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 Protecti on 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DC 20460This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 ii DRAFT—DO NOT CITE OR QUOTE DISCLAIMER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 pr oducts 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. Nati onal 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.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 iii DRAFT—DO NOT CITE OR QUOTE CONTENTS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 ABBREVIAT IONS 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 Consid erations 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 Evalua tion 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 ...................................................... 33This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 iv DRAFT—DO NOT CITE OR QUOTE 4.1.4.2.6. Relevance of Animal Data to Humans.............................. 34 4.1.5. Life Stage-Specific H azard 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 Deri vation 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 App lication of Uncertainty Factors (Including Age-Dependent Adjustment Factors) ................................ 55 4.2.5. Life Stage-Specific Dose-R esponse 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 Da ta 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 Expos ure 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 .......................................................................... 77This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 v DRAFT—DO NOT CITE OR QUOTE 5. LIFE STAGE-SPECIFIC RISK CHARACTERIZATION .................................................... 78 5.1. SUMMARY OF THE MA JOR 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 VA RIABILITY AND UNCERTAINTY ANALYSES .................................................................................................................. 84 5.3. RISK CONTEXT ........................................................................................................... 85 6. SUMMARY AND IDENTIFICA TION OF GAPS IN GUIDANCE FOR CHILDREN’S HEALTH RISK ASSESSMENT ............................................................. 87

GLOSSARY

............................................................................................................................... . 89

REFERENCES ............................................................................................................................ 98 APPENDIX 1. Hazard Characterization – Exampl e Questions for the Data Evaluation of Individual Studies ........................................................................................................... 110This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 vi DRAFT—DO NOT CITE OR QUOTE LIST OF TABLES

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

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

5-2. Issues Addressed in Dose-R esponse Characterization (Section 4.2.) .................................. 82 5-3. Issues Addressed in Expos ure Characterization (Section 4.3.) ............................................ 83

5-4. Issues Addressed in Vari ability and Uncertainty Analyses.................................................. 85 5-5. Types Of Issues To Be Consider ed to Illustrate The Risk Context ...................................... 86This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 vii DRAFT—DO NOT CITE OR QUOTE 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 stag e-specific problem formulation .............................................. 10 3-2. Conceptual Model for Problem ........................................................................................ 14 3-3. Life stage-specifi c database inventory sheet .................................................................... 16 4-1. Framework for life stage-specific analysis with animal and human data ........................ 19 4-2. Flow diagram for life stag e specific hazard characterization ........................................... 20 4-3. Hazard characterization Step 1: Evalua te individual studies with exposures during developmental life stages (including preconception) ....................................................... 22 4-4. Hazard characterization Step 2: Eval uate the database as a whole for potential hazards to children from environmenta l exposures during different life stages .............. 28 4-5. Conceptual view of a we ight of evidence (WOE) assessment ......................................... 30 4-6. Hazard characterization, Step 3: De scribe 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 st age-specific exposure assessment .............................................. 58 4-10. Exposure routes duri ng developmental life stages ........................................................... 62This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 viii DRAFT—DO NOT CITE OR QUOTE 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 C max 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 V max Maximum velocity WOE Weight of evidenceThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 ix DRAFT—DO NOT CITE OR QUOTE PREFACE

The mission of the U. S. Environmental Prot ection 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 a nd children regarding ev aluation of risk to environmental exposures ( NRC, 1993 ). In addition to this report a nd 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 exp licitly as a part of risk assessments generated during its decision-making process, including the setting of standard s to protect public health and the environment. Subsequent provisions in the Food Quality Protection Act (FQPA) (U.S. 104 th Congress, 1996a) and the Safe Drinking Water Act (SDWA) Amendments (U.S. 104 th Congress, 1996b) underscored this policy by requiring a focus on the evaluation of children’s exposures and toxicities in the context of risk assessm ent. In 1997, Presidential Executive Order 13045, Protection of Children from Environm ental Health Risks and Safety Risks (April, 1997) , gave further emphasis to the need for establishi ng 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 issu es 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 h ealth, particularly the a pplication 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 comprehensiv e document that can serve as a resource of information on childre n’s health risk assessment. In 1999, a draft report that collected inform ation on current EPA guidance and practices was developed for the Office of Children’s He alth Protection (ICF Consulting, 1999). This report was a compendium of information on child-related risk assessment policy and methodology guidance, but much has happened sin ce the draft was completed. This frameworkThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 x DRAFT—DO NOT CITE OR QUOTE document builds on that report and other driver s referred to above by updating the information and linking to reference documents and other pub lished information that can be used as a resource for those interested in ch ildren’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 de veloped at other agencies such as the U.S. Food and Drug Administration (FDA), which re gulates pharmaceuticals, medical devices, biologics, food, animal feed and drugs, cosme tics, 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 w ithin 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 grante d. Although the guidance documents may apply specifically to pharmaceutical testing and regula tion, there can be significant overlap with assessments conducted to determine risk to ch ildren from environmental exposures. For example, Guidance to Industry – Nonc linical 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 Associ ated 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. 03/01/06 xi DRAFT—DO NOT CITE OR QUOTE 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 heal th risk assessment are underwa y, and the intent is for this framework on health risks from environmental expos ures to children to be incorporated into the overall framework.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 xii DRAFT—DO NOT CITE OR QUOTE AUTHORS, CONTRIBUTORS, AND REVIEWERS

AUTHORS Stan Barone Jr., National Center for Envir onmental Assessment, Office of Research and Development, U.S. Environmental Protecti on Agency, Washington, DC. (Formerly National Health and Environmental Effects Research Labo ratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC.). Rebecca C. Brown, National Center for Environm ental Assessment, Office of Research and Development, Environmental Protection Agenc y, Washington, DC. (For merly Association of Schools of Public Health Fellow, National Cent er for Environmental Assessment, Office of Research and Development, Environmen tal 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 Comp utational Toxicology, Office of Research and Development, U.S. Environmental Protection Ag ency, Research Triangle Park, NC. (Formerly National Exposure Research Laboratory, Offi ce of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC.) Carole A. Kimmel, formerly Na tional Center for Environmental Assessment, Office of Research and Development, U.S. Environmenta l Protection Agency, Washington, DC. Susan Makris, National Center for Environm ental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. (Formerly Office of Pesticide Programs, Office of Pr evention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC.) Hisham El-Masri, National Center for Envir onmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. Jacqueline Moya, National Center for Envir onmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. Sherry G. Selevan, National Center for Envir onmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. Babasaheb R. Sonawane, National Center for E nvironmental Assessment, Office of Research and Development, U.S. Environmenta l Protection Agency, Washington, DC. Tracey Thomas, formerly American Associati on for the Advancement of Science Fellow, National Center for Environmental Assessment, Office of Research a nd Development, U.S. Environmental Protection Agency, Washington, DC.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 xiii DRAFT—DO NOT CITE OR QUOTE Chad Thompson, National Center for Environm ental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. (Formerly American Association for the Advancemen t of Science Fellow, Nationa l Center for Environmental Assessment, Office of Research and Developm ent, U.S. Environmental Protection Agency, Washington, DC.)

INVITED INTERNAL AGEN CY 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. 03/01/06 1 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 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 re sult of exposures of e nvironmental agents, and (2) an overarching framework for a more complete asse ssment of health risks to children from exposures of environmental agents within EPA’ s risk assessment paradigm, which examines the impact of potential exposures dur ing 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 publ ished sources for more detailed information. Guidance, policies, and other relevant material s are referenced in the document and linked electronically (when copyright a llows) to the actual reference documents for easy access. The term “children” as used in this docume nt 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 throu ghout this document, includes exposure before conception, as well as during the developm ental life stages from conception through adolescence. Health risks may be detected du ring the same life stage as when the exposure occurred or they may not become apparent until much later in life. Life st ages are defined in this document as temporal stages (or intervals) of lif e that have distinct anatomical, physiological, and behavioral or functional characteristics that contribute to potential differences in vulnerability to environmental e xposures. A life stage approach to risk assessment considers the timeframe or life stage of exposure and outcome wh en 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 e xposure, and subsequent outcomes, which may not be expressed until later life stages. Informati on on mode(s) of action and pharmacokinetics that may inform life stages are anothe r main emphasis of this approach. Risk assessment using a life stage approach is a shift in perspective from the current me thodology that focuses primarily on adults, and then, secondarily, looks for informati on that may suggest greater susceptibility from exposures to children an d other subpopulations. The added value of using a life stage appr oach to risk assessment is a more comprehensive evaluation of the pot ential for vulnerability of various populations at different lifeThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 2 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 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, m odes of action (MOAs), anatomy, physiology, and behavior that can affect extern al exposure and internal dose metrics (units of measurement for dose). The use of MOA information is integr al to this framework and is employed in a consistent manner to th e EPA cancer guidelines ( U.S. EPA, 2005b , 2005c ) but is extended to the evaluation all outcomes. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 It is important that one needs to c onsider whether anyt hing is known about developmental life stages that would indicate particular vulnerability and incorporate that information in the assessment. This document al so addresses the difficult issue of integrating toxicity data and exposure information, which is especially challenging wh en data are limited for particular time periods during pregnanc y and early childhood development. The conceptual framework used in this doc ument follows the basic framework developed for other areas of risk assessment and incl udes problem formulation, analysis, and risk characterization as the three major phases in the pr ocess. Within this st ructure, questions for consideration in the process of scoping the problem to be addre ssed, 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 fo r various aspects of children’s health risk assessment are also discussed. In particular, guida nce is lacking for life stage-specific evaluation of several system- and disease- specific areas, related biomar kers and outcomes, MOA(s), doseresponse assessment, and exposure assessment. Also, guidance on the use of specific developmental outcomes for application to risk assessments for variou s 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. 03/01/06 3 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 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 st ages of development. The term “children” as used in this document includes the stages of development fr om conception through adolescence to adulthood. The assessment of health risks to children fr om environmental exposure, or “children’s exposure,” includes exposure to either pare nt before conception as well as during the developmental life stages from conception throu gh adolescence. Health risks may be detected during the same life stage as when the exposure o ccurred 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 fr amework outlines the essential phases in making judgments about the risks of children’s expos ure to environmental agents, singly or in combination. This information can be used in va rious situations, dependi ng 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 assess ment. 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 pr ocess of assessing risks to child ren as a result of exposure, existing sources for more detailed information are referenced and linked to the actual reference documents (when copyright allows). These s ources include guidelines, guidance documents, policies, and other relevant published materials that currently exist. The conceptual framework used in this doc ument follows the basic framework developed for other areas of risk assessment (e.g., Guidance on Cumulative Risk Assessment , U.S. EPA, 27 1997a; Guidelines for Ecological Risk Assessment , U.S. EPA, 1998a ) and includes problem formulation, analysis, and risk characterization as the three majo r phases in the process. Figure 2-1 shows this general health risk assessment framework. 28 29 30

# Risk Communication/Management Problem Formulation

Analysis

Risk CharacterizationAs Necessary, Collect Additional Data, MonitorResults; 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 CharacterizationAs Necessary, Collect Additional Data, MonitorResults; 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 1 Guidance on Cumulative Risk Assessment (U.S. EPA, 1997a) and includes three phases also identified in 2 Guidelines for Ecological Risk Assessment (U.S. EPA, 3 4

5 1998a) : problem formulation, analys is, and risk characterization.

