rice & Barone, 2000; Adams et al., 2000), the cardiovascular and endocrine 

systems (

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Osmond & Barker, 2000; Sadler, 2000; Hoet et al., 2000; Barr et al., 2000), and 

cancer/neoplasms (

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Anderson et al., 2000; Olshan et al., 2000). For epidemiological studies, 

consideration of, and iteration with, the exposure assessment phase (see Section 4.3) is necessary 

at this point in the process and can provide important context for the evaluation of the hazard 

outcomes, characterization of uncertainties, and identification of further testing or research 

needed. 

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4.1.3.4. Outcomes 

A description of study findings, including the relationship of outcome to exposure, is a 

primary goal of hazard characterization. Especially important is the consideration of outcomes 

for specific life stages. The evaluation of each study needs to include whether and how study 

outcomes address issues raised during the problem formulation phase. For example, if the 

problem formulation specifically identifies a potential for exposure to pregnant women in a 
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residential setting, it is important to carefully consider any available human and animal data for 

outcomes following gestational exposures. The adequacy and limitations of exposure-outcome 

associations and their interpretation need to be considered carefully. 

4.1.3.5. Toxicokinetic (TK) Data 

Information on the TK profile may have been identified in the problem formulation 

phase. It is important to include and describe any available life stage-specific TK data, 

particularly, the relevance and impact of the TK data in evaluating the study, and in determining 

the impact of exposure and response across life stages. Toxicokinetic data can be used to verify 

that indirect exposure of the fetus or neonate (e.g., via maternal circulation or milk) occurred 

without relying on observable outcomes. In some situations, internal dose can be measured, 

providing greater accuracy in dose-response metrics. If toxicokinetic data are available across 

life stages, this information can aid in highlighting key life stages for assessment. For example, 

enhanced toxic response in the young can result from immaturity of specific metabolic enzymes 

or renal capabilities (e.g., elimination); information on the developmental profiles of enzymes or 

organ systems can help identify particularly susceptible ages. 

Studies may find increased susceptibility of immature individuals but lack toxicokinetic 

data to assist in the interpretation of these findings. In that case, default assumptions are 

generally applied; typical examples are: 1) internal dose is equivalent to dose at the portal of 

entry 2) the dose to the fetus is equivalent to the dose administered to the mom, or 3) no agerelated differences occur in absorption, distribution, metabolism and elimination (ADME), then 

the internal dose to the immature individual is equivalent to that of adults. However, these 

default assumptions may not be health protective; the availability and use of toxicokinetic data 

will likely decrease uncertainty in the risk assessment. 

4.1.3.6. Toxicodynamic (TD) Data 

TD data includes information about the steps between the toxicant’s first interaction with 

the target organ and the toxic outcome. It is important to describe TD data for specific life 

stages, if available. Furthermore, examination of both TK and TD data may provide 

corroborative evidence of potentially susceptible life stages for a given chemical. For example, 

if TD information for a chemical suggests effects on the nervous system via decreasing 
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luteinizing hormone and disrupts the hypothalamic-pituitary-gonadal axis, greater concern would 

be warranted in the case when there are life stage-specific TK data demonstrating that the 

chemical is found in the brain, as opposed to the case when such data show that it does not cross 

the blood-brain barrier. 

4.1.3.7. Mode of Action (MOA) Information 

Consideration of MOA information (key TK and/or TD steps) is critical because it can be 

useful, for example, in: 1) understanding the susceptibility differences among different life 

stages, 2) determining the most appropriate animal model for relevance to humans or when 

outcome data for exposure during life stages are limited or not available for humans: 3)

predicting types of effects that might be seen during particular life stages, and 4) predicting 

potential critical or susceptible life stages. For example, a given chemical that has as an antiandrogen MOA suggests that in utero and peripubertal intervals might be sensitive exposure 

windows for male reproductive outcomes. In this example, differences in androgen activity by 

life stage can explain the differences in susceptibility. It is also possible that the MOA for a 

given chemical differs among life stages. Although there are no known examples of this, it is 

one possible explanation when exposures during specific life stages and adult exposure lead to 

different outcomes. However, chemicals with more than one MOA, such as methoxychlor, have 

been described, and the different MOAs could be more or less active at different life stages. 

4.1.3.8. Detailed Qualitative Evaluation of the Dose-Response Data Profile 

A detailed qualitative evaluation of the dose-response profile is critical to interpreting the 

outcome for individual studies. For example, a clear dose-related toxicologic response helps 

support the judgment of whether an outcome is due to treatment. Determining the nature of 

adverse responses to an exposure can be an iterative process, because consideration of other 

studies in the database may highlight the importance of borderline or suggestive findings in 

individual studies and, ultimately, refine the interpretation of the data. 

4.1.3.9. Variability Analyses 

There are a number of sources of variability, both intrinsic and extrinsic, in toxicological 

and epidemiological data. Intrinsic variability (often termed “biological variability”) includes 

heterogeneity among individuals in a population or across life stages. It is expressed to some 
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degree in each parameter being measured. Examples of intrinsic variables for animal studies 

include strain, species, and other genetic factors. On the other hand, the sources of extrinsic 

variability are external to the study individuals, and can often be attributed to methodological 

considerations, to errors in study design, or variations in implementation. Examples of extrinsic 

variables for animal studies include handling techniques, ambient temperature, and noise, and for 

epidemiologic studies, variations in recruitment or data collection procedures. 

Variability can be adequately and appropriately characterized by the statistical treatment 

of individual study data through, for example, calculations of central tendency. Nevertheless, 

although the degree of study variability may be controlled to some extent, high levels of 

variability may still be observed, which may affect the ability to identify associations and make 

the interpretation of study data difficult. A detailed consideration of variability with appropriate 

analyses contributes to a determination of the adequacy, strength, and reliability of a study and 

its conclusions. Variability can be a source of uncertainty in the evaluation and interpretation of 

individual studies. High variability can sometimes render a study uninterpretable or result in 

reduced confidence in the veracity of the study findings, thereby decreasing the weight placed on 

the study for use in hazard characterization. 

4.1.3.10. Uncertainty Analyses 

Uncertainty from a variety of sources in life stage-specific data can affect the assessment 

of risk. Thorough consideration and description of the uncertainties for each study are essential. 

Any resulting assumptions, extrapolations, or speculative interpretations must be fully 

characterized. Uncertainties can result from data gaps (i.e., missing information) or inadequacies 

in the study protocol or methodologies, inadequacies in the reporting of study findings, or 

inconclusive results. Characterization of the uncertainties by life stage is important. Due to the 

iterative nature of the evaluation process and the consideration of information from multiple 

sources, data from other human or animal studies, data on structure-activity relationships 

(SARs), or TK or TD information, may be used to address uncertainties in a given study. 
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4.1.4. Evaluation of the Hazard Database 

After relevant studies have been evaluated, those scientifically judged to be potentially 

useful for risk assessment (NRC, 1994) are selected and summarized, and the extent of the 

database is described. Best scientific judgment requires a well-justified decision to include a 

given study or exclude it from further consideration. Specific criteria can be developed for a 

particular assessment if appropriate. Characterization of the extent of the database includes a 

summary of the data gaps, uncertainties, and assumptions made in the assessment of the database 

as a whole (Figure 4-4). The adequacy, strength, and completeness of the database are 

considered. The adequacy of studies and characterization of the database are discussed in 

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Review of the Reference Dose and Reference Concentration Processes (U.S. EPA, 2002b, 

Section 4.3). This information is then used to describe the WOE to identify potential hazards 

from exposures to children. A similar WOE approach in the assessment of environmental risks 

to children is described in the Office of Pesticide Programs report 

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13 Determination of the 

Appropriate FQPA Safety Factor(s) in Tolerance Assessment (U.S. EPA, 2002c, Section III). 

The WOE analysis, described in more detail below, could be framed by factors presented in the 

conceptual model that was developed during the problem formulation phase (see Section 3.2). 

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4.1.4.1. Summarizing the Hazard Database 

The overall hazard database includes detailed descriptions of all studies relevant to and 

critical for evaluating the hazard to children; all studies with developmental exposures, effects, 

or outcomes. It may also include in vitro data, MOA or mechanistic studies, and toxicity data in 

adults that help profile the toxicological response in children or provide support for assumptions 

made during the hazard characterization. A careful review of the studies’ exposure durations and 

life stages may help in determining the relative importance (weight) of the studies in determining 

potential risks to children. Issues to consider include the pathways (including media and route) 

and whether they are relevant to children, the intervals of exposure and whether they included 

critical life stages, and issues suggestive of differential susceptibility of children or specific life 

stages. 
Modifiers & 

Interactions

Describe the WOE for

Effects in Children

(See Section 4.1.4.2.)

Inter- & Intraspecies

Comparisons

Variabilities, Data 

Gaps, and 

Uncertainties

Relevance of

Animal Data to 

Humans

Extent of Database

Toxicokinetics & 

Toxicodynamics

Summarize the

Database

(See Section 4.1.4.1.)

Life Stages of

Exposure

Range of Outcomes

Modifiers & 

Interactions

Describe the WOE for

Effects in Children

(See Section 4.1.4.2.)

Inter- & Intraspecies

Comparisons

Variabilities, Data 

Gaps, and 

Uncertainties

Relevance of

Animal Data to 

Humans

Extent of Database

Toxicokinetics & 

Toxicodynamics

Summarize the

Database

(See Section 4.1.4.1.)

Life Stages of

Exposure

Range of Outcomes

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Figure 4-4. Hazard characterization Step 2: Evaluate the database as a whole for potential 

hazards to children from environmental exposures during different life stages. After each 

individual study has been evaluated, the second step in the hazard analysis is a consideration and 

integration of the entire database of studies. A narrative description of the database is generated, 

using a weight of evidence approach, with a focus on life stage-specific issues and considerations. 

This analysis becomes an integral component of the life stage-specific hazard characterization. 

 A detailed characterization of the study outcomes is also important for the 

characterization of the database. Often, the structure and presentation of data summaries are 

driven by the outcome data. It is important to examine common links across studies. For 

example, for one chemical with detailed MOA information, the summary could focus on hazard 

in relation to that MOA and what the MOA may predict about potential critical windows. For 

other chemicals, the description might focus on specific developmental outcomes, target organs, 

or susceptible life stages. The emphasis of the hazard summary is on the relationships (i.e., 

patterns) across observed outcomes, in relationship to life stages and mode of action. 

 For some chemicals, only very limited human or experimental animal hazard information 

may be available. However detailing the lack of information about an agent (i.e., data gaps and 

uncertainties) is crucial to an adequate characterization of risk to children from environmental 

exposures. 

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4.1.4.2. Description of the Weight of Evidence (WOE) 

 The WOE approach requires a critical evaluation (expert judgment) of all available data 

for consistency and biological plausibility. Criteria for this assessment are not presented here; 

rather, considerations important for the WOE are described. The key to WOE conclusions is the 

provision of a clear justification for decisions. Finally, the extent of the database is summarized, 

and assumptions made in the assessment are explicitly detailed. Further details about EPA’s 

7 WOE approach can be found in the Methods for Derivation of Inhalation Reference 

8 Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994), Guidelines for 

9 Carcinogen Risk Assessment (U.S. EPA, 2005b), and Supplemental Guidance for Assessing 

10 Cancer Susceptibility from Early Life Exposure to Carcinogens (U.S. EPA, 2005c). A Review of 

the Reference Dose and Reference Concentration Processes (U.S. EPA, 2002b, Section 4.3.2.1.) 

and 

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12 Determination of the Appropriate FQPA Safety Factor(s) on Tolerance Assessment (U.S. 

13 EPA, 2002c, Section III) provide additional detail on the WOE. 

14 Key themes for the consideration of toxicity data in a WOE assessment, as adapted from 

Gray et al. (2001), are shown in Figure 4-5. This figure focuses on judging animal studies within 

a WOE assessment. However, if adequate human studies are available they would be given 

more weight. The process for evaluating these considerations is described in the following 

subsections. In this process, the quality of potentially relevant studies is judged, modifiers and 

interactions are detailed, outcomes across species are compared, TK and TD data are examined 

and weighed for comparisons across species, and the uncertainties and data gaps are determined. 

SARs with other chemicals or chemical classes are explored to determine the extent to which 

these data can inform the assessment via an MOA discussion or reduce uncertainties. 

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4.1.4.2.1. Modifiers and Interactions. Consideration needs to be given to effect modifiers and 

confounders in the studies. Then, questions of whether and how these have been evaluated in the 

data analysis are considered. It is important to focus on all potential life stage-specific effect 

modifiers and confounders and how they could affect the study outcomes or interpretation of 

study results. An example of an environmental modifier includes the influence of maternal 

health status (i.e., the effect of compromised maternal or offspring nutrition on development and 

maturation of the young). 
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4.1.4.2.2. Intra- and Interspecies Comparisons of Outcomes. For the chemical under 

assessment, any information on comparative species susceptibility for exposures and outcomes 

needs to be considered carefully, including comparisons between experimental animals and 

Database

Consistency

Human 

Plausibility

Human 

Relevance

Rigor

Statistical

Power

Corroboration

Reproducibility

Weight-ofEvidence 

Assessment 

of the Hazard 

Database

Database

Consistency

Human 

Plausibility

Human 

Relevance

Rigor

Statistical

Power

Corroboration

Reproducibility

Weight-ofEvidence 

Assessment 

of the Hazard 

Database

Figure 4-5. Conceptual view of a weight of evidence (WOE) assessment. This figure illustrates 

the critical considerations within a WOE assessment of toxicity data. Rigor is the degree of proper 

conduct and analysis of a study; greater weight is generally given to more rigorous studies. 

Statistical Power is the ability of a study to detect effects of a given magnitude. Corroboration

means that specific effects are replicated in similar studies, similar effects are observed under 

varied conditions and /or similar effects are observed in multiple laboratories. Reproducibility

means that an effect is observed in multiple species by various routes of exposure. Relevance to 

Humans means that similar effects are observed in humans or in a species taxonomically related to 

humans or at doses similar to those expected in humans. Plausibility to Humans is the 

determination of whether a similar metabolism, mechanisms of damage and repair, and molecular 

target of response could be expected to occur in humans, based on an evaluation of the biologic 

mechanism of a toxic response in animals. Database Consistency is the extent to which all of the 

data are similar in outcome and dose (exposure-response) and are operating under a single 

biologically plausible assumption (mode of action). (Source: Adapted from 

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18 humans as well as comparisons across experimental animal test strains (Spearow et al., 1999, 

19 2001) and species.

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Important life stage-specific information to consider and use (if available) include: 

• Comparative developmental stages between experimental animals and humans for 

the life stages when exposures or specific outcomes occur (i.e., what are the 

comparable developmental events among the species and strains), 
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• Cross-species and cross-strain similarities in outcome for comparable stages of 

development, 

• Differences in developmental timing for certain species or strains that impact 

comparison of exposures during a given life stage for the database as a whole 

(i.e., certain rodent in utero exposure stages are comparable to certain human 

postnatal exposure stages), and 

• The timing and route of exposures between animals and humans (e.g., whether the 

dosing interval in the test animal study is comparable to potential or actual 

exposure timing in humans). 

 A number of relevant papers comparing organ development across species are available 

for reference, as summarized in Hurtt and Sandler (2003a, 2003b). Beckman & Feuston (2003)

compare landmarks in the development of the female reproductive system across species, and 

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Marty et al. (2003) compare some key events in the postnatal development and maturation of the 

male reproductive system across species. 

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Hew & Keller (2003) describe cross-species postnatal 

development of the cardiac system and life stage-related morphological and functional 

differences. 

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Holsapple et al. (2003) address pre- and postnatal immune system development. 

Functional measures of postnatal central nervous system development are detailed in 

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Wood et al.

(2003)

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. Zoetis and Hurtt compare anatomical and functional renal development (2003a) and 

lung development 

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20 (2003b) across species. Postnatal bone growth and development is covered in 

Zoetis et al. (2003). Additionally, information on relative developmental timing across species 

for several systems is addressed in 

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Selevan et al. (2000) and Hattis et al. (2004; 2005) for 

carcinogenesis. 

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4.1.4.2.3. Toxicokinetics (TK) and Toxicodynamics (TD). Available information on TK and 

TD similarities and differences between experimental animals and humans, across experimental 

animal models, or for various life stages are important to a children’s health assessment and 

therefore, are described in detail. Consideration and decisions about how these data contribute to 

the evaluation and interpretation of the hazard database need to be addressed. In addition, data 

gaps need to be identified. 

4.1.4.2.4. Variabilities, Data Gaps, and Uncertainties in the Database. The hazard 

characterization process requires a thorough assessment of the overall variabilities, data gaps, 
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and uncertainties that have been identified in the database, both generally and specifically for 

evaluation across life stages. 

The sources of variability within individual studies are also confounding factors for the 

interpretation of data across or among studies. They can contribute to overall uncertainties in the 

database, including those that are applicable to the analysis of life stage-specific hazard. 

Variability of response across studies and possible reasons for the variability are important to 

assess and consider. For example, the response could vary among studies performed in the same 

animal species but using different strains. Further, the level of confidence in the final risk 

estimates is based on a detailed description of the assumptions and interpretations of the 

uncertainties in the overall database. 

A data gap is defined as missing information. In the evaluation of individual studies, data 

gaps may be identified that could have impact on the quality of the study, and these need to be 

considered in total when evaluating the data base. In addition, when combining the data from all 

the studies, data gaps for the comprehensive data base of information on the chemical can be 

assessed. For example, the combined studies may have assessed outcomes after exposure during 

all developmental stages except for the peripubertal period. If this were the case, then a data gap 

in coverage of this particular developmental life stage of exposure is highlighted. For any 

chemical assessment, there will be inevitable gaps in the available life stage-specific information. 

The relative impact of missing or inadequate information to the overall goals of the assessment 

needs to be judged. In some cases, information gleaned from the toxicological profiles of 

structurally related chemicals or chemicals with a similar MOA may assist in interpreting the 

relative importance of a data insufficiency, or in some cases it can even provide a way of 

bridging a data gap (Julien et al., 2004). When evaluating life stage-specific uncertainties and 

data gaps, it is important to address study design, including measurements, exposure, and 

outcomes across life stages (

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U.S. EPA, 1991, Section 3.1.2.1;1996, Section 3.3.1.5; 2002b, 

Section 4.3.1). The results of individual study assessments and the consideration of those studies 

during the summarization of the database and the WOE assessment will help to focus this 

analysis. Examples of questions that could help to focus the evaluation of life stage-specific data 

gaps and uncertainties are provided in Appendix 1. 

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Finally, the description of data gaps and uncertainties can be framed from the perspective 

of the problem formulation. For example, if the problem formulation analysis suggested that 
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infants had high risks due to biological susceptibility or their probability of exposure, then the 

absence of data to characterize the hazard and dose-response information for that life stage 

would affect the relevancy of the risk assessment to address the identified problem or question of 

the assessment (as defined in the Problem Formulation phase). Additionally, information from 

the exposure assessment could be critical when identifying any remaining uncertainties in the 

hazard characterization. 

 The characterization of data gaps also includes a determination of whether required 

studies are present (those that are required by statute or convention, e.g., a rodent and a nonrodent prenatal developmental toxicity study and a reproduction and fertility effects study). In 

addition, uncertainties arising from the absence of any other data identified as critical to an 

adequate assessment of hazard and dose-response for the specific chemical risk assessment need 

to be addressed. The potential qualitative and quantitative impact of these missing data on the 

risk assessment (e.g., on the POD) is considered in both the hazard characterization and dose 

response assessment phases, because this information may be important in determining the need 

for or the magnitude of a database uncertainty factor (UF) during dose-response assessment 

(U.S. EPA, 2002b). Sometimes, other types or sources of data can assist in satisfying an 

identified data gap. As one example, if for a chemical being evaluated, there are no data relevant 

to the assessment of hazard following exposure during a particular life stage (e.g., the perinatal 

period), data from a similar life stage exposed for a different chemical that has been shown to 

produce the same active metabolite might be useful in informing the assessment and reducing 

uncertainties relevant to this data gap. 

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Concentration Processes (U.S. EPA, 2002b) recommends summarizing the extent of the 

database and gives broad definitions for the range from a “minimal” to a “robust” database (p. 4-

19). These definitions were intended to define the range, of database characteristics, with 

minimal including the least amount of information that would be sufficient to conduct a risk 

assessment and robust as the “gold standard” that fully characterizes the potential toxicity of a 

chemical or group of chemicals. The intent is for the assessors to characterize and justify in a 

narrative form the extent of the database, including data gaps and uncertainties (e.g., life stage24 

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specific exposures and outcomes, TK and TD data, the types of outcomes evaluated, 

reversibility, and latency to response) that aid in determining the extent of the database. 

 For an assessment across life stages, the extent of the database as a whole is then 

evaluated from the perspective of the conceptual model (developed in the problem formulation 

phase). In considering the extent of the database, the quality, quantity (i.e., studies available to 

evaluate), and uncertainties and data gaps in the assessment are considered. 

4.1.4.2.6. Relevance of Animal Data to Humans. Adequate human data are, of course, the 

most relevant for assessing risks to humans. Nevertheless, a major default assumption that is 

used in the absence of human data is that experimental animal data are relevant for humans. This 

concept is integral to the EPA risk assessment guidelines for developmental toxicity, 

12 reproductive toxicity, neurotoxicity, and carcinogenesis (U.S. EPA, 1991, 1996a, 1998b, 2005b, 

2005c). A key step in the assessment is the characterization of assumptions and uncertainties of 

the animal database and the use of these data for predicting risk in humans. Based on the WOE, 

there is strong support regarding the likelihood of effects in humans when (1) the dose-response 

relationship demonstrates a predictable change in effect as a function of dose (or exposure), (2)

qualitative and quantitative comparability exists in the TK or metabolism between animals and 

humans, (3) effects are similar across more than one animal species or between animals and 

humans, (4) a homologous MOA in experimental animals and humans has been demonstrated, 

and (5) the temporal relationship between exposure and effect is consistent (

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4-13 to 4-14). 