The outline for this document adopts the gene ral framework for health risk assessment with a focus on life stage analysis (Figure 2-2, adapted from the framework in Daston et al. 6 7 8 9 10 11 (2004 ), and, in each phase of the proc ess raises questions to consider in assessing health risks to children from environmental exposure. This doc ument incorporates information from relevant risk assessment guidelines and ot her reports while focusing on sus ceptibility, both inherent and acquired, at different life stages, as well as the potential for gr eater exposure of environmental agents to children than adults.

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 4 DRAFT—DO NOT CITE OR QUOTE

## 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 OutcomesAs Necessary, Collect Additional Data, MonitorResults; 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 OutcomesAs Necessary, Collect Additional Data, MonitorResults; 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 incr eased emphasis on life stage-specific evaluations during problem formul ation, analysis, and risk characterization. (Source: Adapted from 1 2 3 Olin & Sonawane, 2003 .) 4

5 6 7 8 9 Assessing health risks to children as a result of e nvironmental exposure to children includes the consideratio n of risk from exposure before c onception, during the prenatal period, and through childhood to adolescence (F igure 2-3). Life stages are defined in this document as periods of life with distinct anatomical, physiological, and behavi oral or functional characteristics that contribute to potential differences in vuln erability to environmental

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 5 DRAFT—DO NOT CITE OR QUOTEFigure 2-3. Life stages of outc omes 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 reproduc tive age overlap between the adolescent and the adult periods. 1 2 3 4 5 6 7 8

9 10 11 12 exposures. 2 The life stages from conception thro ugh 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 processe s that determine susceptibility at the time

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 6 DRAFT—DO NOT CITE OR QUOTE 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. Division s between all life stages are not precise ( U.S. EPA 2001c , U.S. EPA, 2002b , Table 3-1). or Adversity or Outcome Function Effects Effective Dose Internal Dose Period

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

Biological Biologically Exposure

-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 Effective Dose Internal Dose Exposure

Period

Age Adult

Aged Adult Preconception

Infant Risk Prenatal Risk

Adolescent Risk Child Risk

ReproductiveAge Adult Risk

Aged Adult RiskDevelopment Toxicokinetics ToxicodynamicsThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 7 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 of exposure. A life stage approach for evalua tion of risks to children is a hypothesis driven approach that takes into account all relevant periods of exposur e explicitly considering where data do and do not exist for exposur e and health outcomes. It focuses attention on considerations of early life exposure and potential outcomes wh ich may be latent in their expression and is predicated on considerations of mode(s) of action considerations fo r 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 developmen t, even within a life stage. For example, gestational exposure is typically evaluated for each trimester; however, speci fic periods of vulnerability (also known as crit ical windows) for particular out comes might be much shorter period of time as discussed in a series of pub lications that resulted from an EPA-sponsored workshop ( Selevan, et al. 2000 ). 11 12 13 14 15 16 17 18 19 20 21 22 23 This report synthesizes the information curre ntly 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 id entified where further guidance is needed, as are areas in need of resear ch to support guidance. Within this structure, questions to be considered in the process of re viewing 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, pr ocess, 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 assessi ng risk to children. It is not intended to be proscriptive. The intended users of this a pproach are risk assessors involved in hazard characterization, dose response analysis, and expo sure characterization who consider children’s risk to environmental exposures. The central fo cus of this framework is the developing embryo, fetus, and child, thus extending and expanding the approach in Guidelines for Developmental 24 Toxicity Risk Assessment (U.S. EPA, 1991) . The framework also takes a child-protective approach to assessing risk 25 (Landrigan et al., 2004) by putting the child, rather than an environmental agent at the focus of the evalua tion. Because children ar e not a unique population but rather that all individuals pass through a series of life stages, this is considered a public health-oriented approach. 26 27 28 29 30 31 The added value of using a life stage appr oach to assess risks to children from environmental exposure is a comprehensive eval uation of the potential for vulnerability ofThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 8 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 various populations at different life stages. In contrast, assessm ents 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 li fe stages, based on what is known about critical windows of development for different organ sy stems and differences in anatomy, physiology, and behavior that can impact external exposure a nd internal dose metrics. In the course of developing an assessment, the lack of data for cer tain life stages is not meant to imply greater uncertainty in the assessment of risk to childr en. 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 assessm ent. 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 especia lly challenging because of data limitations for particular periods during pregna ncy 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 an d 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, physiol ogy, and behavior that can affect external exposure and internal dose metrics. M OA 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 he alth 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 ( 23 24 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” ( 25 26 U.S. EPA, 2005b , 2005c ). 27 28 29 30 31 32 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.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 9 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 3. PROBLEM FORMULATION

Problem formulation is a systematic planni ng phase that defines the problem to be addressed in the assessment. Th e purpose of a problem formulation step is to aid in efficiency and transparency of the assessment. A genera l 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 whethe r applied to assessment of any life stage of exposure (Figure 3-1). However, some of the speci fic considerations will be different in a risk assessment for childhood exposures. This secti on focuses primarily on the considerations for assessments of childhood exposures. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Problem formulation includes an initial ch aracterization of exposures and outcomes during all developmental life stag es, 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 pol icy factors are identified. Th ese steps include defining and identifying the purpose, scope, participants, appro aches, resources, and relevant past assessments available. The extent of the risk assessments can be site specific, ch emical specific, receptor based or broader in scope. In an assessm ent 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 e xposed via air, soil, and groundwater?

• What other individual or community charac teristics 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 AssessmentDiscussion of possible outcomes of assessmentwith 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 AssessmentDiscussion of possible outcomes of assessmentwith 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) an d 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 in form hazard characterization, dose-response assessment, and exposure assessment. Source: Adapted from 1 2 3 4 5 6 7 8 9 U.S. EPA, 2003a , Figure 1-3. 10 11 This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 10 DRAFT—DO NOT CITE OR QUOTEThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 11 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5

6

7

8

9

10 11 12 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 ar e identified. Risk assessors, risk managers, and stakeholders (e.g

. , impacted community, non governmental orga nizations) are involved in the process (U.S. 13 EPA, 2001b) . Stakeholders are broadly defined as the interested parties w ho are concerned with the decisions made about how a risk may be avoi ded, mitigated, or eliminated, as well as those who may be affected by regulator y decisions. Those participati ng in the problem formulation will depend on the problem being addressed. Gu idelines for stakeholder involvement are provided in 14 15 16 17 Framework for Cumulative Risk Assessment ( U.S. EPA, 2003a , p. 21) and are based on the recommendations in 18 Science and Judgment in Risk Assessment (NRC, 1994) and the 19 Presidential/Commission on Risk Assessment and Risk Management (NAS, 1997)

. 20 21 22 23 24 25 26 The approaches, such as methods and mode ls, 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 ( 27 U.S. EPA 2005b , Section 1.2.2). During planning and scoping, the risk assessment team (which includes the risk planning team; epidemiol ogists; public health specialists; toxicologists, including disciplinary specialist; chemists; and other technical experts) and the risk management team (which may incl ude economists, policy analysts, engineers, and 28 29 30 31This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 12 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 public health specialists) work together, informed by stakeholder input, to develop the rationale, scope, and relevant outputs for the ri sk assessment and characterization. This phase of problem formulation involves a qualitative screening evaluation of existing information to scope the assessment and identi fies whether children might have a greater potential for higher exposures or greater intrin sic susceptibility. The evaluation includes an examination of the quality and quantity of the av ailable 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 poten tial critical windows of exposure, level of exposure, individual and community characteris tics, 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 c onsiderations th at may influence the timing and breadth of the assessment. These factors may influence the risk management options, management goals, key participants, data sour ces, 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 hea lth 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 pr oblem formulation stage will help clarify the approaches needed for data evaluation and quant ification that may be mo st useful for assessing 29 30 31This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 13 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 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 a ssessment 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 identif ying relevant stressors, sources, pathways (including exposure media and routes), recep tors (exposed individua l 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 accumula tion of the information needed to develop a conceptual model (Figure 3-2) th at aids the segue from the pr oblem formulation stage to the analysis phase. The conceptual model forms the ba sis 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 expos ure scenarios, the lif e stage of exposure, the optimum times for evaluation of outcomes to be covered, and the iden tified 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 ex amination of the data to determine the life stages likely to be affected, given the propertie s of the environmental ag ent(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 pa ttern of exposures to parents or children, as appropriate, including the poten tial for dietary, drinki ng 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 specif ic developmental life stage is more vulnerable 28 29 30Source 1

Route 1

Dose 1 absorbed Media 1 Source 2

Route 2

Dose 2 absorbed Media 2 Individual Characteristics:

• Genetic Susceptibility

• Developmental Stage

• Behaviors

• Activities

• Locations

• Product use

• Diet Community Characteristics

Outcomes 

## Child Exposure Exposure 1 Exposure Exposure 2



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

Health assessment values (e .g., reference values for a specific duration) Source 1

Route 1

Dose 1 absorbed Media 1 Source 2

Route 2

Dose 2 absorbed Media 2 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 Exposure 1 Exposure Exposure 2



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

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

1 2 3 4 5 6 7

8 9 10 11 12 13 14 15 16 17 18 19 20 Figure 3-2. Conceptual Model for Problem. This figure shows an example of a conceptual model resulting from the problem formulation pl anning 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 follo wing 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 susc eptibility. A given product’s or compound’s properties, as well as its commercial uses a nd sources of exposure , provide qualitative information on where it is expected to be found in exposure media. Information on exposure pathways and a qua litative understanding of activity patterns (patterns of exposure) can be us ed 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, a nd locations that are a func tion 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 info rmation should be used to identify all potential sources, pathways (exposure media and routes), and s cenarios (population, time frames, locations, and activities).

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7

8 9

10

11

12 13 14

15 16 17 18 19 20 21

22 23

24 25

26

27 28

29 30 31 32 33 3.2.2. Outcome Considerations In this screening approach a preliminary id entification of toxic effects is preformed, including kinetic and dyna mic 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 know n 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 ge neral population? • What are the specific time periods of concern? • Are there toxicokinetic (e.g ., metabolic activation/conj ugation) or toxicodynamics considerations that may make the chem ical more or less toxic during certain developmental life stages?

3.2.3. Integration of Exposure Consideration s and Biological Effects Considerations The concepts of timing and dosimetry are incorporated as unify ing 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 tempor al 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 fo r relevant child health outcomes? • What dose metrics (e.g

. , AUC or C max ) are being considered for child related assessments?

3.3. ANALYSIS PLAN The analysis plan should identify the me thods, 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 workingThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 16 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 outline that provides the rationale for the ex pertise, time, and resources required to complete the assessment. A database inventory may be useful for identifying da ta gaps (Figure 3-3). Negotiation of consensus among the relevant risk managers may be needed on the conceptual model and analysis plan, includi ng the possible outputs of the assessment. This exercise can facilitate identification of strengths a nd 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, whic h comprises hazard characteriza tion, dose-response assessment, and exposure assessment. Further scoping may be considered in each of the three analysis phases, thus leading to a furt her refinement of the conceptu al model and analysis plan.

12 13 14 15 16

17 Figure 3-3. Life stage-speci fic 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 whethe r there are the different types of information for each life stage. For example, are there human studies assessing outcomes after in utero exposure?Hazard CharacterizationExposure AssessmentDose-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 dataThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 17 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 4. LIFE STAGE-SPECIFIC ANALYSIS

The life stage-specific analysis includ es hazard characterization, dose-response assessment, and exposure assessment phases. In these phases, data are analyzed, both qualitatively and quantitatively. Iterations among all three compone nts are necessary for communication among the team members and stakehol ders, as well as to refine the focus on the key assessment questions identified in the pr oblem 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 n ecessary. This includes the identification of data gaps for particular life stages of expos ure and, data that may identify critical windows of exposure . Mode of action informati on based on toxicokinetic and toxicodynamic data may inform th e 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 da ta is important for a robust ri sk characterization, the final phase in the risk assessment proc ess. 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 th e identification of any out comes 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 st ages, taking into consid eration toxicokinetic (TK), toxicodynamic (TD), and dose-response in formation. Information derived from both human data and animal toxicology studies are evaluated in this analysis phase. Additionally,This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 18 DRAFT—DO NOT CITE OR QUOTE 1 2 3 information about differences and similarities in experimental animal models versus humans regarding life stage-specific TK and TD should be considered in the ev aluation. 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 4 (U.S. EPA, 1996) , neurotoxicity (U.S. EPA, 1998b) , and cancer (U.S. EPA, 5 2005c)

. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 4-2 illustrates a detailed approach to characterizing hazard to children from environmental exposures. This framework is base d on the use of a life st age 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 out comes at any life stage up to and including adulthood are considered (i.e., conception to aged adu lt). It provides a temporal context within which to evaluate data for risk a ssessment. Thus, the initial evaluation of data for a chemical or mixture considers what information is available (and not ava ilable, i.e., data gaps) for different life stages and what th e data indicate in terms of life stage-specific susceptibilities. Figure 4-2 presents a flow diagram for life st age-specific hazard characterization. In the scoping step of hazard characterization, information on life stage differences in exposure and susceptibility is described, assembled by lif e stage, and synthesized in the hazard characterization segment of the assessment (S ection 4.1.2). Following the scoping step, there are three major steps in the data evaluation process. In the first step, a deta iled 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 ev idence (WOE) approach. In the final step (Section 4.1.5), the life stage-spec ific hazard characteri zation is summarized. A scientific rationale for the selection of relevant outcomes and susceptible li fe stages is developed based upon the data. The selected outcomes and susceptible life stages are further evaluatedsubsequently in the dose-response assessment phase. Finally, a comprehensive life stagespecific risk characterization is developed that requires iterati ve input among the dose-response, exposure, and hazard characterization assessment teams.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 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 in stances 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 info rmation 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 depi cted 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 in traspecies 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.

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 19 DRAFT—DO NOT CITE OR QUOTE 

### Response Response ResponseResponse ResponseResponse

Toxicity Process ToxicityToxicity Process TD

Tissue Dosimetry Tissue Dosimetry sue Dosimetry TK

Life Stage-Life Stage-Life StageExposureExposureExposure Response ResponseResponse

TD

TK

Life Stage-Life Stage-Life StageSpecificSpecificSpecific ExposureExposureExposure (human) limited informationinformationformation defaultMode of ActionMode of Action



### SpecificSpecificSpecific ExposureExposure (animal)(animal) Qualitative QualitativeQualitative Organization OrganizatOrganization and Analysis Qualitative and Quantitative Qualitative an d Quantitative Analysis AnalysisCharacterization 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 P r o b l e m F o r m u l a t i o n ( S e e S e c t i o n 3 )

D o s e - R e s p o n s e A s s e s s m e n t ( S e e S e c t i o n 4

. 2

. ) L i f e S t a g e S p e c i f i c R i s k C h a r a c t e r i z a t i o n

( S e e S e c t i o n 5 ) Identify Studies and Issues

E x p o s u r e A s s e s s m e n t ( S e e S e c t i o n 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 P r o b l e m F o r m u l a t i o n ( S e e S e c t i o n 3 )

D o s e - R e s p o n s e A s s e s s m e n t ( S e e S e c t i o n 4

. 2

. ) L i f e S t a g e S p e c i f i c R i s k C h a r a c t e r i z a t i o n

( S e e S e c t i o n 5 )

L i f e S t a g e S p e c i f i c R i s k C h a r a c t e r i z a t i o n

( S e e S e c t i o n 5 ) Identify Studies and Issues

E x p o s u r e A s s e s s m e n t ( S e e S e c t i o n 4

. 3

. )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 20 DRAFT—DO NOT CITE OR QUOTE Figure 4-2. Flow diagram for life st age specific hazard characterization. This figure illustrates the flow of information and analysis th at make up hazard characterization. Problem formulation establishes the context of the risk a ssessment 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 characteriza tion include the evaluation of i ndividual 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 illust rated by the solid arrows, hazard characterization, dose-response assessment, and exposure assessm ent contribute to the risk characterization.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 21 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 During each step, it is important to consid er 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 questi ons that can help guide the life stage-specific hazard characteri zation 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 dur ing the hazard characterization focuses on the identification and evaluation of all human a nd animal toxicology data on outcomes resulting from preconception or developmental life stag e 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 st udies 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 characterizat ion. 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 proce ss is a thorough examina tion of all published human and animal studies identified in the sc oping phase. A thorough qua litative evaluation of each human and animal study includes, to the greate st 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 ov erall determination of the adequacy, strength, and completeness of the database for the charact erization 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.)

1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 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), th e first step in the analysis of hazard is an evaluation of each individualstudy, focusing on the details of study conduct, content, and outcomes. This step of the life stagespecific hazard characterization emphasizes a descri ption 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 stag e-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 genera l 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 exposur e, and outcomes assessed (including the timing of assessment in relation to exposure and life stag e). It is helpful to highlight strengths and weaknesses in the study design, partic ularly in relation to life stag e-specific assessments and how they influence issues identified in the problem formulation stage.

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 22 DRAFT—DO NOT CITE OR QUOTEThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 23 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 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 re levance 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 critic al windows of pre- or postnatal development). For example, in laboratory an imal studies, if the t oxicological evaluation characterizes adverse outcomes following exposur es 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 da ta 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 ( 12 13 14 Selevan et al., 2000 ) which addresses the respiratory and immune systems ( 15 Pinkerton & Joad, 2000 ; Holladay & Smialowicz, 2000 ; Peden, 16 2000 ; Dietert et al., 2000 ), the reproductive system ( Pryor, 2000 ; Lemasters et al., 2000 ), the nervous system ( 17 Rice & Barone, 2000 ; Adams et al., 2000 ), the cardiovascular and endocrine systems ( 18 Osmond & Barker, 2000 ; Sadler, 2000 ; Hoet et al., 2000 ; Barr et al., 2000 ), and cancer/neoplasms ( 19 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 im portant context for the evaluation of the hazard outcomes, characterization of uncertainties, and identification of further testing or research needed. 20 21 22 23 24 25 26 27 28 29 30 31 4.1.3.4. Outcomes A description of study findings, including the re lationship of outcome to exposure, is a primary goal of hazard characterization. Especia lly 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 prob lem formulation phase. For example, if the problem formulation specifically identifies a potential for expos ure to pregnant women in aThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 24 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 residential setting, it is important to carefully consider any ava ilable 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 b een identified in the problem formulation phase. It is important to in clude and describe any availabl e life stage-specific TK data, particularly, the relevance and im pact of the TK data in evalua ting the study, and in determining the impact of exposure and respons e across life stages. Toxicokineti c data can be used to verify that indirect exposure of the fe tus 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 highlighti ng 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 deve lopmental 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 fi ndings. 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, distri bution, metabolism and elimination (ADME), then the internal dose to the immature individual is eq uivalent 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, examin ation 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 decreasingThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 25 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 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 da ta 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 ut ero 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 suscepti bility. It is also possible that the MOA for a given chemical differs among life stages. Altho ugh there are no known examples of this, it is one possible explanation when exposures during sp ecific life stages and a dult exposure lead to different outcomes. However, chemicals with mo re 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-re sponse 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 iter ative process, because consideration of other studies in the database may hi ghlight the importance of borderl ine or suggestive findings in individual studies and, ultimately, refi ne the interpretation of the data.

4.1.3.9. Variability Analyses There are a number of sources of variability, both in trinsic 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 someThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 26 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 degree in each parameter being measured. Exampl es of intrinsic variables for animal studies include strain, species, and other genetic factors. On the othe r hand, the sources of extrinsic variability are external to th e study individuals, and can often be attributed to methodological considerations, to errors in st udy design, or variations in implementation. Examples of extrinsic variables for animal studies incl ude handling techniques, ambient temperature, and noise, and for epidemiologic studies, variations in recr uitment or data coll ection procedures. Variability can be adequately and appropriately characterized by the statistical treatment of individual study data through, fo r example, calculations of centr al tendency. Nevertheless, although the degree of study variability may be c ontrolled 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 di fficult. A detailed consideration of variability with appropriate analyses contributes to a determ ination of the adequacy, strength, and reliability of a study and its conclusions. Variability can be a source of uncertainty in the evalua tion and interpretation of individual studies. High variab ility can sometimes render a study uninterpretable or result in reduced confidence in the veracity of the study fi ndings, 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 da ta can affect the assessment of risk. Thorough consideration an d description of the uncertainties for each study are essential. Any resulting assumptions, extrapolations, or speculative interpretations must be fully characterized. Uncertainties can re sult from data gaps (i.e., missing information) or inadequacies in the study protocol or met hodologies, inadequacies in the reporting of study findings, or inconclusive results. Characteri zation 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 st udies, data on structure- activity relationships (SARs), or TK or TD information, may be used to address uncertainties in a given study.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 27 DRAFT—DO NOT CITE OR QUOTE 1 2 4.1.4. Evaluation of the Hazard Database After relevant studies have been evaluated, th ose scientifically judge d to be potentially useful for risk assessment (NRC, 1994) are selected and summarized, and the extent of the database is described. Best scientific judgmen t requires a well-justified decision to include a given study or exclude it from further considerat ion. Specific criteria can be developed for a particular assessment if appropriate. Characteriz ation of the extent of the database includes a summary of the data gaps, uncertainties, and assu mptions made in the assessment of the database as a whole (Figure 4-4). The adequacy, stre ngth, and completeness of the database are considered. The adequacy of studies and char acterization of the database are discussed in 3 4 5 6 7 8 A 9 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 appr oach in the assessment of environmental risks to children is described in the Office of Pesticide Programs report 10 11 12 Determination of the 13 Appropriate FQPA Safety Factor(s) in Tolerance Assessment ( U.S. EPA, 2002c , Section III). The WOE analysis, described in mo re detail below, could be framed by factors presented in the conceptual model that was deve loped during the problem formula tion phase (see Section 3.2). 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 4.1.4.1. Summarizing the Hazard Database The overall hazard database includes detailed de scriptions 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 t oxicological 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. Issu es to consider include the path ways (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 susceptibil ity 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

1 2 3 4 5 6

7 8 9 10 11 12 13 14 15 16 17 18 19 20 Figure 4-4. Hazard characterization Step 2: Evaluate the database as a whole for potential hazards to children from environmenta l 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 st udy outcomes is also important for the characterization of the database . Often, the structure and pres entation 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 th e hazard summary is on the relationships (i.e., patterns) across observed outcome s, 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 characte rization of risk to children from environmental exposures.