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 Discussion of the following issues can be important: the relevance to humans, 

specifically to children, and the dose-response relationship at doses that are relevant to exposure 

at developmental life stages (i.e., environmental levels). A WOE description of these points will 

be used in the life stage-specific hazard characterization phase (see Section 4.1.5). 

4.1.5. Life Stage-Specific Hazard Characterization Narrative 

 In this final step in the hazard characterization (Figure 4-6), a scientific rationale for the 

selection of outcomes relevant for use in quantitative dose-response assessment are clearly and 

concisely summarized. Included in this assessment are considerations of life stage-specific 
Describe Life Stage-Specific

Outcomes in Low-Dose Ranges

NOAELs LOAELs

Determination of 

Life Stage-Relevant Outcomes 

for use in Quantitative 

Dose-Response Assessment 

(See Section 4.2.)

Describe Life Stage-Specific

Outcomes in Low-Dose Ranges

NOAELs LOAELs

Determination of 

Life Stage-Relevant Outcomes 

for use in Quantitative 

Dose-Response Assessment 

(See Section 4.2.)

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Figure 4-6. Hazard characterization, Step 3: Describe and determine life stage-relevant 

outcomes. In the third and final step in the hazard characterization, life stage-relevant outcomes 

in the lower dose ranges are described for use in the next analysis phase, the quantitative doseresponse assessment. Different low dose ranges (e.g., no observed adverse effect levels (NOAELs) 

and lowest observed adverse effect levels (LOAELs)) may have been identified for different 

outcomes or for different life stages of exposure depending upon different routes and durations of 

exposure. 

outcomes, including susceptibility of individuals; the impact of interindividual variability on 

response; and remaining uncertainties in the hazard evaluation. Issues to consider include: 

• Life stage-specific outcomes from the whole database that were identified in the 

lower dose range(s) (not just a single “critical effect”). (If there are data, noobserved-adverse-effect levels (NOAELs) and lowest-observed-adverse-effect 

levels (LOAELs), benchmark doses (BMDs) and BMD lower confidence limits 

(BMDLs), or data supporting other quantitative approaches like quantitative risk 

estimates (QRE) then this information is subsequently considered in dose response 

analysis.) 

• Life stage-specific outcomes relevant for use in quantitative dose-response 

assessment. 

• The most susceptible life stages (e.g., women of childbearing age [preconception 

and fetuses], breastfeeding infants, or toddlers and older children) from the 

available data. Justification for the most susceptible life stage(s) can be provided 

by data to support the relevant outcomes of concern. 

• The development of margin of exposures (MOEs) through iterations among the 

hazard characterization, dose-response, and exposure assessment phases. 

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03/01/06 35 DRAFT—DO NOT CITE OR QUOTE 

This information will subsequently be used in the dose-response assessment phase (Section 4.2.). 

Finally, in risk characterization (see Section 5), the life stage-specific hazard characterization 

information and exposure assessment information are important components for describing risk 

to children. 
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4.2. DOSE-RESPONSE ASSESSMENT 

4.2.1. Introduction 

4.2.1.1. Scoping of the Dose-Response Assessment 

 Figure 4-7 presents a framework for developing a dose-response characterization for 

developmental life stages. The process begins by summarizing the available data and culminates 

with a descriptive characterization of the data, models, estimates, and uncertainties applied. In 

selecting the appropriate dose-response model for life stages, careful consideration of routes of 

exposure, toxicokinetics (TK), toxicodynamics (TD), epidemiological findings, and mode of 

action (MOA) is critical. Where available, resources for aiding a life stage dose-response 

analysis are provided so that risk assessors are aware of some of the guidelines, scientific 

literature, and other useful resources for this phase of analysis in children’s health risk 

assessment. 

4.2.1.2. Extent of Assessment 

 Risk assessment is a broad term with different meanings in different contexts. In the 

past, different approaches have been used to characterize risk, depending on whether the 

outcomes were cancer or noncancer effects. More recently, a harmonized approach is advocated 

in an attempt to characterize outcomes as either having a threshold (i.e. nonlinear) or nonthreshold (i.e., linear) mode of action. This harmonized approach recognizes that both cancer 

and noncancer endpoints can appropriately be characterized as threshold or non-threshold 

depending on the available data. Risk assessment processes also vary somewhat on exposure 

scenario, i.e. duration, route, and source. Regardless of these differences, a life stage approach 

can be utilized in risk assessments. During the problem formulation, the scope and breadth of an 

assessment are established and generally fall into two categories, narrow and broad. In an 

assessment with a relatively narrow scope, outcomes for specific life stages thought to be at risk 

are analyzed. In a broad scope assessment, each life stage is analyzed in the pursuit of a more 

thorough “cradle to grave” assessment. Such a broad scope assessment, however, is not intended 

to characterize risk at each individual life stage, but rather characterize risk for the most sensitive
Conceptualization of 

Mode of Action

(See Section 4.2.2)

Extrapolation and Risk Value Derivation

(See Section 4.2.4.)

• Adjust PODs for route, duration, intraspecies, and 

interspecies (including life stages)

• Derive risk value(s)

• Model uncertainty, sensitivity and variability

• Adjust risk values by appropriate UFs or ADAFs

Analysis in Range of Observation 

(See Section 4.2.3.)

Consider:

• Strengths and weaknesses of available models

• Feasibility of techniques such as categorical regression 

and probabilistic approaches

• Availability of life stage-specific models or adaptability 

of PBTK or BBDR models

Hazard

Characterization

(See Section 4.1.)

Problem

Formulation

(See Section 3.)

Exposure

Assessment

(See Section 4.3.)

Life Stage-Specific Dose-Response 

Characterization

(See Section 4.2.5.)

Consider:

• Strengths and weaknesses of dose-response analyses

• Recommended estimates with WOE descriptors

Dose-Response Scoping

(See Section 4.2.1.)

• Extent of Assessment

• Narrow (life stage, exposure, and outcome of 

interest are considered)

• Broad (all life stages and exposures are considered)

• Regulatory Needs and Considerations

• Risk values and standards setting

Life StageSpecific Risk

Characterization

(See Section 5.)

Conceptualization of 

Mode of Action

(See Section 4.2.2)

Extrapolation and Risk Value Derivation

(See Section 4.2.4.)

• Adjust PODs for route, duration, intraspecies, and 

interspecies (including life stages)

• Derive risk value(s)

• Model uncertainty, sensitivity and variability

• Adjust risk values by appropriate UFs or ADAFs

Analysis in Range of Observation 

(See Section 4.2.3.)

Consider:

• Strengths and weaknesses of available models

• Feasibility of techniques such as categorical regression 

and probabilistic approaches

• Availability of life stage-specific models or adaptability 

of PBTK or BBDR models

Hazard

Characterization

(See Section 4.1.)

Problem

Formulation

(See Section 3.)

Exposure

Assessment

(See Section 4.3.)

Life Stage-Specific Dose-Response 

Characterization

(See Section 4.2.5.)

Consider:

• Strengths and weaknesses of dose-response analyses

• Recommended estimates with WOE descriptors

Dose-Response Scoping

(See Section 4.2.1.)

• Extent of Assessment

• Narrow (life stage, exposure, and outcome of 

interest are considered)

• Broad (all life stages and exposures are considered)

• Regulatory Needs and Considerations

• Risk values and standards setting

Life StageSpecific Risk

Characterization

(See Section 5.)

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Figure 4-7. Flow diagram for life stage-specific dose-response assessment. This figure 

illustrates the flow of information and analysis that comprises dose-response assessment. As 

illustrated by the solid arrows, hazard characterization, dose-response assessment, and exposure 

assessment contribute to the risk characterization. The problem formulation phase establishes the 

context of the risk assessment and feeds into the scoping process to identify the extent of the 

assessment and the output needed. Selection of the dose-response relationships for life stages of 

interest is made, and appropriate extrapolations and risk value derivations are performed and 

subsequently described in the dose-response characterization and risk characterization. 

Throughout dose-response assessment, repeated iterations (dashed arrows) with the problem 

formulation, hazard characterization, and exposure assessment phases identify the need to collect 

more data or conduct more detailed analyses. Abbreviations: PBTK, physiologically based 

toxicokinetic; BBDR, biologically based dose-response; PODs, points of departure; UF, 

uncertainty factors; ADAF, age dependent adjustment factors; WOE, weight of evidence. 

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life stage for the appropriate exposure scenario. Regardless of the breadth of the assessment, the 

exposure scenario, or hypothesized mode of action of the environmental agent, the life stage 

approach can add to the overall soundness and confidence in the assessment, as well as provide a 

thorough as possible starting point for future reassessments. 

4.2.1.3. Regulatory Needs and Considerations 

Based on the needs outlined in the problem formulation of a given risk assessment, an 

approach for carrying out a chemical risk assessment is developed. The approaches will include 

methodologies and standard setting protocols. It is important to re-emphasize that the nature and 

number of risk estimates is governed by the problem formulation and hazard characterization. 

Under a narrow scope assessment (see Section 4.2.1.2), risk may need only be characterized for 

one life stage, exposure scenario (e.g., acute, oral exposure) and outcome (e.g. leukemia). 

Alternatively, under a broader scope assessment, risk may need to be characterized for the most 

susceptible life stages for each exposure scenario of interest. In either approach, age-specific 

information on factors related to exposure and response are needed. 

Risk values are typically categorized on route and duration. Acute toxicity is of 

particular concern in children because the complex processes of embryogenesis, fetal and 

postnatal development provide ample opportunities for toxicant exposures to alter the regulation 

of development. Perhaps less apparent, however, is the applicability of long-term risk values to 

children. For instance, reference dose (RfD) and reference concentration (RfC) values are risk 

estimates calculated for various routes (oral, dermal, inhalation) and durations (acute, short-term, 

chronic) of exposure (U.S. EPA, 2002b). It is important to note that chronic exposure is defined 

as exposure up to 10% of lifetime; thus, chronic risk values (RfVs) may be applicable to 

children, because seven years of exposure meets the EPA definition of chronic human exposure 

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(U.S. EPA, 2002b). Unit risk estimates such as cancer slope factor (CSF) are used to define the 

exposure concentration that yields a given level of risk (e.g., 1 × 10

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-6) during a lifetime. 

Although the latency of time to tumor may mask detection of cancer from exposures occurring in 

early life stages, early exposures may indeed increase the risk of tumor development in later life 

stages. In fact, there is evidence to support the notion that susceptibility to tumor development 

from exposure to mutagenic chemicals during earlier life stages is greater relative to later life 

31 stages (U.S. EPA, 2005c). Depending on the goals stated in the problem formulation of a risk 
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assessment, the literature database should be assessed for studies that have examined cancer in 

adult humans and experimental animals following early life exposure. 

4.2.2. Mode of Action (MOA) Conceptualization 

Dose-response analysis can proceed along two paths, one which is informed by MOA 

information or one where quantitative risk values are developed with little or no insight into the 

MOA of an environmental toxicant. A more informed assessment, however, utilizes the broader 

body of scientific literature to look for: commonalities in responses across studies, similarities to 

other chemicals, and mechanistic data from a wide array of studies and fields of specialization. 

In fact, these data are an important part of the hazard characterization and help to establish the 

MOAs underlying the various dose-response relationships. MOA is increasingly recognized in 

the scientific community as a foundation from which to build a dose-response analysis 

(Andersen & Dennison, 2001; Andersen et al., 2000; Clewell et al., 2002a; Preston, 2004). In 

order to conceptualize a MOA, it is necessary to summarize the dose-response model(s) 

available, the mechanistic data that relates the critical effect(s) of interest to a particular dose 

metric, and the data supporting the choice of a likely or hypothesized dose metric. 

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4.2.2.1. Summarizing the Available Dose-Response Relationships 

Route and duration make up the exposure element for individual life stages. Although 

the problem formulation will have likely identified exposure scenarios that pose risks to 

individual life stages, a quantitative risk assessment requires identification of dose-response 

relationships from which to begin quantifying risk for scenarios and life stages of interest. This 

process presents a critical interface with the exposure assessment, where source-to-dose 

modeling informs assessors about the relevant range of likely external exposure for different 

exposure scenarios and specific life stages. Because low-dose extrapolation has inherent 

uncertainties regarding MOA over dose ranges (Slikker et al., 2004a, 2004b), the exposure 

assessment can help inform selection of the appropriate dose-response model from which to 

obtain a point of departure (POD). It is also important to realize that analysis of dose-response 

data could (under certain circumstances) warrant re-examination of the exposure assessment. 

Data that indicate a sensitive dose-response relationship at environmentally relevant low 

exposure levels, particularly in the context of precursor events, may suggest that certain exposure 

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scenarios are more critical than initially thought and perhaps be an impetus for further 

characterization and refinement of exposure models employed for predicting external doses. 

An exposure-response array can help identify critical outcomes (U.S. EPA, 2002b, 

Section 4.4.1) across dose ranges and aid in the conceptualization of the MOA. For instance, 

different effects at similar doses may originate through common mechanisms, and thus lend 

support to a MOA. Alternatively, different effects across dose ranges may represent a gradient 

of effects operating through common mechanisms, and thus also lend support to a MOA. It is 

also possible, of course, that different MOAs are operational across dose ranges, and an 

exposure-response array can be useful for defining the range of effects. Using this array, 

multiple responses can be described as a continuum of dose, and may be informative in risk 

management. An alternative approach is to assign key outcomes to severity categories and 

analyze by categorical regression (see Section 4.2.3.1). 

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The complexities of developmental processes require that equal consideration be given to 

the life stage at which critical effects (i.e., outcomes or responses) are observed. In 

circumstances where data exist for multiple life stages, it is likely that effects at earlier life stages 

pose greater risk, a priori, due to the potential for irreversible changes or changes that confer an 

increase in risk to subsequent exposures in later life stages3. It is for this reason that doseresponse selection should be informed by MOA considerations in addition to the available 

response data. This provides an important interface with the hazard characterization. Effects 

that are thought to share common key events in the proposed MOAs can give assessors 

confidence in choosing dose-response models that most closely relate to the underlying biology. 

Similarly, effects identified or proposed may have implications for choosing dose-response 

models that are most relevant to the life stages of interest.

There is also opportunity for dose-response analysis to inform hazard characterization. 

For instance, toxicologists adept at hazard characterization may not have the requisite skills to 

thoroughly evaluate certain models such as PBTK models. Therefore, it is possible that 

situations could arise where a thorough analysis of a PBTK model by modeling experts indicates 

that the model inadequately predicts empirical data. This could be due to either deficiencies in 

the model, or could suggest that the dose metric previously hypothesized to be associated with a 

3

 For instance, it is hypothesized that acute lymphocytic leukemia (the most prevalent childhood leukemia) results 

from an early (perhaps prenatal) initiation event forming a fusion gene, followed by a subsequent event in later 

childhood (Greaves, 2003). 
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03/01/06 41 DRAFT—DO NOT CITE OR QUOTE 

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response may not be the appropriate dose metric responsible for the toxicological outcome; the 

latter instance could potentially prompt a reconsideration of the dose metric or MOA. In 

addition, this could be an impetus for instead using the empirical data against which the model 

was evaluated, and for proceeding with the assessment in the absence of a clearly defined MOA. 

Exposure and response considerations for examining plausible MOAs include the 

following: 

• Have exposure scenarios and various life stages (e.g., preconception, pregnancy, 

infancy, childhood been addressed? Are there data concerning early life exposures 

related to latent adult effects data? 

• Are any known developmental windows likely to be affected by exposure? What is 

known about pre- and post-pubertal exposures? 

• Have individual physiological and developmental processes been compared with 

the child behavioral development; i.e., how do life stage behaviors and exposure 

scenarios compare with individual physiological parameters such as enzyme 

ontogeny and renal clearance maturation? (It is possible that maturation of such 

parameters spans multiple behavioral stages. In such cases, behavioral 

susceptibilities and physiological susceptibilities might require time weighting to 

assess exposure to the dose metric.) 

• Are the various outcomes likely linked by MOA or are they different? Do the 

outcomes share common mechanisms? Do the outcomes represent a gradient of the 

same MOA? 

4.2.2.2. Mechanistic Data and Mode of Action 

The complexity of development provides opportunity for toxic exposures to create TD 

effects that may or may not be relevant to adults. Developmental stages or age groupings may be 

based on such metrics as growth rates/spurts, behavioral traits, organ systems, or perhaps 

functional development. It may be possible to plot these metrics for development throughout life 

stages and across species. Examples of organ system development include the respiratory, 

cardiovascular, central and peripheral nervous systems, and immune systems. 

Comparison across species and life stages might allow for identification of systems that 

might be at risk during comparable windows of exposure, and inform the decision of which 

effects and dose-response data are most useful. Across species, matching comparable life stages 

is necessary in order to limit TD differences in the critical response of interest (see Section 
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03/01/06 42 DRAFT—DO NOT CITE OR QUOTE 

1 4.2.4.2). Within species, studies suggest that there is concordance of cancer outcomes across life 

stages, albeit with different potencies (U.S. EPA, 2005c; Hattis et al., 2004). Although the 

results of such studies may lend some confidence in extrapolating effects from adults to children, 

data also indicate the potential for differential tumor responses depending on life stage of 

exposure (

2 

3 

4 

U.S. EPA, 2005c). It is not clear, however, whether these differences relate solely to 

differences in metabolic activation. Considerations include: 

5 

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• Are TD effects known or hypothesized? Are the key players (e.g., receptors, DNA 

repair enzymes) involved in the known or suspected MOA expressed sufficiently 

during the life stage of interest? (As stated above, concordance for cancer 

outcomes is fairly well documented; although this implies a similar MOA, it is 

important to address, if possible, whether the same molecular events are 

responsible.) 

• Based on developmental susceptibilities, have the available studies addressed all 

possible outcomes of concern (e.g., cognitive deficits, immunological effects, 

endocrine disruption.)? Are there data that support the notion that such outcomes 

are likely to be relevant for the life stage of interest? 

4.2.2.3. Selection of Dose Metric 

Selection of the appropriate dose metric is an iterative process. In instances where only a 

few metabolites are formed from a parent compound, the chemical nature of these metabolites 

might aid in the formulation of a plausible MOA. In other instances, particularly when there are 

numerous metabolites, data from biochemical and toxicological studies may be the primary 

driver for formulating a plausible MOA. In practical terms this may not be the toxic moiety at 

the target tissue, but often will be a surrogate such as blood concentration of a particular moiety 

(parent or metabolite). The underlying assumption in dose-response analysis is that the dose 

metric will exact the same effect at equivalent doses irrespective of species and route, provided 

28 there are no TD differences (Andersen & Dennison, 2001; Clewell et al., 2002). 

Clewell et al. (2002) have proposed two criteria for dose metric determination. The first 

criterion is that the dose metric must exhibit plausibility, which they define as consistency with 

MOA and ability to simplify a complex dose-response relationship. The second criterion is 

conservatism, defined as the selection of the dose metric that poses the highest risk or the lowest 

acceptable exposure level 

29 

30 

31 

32 

(Clewell et al., 2002). It is important to recognize that a potent dose 

metric is not synonymous with a potent exposure/applied dose, and it is the environmental 

33 

34 
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03/01/06 43 DRAFT—DO NOT CITE OR QUOTE 

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exposure level to humans that is regulated. For this reason, the choice of dose metric should be 

that which results from the most potent exposure/applied dose. After a dose metric is selected, 

interspecies and intraspecies extrapolations can be applied by adjusting physiological and TK 

parameters (see Section 4.2.4.2.). This might include enzyme activity levels (KM and Vmax), 

relative comparisons of expression levels of xenobiotic metabolizing enzymes, levels of 

cofactors, and physiological parameters (e.g., liver blood flow). Age-related differences in 

7 absorption, distribution, metabolism, and elimination have been reviewed (Besunder et al., 

1988a, 1998b; Clewell et al., 2002b; Clewell et al., 2004) (see Section 4.2.3.1.). Considerations 

include: 

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• What is the human exposure scenario (route, duration, and pattern)? 

• How will chemical-specific factors interplay with the route? (Reactive gases are 

thought to primarily have effects at the portal of entry; thus, life stage differences in 

respiratory rate and tract surface area can be made. Non-reactive gases act more 

systemically; thus, blood: air partition coefficients, cardiac output, and tissue 

partition are important considerations. Additionally, plasma protein binding, 

gastric pH, intestinal pinocytosis, mucocilliary function, skin thickness, and 

irritation, and other parameters will govern several TK factors, and these are likely 

to differ across life stages. 

• Will the distribution differ across life stages and species? (Lipid and water content, 

protein binding, membrane transporters, immaturity of the blood brain barrier, and 

as other parameters will likely alter the volume of distribution and half-life for 

many compounds.) 

• What are the metabolic differences among (and within) species and life stage? What 

does the ontogeny of the xenobiotic metabolizing enzymes involved in the dose 

metric formation and termination predict for the dose metric level and time course? 

(Generally speaking, enzyme levels approach those of adults within the first 6 

months of life. Evidence suggests, however, that drug clearance in children may be 

higher than in adults thereafter. It is important to consider how enzyme ontogeny 

will affect activation or detoxification, as well as how tissue localization and blood 

flow will affect these factors. Additionally, cofactor levels may impact TK; 

glutathione levels, e.g., may differ across life stages.) 

• What is the likely role of maternal and fetal TK factors? 
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03/01/06 44 DRAFT—DO NOT CITE OR QUOTE 

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4.2.3. Analysis in the Range of Observation 

Data for dose-response analysis in the range of observation come in many forms, from 

empirical PODs derived from either a no observable adverse effect level (NOAEL) or a lowest 

observable adverse effect level (LOAEL) to sophisticated models incorporating mechanistic 

data. The nature and amount of data required for each type of dose-response analysis might be 

said to represent a hierarchy, although the more sophisticated dose response models still rely on 

the same animal studies from which a NOAEL or LOAEL can be derived, either as a basis for 

curve fitting mathematical models or a starting point from which to calculate an internal target 

tissue dose using other modeling techniques. Briefly summarized below are some of the doseresponse models available to risk assessors. These models are typically employed in order to 

determine PODs, which are used for extrapolations in dose-response analysis and MOE analysis 

in risk characterization. In Guidelines for Carcinogen Risk Assessment (U.S. EPA 2005b), the 

U.S. EPA has adopted an approach that advocates the use of as much biologically-informed 

dose-response data as possible, and suggests that older “default” approaches be used only in 

instances where little data exists concerning an environmental toxicant of interest. 

Physiologically based toxicokinetic (PBTK) and biologically based dose-response (BBDR) 

models are techniques that provide strong biological foundations for a chemical risk assessment; 

their application in risk assessment is discussed more thoroughly in 

12 

13 

14 

15 

16 

17 

18 Approaches for the 

Application of Physiologically Based Pharmacokinetic Data and Models in Risk Assessment

(U.S. EPA 2005a)

19 

. Furthermore, their use in conjunction with statistical modeling is perhaps the 

most rigorous

20 

21 

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23 

24 

25 

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28 

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30 

 

4

. The following brief descriptions summarize the types of analyses used in risk 

assessment, generally from those based on limited data sets to those requiring very rich data sets 

for dose-response analysis. 

4.2.3.1. Dose-Response Models 

Traditional approaches to dose-response modeling of a toxicant with a nonlinear MOA 

have relied (and continue to rely) heavily on the use of empirical data points for determining 

PODs. Often these are NOAEL and LOAEL values derived from experimental dosing 

conditions in toxicological studies. Two main disadvantages of using these single point estimate 

values is that they do not consider the shape of the dose-response curve, nor do they allow for 

4

 Such an approach was used in a risk assessment for ethylene glycol monobutyl ether (U.S. EPA 1999b), where 

experimental dose conditions were converted to internal dose, followed by benchmark dose analysis. 
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03/01/06 45 DRAFT—DO NOT CITE OR QUOTE 

estimation of risks at any exposure level of interest (Allen et al., 1998). Thus, the use of NOAEL 

and LOAEL values alone represent the bottom tier of dose-response models and are used most 

often when limited data is available concerning the toxicant of interest. 

1 

2 

3 

4 A more sophisticated approach for determining PODs is the use of benchmark dose 

analysis (Crump, 1984)5. This approach attempts to fit statistical models to existing doseresponse data regardless of whether the MOA is linear or nonlinear, but often requires studies 

with more dose groups and a higher number of subjects. For this reason, BMD is usually 

performed when the scientific database for an environmental chemical is relatively large. An 

advantage of the BMD methodology is that statistical models can take into account all of the data 

points in a dose-response study; thus, unlike the NOAEL/LOAEL approach, the BMD is 

influenced by the shape of the dose-response curve 

5 

6 

7 

8 

9 

10 

(Allen et al. 1998). The BMD is defined as 

the dose at which a predetermined change in response incidence (e.g., 5% or 10% change in 

critical effect) occurs; with the 95% lower confidence bound being the BMDL. Because the 

BMDL is a function of the study design, more rigorous studies generally have narrower 

confidence limits 

11 

12 

13 

14 

(Barnes et al., 1995). Importantly, the BMD approach is less sensitive to dose 

spacing, and thus a BMD can be determined in the absence of a NOAEL, as well as for any 

increase in response level (

15 

16 

Barnes et al., 1995; Allen et al., 1998). For further readings on 

choosing studies for BMD analysis, refer to 

17 

18 Benchmark Dose Technical Guidance Document, 

19 External Review Draft (U.S. EPA, 2000a). 

20 One limitation to BMD analysis is that the analysis can only be performed on individual 

studies (Brown & Strickland, 2003). Categorical regression6 analysis, on the other hand, is 

similar to BMD analysis but can be performed on combined studies. In this method, data is 

pooled from different studies (possibly with different endpoints) that are “assigned” to the same 

severity category 

21 

22 

23 

(Brown & Strickland, 2003). An advantage to this approach is that a small 

number of studies (possibly even studies of different duration) can essentially be combined into 

one larger study, and thus can narrow the confidence limits 

24 

25 

(Brown & Strickland, 2003)7. 

Although studies of different duration may be problematic (particularly when dealing with short 

windows of susceptibility), this methodology may be particularly important in a life stage 

26 

27 

28 

 

5

 EPA has developed software for BMD analysis; available from: http://cfpub.epa.gov/ncea/cfm/bmds.cfm

6

 EPA has developed CatReg software, available at: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=18162. 7

 It should be noted that severity categorization may require expert judgment, and thus may be subject to differing 

opinions. 
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03/01/06 46 DRAFT—DO NOT CITE OR QUOTE 

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approach where it is likely that fewer studies will have been performed on the specific life stages 

of interest or critical windows of susceptibility. 

Physiologically based toxicokinetic (PBTK) and biologically based dose-response 

(BBDR) modeling are perhaps the most amenable modeling technique for using a life stage 

approach, as they are designed to mimic true biological processes and model whole organisms. 

Knowledge and understanding of absorption, distribution, excretion, and elimination (ADME) 

are essential for estimating delivered dose. Behavioral, anatomical, and metabolic differences 

during each life stage require modification of available adult models. Several reviews have 

9 described the variation in TK factors between adults and children (Besunder et al., 1988a, 1988b; 

Bruckner, 2000; Clewell et al., 2002a; Hines & McCarver, 2002; McCarver & Hines, 2002). 

Although the use of TK models for internal dose estimates is increasing, more effort is needed in 

developing such models for children’s dosimetric adjustments across life stages and species. 

Some models available in pediatric pharmacology could be appropriately applied for some 

portions of certain risk assessments. For instance, general knowledge of differences between 

adults and children in metabolic clearance of CYP3A-specific pharmaceutical substrates could 

be utilized by incorporating this difference into an adult TK model when the toxicant is thought 

to be metabolized by CYP3A (

10 

11 

12 

13 

14 

15 

16 

Ginsberg et al., 2004a, 2004b). Ginsberg et al. (2002) compiled a 

database of 45 drugs for which TK data are available across life stages; this database can be 

accessed at 

17 

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19 http://www2.clarku.edu/faculty/dhattis. 

20 

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PBTK models can be used to conduct route-to-route extrapolations, duration adjustments, 

interspecies extrapolations, as well as life stage extrapolations. Particularly useful, is the fact 

that these models can mimic any exposure scenario (continuous or otherwise). For instance, if 

children are likely to be exposed to an environmental toxicant for one hour per day for five days 

a week (followed by 48 hours of no exposure), these models can predict the levels of metabolites 

of interest under these conditions. Similarly, numerous small exposure doses from breast milk to 

nursing infants could be modeled to determine steady state levels of a toxicant 

Although PBTK models may be particularly useful in periodic exposure modeling, they 

are not necessarily applicable for extrapolating from short-term exposure studies to longer-term 

predictions because the key events leading to the observed responses are not likely to be 

impervious to the effects of time. Many dose-response relationships may be dependent on 

temporal changes in TD processes due to developmental- and exposure-induced changes; 
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03/01/06 47 DRAFT—DO NOT CITE OR QUOTE 

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examples include cell proliferation rates, DNA repair processes, receptor tolerance and 

desensitization, and age-related changes in physiological parameters. Importantly, many early 

developmental windows are relatively short; thus extrapolation from short-term exposure 

scenarios to longer-term scenarios requires consideration of whether the same windows of 

susceptibility are likely to be operable. 

6 Application and review of PBTK models in risk assessment can be found in (Ginsberg et 

al., 2004b; Pelekis et al., 2001; U.S. EPA 2005a). There are some early life stage PBTK models, 

some of which include infant exposure to chemicals such as dioxin in breast milk (

7 

8 Gentry et al., 

9 2003; Lorber and Phillips, 2002), fetal exposure to ethylene glycol monomethyl ether (Gargas et 

al. 2000), and neonatal exposure to compounds such as lead (O’Flaherty, 1998) and perchlorate 

(

10 

Clewell & Gearhart 2002; Clewell et al., 2003). Several pregnancy and lactation models have 

been reviewed 

11 

12 (Corley et al. 2003). 

13 

14 

15 

BBDR models represent the state of the art in dose-response analysis, where mechanistic 

TD data are modeled in such a way that responses can be predicted, even at low exposure levels. 

Usually, output from a PBTK model serves as the dose input to a BBDR model, relating that 

16 dose to a response outcome (Andersen & Dennison 2001; Ashani & Pistinner 2004; Setzer et al., 

2001). In addition to life stage-specific TK data, the relationship between the internal dose 

metric and response may require life stage-specific TD data. Currently, relatively few BBDR 

models are available due to the inherent complexity of integrating TK and TD data, as well as 

more practical limitations to BBDR model development, such as model transparency, quality 

criteria, and limited shelf-life of some models beyond initial publication 

17 

18 

19 

20 

(DeWoskin et al., 2001). 

It is expected that their use will increase as toxicological studies go beyond more frank effects 

and move toward molecular precursor events (

21 

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Andersen & Dennison, 2001; Faustman et al.,

1999

23 

24 ). 

25 

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27 

In instances where the dose metric of a toxicant of interest is structurally related to 

another compound for which there exists a validated BBDR model, consideration of the 

application of this model to the toxicant being assessed may be warranted8

. As stated in 

Evaluation of BBDR Modeling for Developmental Toxicity: A Workshop Report, “the challenge 

is to define...application of a quantitative BBDR model ...generalizable to other compounds in a 

similar class and perhaps to certain other classes of compounds” 

28 

29 

30 (Lau et al. 2000). For example, 

 

8

 It should be recognized that compounds with common toxicodynamic effects need not be structurally related. 
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03/01/06 48 DRAFT—DO NOT CITE OR QUOTE 

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two chemicals might be hypothesized to affect similar TD processes, yet a BBDR model may 

exist for only one of the chemicals. If a PBTK model is available (or can be developed) for the 

chemical that does not have a corresponding BBDR model, it is conceivable that the existing 

BBDR model might be sufficient for analyzing both chemicals (see Figure 4-8). 

Probabilistic risk assessment has typically been used in exposure assessment. This 

approach, however, is increasingly being applied for dose-response assessment as data become 

available for physiological parameters such as genetic polymorphisms in TK and TD pathways 

(Beck et al., 2001; Pelekis et al., 2003). Readily measurable inputs such as exposure dose and 

duration, intake rate, clearance, and body mass can be expressed as distributions and modeled in 

such a way as to estimate dose for a particular population, over a certain timeframe, or at a 

specific location. Similarly, life stage-specific parameters can be employed in order to estimate 

the variability in dose and response among subpopulations such as infants and children. 

8 

9 

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BBDR model exists for chemical A: {TK

Figure 4-8. Generalized biologically based dose-response (BBDR) model. The top line in this 

figure represents a BBDR model for the dose-response of chemical A, where TKA, TDA, and RA

represent the toxicokinetic, toxicodynamic, and response of interest related to chemical A, 

respectively. In this scenario, the toxicodynamic of chemical B (TDB) are thought to be equivalent 

to those of chemical A (i.e. both have the same mode of action from a toxicodynamic perspective). 

If a physiologically based toxicokinetic (PBTK) model (but not a BBDR model) exists for 

chemical B (TK

16 B

17 

18 

19 BB

20 

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), then the predicted internal target tissue dose of chemical B can be integrated 

into the existing BBDR model for chemical A. 

One limitation applicable to many of the aforementioned dose-response modeling 

approaches, in regards to noncancer endpoints, is that the analyses are based on toxicological 

endpoints as opposed to public health outcomes. Quantitative risk estimation (QRE) is a broadbased method for relating human exposures to non-toxicological endpoints. For example, 

exposure to 1,2-dibromo-3-chloropropane can be linked to increases in infertility rates through 

mathematical modeling (Pease et al., 1991). In this regard it is similar to BMD analysis, but 

whereas risk is typically defined by percent change (e.g. 1 % or 5%) in a biological response 

26 

27 

A→ [TDA = TDB] → RA} 

 ↑

PBTK model exists for chemical B: [TKB] 
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03/01/06 49 DRAFT—DO NOT CITE OR QUOTE 

1 

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4 

(e.g. sperm count), QRE attempts to define risk (e.g. excess infertility cases) for all human 

exposure levels. The advantage is that risk can be defined for any individual based on exposure 

level, as is done for cancer assessments. Other examples of this type of analysis include 

associations between particulate matter and daily mortality and certain measures of morbidity 

(U.S. EPA, 2005d), and associations between acute ozone exposures and respiratory morbidity 

and mortality 

5 

(U.S. EPA, 2005e). An inherent disadvantage to this approach is that acceptable 

levels of risk must be defined, whereas other approaches to non-cancer dose-response modeling 

arguably rely less on value judgment. 

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4.2.4. Extrapolations and Risk Derivation from a Life Stage Approach 

After PODs have been established from various dose-response studies or modeling 

techniques, low dose extrapolation is performed in order to derive measures of risk. Again, this 

may be done for assessments of narrow or broad scope, and will have important regulatory 

implications (Figure 4-7). To this end, various adjustments are made in order to extrapolate to 

the exposure scenarios and life stages of interest. As described below, these adjustments may 

involve sophisticated approaches or default approaches that have developed over time. Despite 

the term default, many of these approaches have been informed by and are supported by 

empirical evidence. For example, empirical analysis supports the use of body weight scaling 

(see below) to adjust for pharmacokinetic differences across species. Additionally, the use of 

more sophisticated techniques does not necessarily result in refinements of final risk values. For 

instance, a recent assessment of xylenes resulted in nearly identical RfC values using either 

default approaches starting from a NOAEL or sophisticated PBTK modeling (U.S. EPA, 2003f). 

Despite the fact that this may be a possible outcome, the use of sophisticated techniques, MOA 

information, and life stage analyses certainly improve the confidence that risk values are health 

protective. 

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4.2.4.1. Duration and Route Adjustments 

Animal exposure studies, almost always being discontinuous, require continuous dose 

adjustment. Although such adjustments are conservative from a risk evaluation standpoint (i.e.,

they shift the dose-response curve leftward), mathematical adjustments do not necessarily 

maintain the dose-response relationship (i.e., AUC) that likely reflects the MOA by which a 
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03/01/06 50 DRAFT—DO NOT CITE OR QUOTE 

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response is generated. An alternative to continuous dose adjustment is to use PBTK models that 

can determine (in silico) an applied dose (continuous or otherwise) that results in the same AUC 

or Cmax as that was likely to have been generated in the test animal under the original laboratory 

study conditions. This may require parameterization with life stage- and species-specific data. 

As stated in section 4.2.3.1, developmental windows of susceptibility are relatively short, thus 

the changing underlying biology during development suggests that Cmax may be a more relevant 

dose metric in young children than AUC. 

For route-to-route extrapolation, default equivalent dose adjustments can be used. 

Standard mg/kg/day adjustments assume similar TK and TD processes; such assumptions are 

tenuous because different cell types, enzymes, and proliferation rates exist across portals of 

entry. PBTK models can be used to predict target dose across routes by incorporation of routespecific TK factors. An important limitation, however, is that route extrapolations are not useful 

in instances where the critical effects are portal of entry specific. For more on route and duration 

14 adjustments, see Approaches for the Application of Physiologically Based Pharmacokinetic Data 

15 and Models in Risk Assessment (U.S. EPA, 2005a) and A Review of the Reference Dose and 

16 Reference Concentration Processes (U.S. EPA, 2002b). 

17 

18 

19 

4.2.4.2. Interspecies and Intraspecies Adjustments 

The EPA RfC process describes the interspecies adjustment from animals to human 

equivalent concentration (HEC) via dosimetric adjustment factors (DAFs), (U.S. EPA 2002b). 

For oral exposures, default interspecies extrapolation based on body weight scaling, either body 

weight (BW

20 

21 

22 

23 

1

) or body weight to the 3⁄4 power (BW3⁄4), have been employed. In particular, BW3⁄4

scaling is typically thought to account for TK differences among species and therefore often 

reduces the interspecies UF from 10 to 3 (U.S. EPA, 2002b). Recent harmonization efforts at 

EPA advocate the adoption of BW

24 

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31 

3⁄4 scaling for RfD derivation in instances where there is 

limited data with which to perform an assessment. This has been proposed in an effort to 

harmonize oral RfD methodology with RfC methodology with the use of DAFs, as well as with 

oral cancer assessments with the use of BW3⁄4 scaling. 

For inhalation exposures, DAFs are applied on the basis of physicochemical, anatomical, 

and physiological parameters. These parameters include such factors as species-to-species ratios 

of surface area:ventilation rate, blood:gas partition coefficients, and regional deposition dose 
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03/01/06 51 DRAFT—DO NOT CITE OR QUOTE 

1 ratios for particulate matter. In the case of children, it is currently recommended that HECs and 

human equivalent doses be determined experimentally and theoretically (U.S. EPA, 2002b). In 

the absence of DAFs, simple ventilation rate adjustments can be made for HECs. Finally, it is 

important to note that DAFs are thought to be most appropriately applied for chronic exposures, 

where the dose metric is likely best represented by AUC; discussion of adjustments for acute 

exposures can be found elsewhere 

2 

3 

4 

5 

6 (U.S. EPA 2002b). Consider: 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 

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20 

• Should the same interspecies factors be applied in deriving HECs and human 

equivalent doses for all life stages? The answer here is equivocal, because more 

empirical data are needed. A priori, rates of deposition, mass transfer, flow limited 

diffusion, and partition coefficients are likely to be affected by life stage-specific 

differences in anatomy, skin composition, lipid/water ratios, and volumes, and 

protein binding can affect diffusion of compounds (e.g., plasma protein binding 

affect on the glomerular filtration rate, GFR). Although age-specific data are 

needed, the problem is exacerbated by the fact that these values are a function of 

both species- and chemical-specific properties, and thus may require both 

chemical- and life stage-specific data. 

In addition to interspecies adjustments, BW3⁄4 scaling may also be useful for intraspecies 

adult-child adjustments. Data from pharmaceutics indicate that TK processes (e.g. chemical half 

life) in children may also scale to BW3⁄4 21 , particularly in children over 2 months of age (Ginsberg 

et al., 2002, 2004a, 2004b; Hattis et al., 2004). Under two months of age, however, the 

immaturity of such processes likely precludes scalability. 

22 

23 

24 

25 

26 

27 

When more data are available for carrying out an assessment, life stage considerations 

can be included in two general ways, each with its own advantages and disadvantages. 

Essentially, these involve either intraspecies adjustments or interspecies extrapolation. 

Adjustments across human life stages from adult to earlier developmental stages requires 

exposure, TK, and TD considerations (Barton, 2005), and this process can be qualitative or 

quantitative 

28 

(Ginsberg et al., 2002). Qualitatively, adult/child ratios for TK processes 

representing various metabolic pathways can be used to predict the relative difference in TK 

processes between children and adults for a toxicant that is metabolized by the same pathway. 

For example, the mean half-lives of several pharmaceuticals metabolized by CYP3A can be 

compared in adults and children. This ratio could then be used to adjust the intraspecies UF for 

an environmental toxicant that is known to be metabolized by CYP3A. Quantitatively, PBTK 

models developed for adult humans (if available) could be parameterized in order to predict the 

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35 
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03/01/06 52 DRAFT—DO NOT CITE OR QUOTE 

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2 

dose metric in children. In the former case, such TK changes might increase the intraspecies UF 

with respect to TK consideration; it has been shown, for example, that such differences between 

adults and young infants can exceed 3.2-fold (Hattis et al., 2004). In the latter case, the 

intraspecies UF may be reduced due to the improved characterization of TK. The advantage to 

this approach is that assessors may have greater confidence in extrapolating within the humans 

species; on the other hand, this approach requires that the underlying toxic response and MOA 

are concordant across life stages. This assumption, if not well-supported by data, may add a 

large degree of uncertainty to the dose-response analysis. 

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4 

5 

6 

7 

8 

9 More often, however, the data needed for life stage extrapolation will be available only in 

animals and thus will often require both qualitative and quantitative adjustments (Barton, 2005). 

Qualitative adjustments include determining the developmental stages in test animals and 

humans that exhibit the same window of susceptibility related to the critical outcome of interest. 

This may require both empirical evidence and expert judgment. Several articles have examined 

the relative development of organ systems across species (reviewed in 

10 

11 

12 

13 

14 Hurtt & Sandler, 2003a, 

2003b; Selevan et al., 2000). Quantitative adjustments are then needed to account for the TK 

differences that exist across species at the equivalent (with respect to the window of 

susceptibility) life stages. For instance, rodents are born at an overall developmental stage 

roughly equivalent to end of the second human trimester. Thus if equivalent windows of 

susceptibility exist at these two different life stages across species, then altogether different 

PBTK models and TK data would be needed to calculate the equivalent internal dose, i.e., a 

lactational model for the rodent and a pregnancy model for the human. 

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An advantage of this approach is that the assessor starts with age-relevant developmental 

effects (e.g., two-generation developmental studies) as opposed to assuming concordance of 

effects across life stages. This will likely have the effect of reducing the interspecies UF due to 

TK adjustments, as well as due to a general increase in confidence that TD differences (if they 

exist) have been minimized. One caveat, however, is that human data (from controlled 

exposures or epidemiological studies) with which to test the predictive capability of the model 

will often be nonexistent. Additionally, if extrapolation requires the use of different model 

structures (e.g., perinatal exposure in rats and fetal exposure in humans), then each model, with 

its own inherent uncertainties, may add to the overall uncertainty in the extrapolation. 
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Because the majority of data concerning a chemical will pertain to nonhuman species, TK 

and TD data are crucial elements for life stage-specific dose-response characterization. It is for 

this reason that PBTK and BBDR models have been emphasized for dose-response modeling 

under the life stages approach. There are several examples where existing adult models have 

been adapted to early life stages. Gentry et al. (2003) incorporated new tissue compartments and 

parameters into a previously published PBTK model for modeling isopropanol and acetone 

metabolism in adult humans and rats 

5 

6 

(Clewell et al., 2001). These additions include 

compartments for the uterus, mammary tissue, placenta, and fetus 

7 

(Gentry et al., 2002), some of 

which are modeled to account for growth throughout gestation. Physiological parameter values 

were derived from numerous previous publications

8 

9 

10 9

; this model was used to derive RfD and RfC 

values based on developmental outcomes. Pelekis et al. (2003) demonstrated the use of a life 

stage approach by applying probabilistic analysis to a previously published PBTK model. 