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 28 DRAFT—DO NOT CITE OR QUOTEThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 29 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 4.1.4.2. Description of the Weight of Evidence (WOE) The WOE approach requires a critical evaluati on (expert judgment) of all available data for consistency and biological plausibility. Crit eria for this assessment are not presented here; rather, considerations important for the WOE ar e 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 exp licitly detailed. Furt her details about EPA’s WOE approach can be found in the Methods for Derivation of Inhalation Reference 7 Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994) , Guidelines for 8 Carcinogen Risk Assessment (U.S. EPA, 2005b) , and Supplemental Guidance for Assessing 9 Cancer Susceptibility from Earl y Life Exposure to Carcinogens (U.S. EPA, 2005c)

. A Review of 10 the Reference Dose and Reference Concentration Processes (U.S. EPA, 2002b , Section 4.3.2.1.) and 11 Determination of the Appropriate FQPA Safety Factor(s) on Tolerance Assessment ( U.S. 12 EPA, 2002c , Section III) provide addi tional detail on the WOE. 13 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, th e quality of potentially relevant studies is judged, modifiers and interactions are detailed, outcomes across specie s are compared, TK and TD data are examined and weighed for comparisons acros s species, and the uncertainties a nd 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 re duce uncertainties. 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 4.1.4.2.1. Modifiers and Interactions. Consideration needs to be gi ven to effect modifiers and confounders in the studies. Then, questions of wh ether and how these have been evaluated in the data analysis are considered. It is important to focus on all poten tial life stage-specific effect modifiers and confounders and how they could af fect 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).This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 30 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4.1.4.2.2. Intra- and Interspecies Comparisons of Outcomes. For the chemical under assessment, any information on comparative spec ies susceptibility for exposures and outcomes needs to be considered carefully, including co mparisons 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 huma ns 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 4 5 6 7 8 9 10 11 12 13 14 15 16 Gray et al. (2001) ). 17

humans as well as comparisons across experimental animal test strains ( Spearow et al., 1999 , 18 2001 ) and species. 19 20 21 22 23 24 Important life stage-specific information to consider and use (if available) include:

• Comparative developmental stages betw een 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),This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 31 DRAFT—DO NOT CITE OR QUOTE 1 2

3 4 5 6

7 8 9

10 11 • Cross-species and cross-strain similariti es in outcome for comparable stages of development, • Differences in developmental timing for certain species or strains that impact comparison of exposures during a given lif e stage for the database as a whole (i.e

. , certain rodent in uter o exposure stages are comp arable 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 12 13 Marty et al

. (2003) compare some key events in the postn atal development and maturation of the male reproductive system across species. 14 Hew & Keller (2003) describe cross-species postnatal development of the cardiac system and life stage-related morphological and functional differences. 15 16 Holsapple et al

. (2003) address pre- and postnatal i mmune system development. Functional measures of postnat al central nervous system development are detailed in 17 Wood et al

. (2003) 18 . Zoetis and Hurtt compare anatomi cal and functional renal development (2003a) and lung development 19 (2003b) across species. Postnatal bone grow th and development is covered in 20 Zoetis et al

. (2003) . Additionally, information on relative developmental timing across species for several systems is addressed in 21 Selevan et al

. (2000) and Hattis et al. ( 2004 ; 2005 ) for carcinogenesis. 22 23 24 25 26 27 28 29 30 31 32 33 4.1.4.2.3. Toxicokinetics (TK) and Toxicodynamics (TD). Available information on TK and TD similarities and differences between experi mental 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,This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 32 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 and uncertainties that have been identified in th e database, both generally and specifically for evaluation across life stages. The sources of variability within individua l studies are also confounding factors for the interpretation of data across or among studies. They can contribute to ove rall uncertainties in the database, including those that are applicable to the analysis of life stage-specific hazard. Variability of response across studies and possibl e reasons for the variab ility are important to assess and consider. For example, the response could vary among studies performed in the same animal species but using different strains. Furt her, 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 i ndividual 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 da ta 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 th e 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 stag e-specific information. The relative impact of missing or inadequate in formation to the overall goals of the assessment needs to be judged. In some cases, informati on 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 measur ements, exposure, and outcomes across life stages ( 23 24 U.S. EPA, 1991 , Section 3.1.2.1; 1996 , Section 3.3.1.5; 2002b , Section 4.3.1). The results of i ndividual 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 eval uation of life stag e-specific data gaps and uncertainties are provided in Appendix 1. 25 26 27 28 29 30 31 Finally, the description of data gaps and uncertainties can be framed from the perspective of the problem formulation. For example, if th e problem formulation an alysis suggested thatThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 33 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 infants had high risks due to biological susceptibili ty 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 id entified problem or question of the assessment (as defined in the Problem Form ulation 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 determ ination of whether required studies are present (those that are required by statute or convention, e.g

. , a rodent and a nonrodent prenatal developmental t oxicity study and a repr oduction 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 qu antitative impact of these missing data on the risk assessment (e.g

. , on the POD) is considered in bot h 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 fo r a different chemical that has been shown to produce the same active metabolite might be usef ul in informing the assessment and reducing uncertainties relevant to this data gap. 16 17 18 19 20 21 22 4.1.4.2.5. Extent of the Database. The report A Review of the Reference Dose and Reference 23 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 informati on that would be sufficient to conduct a risk assessment and robust as the “gold standard” that fully characterizes the pot ential toxicity of a chemical or group of chemicals. The intent is for the assessors to char acterize and justify in a narrative form the extent of the database, including data gaps and uncertainties (e.g

. , life stage24 25 26 27 28 29 30This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 34 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 specific exposures and outcomes, TK and TD data, the types of outcomes evaluated, reversibility, and latency to response) that aid in determini ng 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 databa se, the quality, quantity (i .e., studies available to evaluate), and uncertainties and data ga ps 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 risk s to humans. Nevert heless, a major default assumption that is used in the absence of human data is that experime ntal animal data are relevant for humans. This concept is integral to the EPA risk asse ssment guidelines for developmental toxicity, reproductive toxicity, neurotoxi city, and carcinogenesis ( U.S. EPA, 1991 , 1996a , 1998b , 2005b , 12 2005c ). A key step in the assessment is the char acterization 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 predic table 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 anim als and humans has been demonstrated, and (5) the temporal relationship between e xposure and effect is consistent ( 13 14 15 16 17 18 19 U.S. EPA 2002b , pp. 4-13 to 4-14). 20 21 22 23 24 25 26 27 28 29 30 Discussion of the following issues can be important: the re levance 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 hazar d characterization phase (see Section 4.1.5).

4.1.5. Life Stage-Specific Hazard Characterization Narrative In this final step in the hazard characterizat ion (Figure 4-6), a scientific rationale for the selection of outcomes relevant for use in qua ntitative dose-response assessment are clearly and concisely summarized. Included in this assessment are considerations of life stage-specificDescribe 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.)

1 2 3 4 5 6 7

8 9 10 11 12 13 14 15 16 17

18 19

20 21 22 23

24 25

26 27 28 29 30 Figure 4-6. Hazard characterization, Step 3: Describe and determi ne life stage-relevant outcomes. In the third and final step in the hazard characterization, life st age-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 ha zard evaluation. Issues to consider include:

• Life stage-specific outcomes from the whol e database that were identified in the lower dose range(s) (not just a single “cri tical 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 quantita tive 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 rele vant outcomes of concern. • The development of margin of exposur es (MOEs) through iterations among the hazard characterization, dose-response, and exposure assessment phases.

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 35 DRAFT—DO NOT CITE OR QUOTE This information will subsequently be used in th e 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.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 36 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12

13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 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 deve loping a dose-response characterization for developmental life stages. The process begins by summarizing the available data and culminates with a descriptive characterizati on of the data, models, estimates, and uncertainties applied. In selecting the appropriate dose-res ponse model for life stages, careful consideration of routes of exposure, toxicokinetics (TK), toxicodynamics (TD), epidemiol ogical findings, and mode of action (MOA) is critical. Wh ere available, resources for aiding a life stage dose-response analysis are provided so that ri sk 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 differe nt meanings in differe nt 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 ha rmonized approach recognizes that both cancer and noncancer endpoints can appropriately be ch aracterized as threshold or non-threshold depending on the available data. Risk assessm ent processes also vary somewhat on exposure scenario, i.e. duration, route, and source. Rega rdless of these differences, a life stage approach can be utilized in risk assessments. During the pr oblem formulation, the scope and breadth of an assessment are established and generally fall in to 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 br oad scope assessment, however, is not intended to characterize risk at each indivi dual life stage, but rather charac terize risk for the most sensitiveConceptualization 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 H a z a r d C h a r a c t e r i z a t i o n ( S e e S e c t i o n 4

. 1

. ) P r o b l e m F o r m u l a t i o n ( S e e S e c t i o n 3

. )

E x p o s u r e A s s e s s m e n t ( S e e S e c t i o n 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

L i f e S t a g e S p e c i f i c R i s k C h a r a c t e r i z a t i o n

( S e e S e c t i o n 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 H a z a r d C h a r a c t e r i z a t i o n ( S e e S e c t i o n 4

. 1

. ) P r o b l e m F o r m u l a t i o n ( S e e S e c t i o n 3

. )

E x p o s u r e A s s e s s m e n t ( S e e S e c t i o n 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

L i f e S t a g e S p e c i f i c R i s k C h a r a c t e r i z a t i o n

( S e e S e c t i o n 5

. )

1 2 3 4 5 6 7 8 9 10 11 12 13 Figure 4-7. Flow diagram for life st age-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 characte rization, 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 characterizati on, 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. This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 37 DRAFT—DO NOT CITE OR QUOTEThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 38 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 life stage for the appropriate expos ure scenario. Regardless of the breadth of the assessment, the exposure scenario, or hypothesized mode of action of the envir onmental agent, the life stage approach can add to the overall soundness and conf idence in the assessment, as well as provide a thorough as possible st arting point for future reassessments.