Briefly, this study modeled daily exposure of individuals to dichloromethane from birth to 70 

years of age using age-specific physiological parameters, partition coefficients, and CYP2E1 

age-specific metabolic data. This model does not, however, take into account age-related 

differences in exposure, nor are TD factors addressed. Life stage data have also been used in 

BBDR modeling. For instance, a BBDR model has been developed for relating 5-fluorouracil 

exposure at gestational day 14 to birth defects in rats. This models employs a PBTK component 

that describes the formation of the metabolite, relates the metabolite levels to 

deoxyribonucleotide pool perturbation, and relates this perturbation to low fetal birth weight 

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21 (Shuey et al., 1994) and fetal malformation (Lau et al., 2001; Setzer et al., 2001). 

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4.2.4.3. Low-dose Extrapolation 

Caution should be used when using the shape of the dose-response curve for deciding 

upon the appropriate means of low-dose extrapolation. Although human data, particularly from 

children (if available), may be extremely important for establishing a POD for risk derivation in 

a life stage context, it should be realized that epidemiological data often exhibit linear doseresponse relationships. Lutz et al. (2005) have provided evidence that this linearity may, in part, 

be a result of interindividual genetic and life style differences, as well as other issues related to 

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9

 Currently, several efforts are underway to develop life stage physiological parameters databases that will provide a 

comprehensive and authoritative resource for use in risk assessment. 
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epidemiological studies such as difficulties in dose reconstruction. Conversely, Lutz et al. (2005)

also demonstrated that animal bioassay studies that suggest a threshold effect may also be 

misleading. For instance, in silico simulations of dose-response relationships can result in 

threshold (or J-shaped) relationships by chance; thus animal bioassays, often unrepeated, may 

suggest a relationship that does not exist in reality. 

1 

2 

3 

4 

Conolly et al. (2005), also using in silico

methods, demonstrated that modeling of adaptive responses to DNA damage can result in both 

linear and threshold dose-response relationships depending upon model assumptions. Taken 

together, these studies highlight the importance of a strong understanding of MOA for choosing 

the most appropriate low-dose extrapolation approach. The 

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6 

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9 Guidelines for Carcinogen Risk 

Assessment (U.S. EPA, 2005b) advocate a MOA approach to low-dose extrapolation of cancer 

endpoints, where low-dose linear extrapolation is performed when a carcinogen is thought to act 

through a linear MOA (e.g. mutagenesis) or when the MOA for a carcinogen is not understood. 

This is based, in part, on the concept of additivity 

10 

11 

12 

(Crump et al., 1976), where any amount of a 

carcinogen adds to the underlying biological processes that are responsible for the background 

incidence of a particular cancer. Nonlinear extrapolation for cancer endpoints is used when the 

MOA can be demonstrated to result from a threshold (i.e. nonlinear) MOA. Nonlinear 

extrapolation approaches are also used for noncancer endpoints, although methods for risk based 

approaches to noncancer endpoints, and their relevance to cost-benefit analysis, have been 

proposed (

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Gaylor & Kodell, 2002; Clewell & Crump, 2005).10 In addition, there may also be 

biological support for low-dose linear extrapolation for noncancer endpoints. For example, 1,2-

dibromo-3-chloropropane is thought to reduce sperm count by interaction with DNA; thus, as is 

employed for mutagenic carcinogens, there is scientific rationale for using low-dose linear 

extrapolation for compounds that cause noncancer effects through interaction with DNA, and 

potentially other MOAs as well. 

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4.2.4.4. Model Uncertainty, Sensitivity, and Variability 

Models are approximations of biological processes and therefore have inherent shortfalls. 

Model uncertainty comprises that which is unknown about how well a model reflects the 

underlying biology11. Uncertainty analysis can have both quantitative and qualitative 

10 Some program offices do set standards using risk based approaches for noncancer endpoints. 

11 See the draft Approaches for the Application of Physiologically Based Pharmacokinetic Models and Supporting 

Data in Risk Assessment (U.S. EPA, 2005a) for an in-depth treatment of PBTK model evaluation. 
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components. Quantitative elements include model structure, choice of dose metric, and 

extrapolation procedures. Often these elements can be altered in order to compare model results. 

Results from this type of analysis together with reasons supporting the various choices used in 

each model can be expressed as subjective probabilities that each model is correct. Qualitative 

elements of uncertainty analysis include such things as choice of animal test species or the 

applicability of animal species to the human life stage of interest (see discussion in section 

4.2.4.2). These particular efforts enhance the scientific underpinnings of the dose-response 

analysis and are explicitly carried forward in the dose-response narrative (Section 4.2.5) through 

to the risk characterization (Section 5.1.2). 

Sensitivity analysis allows risk assessors to examine which parameters in a model are 

most critical to the final outcome. This analysis is a key evaluation technique for PBTK models. 

This analysis can identify the key parameters that should be further examined for accuracy, 

either through available data or estimation. In addition, selection of sensitive parameters could 

help in identifying more susceptible life stages. For instance, model sensitivity to ventilation rate 

provides an important starting point for addressing life stage differences. 

Variability analyses evaluate the range of values for a parameter in a population. This is 

particularly useful when sensitivity analysis has identified a key parameter as having an 

important impact on model output. When an outcome is predicted to be sensitive to certain 

parameters, probabilistic approaches (e.g. Monte Carlo simulation) can be incorporated into 

models (U.S. EPA, 2005a). This type of analysis, for instance, allows assessors to predict upper 

and lower bounds on a dose metric level in a test species; thus multiple calculations of the 

relevant exposure concentration for humans could be calculated and perhaps used for subsequent 

risk derivation. 

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It is particularly important that model evaluation not be a final step in the risk assessment 

process. Sensitive parameters provide red flags that should be examined carefully for variability 

of these parameters within the population. Alternatively, the sensitivity might suggest the need 

for careful examination and consideration of susceptible life stages. 

4.2.4.5. Risk Value Derivation and Application of Uncertainty Factors (Including AgeDependent Adjustment Factors) 

A detailed outline for derivation of risk values is beyond the scope of this framework. 

Risk assessors should consult EPA guidelines for procedures and policies for deriving risk values 
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03/01/06 56 DRAFT—DO NOT CITE OR QUOTE 

1 and applying UFs. Current practices for RfC and RfD derivation and the application of UFs are 

2 outlined in A Review of the Reference Dose and Reference Concentration Process (U.S. EPA, 

2002b). As stated in Section 4.2.4.2, life stage extrapolations for risk derivation, depending on 

the initial data from which the extrapolation is based, will affect the magnitude of the UFs 

applied in the final risk value derivation. New guidance on CSF derivation from early life 

exposure to environmental agents can be found in the 

3 

4 

5 

6 Supplemental Guidance for Assessing 

Cancer Susceptibility from Early Life Exposure to Carcinogens (U.S. EPA, 2005c). In brief, the 

new guidance states that for toxicants acting through a mutagenic MOA, where data concerning 

early life susceptibility is lacking, early life susceptibility should be assumed and the following 

age-dependent adjustment factors (ADAFs) should be applied to the CSF: 

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• 10-fold for exposure occurring before 2 years of age 

• 3-fold for exposure occurring between the ages of 2 to 16 

• No adjustment after 16 years of age 

No such adjustments are advocated for toxicants with either an unknown or non-mutagenic 

MOA. These adjustments are based, in part, to analyses indicating an increased incidence of 

tumor formation from early life exposure as compared to adult exposure. For an explanation of 

19 the choice of these values and age groupings see Supplemental Guidance for Assessing Cancer 

20 Susceptibility from Early Life Exposure to Carcinogens (U.S. EPA, 2005c). 

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Historically, life stage-related uncertainties have been folded into the database UF when 

the MOA is nonlinear. It must be reiterated that life stage-specific data gaps do not necessarily 

imply a greater database UF; rather, the method should help focus attention on the most critical 

data gaps deserving of additional uncertainty weighting. Indeed, the rationale for using the life 

stage approach is to better characterize individual risk and thus decrease uncertainty in risk 

assessment. 

4.2.5. Life Stage-Specific Dose-Response Characterization Narrative 

Following derivation of final risk values, a dose-response characterization summarizes 

the dose response information to be used in conjunction with the exposure information for a full 

characterization of risk. This characterization is a narrative description that provides a summary 

of recommended estimates, data supporting those estimates, modeling approaches, a POD 

narrative, key default assumptions, and identification of susceptible life stages or sensitive 
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03/01/06 57 DRAFT—DO NOT CITE OR QUOTE 

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subpopulations and quantification of their susceptibility. A discussion of the strengths and 

limitations of the dose-response assessment should be presented, highlighting significant issues 

in developing risk values, including alternative approaches considered equally plausible, and 

how these issues were resolved. It is important that all estimates be accompanied by the 

descriptors used in the WOE narrative. For instance, a toxicant may be described as “likely to be 

carcinogenic to humans” when exposed by “oral route” (U.S. EPA, 2005b). In this regard, risk 

managers will be able to put each estimate into context. 

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4.3. EXPOSURE ASSESSMENT 

4.3.1. Introduction 

The following section presents a comprehensive approach for characterizing children’s 

exposures to environmental contaminants. The outline for assessing children’s exposure follows 

the steps presented in Figure 4-9. The process begins with scoping of the exposure assessment 

within the context of the broader risk assessment problem formulation. This step refines the 

planning and scoping described in section 3.1 by adding the exposure components. The 

exposure components include identifying the sources of the chemicals or agents of concern, the 

relevant exposure pathways (including media and route) by which children may be exposed, and 

the exposure scenarios specific to children. The preliminary evaluation of sources, pathways, 

and scenarios allows the assessor to refine the goals, the breadth, and the focus of the overall risk 

assessment. For example, the assessment questions may change on the basis of the exposure 

pathways identified during the scoping phase of the exposure assessment. Depending on the risk 

assessment objectives, it may be important to involve stakeholders at this point in the assessment 

to ensure that their concerns are addressed. The conceptual model is then enhanced by adding 

more details describing how relevant exposures may take place. The conceptual model is used to 

identify available exposure information including chemical properties, environmental fate and 

transport mechanisms, media concentrations, and population characteristics and behaviors. The 

available exposure information is used to conduct a life stage-specific exposure analysis. 

Generally, a tiered approach is used beginning with a screening-level assessment and then, 

refining the assessment if necessary to provide more detail for potentially important scenarios or 

potentially vulnerable age groups. The last step in the exposure assessment process is the life 
Life Stage-Specific Exposure Analysis

(See Section 4.3.5.)

Select Approach:

• Screening Assessment

• Refined Assessment

Scoping of Exposure Assessment 

(See Section 4.3.2.)

Consider:

• Sources

• Pathways (Media and Route)

• Scenarios

Refinement of 

Conceptual Model

(See Section 4.3.3)

Review Available Exposure Data 

(See Section 4.3.4.) 

Consider:

• Chemical Properties, Fate, Transport

• Exposure Media Concentrations

• Life Stage-Specific Population Characteristics

• Life Stage-Specific Activity Data

Life Stage-Specific Exposure Characterization

(See Section 4.3.6.)

Consider:

• Variability analyses

• Uncertainty analyses

• Sensitivity analyses

Problem

Formulation

(See Section 3.)

Hazard

Characterization

(See Section 4.1.)

Life StageSpecific Risk

Characterization

(See Section 5.)

Dose-Response

Assessment

(See Section 4.2.)

Life Stage-Specific Exposure Analysis

(See Section 4.3.5.)

Select Approach:

• Screening Assessment

• Refined Assessment

Scoping of Exposure Assessment 

(See Section 4.3.2.)

Consider:

• Sources

• Pathways (Media and Route)

• Scenarios

Refinement of 

Conceptual Model

(See Section 4.3.3)

Review Available Exposure Data 

(See Section 4.3.4.) 

Consider:

• Chemical Properties, Fate, Transport

• Exposure Media Concentrations

• Life Stage-Specific Population Characteristics

• Life Stage-Specific Activity Data

Life Stage-Specific Exposure Characterization

(See Section 4.3.6.)

Consider:

• Variability analyses

• Uncertainty analyses

• Sensitivity analyses

Problem

Formulation

(See Section 3.)

Hazard

Characterization

(See Section 4.1.)

Life StageSpecific Risk

Characterization

(See Section 5.)

Life StageSpecific Risk

Characterization

(See Section 5.)

Dose-Response

Assessment

(See Section 4.2.)

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Figure 4-9. Flow diagram for life stage-specific exposure assessment. This figure illustrates 

the flow of information and analysis that make up exposure assessment. The process begins with 

a scoping phase to identify the sources, pathways, media, and scenarios that are more relevant to 

children’s exposures to the particular environmental contaminant, taking into consideration the 

questions identified in the problem formulation. The scope assists the assessor in the development 

of a conceptual model that describes how the exposure takes place, with consideration of life 

stages. The conceptual model is followed by the review of the available exposure data for the life 

stages of interest. Iteration with hazard and dose-response assessments (illustrated by dashed 

arrows) can occur throughout this process to ensure that critical windows of exposure are 

considered. Exposure is then estimated using a tiered approach. This tiered approach begins with 

a screening-level assessment followed by a more refined level of analysis if necessary. Finally, 

the life stage-specific exposure is characterized by discussing the variability and uncertainty in the 

results. Key sources of variability and uncertainty can be assessed using sensitivity analysis. As 

illustrated by the solid arrows, hazard characterization, dose-response assessment, and exposure 

assessment contribute to the risk characterization. 
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03/01/06 59 DRAFT—DO NOT CITE OR QUOTE 

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stage-specific exposure characterization where the results, analyses, and conclusions are 

summarized. 

Each of these steps is coordinated with the hazard and dose-response characterization. 

For each step in the exposure assessment process discussed below, a series of guiding questions 

is presented to ensure that all relevant environmental exposures are included in the qualitative 

and quantitative evaluation of risk to children. The exposure information described below is 

used to develop estimates of dose. The estimates of dose are later integrated with the doseresponse assessment to develop estimates of likelihood of adverse effects in children who are 

potentially at risk. The primary conclusions about the exposure assessment include a discussion 

about the variability and uncertainty in the dose estimates. This discussion feeds into the risk 

characterization, where the results from hazard, dose, and exposure are integrated and confidence 

about the conclusions is discussed. 

4.3.2. Scoping of Exposure Assessment 

4.3.2.1. Sources 

Much of the information essential for characterizing sources will be similar for any risk 

assessment. The exposure assessor should place particular emphasis on identifying sources in 

the places where children spend time, which may change by developmental stage. For example, 

sources may be identified in: (1) residence and workplace for pregnant and lactating women; (2)

residence, daycare and outdoor play areas for infants and toddlers; (3) residence, school, and 

locations of after-school activities for school-age children; and (4) residence, school, and 

locations of after-school activities and workplace for adolescents. 

• Are there any chemical or agents that are of special concern for children? 

• What are the chemicals or agents of concern? 

4.3.2.2. Pathways 

For a given source, exposure media and exposure routes can define the pathways. 

Exposure media include air, water, soil/dust/sediments, food, and objects/surfaces; exposure 

routes include inhalation, ingestion, dermal absorption, and indirect ingestion (non-dietary and 

31 indirect dietary routes) (U.S. EPA, 2002a, 2003a.). The result of this evaluation would be a table 
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03/01/06 60 DRAFT—DO NOT CITE OR QUOTE 

1 in which potential exposure routes are identified for each exposure medium (direct and indirect) 

2 (Hubal et al., 2000).

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Exposure media may change with life stage. For example, the fetus will be exposed to 

cord blood and amniotic fluid, the infant to breast milk, the teething child to many objects (both 

intended and unintended) for mouthing, the school-age child to pesticides used in the classroom, 

and the adolescent to vocational or recreational hazards. 

• What are all the potential exposure media? 

• What are all the potential exposure routes? 

• What are the potential exposure pathways in the conceptual model? What are the 

specific pathways that may be of concern for children? 

• How are the chemicals or agents getting from a source to the receptor child? 

4.3.2.3. Scenarios 

For any given pathway, a set of associated exposure scenarios describes how an exposure 

takes place. This information is used to estimate distribution of exposure by any given pathway. 

17 An exposure scenario is defined by the combination of the following details (adapted from Hubal 

18 et al., 2000): 

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• What are the relevant sources of exposure? 

• What are the potentially exposed populations (e.g., age or developmental stage)? 

• What is the relevant time frame of exposure (e.g., acute, short term, chronic, 

intermittent)? 

• What are the potential locations of exposure (e.g., residence, school, outdoors, 

indoors)?

• What are the potential activities (e.g., mouthing, playing soccer, mowing lawns) 

that may lead to exposure?

Potential exposure scenarios should be identified at this point on the conceptual basis of 

the exposure model as well as the problem formulation for the life stage risk assessment. Once 

available data are evaluated, additional scenarios may be added. 
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03/01/06 61 DRAFT—DO NOT CITE OR QUOTE 

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4.3.3. Refinement of the Conceptual Model 

The exposure assessment component of the conceptual model for children’s risks 

described in Section 3.1 would need to consider important life stages. Within each life stage 

there may be a series of developmental periods for which exposure would need to be 

characterized. These periods may be defined on the basis of exposures that can affect 

development (e.g., parental preconception exposures, U.S. EPA, 1991,1996), other potential 

windows of susceptibility identified through the hazard characterization (e.g., those during 

prenatal development), or windows of potentially high exposure due to age-specific behaviors 

and physiology (e.g., crawling, teething). Several important life stages would need to be 

considered in exposure assessments for children (Figure 4-10): 

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17 

• Are there possible parental preconception exposures? 

• Might there be exposure during the pregnancy that affects embryonic/fetal stages? 

• Are there possible exposures during infancy and early childhood? 

• Are there possible exposures during older childhood and adolescence? 

Typically, the conceptual model will consider human exposure in the context of the 

source-to-effects paradigm (U.S. EPA, 2003c, Figure 1-3). When formulating an exposure 

assessment, it is useful to qualitatively evaluate this model from the “effects” back to the 

“source.” In this way, potentially important time periods of exposure, exposure pathways, and 

vulnerable subpopulations can be identified. 

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However, as the risk assessment becomes more complex, some limitations in the sourceto-effect model become apparent. Exposure assessments using a source-to-effects model are 

based on the characteristics of the specific source of the exposure (e.g., geographical location, 

release rate, point source) and not the characteristics of the population being exposed. As a 

result, only populations with exposure to this specific source are included in the model. Yet, 

exposure may result from multiple independent sources, all of which could be used to generate 

information on total exposure to a chemical or mixture of chemicals. In this case, a personoriented exposure assessment better characterizes the person or population of interest and the 

applicable sources (Figure 3-2). 
Prenatal:

All exposures to the fetus occur 

transplacentally or via physical 

factors. The mother’s exposure to 

environmental media can be a 

significant source of exposure for 

environmental media for the fetus.

Physical

Factors

Infant/Young Child:

Exposures for the infant and 

young adult can occur through all 

environmental media. When 

breastfed, the mother’s exposure 

to environmental media can be an 

additional source of exposure to 

the infant.

Older Child/Adolescent:

Exposures to the child and 

adolescent can occur through all 

environmental media. The 

mother’s exposure is no longer a 

factor for the child.

Physical

Factors

Older Child/

Adolescent

Other

Inhalation,

Ingestion,

Dermal

Ingestion, 

Dermal

Ingestion,

Inhalation,

Dermal

Inhalation

Mother

Other Diet

Air Water

Diet

Water

Air

Physical

Factors

Fetus

Other

Air

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03/01/06 62 DRAFT—DO NOT CITE OR QUOTE 

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2 

3 

4 

5 

6 

7 

Figure 4-10. Exposure routes during developmental life stages. These three figures show the 

different routes of exposure by life stage for children. The solid lines in the figure represent 

relevant exposure, while dotted lines represent exposures that are not relevant to the specific lifestage. During gestation, the majority of exposures (except for physical factors) occur 

transplacentally through exposure to the mother. After birth, exposures may either be directly to 

the child, with an additional route from the mother for those agents that may be present in human 

milk. 

Transplacental

Inhalation,

Ingestion,

Dermal

Ingestion, 

Dermal

Ingestion,

Inhalation,

Dermal

Inhalation

Mother

Other Diet

Air Water

Water

Physical

Factors

Diet

Physical

Factors

Infant/

Young Child

Other

Air

Breas

m

t

ilk

Inhalation,

Ingestion,

Dermal

Ingestion, 

Dermal

Ingestion,

Inhalation,

Dermal

Inhalation

Mother

Other Diet

Air Water

Water

Physical

Factors

Diet
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03/01/06 63 DRAFT—DO NOT CITE OR QUOTE 

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Since this approach puts children in the center as the population of interest, it is 

particularly useful in focusing the assessment to address the following issues: 

• What child-specific questions is the assessment trying to answer? 

• How are parents and/or children being exposed, from the source to the absorbed 

dose for all pathways of exposure? 

4.3.4. Review of the Available Exposure Data 

 Exposure data are used to estimate distributions of exposure in the exposed population. 

In children especially, different factors might affect the child’s dose. Some questions to get at 

these issues include: 

• What types of exposure data are available for infants and children (direct or indirect 

measurements of exposure)? 

• Are children’s activity data available? 

• Are there biomonitoring data that demonstrate exposure potential and that can be 

used to estimate an individual’s exposure level? 

• Are data available for other children’s exposure factors (e.g., contact rates for the 

individual with exposure media, contaminant transfer efficiency from the 

contaminated medium to the individual)? 

• Do children’s physiological parameters influence exposure to the specific agent 

(e.g., body weight, uptake rates – inhalation, dermal absorption, gastrointestinal 

23 absorption)? If so, are there data available (Hattis, 2004)? 