4.2.1.3. Regulatory Needs and Considerations Based on the needs outlined in the problem fo rmulation of a given risk assessment, an approach for carrying out a chemical risk assessm ent is developed. The approaches will include methodologies and standard setting pr otocols. It is important to re-emphasize that the nature and number of risk estimates is governed by the pr oblem 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, expos ure scenario (e.g ., acute, oral exposure) a nd 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 r oute and duration. Acute toxicity is of particular concern in children because the complex processes of em bryogenesis, fetal and postnatal development provide ample opportunities for toxicant exposures to alter the regulation of development. Perhaps less apparent, however, is the applicability of lo ng-term risk values to children. For instance, reference dose (RfD) and reference concentration (RfC) values are risk estimates calculated for various r outes (oral, dermal, inhalation) and durations (acute, short-term, chronic) of exposure (U.S. EPA, 2002b) . It is important to note th at chronic exposure is defined as exposure up to 10% of lifetime; thus, chroni c risk values (RfVs) may be applicable to children, because seven years of exposure meet s the EPA definition of chronic human exposure 22 23 24 (U.S. EPA, 2002b) . Unit risk estimates such as cancer sl ope factor (CSF) are used to define the exposure concentration that yields a given level of risk (e.g., 1 × 10 25 26 27 28 29 30 -6 ) during a lifetime. Although the latency of time to tu mor 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 evid ence to support the notion that susceptibility to tumor development from exposure to mutagenic chemicals during earlier life stages is greater re lative to later life stages (U.S. EPA, 2005c) . Depending on the goals stated in the problem formulation of a risk 31This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 39 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 assessment, the literature databa se should be assessed for studies that have examined cancer in adult humans and experimental animal s 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 in formed assessment, however, utilizes the broader body of scientific literatu re to look for: commonalities in re sponses 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 th e hazard characterization an d help to establish the MOAs underlying the various dose-response relati onships. 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 cr itical effect(s) of interest to a particular dose metric, and the data supporting the choice of a likely or hypothesized dose metric. 13 14 15 16 17 18 19 20 21 22 23 24 25 4.2.2.1. Summarizing the Available Dose-Response Relationships Route and duration make up the exposure elem ent for individual life stages. Although the problem formulation will have likely iden tified exposure scenarios that pose risks to individual life stages, a quantit ative 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 ex ternal exposure for different exposure scenarios and specific life stages. Be cause 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 im portant to realize that analysis of dose-response data could (under certain circumstances) warran t re-examination of the exposure assessment. Data that indicate a sensitive dose-response re lationship at environmentally relevant low exposure levels, particularly in the context of pr ecursor events, may suggest that certain exposure 26 27 28 29 30 31This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 40 DRAFT—DO NOT CITE OR QUOTE 1 2 scenarios are more critical th an initially thought and perhap s be an impetus for further characterization and refinement of exposure mode ls 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 conceptualizati on of the MOA. For instance, different effects at similar doses may originate through common mechanisms, and thus lend support to a MOA. Alternatively, different eff ects across dose ranges may represent a gradient of effects operating th rough common mechanisms, and thus al so lend support to a MOA. It is also possible, of course, that different M OAs are operational across dose ranges, and an exposure-response array can be useful for defini ng the range of effects. Using this array, multiple responses can be described as a contin uum of dose, and may be informative in risk management. An alternative approach is to assign key outcomes to severity categories and analyze by categorical regressi on (see Section 4.2.3.1). 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 The complexities of developmental processes re quire 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 cha nges or changes that confer an increase in risk to subsequent exposures in later life stages 3 . It is for this reason that doseresponse selection should be informed by MOA c onsiderations in addition to the available response data. This provides an important interface with the hazard charac terization. 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 anal ysis to inform hazard characterization. For instance, toxicologists adept at hazard charac terization 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 modeli ng 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)

.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 41 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10

11 12

13 14 15 16 17 18 19

20 21 22

23 24 25 26 27 28 29 30 31 32 33 34 response may not be the appropriate dose metric responsible for the toxi cological outcome; the latter instance could potentially prompt a reconsideration of the dose metric or MOA. In addition, this could be an impetus for instead us ing 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 a nd various life stages (e.g ., preconception, pregnancy, infancy, childhood been addressed? Are ther e 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 po st-pubertal exposures? • Have individual physiological and devel opmental processes been compared with the child behavioral development; i.e ., how do life stage behaviors and exposure scenarios compare with i ndividual physiological para meters such as enzyme ontogeny and renal clearance maturation? ( It is possible that maturation of such parameters spans multiple behavioral st ages. In such cases, behavioral susceptibilities and physiologi cal susceptibil ities 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 oppor tunity for toxic exposures to create TD effects that may or may not be re levant to adults. Developmental stages or age groupings may be based on such metrics as growth rates/spurts, behavioral trai ts, organ systems, or perhaps functional development. It may be possible to plot these metrics for development throughout life stages and across species. Examples of orga n 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 compar able 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 re sponse of interest (see SectionThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 42 DRAFT—DO NOT CITE OR QUOTE 1 4.2.4.2). Within species, studies suggest that ther e is concordance of ca ncer 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 differen tial tumor responses depe nding on life stage of exposure ( 2 3 4 U.S. EPA, 2005c ). It is not clear, however, whethe r these differences relate solely to differences in metabolic activati on. Considerations include: 5 6 7 8 9 10 11 12 13

14 15 16 17

18 19 20 21 22 23 24 25 26 27 • 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; alt hough this implies a si milar MOA, it is important to address, if possible, wh ether 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 th at 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 com pound, the chemical nature of these metabolites might aid in the formulation of a plausible MOA. In other instances, part icularly when there are numerous metabolites, data from biochemical and toxicological studies may be the primary driver for formulating a plausible MOA. In prac tical terms this may not be the toxic moiety at the target tissue, but of ten will be a surrogate such as blood c oncentration of a particular moiety (parent or metabolite). The underlying assumption in dose-res ponse analysis is that the dose metric will exact the same effect at equivalent doses irrespective of species and route, provided there are no TD differences ( Andersen & Dennison, 2001 ; Clewell et al., 2002 ). 28 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-re sponse relationship. The second criterion is conservatism, defined as the selection of the dose me tric 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 exposur e/applied dose, and it is the environmental 33 34This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 43 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 exposure level to humans that is regulated. For th is 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 mi ght include enzyme activity levels (K M and V max ), relative comparisons of expre ssion levels of xenobiotic meta bolizing enzymes, levels of cofactors, and physiological para meters (e.g., liver blood flow). Age-related differences in absorption, distribution, metabolism, and elimination have been reviewed ( Besunder et al., 7 1988a , 1998b ; Clewell et al., 2002b ; Clewell et al., 2004 ) (see Section 4.2.3.1.). Considerations include: 8 9 10 11

12 13 14 15 16 17 18 19

20 21 22 23

24 25 26 27 28 29 30 31 32

33

34 • What is the human exposure scenar io (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 c an 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, muco cilliary function, sk in 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, i mmaturity 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 meta bolizing enzymes involved in the dose metric formation and termination predict fo r the dose metric level and time course? ( Generally speaking, enzyme levels approac h 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 im portant 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?This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 44 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 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 e ither a no observable adverse eff ect level (NOAEL) or a lowest observable adverse effect level (LOAEL) to s ophisticated models inco rporating mechanistic data. The nature and amount of data required fo r 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 targettissue dose using other modeling techniques. Briefly summarized below are some of the doseresponse models available to risk assessors. Th ese models are typically employed in order to determine PODs, which are used for extrapolatio ns 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 advocat es the use of as much biologically-informed dose-response data as possible, and suggests that olde r “default” approaches be used only in instances where little data exists concer ning an environmental toxicant of interest. Physiologically based toxicoki netic (PBTK) and biologically based dose-response (BBDR) models are techniques that prov ide strong biological foundations for a chemical risk assessment; their application in risk assessmen t is discussed more thoroughly in 12 13 14 15 16 17 Approaches for the 18 Application of Physiologically Based Pharmaco kinetic Data and Models in Risk Assessment (U.S. EPA 2005a) 19 . Furthermore, their use in conjunction wi th statistical modeling is perhaps the most rigorous 20 21 22 23 24 25 26 27 28 29 30 4 . The following brief descriptions summari ze the types of analyses used in risk assessment, generally from those based on limited data sets to those requiri ng very rich data sets for dose-response analysis.

4.2.3.1. Dose-Response Models Traditional approaches to dose-response m odeling 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 va lues derived from experimental dosing conditions in toxicological studies . Two main disadvantages of us ing 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.This document is a draft for review purposes only and does not constitute Agency policy. 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 tie r of dose-response models and are used most often when limited data is available c oncerning the toxicant of interest. 1 2 3 4 A more sophisticated approach for determ ining 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 en vironmental 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 st udy; thus, unlike the NOAEL/LO AEL 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% lowe r 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 Benchmark Dose Technical Guidance Document, 18 External Review Draft (U.S. EPA, 2000a)

. 19 20 One limitation to BMD analysis is that the an alysis can only be performed on individual studies (Brown & Strickland, 2003) . Categorical regression 6 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) th at 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 durati on may be problematic (particu larly 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.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 46 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 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 (PBT K) 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, dist ribution, excretion, and elimination (ADME) are essential for estimating delivered dose. Behavioral, anatomical, and metabolic differences during each life stage require m odification of available adult m odels. Several reviews have described the variation in TK fact ors between adults and children ( Besunder et al

. , 1988a , 1988b ; 9 Bruckner, 2000 ; Clewell et al

. , 2002a ; Hines & McCarver, 2002 ; McCarver & Hines, 2002 ). Although the use of TK mode ls for internal dose estimates is in creasing, more effort is needed in developing such models for children’s dosimetric adjustments across life stages and species. Some models available in pediatric pharmaco logy could be appropriate ly applied for some portions of certain risk assessments. For inst ance, 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 avai lable across life stages; this database can be accessed at 17 18 http://www2.clarku.edu/faculty/dhattis

. 19 20 21 22 23 24 25 26 27 28 29 30 31 PBTK models can be used to conduct route-to -route extrapolations, duration adjustments, interspecies extrapolations, as well as life stage ex trapolations. Particular ly useful, is the fact that these models can mimic any exposure scenario (continuous or otherwis e). For instance, if children are likely to be exposed to an environm ental 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, nu merous small exposure doses from breast milk to nursing infants could be mode led to determine steady state levels of a toxicant Although PBTK models may be particularly us eful in periodic e xposure 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 expos ure-induced changes;This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 47 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 examples include cell proliferation rates, DNA repair processes, receptor tolerance and desensitization, and age-related changes in physiological parame ters. Importantly, many early developmental windows are relatively short; thus extrapolation from short-term exposure scenarios to longer-term scenar ios requires consideration of whether the same windows of susceptibility are likely to be operable. Application and review of PBTK models in risk a ssessment can be found in ( Ginsberg et 6 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 ch emicals such as dioxin in breast milk ( 7 Gentry et al

. , 8 2003 ; Lorber and Phillips, 2002 ), fetal exposure to ethylene glycol monomethyl ether (Gargas et 9 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 (Corley et al

. 2003)

. 12 13 14 15 BBDR models represent the state of the art in dose-response analys is, where mechanistic TD data are modeled in such a wa y that responses can be predicte d, even at low exposure levels. Usually, output from a PBTK model serves as the dose input to a BBDR model, relating that dose to a response outcome ( Andersen & Dennison 2001 ; Ashani & Pistinner 2004 ; Setzer et al