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4.3.4.1. Chemical Properties, Fate, and Transport 

 Once a chemical is released into the environment, it can change chemically or be 

transported from one place to another. Scientists and engineers can predict the environmental 

movement of a chemical by its chemical properties, (e.g., volatilization rate, water solubility, 

soil/water partitioning coefficients). In addition, it is important to know the conditions of the 

environment that may affect the chemical’s fate and transport. These conditions include for 
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example: soil characteristics, amount of rainfall, wind direction, and presence of water bodies. 

Some questions to consider include: 

• What are the release rates? What is known about the manufacturing processes that 

may lead to information on releases? 

• What are the physical and chemical properties of the chemicals or agents? What is 

known about their fate and transport? 

• What are the environmental conditions (e.g., wind direction, rainfall, etc.) that may 

affect the fate and transport of the chemical(s)?

• Where in the environment can the child come into contact with the chemical? In 

what quantities? If it is a consumer product, how is it used by children?

4.3.4.2. Media Concentrations 

 Media concentrations refers to the amount of chemical present in an environmental (e.g., 

soil, water, air, food) or biological medium (e.g., blood, hair, urine, breath). It is critical to give 

special considerations for the measurement techniques at the physical locations where the child 

spends his/her time (e.g., home, school, daycare), as well as the child’s characteristics and 

behaviors. For example, the breathing zone of a child is closer to the floor than the breathing 

zone of an adult, and concentrations of chemicals that are heavier than air may be higher in areas 

closer to the ground. Important questions to consider include: 

• Are environmental measurements available (e.g., contaminant concentrations in the 

exposure media in which the child spends time)? 

• If monitoring data are not available, are there models that can be used to predict the 

concentration at the exposure point? 

• Are biomonitoring data available? (These data are useful for quantifying exposures 

if the relationship between the substance found in the body and the amount of 

substance the child was in contact with can be established.)

• What are the concentrations of the chemicals that will be contacted by the child 

during an exposure period? 

• How are the concentrations changing over time? 
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4.3.4.3. Life Stage-Specific Population Characteristics 

For children, behavior varies by developmental stage, and this may have a significant impact on 

exposure. Children should be classified and exposure assessed for each age grouping (age bin) 

to characterize all relevant scenarios for children’s risk (i.e., to identify highly exposed 

5 populations). Currently, EPA’s Draft Guidance on Selecting the Appropriate Age Groups for 

Assessing Childhood Exposures to Environmental Contaminants (U.S. EPA, 2003b) should be 

used as a starting point for identifying and selecting age bins for analysis (see Table 4-1). This 

guidance provides a detailed discussion of how these age groups were developed and how they 

should be implemented in an assessment. In brief, the recommended age groups are based on the 

current understanding of differences in behavior and physiology that may impact exposures in 

children. 

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Exposure factors and resulting effects during developmental stages may be a function of 

additional individual and population characteristics. These factors may be characteristics of the 

communities in which children live and include, for example, SES, family size, ethnicity, 

cultural setting, geographical location, and seasonal considerations. Other factors specific to the 

individual child include genetic susceptibility, nutritional status, and health status. Mechanisms 

of vulnerabilities associated with individual and community characteristics include differences in 

susceptibility, differential exposure, differential preparedness, and differential ability to recover. 

These mechanisms are defined and discussed in the Framework for Cumulative Risk Assessment

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Section 3.3.1.5.3, pp. 60–61). 

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 The following questions could be considered in order to characterize life stage-specific 

populations: 

• What groups are exposed (e.g., general population, highly exposed groups, highly 

susceptible groups, specific life stages)? 

• What are the adverse health effects of importance to the population of interest? 

How do these inform the identification of exposures of greatest importance for the 

observed outcomes? 
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Table 4-1. Developmental life stages and age groups for exposure 

assessments 

Life Stages Age Groupsa

Preconception reproductive age adult

Prenatal conception to birth

birth to <1 month

1 to <3 months

3 to <6 months

Infant

6 to <12 months

1 to <2 years

2 to <3 years

3 to <6 years

Child

6 to <11 years

11 to <16 years

16 to <18 years Adolescent

18 to <21 years b

Life Stages Age Groupsa

Preconception reproductive age adult

Prenatal conception to birth

birth to <1 month

1 to <3 months

3 to <6 months

Infant

6 to <12 months

1 to <2 years

2 to <3 years

3 to <6 years

Child

6 to <11 years

11 to <16 years

16 to <18 years Adolescent

18 to <21 years b

a The age groupings from birth to adulthood are from U.S. EPA, 2003b. b

These age groupings were arrived at by the behavior subgroup of the Technical Workshop 

(U.S. EPA, 2000b) considering key factors or “major domains of behavioral development” for 

each route of exposure these are to be considered on a case by case basis. 

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• Are there any highly exposed age groups? 

• Are there any community factors that may put a subgroup of children at higher risk 

(e.g., ethnic, cultural, racial, or socioeconomic groups)? 

• Are there any individual characteristics that may put an individual child at higher 

risk (e.g., health status, nutritional status, genetic susceptibility)? 

• What are the child-specific exposure factors necessary to characterize the exposure 

scenarios? 

• What are the ranges or distributions of exposure factors? 

Although the focus of this section is the examination of vulnerability associated with 

differential exposure due to life stage, it is recognized that it is impossible to completely separate 
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consideration of vulnerability due to life stage from consideration of vulnerability due to other 

key individual and community characteristics. EPA is examining the full range of issues related 

to characterizing risks to children through a variety of initiatives, including development of 

Framework for Cumulative Risk Assessment (U.S. EPA, 2003a). As EPA develops further 

guidance for cumulative risk assessment, the full range of vulnerabilities will be considered more 

consistently in both hazard characterization and exposure assessment. 

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4.3.4.4. Life Stage-Specific Activity Data 

It is important to characterize activities and behaviors that result in significant exposures 

(e.g., breastfeeding, mouthing, sports, after-school employment) for each life stage (associated 

with age bins and with other important characteristics of the group). The most current version of 

Child-Specific Exposure Factor Handbook (U.S. EPA, 2002a) could be the starting point for 

identifying these values. Age-specific activity data are also available from the Consolidated 

Human Activity Database (CHAD) available online at 

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• What activities of the parent or child may result in exposure? 

• What developmental stage-specific behaviors may lead to contact with the 

chemicals? How do the behaviors vary among children of various ages? 

4.3.4.5. Iteration of the Review of Data with Hazard and Dose-Response Characterization 

As discussed in EPA’s Framework for Cumulative Risk Assessment (U.S. EPA, 2003a), 

vulnerability to environmentally mediated health effects can

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[0] vary on the basis of susceptibility, 

differential exposure, differential preparedness, and differential ability to recover[0]. The key 

issue is how to capture these changes in an assessment of risks from exposure to environmental 

contaminants. In conducting the hazard and dose-response characterization portion of a risk 

assessment, the assessor must consider critical windows within development that result in greater 

vulnerability to toxic effects. In developing the exposure assessment, the assessor must also

consider windows of vulnerability based on, for example, behaviors (crawling, mouthing), 

activities (locations, product use, diet), and physiological characteristics (oxygen requirements, 

caloric requirements) that may lead to particularly high levels of exposure. For example, 

information on the environmental fate of a compound and a child’s subsequent contact with it is 
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critical to ensure that hazard information is relevant to the measured exposure. As another 

example, understanding the dosimetry of an absorbed agent can inform the temporal resolution 

needed in the exposure data and assessment. The hazard, dose-response and exposure analyses 

are combined to identify the life stages that are at greatest risk. 

The focus of the exposure assessment is to identify age groups and address vulnerability 

resulting from differential exposure. Because the focus here is on exposure or potential dose, TK 

considerations (i.e., ADME) are not explicitly considered unless they have direct impacts on 

potential dose (e.g., absorption at the portal of entry). However, it is impossible to completely 

separate consideration of exposure and potential dose from consideration of internal dosimetry 

and response. This is the reason why hazard assessment, dose-response assessment, and 

exposure assessments are intimately linked. 

Initial hazard information could be used to guide problem formulation (scoping) for the 

exposure assessment. After a preliminary exposure assessment, the hazard characterization may 

need modification. The following questions identify those issues that might suggest changes in 

the initial hazard characterization: 

• How do patterns of exposure (continuous vs. intermittent) and half-life in the body 

influence the health outcome? What are the exposures during critical windows in 

development? 

• Are there particular developmental stages during which children are highly 

exposed? Do health outcomes vary during different developmental periods? How 

does this inform identification of the exposures of greatest biological significance 

for the observed outcomes? 

• How does information on dosimetry indicate the level of temporal resolution 

needed in exposure data and modeling? What dose metrics are being considered for 

child-related assessments? 

• How does the fate of the agent being evaluated affect exposure in children? Are 

children exposed to other agents with a similar MOA to the one being assessed? Is 

sufficient MOA information available to consider a cumulative exposure 

assessment? 

• What other crosscutting issues may need to be considered at this stage in the 

assessment? 

 
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4.3.5. Life Stage-Specific Exposure Analysis

Exposure estimates may be developed for all relevant life stage-specific scenarios. The 

data identified in Section 4.3.4 are used to estimate exposure for all of the potentially important 

pathways and scenarios identified in the conceptual model (Section 4.3.3). At this point in the 

assessment, vulnerable age groups will be identified, patterns of exposure will be characterized 

(e.g., intermittent, continuous, acute, or chronic), and exposures levels will be quantified. 

Identifying children with potentially higher exposures or significant exposures during critical 

windows is critical for a complete exposure assessment for children. These considerations are of 

particular interest when assessing children’s exposures because the timing of exposure can affect 

the outcomes observed. Children may experience unique exposure patterns that would need to 

be considered in relation to their critical windows of development. 

The health effect of concern would need to be considered when selecting the appropriate 

temporal scale for estimating exposure/dose. It may be important to consider peak exposures as 

well as exposures that have been averaged over a specified period of time (U.S. EPA, 2003b). 

Assessments of agents with multiple sources or in multiple media may require additional work to 

estimate children’s exposure patterns. This means that, even at the screening level, a large 

number of factors may need to be collected and tracked, along with their associated variabilities 

and uncertainties. Thus, to efficiently and effectively assess children’s exposures, a 

person/population-oriented approach may be needed for all but the most basic assessments. 

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To conduct the life stage-specific exposure analysis, a calculation approach described in 

section 4.3.5.1 is selected on the basis of available data and the risk assessment questions that 

were defined during the problem formulation stage. Often, two or more calculation approaches 

will be used and the results compared in the exposure characterization stage. Typically, an 

exposure analysis will begin with a screening-level assessment and then, if there appear to be 

significant exposures or an unacceptable level of uncertainty, a second, more refined level of 

analysis will be conducted. This type of tiered level analysis discussed in Section 4.3.5.2 is often 

used to facilitate efficient allocation of resources. 

4.3.5.1. Exposure Measurement and Estimation Approach 

Three approaches may be used to calculate exposures: the point-of-contact approach, the 

scenario evaluation approach, and the dose reconstruction approach.
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Point-of-contact approach: Sometimes referred to as the direct approach, this involves 

measurements of chemical concentrations at the point where exposure occurs (at the interface 

between the person and the environment) and records of the length of contact with each 

chemical. It does not take into account an individual’s characteristics. 

Scenario evaluation approach: Sometimes referred to as the indirect approach and it requires 

data on chemical concentration and frequency and duration of exposure, as well as information 

on the exposed population. Child-specific behaviors and physiologic characteristics may be 

assumed on the basis of exposure factor data (U.S. EPA, 2002a) or from exposure study 

databases (the Consolidated Human Activity Database [CHAD], available from 

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http://www.epa.gov/heds), or they can be obtained specifically for the assessment (e.g., by 

questionnaire, diary, videotaping). Chemical concentration may be determined by sampling and 

analysis or by use of fate and transport models (including simple dilution models). Models can 

be particularly helpful when resources for additional sampling are limited but some analytical 

data are available. 

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Dose reconstruction approach: This approach allows exposure to be estimated from dose, 

which can be reconstructed through internal indicators (e.g., biomarkers, body burden, excretion 

levels) after the exposure has taken place. The use of biomarkers of exposure or effect may 

allow simplification of risk assessment; however, only a few examples currently exist for 

applying this approach successfully. At the present time, biomarker data are difficult to 

interpret, either because the presence of a biomarker may not be unique (many stressors may 

result in a change in the same biomarker) or there may not be adequate exposure pathway 

information to link the biomarker to the exposure. Currently, this approach is most successful 

for persistent compounds 

4.3.5.2. Analysis Level or Tier 

 Typically, an exposure analysis will begin with a screening-level assessment and then, if 

there appears to be significant exposures or an unacceptable level of uncertainty, a second, more 
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refined level of analysis will be conducted. The first tier described below is a screening-level 

assessment used to identify and prioritize potentially important exposures. The screening level 

assessment uses bounding values for exposure factors and conservative simplifying assumptions. 

Therefore, the output may have a high level of uncertainty. After results of the screening 

assessment are compared with results of the hazard characterization, a more refined assessment 

may be required to reduce uncertainty in the initial exposure estimates. The second tier is 

generally more resource intensive than the first tier and is used to refine estimates for exposure 

scenarios that were identified as potentially significant in the screening assessment. The major 

difference between the two levels of assessment described below is related to the assumptions 

that are used. The screening level uses bounding assumptions, and resulting exposure estimates 

may have a high degree of uncertainty. In the refined assessment, more realistic estimates of 

exposure are developed for selected scenarios to reduce the uncertainty. It is important to note 

that probabilistic techniques may be used at either level of analysis depending on the types of 

scenarios that are being evaluated. Finally, if a high level of uncertainty remains around 

estimates of exposure following a refined assessment, supplemental data collection may be 

needed. 

 4.3.5.2.1. Screeening Assessment. The purpose of a screening tier is to identify important 

pathways and scenarios, as well as to rule out insignificant ones. Bounding values for exposure 

factors and conservative simplifying assumptions are used at this level of analysis. As a result, 

the output may have a high level of uncertainty. Historically, deterministic calculations were 

used in most screening-level exposure analyses. However, exposure assessments have become 

increasingly complex and probabilistic techniques may be useful when, for example, exposure 

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 In the screening-level analysis, important differences in exposure between children of 

different developmental stages are identified. For some specific exposure scenarios and 

compounds, combining some of the age groups may be appropriate, for example, where variation 

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age groups and for making decisions regarding combining or eliminating age groups. In these 

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information leads the assessor to identify potentially significant differences within a 

recommended age bin. A possible approach to estimating exposure factors and dose when data 

are not available uses age-dependent curve fitting to help fill in the data gaps. Any assumptions 

used in assessing exposure for a particular age bin should be discussed in the assessment. 

 Once screening-level estimates of exposure are developed for each scenario and each age 

group, the following questions could be considered. 

• Do these results address the questions posed in the problem definition stage of the 

risk assessment? 

• What are the bounding assumptions used to identify potentially important sources, 

pathways, and scenarios? 

• What is the potential magnitude of exposures? 

• How do potentially important scenarios and potentially vulnerable age groups 

compare with critical windows identified in the hazard characterization? 

• How do potential exposure levels compare with hazard levels (e.g., margin of 

exposure)? 

• Which exposure factors drive the results of the screening assessment and why? 

What is the potential variability of exposure factors (e.g., orders of magnitude 

versus factor of 2 or 3)? 

• Is the information currently available adequate? What criteria are used to determine 

adequacy? What are the significant data needs? Is there a need to collect additional 

data? 

Based on the bounding assumptions used in this level of analysis and comparison with the hazard 

analysis, a set of potentially significant exposure scenarios for important age groups will be 

identified. In order to identify and understand the important parameters and uncertainties in 

these exposure estimates, a sensitivity analysis is generally conducted on the potentially 

significant scenarios. For a screening assessment to have value, the potential range of parameter 

values are considered when conducting the sensitivity analysis (e.g., some parameters can vary 

only between 0 and 1; others can vary by three orders of magnitude.) In addition, the uncertainty 

associated with assumptions that are based on little or no data would need to be evaluated before 

any conclusions about the level of "conservatism" can be made. Methods for conducting a 

sensitivity analysis are discussed further in the next section. 
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4.3.5.2.2. Refined Assessment. This tier provides more detail for potentially important 

scenarios and potentially vulnerable age groups. The goal is often to estimate the distribution of 

exposure for each of the important life stages. Based on results of the sensitivity analysis 

conducted for the screening-level assessment, significant exposure factors and important 

assumptions are revisited to develop more realistic estimates of exposure. 

• Again, do these results address the questions posed in the problem formulation 

stage of the risk assessment? 

• What is the central tendency of the distribution of the exposure when compared 

with the high-end exposures? 

• How do potential exposure levels compare with dose-response assessment results? 

• Which groups of children present the highest exposures on the basis of their current 

developmental stage? 

• Is the exposure information currently available adequate? What criteria are used to 

determine adequacy? What are the significant exposure data needs? Is there a need 

to collect additional data? 

This more advanced analysis may include the application of sophisticated modeling tools 

to develop exposure estimates for use in regulatory decisions. A variety of modeling tools have 

been developed over the years to facilitate exposure assessment (see Price et al., 2003, and 

references therein for review of available tools). Some of the types of models available include 

total source models (e.g., aggregate and cumulative models developed to meet requirements of 

the 

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models, tap-water exposure models), models of exposures to specific sources or routes (e.g., 

dietary models, consumer product models), indoor air models, and occupational models. 

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It is important to note that few of these models are designed currently to specifically 

address life stage exposures. As a result, data on the age bins used in the models and outputs 

produced by the models may not address the specific age groups of interest for a complete life 

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Limitations of the data, model results, and associated uncertainties are considered and 

addressed in the refined analysis. For example, were the exposure data adequate to sufficiently 

investigate and identify important differences across the age groups? Available exposure data 

sets may not allow modelers or risk assessors to directly extract data from the underlying sources 

to conduct age group-specific analyses. Potential approaches to address this issue include 1)

reorganizing the exposure input data set to conform to the age groupings needed, 2) using 

probabilistic sampling techniques to go beyond the categorical limits of the underlying database 

to utilize all the data, and then formatting the probabilistic model output into the desired age 

groupings to represent exposure doses, and 3) developing a weighting scheme for the underlying 

data set to align it with the desired age groupings. The exposure data may need to be statistically 

weighted so that equal weight is given to all ages within the group when estimating the group 

mean and variability statistics. 

The assessor may reconsider: 

• What are the available models? 

• Are distributions available for exposures of interest (e.g., by media, source, 

pathway)? If not, do they need to be developed? Are there sufficient data for their 

development? 

• How will variability and uncertainty be addressed? 

• What are the time patterns of exposure? 

• How will exposure monitoring data, PBTK modeling, and biomonitoring data be 

incorporated? 

• What are the additional stressors and their cumulative impact? 

4.3.5.2.3. Supplemental Data Collection. Based on results of the refined assessment and the 

associated sensitivity and uncertainty analyses, specific data needs may be identified. If the 

objectives of the risk assessment indicate that any specific uncertainties in the exposure 

assessment be addressed, collection of new data to address them may be needed. 
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4.3.6. Life Stage-Specific Exposure Characterization Narrative 

 The results of the exposure assessment should be summarized in a narrative that includes 

a discussion of the results, analysis, and conclusions derived from the analysis. More 

importantly, the narrative should include a discussion of the key assumptions, limitations, and 

uncertainties associated with the exposure estimates and any potential bias in the results. Results 

of the uncertainty analysis and sensitivity analyses should also be discussed. The variability in 

the population can be presented by providing ranges or distributions of the exposure. It is useful 

to also include a description of how the assessment can be improved and uncertainties be 

reduced by additional research or collection of data. 

 It is important that the results of the assessment are communicated in a clear and concise 

manner to the risk manager, and include considerations of childhood variability and uncertainty 

within the exposure analysis. The following questions could also be considered by the assessor. 

• If different approaches were used to estimate exposure for different life stages or 

within a life stage, what were the results? Can they be compared and, if so, how do 

they compare? Which approach is more appropriate? 

• Does the life stage-specific assessment capture the variability in the exposed 

groups? What are the ranges or distributions of exposure? 

• What are the uncertainties in the estimates, both within and across life stages? 

• What are the data limitations and how do they compare across life stages? 

• What data gaps exist, both within and across life stages? How significant are these 

data gaps? How sensitive are the results to these data gaps? 

• Is it feasible or desirable to collect more data pertaining to particular life stages? 

Could the exposure estimates be refined if more data were available? 

4.3.6.1. Variability Analyses 

 Distinguishing between uncertainty and inter individual variability is an important issue 

in exposure assessments for children. Variability refers to the lack of uniformity in a population. 

It is an inherent characteristic of the population that cannot be reduced with additional data. 

Differences among individuals in a population are referred to as inter individual variability. 

Differences associated with an individual overtime are referred to as intra individual variability. 
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 Among children, inter individual variability can be important due to rapid physiological 

and behavioral changes. Even within a relatively narrow age group, variability may be large. 

This variability affects the determination of upper percentiles of exposure and its associated risk, 

and so can be critical to children’s risk assessment. That is, given a high-quality, high-quantity 

set of data for each age group, there may still be significant variability for a particular exposure 

factor, set of factors, or exposure pathway. The better the data and the characterization of this 

variability, the better the basis for final selection of age groups for a specific assessment. 

Variability in children’s exposure and dose is due to differences in behavior and 

physiology. For oral and dermal exposures, variability in exposure/dose is due to factors such as 

gross motor development, fine motor development, cognitive development, and social 

development. For inhalation exposures, relevant factors influencing variability in exposure/dose 

include activity level and breathing behavior (e.g., the transition from mouth to nasal breathing), 

for example (U.S. EPA, 2003b). Infants may be breast fed or bottle fed. Young children may 

have higher contact with surfaces than do older children and they explore their environment by 

mouthing objects. Physiological characteristics affecting variability in exposure/dose include 

anatomical characteristics (e.g., body weight and proportion of body fat) and specific organ and 

physiological systems (e.g., skin, skeleton, liver, immune system, reproductive system, renal 

system, cardiac system, central nervous system, muscle, and sensory organs). For example, 

infants have immature immune systems, and renal functions are less than those predicted by 

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4.3.6.2. Uncertainty Analyses 

 Uncertainty is described as a lack of knowledge about factors affecting exposure or risk. 