. , 16 2001 ). In addition to life stag e-specific TK data, the relationship between the internal dose metric and response may require life stage-spec ific TD data. Current ly, relatively few BBDR models are available due to the inherent complexi ty of integrating TK and TD data, as well as more practical limitations to BBDR model develo pment, such as model transparency, quality criteria, and limited shelf-life of some models beyond in itial 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 22 Andersen & Dennison, 2001 ; Faustman et al ., 1999 23 ). 24 25 26 27 In instances where the dose metric of a toxi cant of interest is structurally related to another compound for which there exists a va lidated BBDR model, consideration of the application of this model to the t oxicant being assessed may be warranted 8 . As stated in Evaluation of BBDR Modeling for Developm ental Toxicity: A Workshop Report , “the challenge is to define...application of a quantitative BBD R model ...generalizable to other compounds in a similar class and perhaps to certa in other classes of compounds” 28 29 (Lau et al

. 2000) . For example, 30

8 It should be recognized that compounds with common toxicodynamic effects need not be structurally related.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 48 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 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 BBD R model, it is conceivable that the existing BBDR model might be sufficient for anal yzing both chemicals (see Figure 4-8). Probabilistic risk assess ment has typically been used in exposure assessment. This approach, however, is increasingly being applie d 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 distri butions 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 parame ters can be employed in order to estimate the variability in dose and response among subpopul ations such as infants and children. 8 9 10 11 12

13 14 15 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 TK A , TD A , and R A represent the toxicokinetic, toxicodynamic, and response of interest related to chemical A, respectively. In this scenario, th e toxicodynamic of chemical B (TD B ) 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 B 16 17 18

B

B 19 20

21 22 23 24 25 ), 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 th e aforementioned dose-response modeling approaches, in regards to noncan cer endpoints, is that the anal yses 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-chloropr opane 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 defi ned by percent change (e.g. 1 % or 5%) in a biol ogical response 26 27 A → [TD A = TD ] → R B A } ↑ PBTK model exists for chemical B: [TK ] BThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 49 DRAFT—DO NOT CITE OR QUOTE 1 2 3 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 indi vidual based on exposure level, as is done for cancer assessments. Othe r 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 othe r approaches to non-can cer dose-response modeling arguably rely less on value judgment. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 4.2.4. Extrapolations and Risk Deri vation 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 broa d 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 stag es of interest. As described below, these adjustments may involve sophisticated approaches or default appr oaches 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 an alysis supports the use of body weight scaling (see below) to adjust for pharmacokinetic differe nces across species. Additionally, the use of more sophisticated techniques does not necessarily re sult 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 N OAEL 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. 22 23 24 25 26 27 28 29 30 31 4.2.4.1. Duration and Route Adjustments Animal exposure studies, almost always be ing discontinuous, require continuous dose adjustment. Although such adjustments are conser vative 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 aThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 50 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 response is generated. An altern ative to continuous dose adjustment is to use PBTK models that can determine ( in silico ) an applied dose (continuous or otherw ise) that results in the same AUC or C max as that was likely to have been generated in the test animal under the original laboratory study conditions. This may require parameterizati on with life stage- and species-specific data. As stated in section 4.2.3.1, deve lopmental windows of susceptibilit y are relatively short, thus the changing underlying biology dur ing development suggests that C max may be a more relevant dose metric in young children than AUC. For route-to-route extrapolation, default eq uivalent 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, a nd proliferation rates ex ist across portals of entry. PBTK models can be used to predict target dose across routes by incorporation of routespecific TK factors. An important limitation, howev er, is that route extra polations are not useful in instances where the critical e ffects are portal of entry specific . For more on route and duration adjustments, see Approaches for the Application of Physiologicall y Based Pharmacokinetic Data 14 and Models in Risk Assessment (U.S. EPA, 2005a) and A Review of the Reference Dose and 15 Reference Concentration Processes (U.S. EPA, 2002b)

. 16 17 18 19 4.2.4.2. Interspecies and Intraspecies Adjustments The EPA RfC process describes the interspe cies adjustment from animals to human equivalent concentration (HEC) via dos imetric adjustment factors (DAFs), (U.S. EPA 2002b)

. For oral exposures, default interspecies extr apolation based on body weight scaling, either body weight (BW 20 21 22 23 1 ) or body weight to the 3⁄4 power (BW 3⁄4 ), have been employed. In particular, BW 3⁄4 scaling is typically t hought 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 25 26 27 28 29 30 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 BW 3⁄4 scaling. For inhalation exposures, DAFs are applied on the basis of physicochemical, anatomical, and physiological parameters. These parameters in clude such factors as sp ecies-to-species ratios of surface area:ventilation rate, blood:gas partition coefficients, and regional deposition doseThis document is a draft for review purposes only and does not constitute Agency policy. 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 ad justments can be made for HECs. Finally, it is important to note that DAFs are thought to be mo st appropriately applie d for chronic exposures, where the dose metric is likely best represen ted by AUC; discussion of adjustments for acute exposures can be found elsewhere 2 3 4 5 (U.S. EPA 2002b) . Consider: 6 7 8 9 10 11 12 13 14 15 16 17 18 19 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 n eeded. A priori, rates of deposition, mass transfer, flow limited diffusion, and partition coefficients are likel y to be affected by life stage-specific differences in anatomy, skin compositi on, 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 prope rties, and thus may require both chemical- and life stage-specific data.

In addition to interspecies adjustments, BW 3⁄4 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 BW 3⁄4 , particularly in children over 2 months of age ( Ginsberg 21 et al., 2002 , 2004a , 2004b ; Hattis et al., 2004 ). Under two months of age, however, the immaturity of such processes li kely 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 inters pecies extrapolation. Adjustments across human life stages from a dult 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 toxi cant that is metabolized by the same pathway. For example, the mean half-lives of seve ral 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 29 30 31 32 33 34 35This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 52 DRAFT—DO NOT CITE OR QUOTE 1 2 dose metric in children. In the former case, such TK changes might increa se the intraspecies UF with respect to TK considerati on; 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 impr oved characterization of TK. The advantage to this approach is that assessors may have greate r confidence in extrapolating within the humans species; on the other hand, this approach requires that the und erlying toxic response and MOA are concordant across life stages. This assu mption, if not well-supported by data, may add a large degree of uncertainty to the dose-response analysis. 3 4 5 6 7 8 9 More often, however, the data ne eded for life stage extrapolati on 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 susceptibil ity related to the criti cal outcome of interest. This may require both empirical evidence and expe rt judgment. Several articles have examined the relative development of organ systems across species (reviewed in 10 11 12 13 Hurtt & Sandler, 2003a , 14 2003b ; Selevan et al., 2000 ). Quantitative adjustments are then needed to account for the TK differences that exist across species at the equivalent (with resp ect to the window of susceptibility) life stages. For instance, rode nts are born at an overall developmental stage roughly equivalent to end of th e second human trimester. Thus if equivalent windows of susceptibility exist at these two different life st ages across species, then altogether different PBTK models and TK data would be needed to calculate the equi valent internal dose, i.e., a lactational model for the rodent an d a pregnancy model for the human. 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 An advantage of this approach is that the a ssessor starts with age-relevant developmental effects (e.g ., two-generation developmental studies) as opposed to assuming concordance of effects across life stages. This w ill likely have the effect of reduc ing the interspecies UF due to TK adjustments, as well as due to a general incr ease in confidence that TD differences (if they exist) have been minimized. One caveat, howev er, is that human da ta (from controlled exposures or epidemiological studies) with which to test the predictive ca pability of the model will often be nonexistent. Add itionally, 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 th e overall uncertainty in the extrapolation.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 53 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 Because the majority of data concerning a ch emical 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 severa l 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 throug hout gestation. Physiol ogical parameter values were derived from numer ous 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 analys is to a previously published PBTK model. Briefly, this study modeled daily exposure of i ndividuals to dichloromethane from birth to 70 years of age using age-specific physiological parameters, partit ion coefficients, and CYP2E1 age-specific metabolic data. This model doe s 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 ha s been developed for relating 5-fluorouracil exposure at gestational day 14 to birth defects in rats. This m odels employs a PBTK component that describes the formation of the metabolite, relates the metabolite levels to deoxyribonucleotide pool perturbatio n, and relates this perturbati on to low fetal birth weight 11 12 13 14 15 16 17 18 19 20 (Shuey et al

. , 1994) and fetal malformation ( Lau et al

. , 2001 ; Setzer et al

. , 2001 ). 21 22 23 24 25 26 27 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 lo w-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 styl e differences, as well as other issues related to 28 29

9 Currently, several efforts are underway to develop life stag e physiological parameters databases that will provide a comprehensive and authoritative resource for use in risk assessment.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 54 DRAFT—DO NOT CITE OR QUOTE epidemiological studies such as difficu lties 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 adaptiv e responses to DNA damage can result in both linear and threshold dose-res ponse relationships depending up on model assumptions. Taken together, these studies highlight the importance of a strong understandi ng of MOA for choosing the most appropriate low-dose extrapolation approach. The 5 6 7 8 Guidelines for Carcinogen Risk 9 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 pro cesses 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 nonc ancer endpoints, although methods for risk based approaches to noncancer endpoints, and their rele vance to cost-benefit analysis, have been proposed ( 13 14 15 16 17 18 Gaylor & Kodell, 2002 ; Clewell & Crump, 2005 ). 10 In addition, there may also be biological support for low-dose linear extrapolat ion for noncancer endpoints. For example, 1,2- dibromo-3-chloropropane is though t to reduce sperm count by inter action with DNA; thus, as is employed for mutagenic carcinogens, there is sc ientific rationale for using low-dose linear extrapolation for compounds th at cause noncancer effects thr ough interaction with DNA, and potentially other MOAs as well. 19 20 21 22 23 24 25 26 27 28 29 4.2.4.4. Model Uncertainty, Sensitivity, and Variability Models are approximations of biological proces ses and therefore have inherent shortfalls. Model uncertainty comprises that which is unknown about how well a model reflects the underlying biology 11 . 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 A pproaches 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.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 55 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 components. Quantitative elements include mode l 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 analys is together with reasons suppor ting the various choices used in each model can be expressed as subjective probab ilities that each model is correct. Qualitative elements of uncertainty analysis include such th ings as choice of animal test species or the applicability of animal species to the human lif e stage of interest (s ee 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 narrat ive (Section 4.2.5) through to the risk characte rization (Section 5.1.2). Sensitivity analysis allows risk assessors to examine which parameters in a model are most critical to the final outcome. This analys is is a key evaluation t echnique 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 susceptibl e life stages. For instance, mode l sensitivity to ventilation rate provides an important star ting point for addressing life stage differences. Variability analyses evaluate the range of va lues 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 instan ce, allows assessors to predict upper and lower bounds on a dose metric level in a te st species; thus multiple calculations of the relevant exposure concentration for humans could be calculated a nd perhaps used for subsequent risk derivation. 20 21 22 23 24 25 26 27 28 29 30 31 32 It is particularly important that model evalua tion not be a final step in the risk assessment process. Sensitive parameters provide red flags th at should be examined carefully for variability of these parameters within the population. Altern atively, the sensitivity might suggest the need for careful examination and considera tion of susceptible life stages.