Uncertainty in the exposure estimates may be a result of limited data for significant exposure 

factors for a particular age group or with assumptions made in development of the model. For 

example, soil ingestion studies in the literature have focused on children between 2 and 7 years 

of age. Data for children under 2 years of age are lacking. Uncertainties need to be 

acknowledged and characterized to the extent possible. 

 Probabilistic assessments can be useful statistical tools for analyzing variability and 

uncertainty in risk assessments, given that adequate data are available. General issues to 

31 consider when applying these quantitative methods are described in EPA’s Guiding Principles 
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for Monte Carlo Analysis (U.S. EPA, 1997b). An EPA workshop was held in 1998 to discuss 

issues regarding the selection of input distributions for probabilistic assessments 

1 

2 (U.S. EPA, 

1999a). Methodologies for selecting parametric distributions to be used in probabilistic 

assessments are described in 

3 

4 Options for Developing Parametric Probability Distributions for 

5 Exposure Factors (U.S. EPA, 2000b). 

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4.3.6.3. Sensitivity Analyses 

 Sensitivity analysis has been defined as the assessment of the impact of changes in input 

values on model outputs. Its main purpose in any exposure assessment is to determine which 

variables in the model equations and what pathways or scenarios most affect the exposure 

estimate. These techniques can also be used to assess key sources of variability and uncertainty 

for the purpose of prioritizing additional data collection or research. This is particularly 

important in children’s assessments because they are often based on limited data. Because the 

variables of particular interest are those that have an impact on life stage-specific estimates, the 

sensitivity analysis may need to focus considerable attention on the impact of exposure factors 

related to children’s behavior. These factors affect the exposure patterns in space and time and 

are also typically the most uncertain. 

4.4. SUMMARY OF ANALYSIS PHASE 

 This section presented a comprehensive approach for characterizing children’s exposures 

to environmental contaminants. This life stage-specific analyses results in a thorough 

characterization of the magnitude, frequency, and duration of exposure received for various 

exposure pathways. The results of the exposure assessment are then combined with the results 

from the hazard and dose response analysis to characterize potential risks to children. The 

conclusions from the exposure assessment and the discussion about key assumptions, limitations, 

and uncertainties are later integrated with the conclusions from the hazard and dose response 

assessments to provide a characterization of risk. 
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5 

5. LIFE STAGE-SPECIFIC RISK CHARACTERIZATION 

 Risk characterization is the final phase of the risk assessment process, in which the 

hazard, dose-response, and exposure assessment components of the risk assessment are 

integrated, summarized, and major conclusions are drawn. Risk characterization should be done 

in accordance with EPA’s science policy handbook on risk characterization (U.S. EPA, 2000c), 

which provides detailed guidance for EPA staff. Other sources of information that were 

consulted in the development of this risk characterization section were the developmental 

toxicity, reproductive toxicity, neurotoxicity and cancer risk assessment guidelines (

6 

7 

8 

9 U.S. EPA 

10 1991, 1996, 1998b, 2005b, 2005c) and the National Research Council’s report Science and 

11 Judgment in Risk Assessment (NRC, 1994). 

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13 

14 

15 

 As with other sections of this framework, the issues to be addressed in risk 

characterization are pointed out in a list of questions that guide the assessor through this process, 

with particular focus on the life stage-specific issues. The following lists of questions are a 

modification of those developed the for risk characterization of reproductive toxicity risk 

assessment guidelines (U.S. EPA, 1996). The information for these questions is assessed and 

described in the analysis phases and used in the risk characterization narrative. 

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5.1. SUMMARY OF THE MAJOR CONCLUSIONS IN LIFE STAGE-SPECIFIC RISK 

CHARACTERIZATION 

 This summary includes a narrative of the major conclusions from the analysis phases of 

this framework with a concise description of the major qualitative and quantitative aspects, 

including discussion of critical windows of development identified in the hazard assessment and 

the associated exposure assessment. This nontechnical narrative describes the overall picture of 

health risks resulting from children’s exposures, based on the hazard, quantitative dose-response, 

and exposure characterizations. The assumptions and uncertainties should be clearly identified 

and described. In addition, significant data gaps that could affect the respective major 

conclusions should be identified and described. Finally, the summary provides the qualitative 

and quantitative justification for the application of life stage-specific adjustments for durationspecific health values (e.g., use of life stage-specific RfV for a specific duration of exposure) if 

the assessment warrants it.
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5.1.1. Hazard Characterization 

 This section includes the integrative summary of information on the capacity of an 

environmental agent to cause adverse effects in laboratory animals and humans at different life 

stages. The qualitative description is based both on the type of data and quality of data derived 

from humans and laboratory animals and on the integration of ancillary data (e.g., structure 

activity analyses, genetic toxicity, TK, TD, and MOA) into a WOE narrative. Tables 5-1 

through 5-3 are not intended to be proscriptive but are provided to assist the preparation of the 

narrative. 

5.1.2. Dose-Response Characterization 

 The dose-response characterization focuses on quantitative relationships between 

exposure (dose) and effects. Critical outcomes and life stages of concern from the hazard 

characterization are examined quantitatively and summarized in this section. For outputs of this 

analysis to be useful in benefits analysis, the endpoints that are quantified must be expressed as 

changes in adverse outcomes (e.g., change in incidence of illness or symptoms) that are readily 

understood and perceptible by the public. Methods for assessing dose-response relationships 

often depend on assumptions used in the absence of data. These approaches can strongly 

influence the overall assessment; thus, assumptions need to be clearly articulated in the risk 

characterization section. 

5.1.3. Exposure Characterization 

 The exposure characterization includes a narrative describing the basis for values used in 

exposure scenarios. If the values are based on data, then the quality, purpose, and 

representativeness of the database should be described. Alternatively, if they are based on 

assumptions, the sources and general logic used to develop the assumptions should be described. 

The major factors thought to account for the greatest uncertainty in the exposure assessment 

should be described and linked to information from sensitivity analyses or lack of particular data. 
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1 Table 5-1. Issues Addressed in Hazard Characterization (Section 4.1.) 

Toxicological 

Evidence 

What are the key toxicological studies that provide the basis for health 

concerns following children’s exposures? 

To what degree do key studies meet data quality objectives (U.S. EPA, 

2002b)? 

Are the data from laboratory animals or human studies? In a single or 

multiple species? 

What adverse outcomes at the lowest exposure levels were observed, 

and what is the basis for these observed outcomes? 

Have precursor events been identified? 

Was dosing/exposure during potential or known critical windows of 

exposure identified? 

Is there intraspecies concordance of effects? 

Are all studies supporting these findings discussed, and do any valid 

studies contradict these findings? 

Besides the developmental life stage effects observed in the key 

studies, are there other health outcomes of concern? 

Are negative toxicological studies (data) considered in the hazard 

characterization? 

What are the significant data gaps? 

Do the cited studies include data relevant to humans? 

In the case of animal study data, what is known about the comparative 

developmental life stages of exposure in humans? 

Are the routes of exposure relevant to humans? 

Is there concordance of effects between animals and humans? If not, 

are there underlying biological reasons to explain these differences? 
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Human 

Evidence 

What human data are available? 

What types of studies are available (e.g., case-control, cohort or human 

ecologic studies, or case reports or series)? 

To what degree were exposures described (e.g., the exposure level and 

the life stage of exposure)? 

To what degree were confounding factors, effect modifiers, and other 

risk factors considered? 

What were the major demographic and other personal/community 

characteristics examined (e.g., age, sex, ethnic group, socioeconomic 

status, smoking status, occupational exposure)? 

Were the findings examined for biologic plausibility, internal and 

external consistency, and the influence of limitations of the design, 

data sources, and analytic methods? 

Are “negative” human studies (data) considered in the hazard 

characterization? Did included studies have sufficient power for 

confidence in the results? 

Mode of Action 

(MOA) 

What were the relevant studies of MOA and toxicokinetics? 

How much is known about how (through what biological 

mechanism or MOA) the chemical produces adverse effects? 

Does this MOA information aid in the interpretation of the hazard 

data for different life stages? 

What are the implications of specified MOAs for potential adverse 

effects and their relationship to risk? 

Weight of 

Evidence 

(WOE): 

What is the confidence in the conclusions? 

Are there alternative conclusions that are also supported by the data? 

Are there significant data gaps? How do these impact the magnitude 

of uncertainty in the assessment? 

What are the identified uncertainties? 

What are the major assumptions? 

What is the relevance of animal studies to humans at particular life 

stages? 

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Table 5-2. Issues Addressed in Dose-Response Characterization 

(Section 4.2.) 

Nature and 

Extent of the 

Database: 

What data were used to develop the dose-response curve? 

Would the results have been significantly different if based on a 

different data set? Were there differences in the dose-response curves 

for different life stages? 

If laboratory animal data were used, consider the following: 

Which species were used? Was it the most sensitive species, the 

average of all species, or another species? 

Were any studies excluded? Why? 

If human data were used, consider the following: 

Which studies were used? Were they only positive studies, all 

studies, or some other combination? Were any studies excluded? 

Why? 

Was a meta-analysis performed to combine epidemiological studies? 

What approach was used? 

Dose-Response 

Curve 

Was a model used to develop the dose-response curve and, if so, which 

one? What rationale supports this choice? Is chemical-specific 

information available to support this approach? Is life stage-specific 

information available for modeling? What other models were 

considered? 

How was the benchmark response chosen? How were the benchmark 

doses (BMDs) determined? Were the life stage data applied 

appropriately to different duration BMDs? 

What assumptions and uncertainty factors were used? Did these 

appropriately account for life stage information or data gaps? 

How were the slope factors derived? How were life stage issues 

incorporated into the assessment? 

What were the results of uncertainty analyses? 

What were the results of sensitivity analyses? 

Were data needs identified from either uncertainty or sensitivity 

analyses? 

What is the confidence in the risk estimates? 
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Expected 

Exposures 

Discuss the route, level, timing (i.e., life stage), and duration of 

exposure used in the studies, as compared with expected human 

exposures. 

Are the available data from the same route of exposure as the expected 

human exposures? If not, are toxicokinetic data available to extrapolate 

across routes of exposure? 

Are data available from the same life stages as the expected exposed 

human populations? If not, are toxicokinetic data available to 

extrapolate across life stages? 

What information was used to support duration adjustment and to 

calculate the human equivalent concentration or dose? 

How far does one need to extrapolate from the observed data to 

environmental exposures, i.e., the margin of exposure? One to two 

orders of magnitude? Multiple orders of magnitude? What is the 

impact of such an extrapolation? 

1 Table 5-3. Issues Addressed in Exposure Characterization (Section 4.3.) 

Pathways of 

Exposure

What are the most significant pathways of environmental exposure? 

What are the likely routes of exposure? 

Sources of 

Exposure 

What are the most significant sources of environmental exposure? 

Are there data on pathways of exposure from different media? 

What is the relative contribution of different pathways of exposure? 

What are the most significant environmental pathways for exposure? 

Populations Describe the groups assessed, including parents before conception, 

and different developmental life stages (e.g., pregnant women, 

infants, young children, adolescents, highly exposed groups of 

children, and highly susceptible groups of children). 

Time Frame of 

Exposure 

Describe the time frame of exposure, including pattern (continuous, 

intermittent) and duration of exposure (acute, short term, subchronic, 

or chronic). 

Location of 

Exposure

Discuss locations where children are being exposed (e.g., residence, 

school, outdoors). 

Activities Leading 

To Exposure 

Discuss activities that result in significant exposures (e.g., 

breastfeeding, mouthing, sports, and after-school employment). 
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Exposure 

Characterization 

Describe the basis for the exposure assessment, including any 

monitoring, modeling, or other analyses of exposure distributions. 

What are the key descriptors of exposure? 

Describe the range of exposures for the various categories of 

individuals (e.g., “average” individuals, the most highly exposed 

individuals, the general population, children, aged, males, and 

pregnant or lactating females). 

How was the central tendency estimate developed? What factors or 

methods were used in developing this estimate? 

How was the high-end estimate developed? What factors or methods 

were used in developing this estimate? 

Is there information on highly exposed subgroups? Who are they? 

What are their levels of exposure? How are they accounted for in the 

assessment? 

Cumulative and 

Multiple 

Exposures 

Is there reason to be concerned about cumulative or multiple 

exposures to classes of agents with a similar mechanism or mode of 

action? 

Are there biological, behavioral, ethnic, racial, or socioeconomic 

factors that may affect exposures? 

Exposure 

Conclusions 

Summarize exposure conclusions, including the following: 

What are the results of different approaches (i.e., modeling, 

monitoring, and probability distributions)? 

What are the life stage-specific exposures and ranges of exposure? 

What are the limitations of each exposure assessment methodology 

and the range of the most reasonable values? 

What is the confidence in the results obtained and the limitations of 

the results? 

What were the results of uncertainty analyses? 

What were the results of sensitivity analyses? 

Were data needs identified from either uncertainty or sensitivity 

analyses? 

1 5.2. SUMMARY OF ALL THE VARIABILITY AND UNCERTAINTY ANALYSES 

2 

3 

 Determine whether different approaches used to estimate exposure or health outcome 

provide similar risk estimates. Information from different sources can carry different kinds of 
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variability and uncertainty. Knowledge of these sources of variability and uncertainty are 

important when considering integration of the uncertainties in the risk characterization. This 

knowledge can have an impact on decisions that must be made about the need to acquire more 

data/knowledge to reduce these uncertainties. This summary includes clear and concise 

statements about the limitations of the risk assessment and may include discussion of 

uncertainties in other related assessments. Critical data gaps, defined by the impact they have on 

the risk assessment, should be identified and described. These critical data gaps and the 

attendant research needs may provide insight into future reductions in uncertainties in risk 

assessment 

Table 5-4. Issues Addressed in Variability and Uncertainty Analyses 

Variability and 

Uncertainty 

Analyses 

Does the assessment capture the variability in the exposed 

population? 

What are the uncertainties in the assessment for different life stages 

of development? 

What are the limitations of the data available? 

What data gaps exist? What are the priority data needs for reducing 

uncertainties? How can additional data reduce uncertainties in life 

stage-specific risk assessment? 

12 5.3. RISK CONTEXT 

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 The risk characterization must be presented in a context that relates to the original 

problem identified in the planning and scoping phase of the framework. Risk assessment is an 

iterative process that grows in depth and scope; this occurs in stages, from screening for priority 

making, to preliminary estimation of risk, to fuller examination in support complex regulatory 

decisions. If the statement of the problem evolved during the analyses, this process needs to be 

summarized. The risk context of major conclusions and strengths of the assessment in each of 

the three main phases of the analyses (i.e., hazard characterization, quantitative dose-response, 

and exposure assessment) should be discussed along with the major limitations and uncertainties. 

This summary should include what the decision makers and the public need to know about the 
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key conclusions and assumptions and a balance between confidence and uncertainty in the 

assessment. 

Table 5-5. Types Of Issues To Be Considered to Illustrate The Risk Context 

Risk Context What are the science policy assumptions in each of the three major 

components of the analyses? 

What are the alternative approaches evaluated? What are the reasons 

for the choices made?

What are the qualitative characteristics of the hazard to children (e.g., 

voluntary vs. involuntary, technological vs. natural.)? (Comment on 

findings, if any, from studies of risk perception that relate to this 

hazard or similar hazards.)

How do life stage-specific risks compare? 

How does this risk compare with other risks in this regulatory 

program, or other similar risks that EPA has evaluated? 

How can benefit analysis utilize the information derived from the risk 

characterization? 

Where appropriate, can this risk be compared with other risks 

characterized by EPA, characterized risks by other federal or state 

agencies, or common risks with which people may be familiar? 

What are the limitations of making these comparisons? 

Are there significant community concerns that influence public 

perception of risk? 

Existing Risk 

Information 

Comment on other risk assessments that have included consideration 

of health risks from children’s exposures on this chemical by EPA, 

other federal agencies, or other organizations. 

Are there significantly different conclusions that merit discussion? 

Other 

Information 

Is there other information that would be useful to the risk manager or 

the public in this situation that has not been described above? 

5 
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6. SUMMARY AND IDENTIFICATION OF GAPS IN GUIDANCE FOR 

CHILDREN’S HEALTH RISK ASSESSMENT 

This report summarizes the process for assessing health risks resulting from children’s 

exposure to environmental agents using a phased approach that includes problem formulation, 

analysis, and risk characterization. It utilizes EPA documents that have outlined a similar 

approach (U.S. EPA, 1998a, 2003a) as well as the report of a workshop (ILSI, 2003) that formed 

the basis for a children’s health risk assessment framework. The approach here is not to provide 

guidance per se, but rather, using the existing framework approach, to pose targeted questions to 

address each phase of the process. In addition, the report references appropriate guidelines, 

guidance documents, and other relevant reports and literature that can be drawn upon for more 

detailed information. 

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As indicated in this report, several EPA risk assessment guidelines relate to health risks 

from children’s exposures. The most relevant are the developmental toxicity risk assessment 

guidelines (U.S. EPA, 1991) that deal with the whole organism during development, but focus 

primarily on the effects of prenatal exposures and, to a limited extent, on postnatal exposures and 

outcomes. Other guidelines/guidance are focused on system- or disease-specific issues that 

include the effects of developmental exposures, e.g., reproductive toxicity 

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(U.S. EPA, 1996), 

neurotoxicity 

18 

(U.S. EPA, 1998b), or cancer (U.S. EPA, 2005b, 2005c). Guidelines or guidance 

on the effects of developmental exposures on other systems (e.g., respiratory, immune, renal, 

hepatic, cardiovascular, and to some extent endocrine) or outcomes (e.g., biomarkers of exposure 

or effect, TK, or genomics data) are lacking. 

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The relevance of specific developmental outcomes for application to risk assessments for 

various durations of exposure (i.e., acute, short term, longer term, and chronic) has not been 

generally defined, although this issue is considered in many of the risk assessments currently 

26 being generated across EPA. Gaps identified in the document A Review of the Reference Dose 

and Reference Concentration Processes regarding data needs and alternative approaches and 

strategies for developing testing guidelines are still necessary (

27 

U.S. EPA, 2002b, Section 5). In 

addition, there has not been a focused guidance document on dose-response assessment with 

developmental exposures, despite the fact that a good deal of research and methods development 

on BMD 

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31 (U.S. EPA, 2000a) and pharmacokinetic modeling (e.g., Clewell et al. 2002a; Ginsberg 

32 et al. 2004b) has been done using developmental data in animals and humans. 
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1 With regard to exposure assessment, there is very little guidance on approaches specific 

2 to children at different life stages, except for Child Specific Exposure Factor Handbook (U.S. 

EPA, 2002a) and the guidance on selecting appropriate age groups for assessing childhood 

exposures 

3 

(U.S. EPA, 2003b). Much more is needed on methods for both screening level and 

more detailed quantitative estimates of children’s exposures. Data for exposure factors 

determinations for all the recommended age groups are limited or nonexistent for some exposure 

factors. 

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Finally, one issue addressed briefly in this report is the integration of toxicity data and children’s 

exposure estimates, an issue for which essentially no guidance exists. Because the age groupings 

of concern for exposure and susceptibility to environmental agents can differ significantly, 

guidance is needed on using information on biological processes underlying development, MOA 

information, chemical-specific mechanisms, anatomical, physiological, and behavioral 

characteristics at different developmental life stages to determine critical times for exposure and 

the corresponding outcomes of concern. 

 At this time, significant research questions remain unanswered on the use of available 

exposure data to assess children’s risk. Some of these questions are: 

• How can adult biomonitoring data be applied to children? 

• How can biomonitoring data be interpreted to characterize exposure? 

• How can data from children be interpreted across developmental stage? 

• How can activity pattern data be used to classify children for exposure assessment? 

Many of these questions are actively being investigated. These efforts will likely 

contribute to future guidance and policy papers on specific issues. However this framework 

attempts only to outline the issues these issues and does not attempt to predict outcome or 

positions. 
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GLOSSARY 

Activity Pattern Data – Information on human activities used in exposure assessments. The 

information may include a description of the activity, frequency of activity, duration spent 

performing the activity, and the microenvironment in which the activity occurs. 

Adverse Effect – A biochemical change, functional impairment, or pathologic lesion that affects 

the performance of the whole organism or reduces an organism’s ability to respond to an 

additional environmental challenge. 

Age-Dependent Adjustment Factors (ADAF) – Adjustments to cancer slope factors that 

recognize the increased susceptibility to cancer from early life exposures to mutagens in the 

absence of chemical-specific data. 

Area Under the Curve (AUC) – The area of the time x concentration curve that helps to define 

the internal dose. 

Benchmark Dose (BMD) – A dose that produces a predetermined change in response rate of an 

adverse effect (called the benchmark response or BMR) compared to background. 

Benchmark Dose Lower Confidence Level (BMDL) – A statistical lower confidence limit on 

the dose at the BMD. 

Biologically Based Dose-Response (BBDR) Model – A predictive model that describes 

biological processes at the cellular and molecular level linking the target organ dose to the 

adverse effect. 

Biomarker – A biological molecule or biochemical indicator of exposure or biological changes 

resulting from exposures, or markers of risk or susceptibility. 

Biomonitoring – The assessment of human exposure to chemicals by the measurement of the 

chemicals or their metabolites (breakdown products) in human tissues or fluids such as blood or 

urine. Blood and urine levels reflect the amount of the chemical in the environment that actually 

gets into the body. 

Body Burden – The amount of a particular chemical, especially a potentially toxic chemical, 

stored in the body at a particular time as a result of exposure. Body burdens can be the result of 

long-term or short-term storage, e.g., the amount of a metal in bone, the amount of a lipophilic 

substance such as PCB in adipose tissue, or the amount of carbon monoxide (as 

carboxyhemoglobin) in the blood. 

Cancer – A disease of heritable, somatic mutations affecting cell growth and differentiation and 

characterized by an abnormal, uncontrolled growth of cells. 

Case-Control Study – An epidemiologic study that compares subjects with the disease of 

interest (cases) to subjects without the disease (controls). The groups are compared with respect 
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to exposure history to ascertain whether they differ in the proportion exposed to the chemical(s) 

under investigation. 

Case Report – A description of a person in a population or study group identified as having a 

particular disease, health disorder, or condition under investigation, without a comparison made 

to a control. 

Child – Conception to maturation of all organ systems, approximately 21 years of age. 

Concentration – The ratio of the mass or volume of a solute to the mass or volume of the 

solution or solvent. 

Conceptual Model – A written description or a visual representation of actual or predicted 

relationships between humans or ecological entities and the chemicals or other stressors to which 

they may be exposed. 

Confounder (or Confounding Factor) – A condition or variable that is both a risk factor for 

disease and is associated with an exposure of interest. This association between the exposure of 

interest and the confounder (a true risk factor for disease) may make it falsely appear that the 

exposure of interest is associated with disease. 

Critical Effect – The first adverse effect, or its known precursor, that occurs to the most 

sensitive species as the dose rate of an agent increases. 

Critical Window of Exposure – Developmental period when vulnerability to exposures is 

increased and can result in developmental effects. 

Cumulative Impact – The combination of aggregate exposures to multiple agents or stressors. 

Detoxificaton – Process, or of chemical modification that make a toxic molecule less toxic. 

Dose – The amount of a substance available for interaction with metabolic processes or 

biologically significant receptors after crossing the outer boundary of an organism. Absorbed

Dose is the amount crossing a specific absorption barrier (e.g., the exchange boundaries of skin, 

lung, and digestive tract) through uptake processes. Biologically Effective Dose is the amount of 

the chemical available for interaction by any particular organ or cell. Internal Dose is a more 

general term denoting the amount absorbed without respect to specific absorption barriers or 

exchange boundaries. Potential Dose is the amount ingested, inhaled, or applied to the skin. 

Dose Metric – The target tissue dose that is closely related to ensuing adverse response. Dose 

metrics should reflect the biologically active form of the chemical, its level, and duration of 

exposure, as well as intensity. Examples of units of measurement for dose are AUC, maximum

concentration. 

Dose-Response Assessment – The determination of the relationship between the magnitude of 

administered, applied, or internal dose and a specific biological response. Response can be 
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expressed as measured or observed incidence, percent response in groups of subjects (or 

populations), or the probability of occurrence of a response in a population. 

Dose-Response Curve – A graphical representation of the quantitative relationship between 

administered, applied, or internal dose of a chemical or agent, and a specific biological response 

to that chemical or agent. 

Dosimetric Adjustment Factor (DAF) – A multiplicative factor used to adjust observed 

experimental or epidemiological data to human equivalent concentration for assumed ambient 

scenario. 

Dosimetry – Process of measuring or estimating dose. 

Environmental Fate – The destiny of a chemical or biological pollutant after release into the 

environment. Environmental fate involves temporal and spatial considerations of transport, 

transfer, storage, and transformation. 

Epidemiology – The study of the distribution and determinants of health-related states or events 

in specified populations. 

Exposure – Contact made between a chemical, physical, or biological agent and the outer 

boundary of an organism. Exposure is quantified as the amount of an agent available at the 

exchange boundaries of the organism (e.g., skin, lungs, gut). Acute Exposure is exposure by the 

oral, dermal, or inhalation route for 24 hours or less. Chronic Exposure is repeated exposure by 

the oral, dermal, or inhalation route for more than approximately 10% of the life span in humans 

(more than approximately 90 days to 2 years in typically used laboratory animal species). 

Intermittent Exposure is a repeated exposure in which there is no effect of one exposure on the 

effect of the next; this definition implies sufficient time for the chemical and its metabolites to 

clear the biological system before the subsequent exposure (i.e., non-cumulative toxicokinetics). 

Longer-Term Exposure is repeated exposure by the oral, dermal, or inhalation route for more 

than 30 days, up to approximately 10% of the life span in humans (more than 30 days up to 

approximately 90 days in typically used laboratory animal species). Short-Term Exposure is

multiple or continuous exposure to an agent for a short period of time, usually 1 week. 

Exposure Assessment – An identification and evaluation of the human population exposed to a 

toxic agent that describes its composition and size and the type, magnitude, frequency, route, and 

duration of exposure. 

Exposure Concentration – The concentration of a chemical in its transport or carrier medium at 

the point of contact. 

Exposure Factor – Variables that define how exposure to a chemical or agent takes place (e.g., 

concentration, intake, body weight). 
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Exposure Media – Major environmental categories that surround or contact humans, animals, 

plants, and other organisms (e.g., surface water, ground water, soil or air) and through which 

chemicals or pollutants move. 

Exposure Pathway – The physical course a chemical or pollutant takes from its source to the 

organism exposed. 

Exposure Route – The way a chemical or pollutant enters an organism after contact, e.g., by 

ingestion, inhalation, or dermal absorption. 

Exposure Scenario – A combination of facts, assumptions, and inferences that define a discrete 

situation where potential exposures may occur. These may include the source, the exposed 

population, the time frame of exposure, microenvironment(s), and activities. Scenarios are often 

created to aid exposure assessors in estimating exposure. 

Database (Extent of) – Minimal Database is a database in which no human data are available, 

and route-specific toxicity data are limited to dose-response data applicable to the duration in 

question with assessment of outcomes other than mortality. A study showing only effect levels 

for mortality or other extremely severe toxicity would not be sufficient to set a reference value.

Robust Database is a database that includes extensive human and/or animal toxicology data that 

cover route-specific information on many health outcomes, durations of exposure, timing of 

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Hazard Assessment – The process of determining whether exposure to an agent can cause an 

increase in the incidence of a particular adverse health effect (e.g., cancer, birth defect) and 

whether the adverse health effect is likely to occur in humans. 

Hazard Characterization – A description of the potential adverse health effects attributable to a 

specific environmental agent, the mechanisms by which agents exert their toxic effects, and the 

associated dose, route, duration, and timing of exposure. 

Human Equivalent Concentration (HEC) or Dose (HED) – The human concentration (for 

inhalation exposure) or dose (for other routes of exposure) of an agent that is believed to induce 

the same magnitude of toxic effect as the experimental animal species concentration or dose. 

This adjustment may incorporate toxicokinetic information on the particular agent, if available, 

or use a default procedure, such as assuming that daily oral doses experienced for a lifetime are 

proportional to body weight raised to the 0.75 power. 

Intake Rate – Rate of inhalation, ingestion, and dermal contact, depending on the route of 

exposure. For ingestion, the intake rate is simply the amount of food containing the 

contaminant of interest that an individual ingests during some specific time period (units of 

mass/time). For inhalation, the intake rate is the rate at which contaminated air is inhaled. 

Factors that affect dermal exposure are the amount of material that comes into contact with the 

skin and the rate at which the contaminant is absorbed. 
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1 Key Event: A key event is an empirically observable precursor step that is itself a necessary 

element of the mode of action (U.S. EPA, 2005b, 2005c). Toxicokinetic and toxicodynamic 

steps that lead to a toxic response can be considered as key event(s). 

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Life Stage Approach – The comparison of exposure and effect data across different life stages 

from conception to old age. This approach provides a temporal context in which to evaluate data 

for risk assessment. 

Longitudinal Study – An epidemiologic study comparing subject with an exposure of interest to 

those without the exposure. These two cohorts are then followed over time to determine the 

differences in the rates of disease between the exposure subjects. 

Low-Dose Extrapolation – An estimate of the response at a point below the range of the 

experimental data, generally through the use of a mathematical model. 

Lowest-Observed-Adverse-Effect Level (LOAEL) – The lowest exposure level at which there 

are biologically significant increases in frequency or severity of adverse effects among the 

exposed population when compared with an appropriate control group. 

Margin of Exposure (MOE) – The ratio of the point of departure (POD) over an exposure 

estimate (MOE = POD/Exposure). 

Mechanism of Action – The complete sequence of biological events (i.e., including 

toxicokinetic and toxicodynamic events) from exposure to the chemical to the ultimate cellular 

and molecular consequences of chemical exposure that are required in order to produce the toxic 

effect. However, events that are coincident but not required to produce the toxic outcome are not 

included. 

Media – see Exposure Media. 

Meta-Analysis – Any systematic method that uses statistical analysis to integrate the data from a 

number of independent studies. 

Mode of Action – The sequence of key event(s) (i.e., toxicokinetics and toxicodynamics) after 

chemical exposure upon which the toxic outcome depend. 

Model – A mathematical function with parameters that can be adjusted so that the function 

closely describes a set of empirical data. A mechanistic model usually reflects observed or 

hypothesized biological or physical mechanisms and has model parameters with real world 

interpretation. In contrast, statistical or empirical models selected for particular numerical 

properties are fitted to data; model parameters may or may not have real world interpretation. 

When data quality is otherwise equivalent, extrapolation from mechanistic models (e.g., 

biologically based dose-response models) often carries higher confidence than extrapolation 

using empirical models (e.g., logistic model). 

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

no biologically significant increases in the frequency or severity of adverse effect between the 
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exposed population and its appropriate control; some effects may be produced at this level, but 

they are not considered adverse or precursors of adverse effects. 

Outcome – A clinical manifestation of biological effects that result from an exposure. 

Pathway – see Exposure Pathway. 

Person-Oriented Model – An approach in which the individual’s exposure-related 

characteristics are defined first and then used to determine the probability of the individuals’ 

being exposed to a specific source and the resulting dose. 

Physiologically based Toxicokinetic (PBTK) Model – A model that estimates the dose to a 

target tissue or organ by taking into account the rate of absorption into the body, distribution 

among target organs and tissues, metabolism, and excretion. (Also referred to as physiologically 

based pharmacokinetic model.) 

Point-of-Contact Approach – An approach to quantifying exposure by taking measurements of 

concentration over time at or near the point of contact between the chemical and an organism 

while the exposure is taking place. 

Point of Departure (POD) – The dose-response point that marks the beginning of a low-dose 

extrapolation. This point can be the lower bound on dose for an estimated incidence or a change 

in response level from a dose-response model (BMD) or a NOAEL or LOAEL for an observed 

incidence, or change in level of response. 

Portal of Entry – The point at which the contaminant enters the body (e.g., mouth, nose, skin). 

Precursor Event – An early condition or state preceding the pathological onset of a disease. 

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

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

subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. 

It can be derived from a NOAEL, a LOAEL, or a benchmark concentration, with uncertainty 

factors generally applied to reflect limitations of the data used. It is generally used in EPA's 

noncancer health assessments. 

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

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

be without an appreciable risk of deleterious effects during a lifetime. It can be derived from a 

NOAEL, a LOAEL, or a benchmark dose, with uncertainty factors generally applied to reflect 

limitations of the data used. It is generally used in U.S. EPA’s non-cancer health assessments. 

Reference Value (RfV) – An estimation of an exposure for (a given duration) to the human 

population (including susceptible subgroups) that is likely to be without an appreciable risk of 

adverse effects over a lifetime. It is derived from a BMDL, a NOAEL, a LOAEL, or another 

suitable POD, with uncertainty/variability factors applied to reflect limitations of the data used. 
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(Durations include acute, short term, longer term, and chronic and are defined individually in this 

glossary.) 

Risk (in the context of human health) – The probability of adverse effects resulting from 

exposure to an environmental agent or mixture of agents. 

Risk Assessment (in the context of human health) – The evaluation of scientific information 

on the hazardous properties of environmental agents (hazard characterization), the dose-response 

relationship (dose-response assessment), and the extent of human exposure to those agents 

(exposure assessment). The product of the risk assessment is a statement regarding the 

probability that populations or individuals so exposed will be harmed and to what degree (risk 

characterization). 

Risk Characterization – The integration of information on hazard, exposure, and dose-response 

to provide an estimate of the likelihood that any of the identified adverse effects will occur in 

exposed people. 

Risk Management (in the context of human health) – A decision-making process that 

accounts for political, social, economic, and engineering implications together with risk-related 

information in order to develop, analyze, and compare management options and select the 

appropriate managerial response to a potential chronic health hazard. 

Route – see Exposure Route. 

Structure-Activity Relationship (SAR) approach to toxicology screening – This approach 

elucidates the relationship between features of chemical structure and biological activity. It is 

based on the premise that the biological fate and activity of a chemical (i.e., whether it is 

absorbed, metabolized, or bioaccumulated and whether it interacts at a molecular level to exert a 

response) is ultimately determined by chemical structure. 

Scenario Evaluation Approach – An approach to quantifying exposure by measurement or 

estimation of both the amount of a substance contacted and the frequency/duration of contact and 

subsequently linking these together to estimate exposure or dose. 

Sensitivity Analysis – Refers to the variation in output of a model with respect to changes in the 

values of the model input(s). Sensitivity analysis can provide a quantitative ranking of the model 

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Short-Term Exposure – Repeated exposure by the oral, dermal, or inhalation route for more 

than 24 hours, up to 30 days. 

Slope Factor – An upper bound, approximating a 95% confidence limit, on the increased cancer 

risk from a lifetime exposure to an agent. This estimate, usually expressed in units of proportion 

(of a population) affected per mg/kg/day, is generally reserved for use in the low-dose region of 

the dose-response relationship, i.e., for exposures corresponding to risks less than 1 in 100. 
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Source – The origin of an agent for the purposes of an exposure assessment. 

Source-to-Dose Model – An approach where an environmental agent is followed from its source 

to the resulting dose. 

Stakeholder – An interested party who is concerned with the decisions made about how a risk 

may be mitigated, avoided, reduced, or eliminated, and the communities that may be impacted by 

regulatory decisions.

Stressor – Any entity, stimulus, or condition that can modulate normal functions of the organism 

or induce an adverse response (e.g., agent, lack of food, drought). 

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Compensation, and Liability Act (CERCLA) (U.S. 96th Congress, 1980) to respond directly to 

releases or threatened releases of hazardous substances that may endanger health or welfare. 

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Susceptibility – Increased likelihood of an adverse effect or an exposure, often discussed in 

terms of relationship to a factor that can be used to describe a human subpopulation (e.g., life 

stage, demographic feature, or genetic characteristic). 

Susceptible Subgroups – May refer to life stages, e.g., children or the elderly, or to other 

segments of the population, e.g., asthmatics, the immune-compromised, or the highly exposed. 

The term is likely to be somewhat chemical-specific, and may not be consistently defined in all 

cases. 

Target Organ – The biological organ most adversely affected by exposure to a chemical, 

physical, or biological agent. 

Toxicity – Deleterious or adverse biological effects elicited by a chemical, physical, or 

biological agent. 

Toxicodynamics (TD) – The determination and quantification of the sequence of events at the 

cellular and molecular levels leading to a toxic response to an environmental agent (sometimes 

referred to as pharmacodynamics, also MOA. 

Toxicokinetics (TK) – The determination and quantification of the time course of absorption, 

distribution, metabolism, and excretion of chemicals (sometimes referred to as 

pharmacokinetics). 

Toxification – Metabolic conversion of a potentially toxic substance to a product that is more 

toxic. 

Uncertainty – Uncertainty occurs because of a lack of knowledge. It is not the same as 

variability. For example, a risk assessor may be very certain that different people drink different 

amounts of water but may be uncertain about how much variability there is in water intakes 

within the population. Uncertainty can often be reduced by collecting more and better data, 

whereas variability is an inherent property of the population being evaluated. Variability can be 
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better characterized with more data but it cannot be reduced or eliminated. Efforts to clearly 

distinguish between variability and uncertainty are important for both risk assessment and risk 

characterization. 

Uncertainty Factor (UF) – One of several, generally 10-fold, default factors used in 

operationally deriving the RfD and RfC from experimental data. The factors are intended to 

account for 1) variation in susceptibility among the members of the human population (i.e., 

interindividual or intraspecies variability); 2) uncertainty in extrapolating animal data to humans 

(i.e., interspecies uncertainty); 3) uncertainty in extrapolating from data obtained in a study with 

less-than-lifetime exposure (i.e., extrapolating from subchronic to chronic exposure); 4)

uncertainty in extrapolating from a LOAEL rather than from a NOAEL; and 5) uncertainty 

associated with extrapolation when the database is incomplete. 

Variability – Variability refers to true heterogeneity or diversity. For example, among a 

population that drinks water from the same source and with the same contaminant concentration, 

the risks from consuming the water may vary. This may be due to differences in exposure (i.e., 

different people drinking different amounts of water and having different body weights, different 

exposure frequencies, and different exposure durations) as well as differences in response (e.g., 

genetic differences in resistance to a chemical dose). Those inherent differences are referred to 

as variability. Differences among individuals in a population are referred to as interindividual 

variability; differences for one individual over time is referred to as intraindividual variability. 

Vulnerability – A matrix of physical, chemical, biological, social, and cultural factors which 

result in certain communities and sub-populations being more susceptible to environmental 

toxins, being more exposed to toxins, or having compromised ability to cope with and/or 

recover from such exposure. Four types of vulnerability are considered with regard to a life 

stage approach: susceptibility or sensitivity, differential exposure, differential preparedness, 

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Weight of Evidence (WOE) – An approach requiring a critical evaluation of the entire body of 

available data for consistency and biological plausibility. Potentially relevant studies should be 

judged for quality and studies of high quality given much more weight than those of lower 

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51 Executive Order. (1997) Executive Order13045–Protection of children from environmental health risks and safety 

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55 Hattis, D. (2004) Human interindividual variability in parameters related to susceptibility for toxic effects. 

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32 Lorber, M; Phillips, L. (2002) Infant exposure to dioxin-like compounds in breast milk. Environmental Health 

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Price, PS; Chaisson, CF; Koontz, M; Wilkes, C; Ryan, B; Macintosh, D; Georgopoulos, P. (2003) Construction of a 

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7 

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11 U.S. EPA (Environmental Protection Agency). (1991) Guidelines for developmental toxicity risk assessment. 

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U.S. EPA (Environmental Protection Agency). (1994) Methods for derivation of inhalation reference concentrations 

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Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-90/066F. 

20 Available online at http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993

21 

22 U.S. EPA (Environmental Protection Agency). (1995a) Policy on evaluating health risks to children. Office of the 

23 Administrator, Washington, DC. Available online at http://www.epa.gov/osa/spc/htm/memohlth.htm

24 

25 

26 

U.S. EPA (Environmental Protection Agency). (1995b) Application of benchmark dose methodology to data from 

prenatal developmental toxicity studies. Washington, DC; EPA/600/A-95/135. Available online at 

27 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=40957. 

28 

29 

30 

U.S. EPA (Environmental Protection Agency). (1996) Guidelines for reproductive toxicity risk assessment. Risk 

Assessment Forum, Washington, DC; 630/R-96/0009. Available online at 

31 http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=2838

32 

33 

34 

U.S. EPA (Environmental Protection Agency). (1997a) Guidance on cumulative risk assessment. Part 1: Planning 

and scoping. Office of the Administrator, Washington, DC. Available online at 

35 http://epa.gov/osa/spc/htm/cumrisk2.htm

36 

37 

38 

U.S. EPA (Environmental Protection Agency). (1997b) Guiding principles for Monte Carlo analysis. Office of 

Research and Development, Risk Assessment Forum. Washington, DC; EPA/630/R-97/001. Available online at 

39 http://www.epa.gov/ncea/raf/montecar.pdf

40 

41 

42 

U.S. EPA (Environmental Protection Agency). (1997c) Summary of the U.S. EPA Colloquia on a Framework for 

Human Health Risk Assessment: Volume 1. Risk Assessment Forum, Washington, DC; EPA/600/R-99/001. 

43 Available online at http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=12186

44 

45 U.S. EPA (Environmental Protection Agency). (1998a) Guidelines for ecological risk assessment. Federal Register 

46 63(93):26846-26924. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=36512

47 

48 

49 

U.S. EPA (Environmental Protection Agency). (1998b) Guidelines for neurotoxicity risk assessment. Federal 

Register 63(93):26926-26954. Available online at 

50 http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=4555

51 

52 

53 

U.S. EPA (Environmental Protection Agency). (1998c) Summary of the U.S. EPA Colloquium on a Framework for 

Human Health Risk Assessment: Volume 2. Risk Assessment Forum, Washington, DC. Available online at 

54 http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=55007

55 
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03/01/06 107 DRAFT—DO NOT CITE OR QUOTE 

1 

2 

U.S. EPA (Environmental Protection Agency). (1999a) Report of the workshop for selecting input distributions for 

probabilistic assessments. Office of Research and Development, Washington, DC; EPA/630/R-98/004. Available 

3 online at http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=12487

4 

5 U.S. EPA (Environmental Protection Agency) (1999b) Toxicological review for ethylene glycol monobutyl ether. 

6 Available online at http://www.epa.gov/iris/toxreviews/0500-tr.pdf

7 

8 

9 

U.S. EPA (Environmental Protection Agency). (2000a) Benchmark dose technical guidance document (external 

review draft). Risk Assessment Forum, Washington, DC; EPA/630/R-00/001. Available online at 

10 http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=4727

11 

12 

13 

14 

U.S. EPA (Environmental Protection Agency). (2000b) Options for developing parametric probability distributions 

for exposure factors. National Center for Environmental Assessment, Office of Research and Development, 

Washington DC; EPA/600/R-00/058. Available online at 

15 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=20867

16 

17 

18 

U.S. EPA (Environmental Protection Agency). (2000c) Science policy handbook: risk characterization. Science 

Policy Council, Washington, DC; EPA/100/B/00/002. Available online at 

19 http://www.epa.gov/osa/spc/htm/rchandbk.pdf

20 

21 

22 

U.S. EPA. (Environmental Protection Agency). (2000d) Strategy for research on environmental risks to children. 