4.2.4.5. Risk Value Derivation and Applicatio n of Uncertainty Factors (Including AgeDependent Adjustment Factors) A detailed outline for derivation of risk valu es is beyond the scope of this framework. Risk assessors should consult EPA guidelines for pr ocedures and policies fo r deriving risk valuesThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 56 DRAFT—DO NOT CITE OR QUOTE 1 and applying UFs. Current practices for RfC a nd RfD derivation and the application of UFs are outlined in A Review of the Reference Dose and Reference Concentration Process (U.S. EPA, 2 2002b) . As stated in Section 4.2.4.2, life stage extr apolations 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 va lue derivation. New guidance on CS F derivation from early life exposure to environmental agents can be found in the 3 4 5 Supplemental Guidance for Assessing 6 Cancer Susceptibility from Earl y Life Exposure to Carcinogens (U.S. EPA, 2005c) . In brief, the new guidance states that for t oxicants acting through a mutageni c MOA, where data concerning early life susceptibility is lacking, early life susceptibility should be assumed and the following age-dependent adjustment factors (ADAF s) should be applied to the CSF: 7 8 9 10 11 12 13 14 15 16 17 18 • 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 toxi cants 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 comp ared to adult exposure. For an explanation of the choice of these values and age groupings see Supplemental Guidance for Assessing Cancer 19 Susceptibility from Early Life Exposure to Carcinogens (U.S. EPA, 2005c)

. 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Historically, life stage-related uncertainties ha ve 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 s hould help focus attention on the most critical data gaps deserving of additional uncertainty wei ghting. Indeed, the rationale for using the life stage approach is to better characterize individua l risk and thus decrease uncertainty in risk

assessment.

4.2.5. Life Stage-Specific Dose-Respo nse Characterization Narrative Following derivation of final risk values, a dose-response characterization summarizes the dose response information to be used in co njunction with the exposure information for a full characterization of risk. This characterization is a narrative desc ription that provides a summary of recommended estimates, data supporting t hose estimates, modeling approaches, a POD narrative, key default assumptions, and identifica tion of susceptible life stages or sensitiveThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 57 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 subpopulations and quantification of their suscep tibility. A discussion of the strengths and limitations of the dose-response assessment should be presented, highlighting significant issues in developing risk values, incl uding alternative approaches cons idered equally plausible, and how these issues were resolved. It is impor tant that all estimates be accompanied by the descriptors used in the WOE narrativ e. 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. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 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 broade r risk assessment problem formul ation. 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 chemical s or agents of concern, the relevant exposure pathways (including media an d route) by which children may be exposed, and the exposure scenarios specific to children. Th e preliminary evaluation of sources, pathways, and scenarios allows the assessor to refine the goal s, 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 sc oping phase of the exposure assessment. Depending on the risk assessment objectives, it may be important to involv e 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 rele vant exposures may take place. The conceptual model is used to identify available exposure information includin g chemical properties, environmental fate and transport mechanisms, media concentrations, and population characteristics and behaviors. The available exposure information is used to c onduct 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 mo re detail for potentially important scenarios or potentially vulnerable age groups. The last step in the exposure assessment process is the lifeLife 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 P r o b l e m F o r m u l a t i o n ( S e e S e c t i o n 3

. )

H a z a r d C h a r a c t e r i z a t i o n ( S e e S e c t i o n 4

. 1

. )

L i f e S t a g e S p e c i f i c R i s k C h a r a c t e r i z a t i o n

( S e e S e c t i o n 5

. ) D o s e - R e s p o n s e

A s s e s s m e n t ( S e e S e c t i o n 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 P r o b l e m F o r m u l a t i o n ( S e e S e c t i o n 3

. )

H a z a r d C h a r a c t e r i z a t i o n ( S e e S e c t i o n 4

. 1

. )

L i f e S t a g e S p e c i f i c R i s k C h a r a c t e r i z a t i o n

( S e e S e c t i o n 5

. )

L i f e S t a g e S p e c i f i c R i s k C h a r a c t e r i z a t i o n

( S e e S e c t i o n 5

. ) D o s e - R e s p o n s e

A s s e s s m e n t ( S e e S e c t i o n 4

. 2

. )

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 58 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Figure 4-9. Flow diagram for lif e 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 ex posure 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 wi ndows of exposure are considered. Exposure is then estimated using a tie red approach. This tiered approach begins with a screening-level assessment followed by a more re fined 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 uncertaint y can be assessed using sensitivity analysis. As illustrated by the solid arrows, hazard characte rization, dose-response assessment, and exposure assessment contribute to the risk characterization.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 59 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 stage-specific exposure charac terization where the results, analyses, and conclusions are summarized. Each of these steps is coor dinated 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 al l relevant environmental exposure s are included in the qualitative and quantitative evaluation of ri sk to children. The exposure information described below is used to develop estimates of dose. The estima tes of dose are later integrated with the doseresponse assessment to develop estimates of lik elihood of adverse effect s 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 di scussion feeds into the risk characterization, where the result s from hazard, dose, and exposure ar e 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 pr egnant and lactating women; (2) residence, daycare and outdoor play areas for infants and toddlers; (3) residence, school, and locations of after-sc hool 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 e xposure routes can define the pathways. Exposure media include air, water, soil/dust/se diments, food, and objects/surfaces; exposure routes include inhalation, ingesti on, dermal absorption, and indire ct ingestion (non-dietary and indirect dietary routes) ( U.S. EPA, 2002a , 2003a. ). The result of this evaluation would be a table 31This document is a draft for review purposes only and does not constitute Agency policy. 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) ( Hubal et al ., 2000 ). 2 3 4 5 6 7 8

9

10 11

12

13 14 15 16 Exposure media may change with life stage. For example, the fetus will be exposed to cord blood and amniotic fluid, the infant to br east milk, the teething child to many objects (both intended and unintended) for mouthi ng, the school-age child to pest icides used in the classroom, and the adolescent to vocationa l or recreational hazards.

• What are all the potential exposure media? • What are all the pot ential 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 fr om 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 estima te distribution of exposur e by any given pathway. An exposure scenario is defined by the combin ation of the following details (adapted from Hubal 17 et al., 2000 ): 18 19 20

21

22 23

24 25

26 27

28 29 30 31 • What are the relevant sources of exposure? • What are the potentially exposed populati ons (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 e xposure (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 identifi ed at this point on th e conceptual basis of the exposure model as well as the problem formul ation for the life stage risk assessment. Once available data are evaluated, addi tional scenarios may be added.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 61 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 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 pe riods for which exposure would need to be characterized. These periods may be defined on the basis of exposur es 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 ag e-specific behaviors and physiology (e.g

. , crawling, teething). Se veral important life stages would need to be considered in exposure assessments for children (Figure 4-10): 6 7 8 9 10 11 12

13

14

15

16

17 • Are there possible parent al preconception exposures? • Might there be exposure dur ing the pregnancy that aff ects embryonic/fetal stages? • Are there possible exposures dur ing infancy and early childhood? • Are there possible exposures duri ng older childhood and adolescence?

Typically, the conceptual model will consid er 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 evalua te this model from the “effects” back to the “source.” In this way, potentially important tim e periods of exposure, exposure pathways, and vulnerable subpopulations can be identified. 18 19 20 21 22 23 24 25 26 27 28 29 30 However, as the risk assessment becomes more complex, some limitations in the sourceto-effect model become apparent. Exposure as sessments using a source-to-effects model are based on the characteristics of the specific so urce 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 exposur e to this specific source are included in the model. Yet, exposure may result from multiple independent sour ces, 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 populatio n 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

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Diet Water Air

Physical Factors Fetus

Other Air

This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 62 DRAFT—DO NOT CITE OR QUOTE 1 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 child ren. The solid lines in the figure represent relevant exposure, while dotted lines represent expo sures that are not releva nt to the specific lifestage. During gestation, the majority of exposures (except for physical factors) occur transplacentally through ex posure to the mother. After birth, ex posures may either be directly to the child, with an additional route from the mother for those agents that may be present in human milk. T r a n s

p

l a c e n t a l

I n h a l a t i o n ,

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Physical Factors Infant/ Young Child

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I n h a l a t i o n ,

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I n h a l a t i o n , D

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Other Diet Water Air Water Physical Factors

DietThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 63 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4

5 6

7

8 9 10 11 12 13 14

15

16 17

18 19 20

21 22 Since this approach puts ch ildren 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 distribu tions of exposure in the exposed population. In children especially, different factors might affect the child’s dos e. Some questions to get at these issues include:

• What types of exposure data are available fo r infants and children (direct or indirect measurements of exposure)? • Are children’s activity data available? • Are there biomonitoring da ta that demonstrate exposur e 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, contam inant transfer efficiency from the contaminated medium to the individual)? • Do children’s physiological parameters in fluence exposure to the specific agent (e.g

. , body weight, uptake rates – inhalation, dermal absorption, gastrointestinal absorption)? If so, are there data available (Hattis, 2004) ? 23

24 25 26 27 28 29 30 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. Scientis ts 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 additi on, it is important to know the conditions of the environment that may affect the chemical’s fate and transport. Thes e conditions include forThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 64 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5

6 7

8 9

10 11 12 13 14 15 16 17 18 19 20 21 22 23

24 25

26 27 28

29 30

31 32 33 example: soil characteristics, amount of rainfa ll, 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 propertie s of the chemicals or agents? What is known about their fate and transport? • What are the environmental conditions (e .g., wind direction, rain fall, etc.) that may affect the fate and transport of the chemical(s)?

• Where in the environment can the child co me 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 pres ent in an environmental (e.g., soil, water, air, food) or biological medium (e.g., bl ood, hair, urine, breath). It is critical to give special considerations for the measurement tec hniques 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 chemical s 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 th ere 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 cont act 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?This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 65 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 4.3.4.3. Life Stage-Specific Population Characteristics For children, behavior varies by developmental st age, 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 s cenarios for children’s risk (i.e ., to identify highly exposed populations). Currently, EPA’s Draft Guidance on Selecting the Appropriate Age Groups for 5 Assessing Childhood Exposures to Environmental Contaminants (U.S. EPA, 2003b) should be used as a starting point for identifying and select ing age bins for analysis (see Table 4-1). This guidance provides a detailed discussion of how th ese 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. 6 7 8 9 10 11 12 13 14 15 16 17 18 Exposure factors and resulting effects during de velopmental stages may be a function of additional individual and population ch aracteristics. 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 characte ristics include differences in susceptibility, differential exposure, differential preparedness, and di fferential ability to recover. These mechanisms are defined and discussed in the Framework for Cumulative Risk Assessment ( 19 U.S. EPA, 2003a , p. 39–42). Discussion on other risk factor s, effect modifiers, and confounders is detailed in 20 Guidelines for Developmental Toxicity Risk Assessment ( U.S. EPA,1991 , Section 3.1.2.1.1.c, pp. 24–25) and 21 Guidelines for Reproductive Toxicity Risk Assessment (EPA, 1996 Section 3.3.1.5.3, pp. 60–61). 22 23 24 25 26 27 28 29 30

31 32 33

34 35 The following questions could be considered in order to characteri ze 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?This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 66 DRAFT—DO NOT CITE OR QUOTE 1 2 Table 4-1. Developmental life stages and age groups for exposure assessments Life Stages Age Groups a 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 Groups a 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.