Office of Research and Development, Washington, DC; EPA/600/R-00/068. Available online at 

23 http://www.epa.gov/ncea/pdfs/strat4resrch.pdf

24 

25 

26 

U.S. EPA (Environmental Protection Agency). (2000e) Guidelines for preparing economic analyses. Office of the 

Administrator, Washington DC; EPA/240-R-00-003. Available online at 

27 http://yosemite.epa.gov/ee/epa/eed.nsf/webpages/Guidelines.html

28 

29 

30 

31 

U.S. EPA (Environmental Protection Agency). (2001a) Risk assessment guidance for Superfund: process for 

conducting probabilistic risk assessments. Volume 3, Part A. Office of Solid Waste and Emergency Response, 

Washington, DC; EPA/540/R-02/002. Available online at 

32 http://www.epa.gov/oswer/riskassessment/rags3a/index.htm

33 

34 

35 

36 

U.S. EPA (Environmental Protection Agency). (2001b) Risk assessment guidance for Superfund: Volume I - Human 

Health Evaluation Manual (Part D, Standardized Planning, Reporting and Review of Superfund Risk Assessments). 

Office of Emergency and Remedial Response, Washington, DC; 9285.7-01D. Available online at 

37 http://www.epa.gov/oswer/riskassessment/ragsd/index.htm

38 

39 

40 

U.S.EPA (Environmental Protection Agency). (2001c) Exploration of aging & toxic response issues. Risk 

Assessment Forum, Washington, DC; EPA/630/R-01/003. Available online at 

41 http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=8298

42 

43 

44 

U.S. EPA (Environmental Protection Agency). (2002a) Child-specific exposure factor handbook (interim report). 

Office of Research and Development, National Center for Environmental Assessment, Washington, DC; 

45 EPA/600/P/00/002B. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=36528

46 

47 

48 

U.S. EPA (Environmental Protection Agency). (2002b) A review of the reference dose and reference concentration 

processes. Risk Assessment Forum, Washington, DC; EPA/630/P-02/002F. Available online at 

49 http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=36836

50 

51 

52 

U.S. EPA (Environmental Protection Agency). (2002c) Determination of the appropriate FQPA safety factor(s) in 

tolerance assessment. Office of Pesticide Programs, Office of Pesticide Programs, Washington, DC. Available 

53 online at http://www.epa.gov/oppfead1/trac/science/determ.pdf. 

54 
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03/01/06 108 DRAFT—DO NOT CITE OR QUOTE 

1 

2 

U.S. EPA (Environmental Protection Agency). (2003a) Framework for cumulative risk assessment. Risk 

Assessment Forum, Washington, DC; EPA/630/P-02/001F. Available online at 

3 http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=54944 

4 

5 

6 

7 

U.S. EPA (Environmental Protection Agency). (2003b) Guidance on selecting the appropriate age groups for 

assessing childhood exposures to environmental contaminants. (external review draft). Risk Assessment Forum, 

Washington, DC; EPA/630/P-03/003A. Available online at 

8 http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=429113

9 

10 

11 

U.S. EPA (Environmental Protection Agency). (2003c) Human health research strategy. Office of Research and 

Development, Washington, DC; EPA/600/R-02/050. Available online at 

12 http://www.epa.gov/nheerl/humanhealth/HHRS_final_web.pdf

13 

14 

15 

16 

U.S. EPA (Environmental Protection Agency). (2003e) Children’s health valuation handbook. Office of Children’s 

Health Protection and National Center for Environmental Economics. Office of Policy, Economics and Innovation, 

Washington, DC; EPA-100-R-03-003. Available online at 

17 http://yosemite.epa.gov/ee/epa/eed.nsf/webpages/HandbookChildrensHealthValuation.html

18 

19 U.S. EPA (Environmental Protection Agency) (2003f) Toxicological review of xylenes (EPA 635/R-03/001). 

20 Available online at http://www.epa.gov/iris/toxreviews/0270-tr.pdf

21 

22 

23 

24 

U.S. EPA (Environmental Protection Agency). (2005a) Approaches for the application of physiologically based 

pharmacokinetic data and models in risk assessment. Office of Research and Development, National Center for 

Environmental Assessment, Washington, DC. Available online at 

25 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=135427

26 

27 

28 

U.S. EPA (Environmental Protection Agency). (2005b) Guidelines for carcinogen risk assessment. Risk Assessment 

Forum, Washington, DC. EPA/630/P-R-03/001B.003. Available online at 

29 http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=439797

30 

31 

32 

U.S. EPA (Environmental Protection Agency). (2005c) Supplemental guidance for assessing cancer susceptibility 

from early-life exposure to carcinogens. Risk Assessment Forum, Washington, DC; EPA/630600/R-03/003F. 

33 Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=439798

34 

35 

36 

U.S. EPA (Environmental Protection Agency) (2005d) Review of the National Ambient Air Quality Standards for 

Particulate Matter: Policy Assessment of Scientific and Technical Information, OAQPS Staff Paper (EPA-452/R-05-

37 005). Available online at http://www.epa.gov/ttn/naaqs/standards/pm/s_pm_cr_sp.html

38 

39 

40 

U.S. EPA (Environmental Protection Agency) (2005e) Air quality criteria for ozone and related photochemical 

oxidants (Second external review draft) (EPA/600/R-05/004aB). Available online at 

41 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=137307

42 

43 

44 

U.S. EPA (Environmental Protection Agency) (2005f) Guidance on Selecting the Appropriate Age Groups for 

Assessing Childhood Exposures to Environmental Contaminants. Risk Assessment Forum, Washington, DC, 

45 EPA/630/P-03/003F. Available online at http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=146583

46 

47 U.S. FDA (Food and Drug Administration). (1997) Food and drug administration modernization act. PL 105-115. 

48 Available online at http://www.fda.gov/cder/guidance/105-115.htm

49 

50 U.S. FDA (Food and Drug Administration). (2002) Best pharmaceuticals for children act. PL 107-109. Available 

51 online at http://www.fda.gov/opacom/laws/pharmkids/contents.html

52 

53 

54 

U.S. FDA (Food and Drug Administration). (2003a) Guidance for industry – nonclinical safety evaluation of 

pediatric drug products. U.S. Department of Health and Human Services. Food and Drug Administration. Center for 

55 Drug Evaluation and Research (CDER). Available online at http://www.fda.gov/cder/guidance/3816dft.PDF

56 
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03/01/06 109 DRAFT—DO NOT CITE OR QUOTE 

1 U.S. FDA (Food and Drug Administration). (2003b) Pediatric research equity act. PL 108-155. Available online at 

2 http://www.fda.gov/opacom/laws/prea.html

3 

4 

5 

6 

Wood, SL; Beyer, BK; Cappon, GD. (2003) Species comparison of postnatal CNS development: functional 

measures. Birth Defects Research Part B: Developmental and Reproductive Toxicology 68(5):391-407. Available 

online at 

7 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14745989&

8 query_hl=163

9 

10 

11 

World Health Organization (WHO). Principles for evaluating health risks in children associated with exposure to 

chemicals (Provisional outline). International Programme on Chemical Safety (IPCS) Environmental Health Criteria 

12 document (EHC). Available online at http://www.who.int/ipcs/publications/ehc/provisional_outline/en/

13 

14 

15 

Zoetis, T; Hurtt, ME. (2003a) Species comparison of anatomical and functional renal development. Birth Defects 

Research Part B: Developmental and Reproductive Toxicology 68(2):111-120. Available online at 

16 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12866702&

17 query_hl=160

18 

19 

20 

Zoetis, T; Hurtt, ME. (2003b) Species comparison of lung development. Birth Defects Research Part B: 

Developmental and Reproductive Toxicology 68(2):121-124. Available online at 

21 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12866703&

22 query_hl=158

23 

24 

25 

Zoetis, T; Walls, I. (ed.) (2003) Principles and practices for direct dosing of pre-weaning mammals in toxicity 

testing and research. Risk Science Institute, Washington, DC: ILSI Press. Available online at 

26 http://www.ilsi.org/publications/pubslist.cfm?publicationid=520

27 

28 

29 

30 

Zoetis T; Tassinar, MS; Bag, C; Walthall, K; Hurtt, ME. (2003) Species comparison of postnatal bone growth and 

development. Birth Defects Research Part B: Developmental and Reproductive Toxicology 68(2): 86-110. 

Available online at 

31 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12866701&

32 query_hl=155

33 
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03/01/06 110 DRAFT—DO NOT CITE OR QUOTE 

1 

2 

APPENDIX 1. HAZARD CHARACTERIZATION – EXAMPLE QUESTIONS FOR 

THE DATA EVALUATION OF INDIVIDUAL STUDIES 

Topic/Subject 

(Section) 

Study 

Type 

General Questions Life-Stage Specific Questions 

Study Purpose 

(4.1.3.1.) 

All 

Studies 

►What was the purpose of the 

study? Was the study testing a 

hypothesis? 

►Was the study conducted in 

response to a public health concern? 

►Were life-stage-specific exposures and 

associated outcomes addressed in the 

study? 

►What was the study design (e.g., 

cross-sectional, longitudinal, 

multigenerational)? 

►What life stages were represented in the 

study (for both exposure and outcome)? 

Do the representative life stages include 

developmental life stages? 

All 

Studies 

►What were the study protocol, 

exposure paradigm, exposure 

timing, exposure frequency, and 

outcomes assessed? 

►Did the study methods address specific 

life stages? If so, how? 

►What were the sources of data for 

exposure, health outcome, and risk 

factors/confounders/effect 

modifiers? What were the strengths 

and limitations? 

►Did the available studies assess 

exposures during development? 

►What methods were used to 

control, measure, or reduce various 

forms of potential error (e.g., 

selection bias, misclassification 

bias) and their potential impact on 

the findings? Does this impact the 

validity and reliability of the 

methods used to determine exposure 

and outcome? If so, how? What 

were the response rates? 

►How do the methods impact the validity 

and reliability to determine children’s 

exposure and outcome? 

►What demographic and other 

personal/host factors were 

examined? 

►Were potential confounders and 

effect modifiers examined and 

adjusted for, where appropriate? 

►How was life stage/age measured (this is 

particularly important for gestation 

exposures)? 

►Were other life stage factors important 

for the outcomes and exposures assessed? 

Study Design 

(4.1.3.2.) 

Human 

Studies 

►Was a biological explanation of 

the findings proposed? If so, were 

the findings examined for biological 

plausibility, internal and external 

consistency of findings, and the 

influence of limitations of design, 

data sources, and analytic methods? 

►Were biological plausibility, internal 

and external consistency of findings, and 

limitations considered for life stagespecific data? 
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Topic/Subject 

(Section) 

Study 

Type 

General Questions Life-Stage Specific Questions 

►Was the study conducted in 

accordance with good laboratory 

practices? 

►Were life stage -specific studies 

conducted in accordance with good 

laboratory practice? 

Animal 

Studies 

►Were appropriate analytical 

techniques used to measure the 

stability, homogeneity, and actual 

dose level of the test substance in 

the study (in the water, feed, air, 

etc.)? Was target dose assessed or 

modeled? 

►Were perinatal doses assessed or 

modeled? 

►Were an appropriate number of 

animals used? Were both sexes 

examined, as appropriate? Were 

adequate sample sizes assessed for 

each outcome? 

►For developmental outcomes, were 

adequate sample sizes assessed; were 

appropriate numbers of litters used; were 

both sexes considered as appropriate? 

►Were the dose range and levels 

appropriate? What was the basis for 

selecting doses? 

►Was an appropriate method used 

to assign animals to dose or test 

groups? 

►Were the dose range and levels 

appropriate across life stages evaluated? 

►Was an appropriate method used to 

assign animals to dose or test groups at 

various life stages? 

►Was an appropriate route and 

matrix (e.g., vehicle, formulation, 

duration) of exposure employed? 

►Was an appropriate route and matrix 

(e.g., vehicle, formulation, duration) of 

exposure employed across various life 

stages studied? 

►What were the animal species and 

strain used in the study? Is this the 

most relevant animal model and 

why? 

►What is known about the sensitivity of 

this animal species and strain for the 

exposure and outcomes of concern? 

►What is known about critical windows 

of exposure (e.g., developmental windows 

of susceptibility) or effect (e.g., latent 

expression of developmental toxicity) for 

the animal species and strain? 
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03/01/06 112 DRAFT—DO NOT CITE OR QUOTE 

Topic/Subject 

(Section) 

Study 

Type 

General Questions Life-Stage Specific Questions 

►Which outcomes were observed 

in the study? 

►Were all appropriate outcomes 

assessed (as determined by 

toxicological information about the 

chemical, including mode of action 

(MOA), target organ toxicity, etc.)? 

►At which life stages were outcomes 

assessed? Describe these outcomes. 

► Were there outcomes in the study that 

occurred at different life stages? Which 

outcomes occurred during developmental 

stages and which occurred during adult 

stages? 

►Were the outcomes life- stage 

dependent? 

►Were there life stage-specific outcomes 

that should have been assessed, but were 

not? 

►Were methods of assessing 

outcomes appropriate and optimum 

(if not, state limitations)? 

►Were methods to assess life stagespecific outcomes appropriate? 

►Were methods to assess outcomes after 

exposures at different life stages 

appropriate? If not, what were any possible 

restrictions or errors in the methods of 

assessments used in the study? 

Outcomes 

(4.1.3.4.) 

All 

Studies 

►What is known about the 

temporal relationship between 

exposure and outcome? 

►Describe the outcomes for exposures at 

different life stages. Were outcomes 

dependent upon the exposures during 

critical stages of development? 

►Is there a known MOA? Are 

outcomes consistent with what is 

known about 

MOA? 

►If there is a known MOA, is it relevant 

for life stages of exposure and 

the outcomes represented in the study, or 

would you expect the MOA to be 

different? Are there different MOAs 

suspected for different life stages? 

►Are there inconsistencies between the 

outcome and the assumed MOA at 

different life stages? For the outcomes 

assessed, have precursor events been 

identified? If so, were precursor events 

similar across life stages? 

►Are author interpretations and 

conclusions supported by the data? 

►Do the authors interpret the results of 

the study according to life stages or in a 

way that acknowledges differences in life 

stages? Do the authors make 

developmental stage-specific conclusions 

in the study? If so, describe. 

►Are the author’s assumptions and 

interpretations about life stage-specific 

results supported by the data? 
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03/01/06 113 DRAFT—DO NOT CITE OR QUOTE 

Topic/Subject 

(Section) 

Study 

Type 

General Questions Life-Stage Specific Questions 

►What was the type (i.e., single or 

multiple chemicals), route and 

method of exposure(s)? 

►Was the route the same throughout all 

life stages? 

►Were the methods of exposure 

appropriate (i.e., relevant to the age-related 

exposure pathways) for the age groups 

exposed? 

Study 

Exposures 

(4.1.3.3.) 

All 

Studies 

►What was the exposure/dose 

concentration? 

►Was the applied/target concentration 

(animal studies)/exposure/dose 

concentration validated or confirmed 

analytically? 

►Did exposure occur across more than 

one developmental life stage(s) in the 

study? If so, which exposures/doses were 

assessed during specific stage(s) of 

development? 

►Were the dose levels the same across all 

the life stage(s) identified in the study? If 

not, what were the exposure/dose level 

differences between different life stages? 

►Were the differences attributable to 

factors at specific life stages (e.g., behavior 

or activities)? 

►Were there developmental stage-specific 

behaviors that could influence the 

exposure (e.g., maternal nurturing 

behaviors, offspring nursing or weaning 

activities, or exploratory/play behaviors in 

the immature individual)? If so, in what 

direction would the dose likely be 

affected? 

►What was the exposure source(s)? ► Was there more likely to be exposure(s) 

from this source during certain life stages 

than others? If so, would this be expected 

to affect the results of the study? Was this 

accounted for in the study? 

Human 

Studies 

►Were other possible sources of 

exposure considered? 

►Were other possible sources of exposure 

considered for various life stages? 

Animal 

Studies 

►Was the duration of exposure 

adequate and relevant for the study? 

►Did the exposure interval cover different 

life stages, partially or completely? 

►Was exposure verified for critical life 

stages? 

Toxicokinetics 

(4.1.3.5.) 

All 

Studies 

►Are there available toxicokinetic 

(TK) data? 

►Are there TK data for the specific life 

stage(s) assessed in the study? 

►Are there life stage-specific differences 
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03/01/06 114 DRAFT—DO NOT CITE OR QUOTE 

Topic/Subject 

(Section) 

Study 

Type 

General Questions Life-Stage Specific Questions 

in toxification/ or detoxification? 

Animal 

Studies 

►Were possible alterations in 

metabolism considered at the higher 

exposure/dose levels? 

►Are there data to suggest life stagespecific metabolic differences at the higher 

exposures/doses? 

Toxicodynamics 

(4.1.3.6.) 

►Are there available 

toxicodynamic (TD) data? 

►Are there any life stage-specific TD 

data? 

All 

Studies 

►What is known about the MOA 

for the toxicant? 

►Are MOA data known for other life 

stages and outcomes relevant to the life 

stages of concern in this study? 

Qualitative 

Dose-Response 

(4.1.3.7.) 

All 

Studies 

►What is the dose-response 

relationship for adverse outcomes? 

►Are there life stage-specific doseresponse relationships? Do they vary by 

life stage? 

Uncertainties 

(4.1.3.8.) 

►Are there data gaps or 

inadequacies in the study protocol 

or methodologies that lead to 

uncertainties in the evaluation of the 

study? 

►Are any of these data gaps or 

uncertainty considerations life stagespecific, i.e., were some life stages 

assessed, while and others were not? 

►Were critical windows of exposure and 

associated outcomes adequately 

addressed? 

►Are there any data or other 

information that are critical to the 

evaluation of the study that were not 

included or not fully reported? 

►Were these inadequacies in data 

presentation specific to critical life stages 

or windows of exposure? 

All 

Studies 

►Are there data or analyses that are 

inconclusive? 

►Were there inconclusive data analyses 

for the interpretation of outcomes for 

specific life stages? 

►What pathways (including media 

and route) of exposure were 

covered in the studies? 

►What intervals of exposure were 

examined? 

►Are they pathways of exposure relevant 

to children? 

►What intervals of exposure were 

examined? 

►Did these exposure intervals include all 

relevant life stages? 

Summarizing 

the Hazard 

Database 

(4.1.4.1)

All 

Studies 

►What outcomes were observed? ►Do the data provide information about 

the susceptibility of children at specific 

life stages? Is the relationship consistent 

across life stages? 

►What is the relationship among 

the different outcomes (i.e., what is 

the pattern of outcomes observed)? 

►Have the appropriate studies been 

performed (within the database or 

elsewhere) to determine critical windows 

of exposure (Selevan et al. 2000)? If so, 
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03/01/06 115 DRAFT—DO NOT CITE OR QUOTE 

Topic/Subject 

(Section) 

Study 

Type 

General Questions Life-Stage Specific Questions 

what are they? Did exposure intervals 

include known or suspected critical 

windows? 

►Does the pattern of outcomes suggest a 

syndrome? 

►What are the data gaps for 

exposure? 

►Which life stages of exposure were 

assessed? Were all life stage-relevant 

exposure intervals evaluated? Did 

exposure occur throughout all critical life 

stages? Were there developmental stages 

during which exposure was intermittent or 

did not occur, and what was the potential 

impact of these gaps in exposure? 

►Were all life stage-relevant pathways of 

exposure evaluated? Are there 

toxicokinetic data that support the study 

design and the interpretation of the data for 

critical life stages? 

►Are there additional exposures beyond 

those present that might provide additional 

information relevant to children’s health 

risk assessment? 

►Were life stage-appropriate biomarkers 

of exposure assessed? 

Uncertainties, 

Gaps, and 

Variabilites in 

the Database 

(4.1.4.2.4) 

All 

studies 

►What are the data gaps for 

outcome? 

►Were all critical outcomes (both broad 

screening level and chemical- or MOAspecific outcomes) evaluated across life 

stages? For example, have appropriate 

organ systems, tissues, and outcomes been 

adequately assessed for all life stages of 

concern? 

►Were life stage-appropriate biomarkers 

of outcome assessed? 
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03/01/06 116 DRAFT—DO NOT CITE OR QUOTE 

Topic/Subject 

(Section) 

Study 

Type 

General Questions Life-Stage Specific Questions 

►What uncertainties have been 

identified? 

►Did the conduct of the study 

result in uncertainties in study 

results or data interpretation? Do 

some studies or data need to be 

excluded on the basis of poor 

quality? 

►Can information from the 

comparison of structurally related 

chemicals, or chemicals with a 

similar MOA, be used to modify the 

impact of identified uncertainties or 

data gaps? 

►Have any uncertainties specific to the 

assessment of risk to children’s health been 

identified? 

►Did the conduct of the study result in 

uncertainties in study results that are 

particularly pertinent to children’s health 

risk assessment or life stage-specific data 

interpretation? Do some studies or data 

need to be excluded on the basis of poor 

quality? 

►Can information from the comparison of 

structurally related chemicals, or chemicals 

with a similar MOA, be used to modify the 

impact of identified uncertainties or data 

gaps for life stage-specific data? 
This document is a draft for review purposes only and does not constitute Agency policy. 

03/01/06 117 DRAFT—DO NOT CITE OR QUOTE 

Topic/Subject 

(Section) 

Study 

Type 

General Questions Life-Stage Specific 

Questions 

Extent of the 

Database 

(4.1.4.2.5)

All 

Studies 

►What is the extent of the database? 

►What is the quality of the database? 

►What is the quantity of the database 

(i.e., what studies were available for 

evaluation)? 

►On what information is the 

characterization of the extent of the 

database established? How do the 

quality and quantity of the database 

affect the uncertainties and data gaps? 

►What is the extent of the database 

for children’s health risk assessment? 

►What is the quality of life stagespecific data included in the database? 

►What is the quantity of life stagespecific data in the database? 

►Does the extent of the database for 

children’s health hazards indicate the 

need for follow-up studies to better 

define uncertainties, e.g., for the 

specific assessment question and 

issues?