3

4 5

6 7

8 9

10

11 12 13 • Are there any highly exposed age groups? • Are there any community factors that ma y 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 st atus, genetic susceptibility)? • What are the child-specific exposure fact ors necessary to characterize the exposure scenarios? • What are the ranges or distribu tions of exposure factors?

Although the focus of this sec tion is the examination of vul nerability associated with differential exposure due to life stag e, it is recognized that it is impossible to completely separateThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 67 DRAFT—DO NOT CITE OR QUOTE 1 2 3 consideration of vulnerability due to life stage from consideration of vulnerability due to other key individual and community characteristics. EP A is examining the full range of issues related to characterizing risks to child ren through a variety of initiativ es, 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 charact erization and exposure assessment. 4 5 6 7 8 9 10 11 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 characteris tics 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 act ivity data are also available from the Consolidated Human Activity Database ( CHAD) available online at 12 13 http://www.epa.gov/chadnet1/ . Some considerations to include: 14 15 16 17

18 19

20 21 • What activities of the parent or child may result in exposure? • What developmental stage-specific be haviors 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 environmentall y mediated health effects can 22 23 24 25 26 27 28 29 30 31 32 [0] vary on the basis of susceptibility, differential exposure, differential prepare dness, 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 characteriza tion portion of a risk assessment, the assessor must cons ider critical windows within deve lopment that result in greater vulnerability to toxic effects. In developi ng the exposure assessment, the assessor must also consider windows of vulnerability based on, fo r example, behaviors (crawling, mouthing), activities (locations, product use, diet), and physiological characteristi cs (oxygen requirements, caloric requirements) that may lead to particul arly high levels of exposure. For example, information on the environmental fate of a compound and a child’s subsequent contact with it isThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 68 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

20 21 22 23

24 25 26

27 28 29 30

31 32

33 34 critical to ensure that hazard information is relevant to the measured exposure. As another example, understanding the dosimetry of an abso rbed 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 st ages that are at greatest risk. The focus of the exposure assessment is to identify age groups and address vulnerability resulting from differential exposure. Because th e 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). Ho wever, 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 expos ure assessment, the hazard characterization may need modification. The following questions identif y those issues that mi ght 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 cr itical windows in development? • Are there particular developmental stages during which children are highly exposed? Do health outcomes vary duri ng different developmental periods? How does this inform identification of the expos ures of greatest biological significance for the observed outcomes? • How does information on dosimetry indica te the level of temporal resolution needed in exposure data and modeling? Wh at dose metrics are being considered for child-related assessments? • How does the fate of the agent being eval uated affect exposure in children? Are children exposed to other agents with a si milar 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?This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 69 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 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 a ll of the potentially important pathways and scenarios identified in the conceptu al model (Section 4.3.3). At this point in the assessment, vulnerable age groups will be identifie d, patterns of exposure will be characterized (e.g ., intermittent, continuous , acute, or chronic), and exposures levels will be quantified. Identifying children with potentially higher expo sures or significant e xposures during critical windows is critical for a complete exposure assess ment for children. These considerations are of particular interest when assess ing children’s exposures because the timing of exposure can affect the outcomes observed. Children may experience uni que exposure patterns that would need to be considered in relation to thei r 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 ma y be important to consider peak exposures as well as exposures that have been av eraged 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 mean s 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 a nd effectively assess children’s exposures, a person/population-oriented approach may be need ed for all but the most basic assessments. 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 To conduct the life stage-specific exposure anal ysis, a calculation approach described in section 4.3.5.1 is selected on the basis of availabl e 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 e xposure 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 di scussed in Section 4.3.5.2 is often used to facilitate effici ent allocation of resources.

4.3.5.1. Exposure Measurement and Estimation Approach Three approaches may be used to calculate e xposures: the point-of-c ontact approach, the scenario evaluation approach, and the dose reconstruction approach.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 70 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 Point-of-contact approach: Sometimes referred to as the di rect 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 a nd duration of exposure, as well as information on the exposed population. Child-specific behavi ors 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 Activ ity Database [CHAD], available from 10 11 http://www.epa.gov/chadnet1 ; the Human Exposure Database System [HEDS], available from 12 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 addi tional sampling are limited but some analytical data are available. 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Dose reconstruction approach: This approach allows exposure to be estimated from dose, which can be reconstructed th rough 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; howev er, only a few examples currently exist for applying this approach successfully. At the pr esent 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 unc ertainty, a second, moreThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 71 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 refined level of analysis will be conducted. The first tier described below is a screening-level assessment used to identify and prioritize potenti ally important exposures. The screening level assessment uses bounding values for exposure factor s 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 h azard 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 boundi ng 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 an alysis depending on the types of scenarios that are being evalua ted. 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 tie r is to identify important pathways and scenarios, as well as to rule out insignificant on es. 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 probabi listic techniques may be useful when, for example, exposure parameters have large variability or when multiple sources exist (U.S. EPA, 2001a)

. 24 25 26 27 In the screening-level analys is, important differences in exposure between children of different developmental stages are identifie d. For some specific exposure scenarios and compounds, combining some of the age groups may be appropriate, for example, where variation in exposure factors and result ing exposures is insignificant (U.S. EPA, 2003b)

. 28 29 30 Limited data may be a critical impediment in conducting assessments for each of these age groups and for making decisions regarding co mbining or eliminating age groups. In these cases, the recommended age groups (U.S. EPA, 2003b) should be used unless qualitative 31This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 72 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9

10 11

12

13 14

15 16

17 18 19

20 21 22

23 24 25 26 27 28 29 30 31 32 33 information leads the assessor to identify pot entially 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 pos ed 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 compar e 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 ade quate? What criteria are used to determine adequacy? What are the significant data need s? Is there a need to collect additional data?

Based on the bounding assumptions used in this leve l of analysis and comparison with the hazard analysis, a set of potentially significant expos ure scenarios for important age groups will be identified. In order to identify and understa nd the important paramete rs and uncertainties in these exposure estimates, a sensitivity analys is is generally conduc ted 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 orde rs 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 "conserva tism" can be made. Methods for conducting a sensitivity analysis are discussed further in the next section.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 73 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8

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17 18 19 4.3.5.2.2. Refined Assessment. This tier provides more de tail for potentially important scenarios and potentially vulnerabl e 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 ques tions posed in the problem formulation stage of the risk assessment? • What is the central tendency of the di stribution 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 basi s of their current developmental stage? • Is the exposure information currently avai lable adequate? What criteria are used to determine adequacy? What are the significan t exposure data needs? Is there a need to collect additional data?

This more advanced analysis may include th e application of sophist icated modeling tools to develop exposure estimates for use in regulatory decisions. A variety of modeling tools have been developed over the years to fa cilitate exposure assessment (see Price et al., 2003 , and references therein for review of available tools). Some of the t ypes of models available include total source models (e.g

. , aggregate and cumulative models de veloped to meet requirements of the 20 21 22 Food Quality Protection Act (FQPA) ; multi-route models of exposure (e.g

. , local waste site models, tap-water exposure models), models of exposures to specific sources or routes (e.g

. , dietary models, consumer product models), i ndoor air models, and occupational models. 23 24 25 26 27 28 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 specif ic age groups of interest for a complete life stage assessment. This issue is discussed further in Draft Guidance on Selecting the Appropriate 29 Age Groups for Assessing Childhood Expos ures to Environmental Contaminants (U.S. EPA, 30 2003b)

. 31This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 74 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

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24 25 26 27 28 29 Limitations of the data, model results, and a ssociated 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? Av ailable exposure data sets may not allow modelers or risk assessors to directly extract data from the underlying sources to conduct age group-specific analyses. Potentia l 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 cat egorical limits of the underlying database to utilize all the data, and then formatting the probabilistic model outpu t 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 fo r exposures of interest (e.g ., by media, source, pathway)? If not, do they need to be devel oped? Are there sufficient data for their development? • How will variability and uncer tainty 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 da ta to address them may be needed.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 75 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

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25 26 27 28 29 30 31 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 c onclusions 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 expos ure. It is useful to also include a description of how the a ssessment can be improved and uncertainties be reduced by additional research or collection of data. It is important that the results of the a ssessment are communicated in a clear and concise manner to the risk manager, and include consid erations of childhood variability and uncertainty within the exposure analysis. The following questi ons could also be cons idered by the assessor.

• If different approaches were used to es timate exposure for different life stages or within a life stage, what we re the results? Can they be compared and, if so, how do they compare? Which approach is more appropriate? • Does the life stage-specific assessmen t capture the variability in the exposed groups? What are the ranges or distributions of exposure?

• What are the uncertainties in the estim ates, 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 th e results to these data gaps?

• Is it feasible or desirable to collect more data pertaining to pa rticular life stages? Could the exposure estimates be refine d 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 characteristi c 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 ar e referred to as intra i ndividual variability.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 76 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 12 Among children, inter individual variability can be important due to rapid physiological and behavioral changes. Even within a relativ ely narrow age group, variab ility may be large. This variability affects the dete rmination of upper percentiles of exposure and its associated risk, and so can be critical to childre n’s risk assessment. That is, gi ven 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 da ta and the characte rization 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, variabil ity 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 an d breathing behavior (e.g

. , the transition from m outh 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, live r, immune system, reproductive system, renal system, cardiac system, central nervous system, muscle, and sensory organs). For example, infants have immature immune systems, and re nal functions are less th an those predicted by surface area 13 14 15 16 17 18 19 (U.S. EPA, 2003b)

. 20 21 22 23 24 25 26 27 28 29 30 4.3.6.2 . Uncertainty Analyses Uncertainty is described as a lack of knowledge about factor s 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 assump tions made in development of the model. For example, soil ingestion studies in the literatur e 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 st atistical tools for anal yzing variability and uncertainty in risk assessments, given that ade quate data are available. General issues to consider when applying these quantita tive methods are described in EPA’s Guiding Principles 31This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 77 DRAFT—DO NOT CITE OR QUOTE 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 (U.S. EPA, 2 1999a) . Methodologies for selecting parametric di stributions to be used in probabilistic assessments are described in 3 Options for Developing Parametric Probability Distributions for 4 Exposure Factors (U.S. EPA, 2000b)

. 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 4.3.6.3. Sensitivity Analyses Sensitivity analysis has been defined as the as sessment of the impact of changes in input values on model outputs. Its main purpose in any exposure a ssessment is to determine which variables in the model equations and what path ways or scenarios most affect the exposure estimate. These techniques can also be used to assess key sources of va riability and uncertainty for the purpose of prioritizing additional data co llection 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 consider able attention on the imp act 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 appr oach for characterizi ng children’s exposures to environmental contaminants. This life st age-specific analyses results in a thorough characterization of the magnitude, frequency, a nd duration of exposure received for various exposure pathways. The results of the exposure assessment are then comb ined with the results from the hazard and dose response analysis to characterize potential ri sks to children. The conclusions from the exposure assessment and the discussion about key assumptions, limitations, and uncertainties are later integr ated with the conclusions from the hazard and dose response assessments to provide a characterization of risk.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 78 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 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 expos ure assessment components of the risk assessment are integrated, summarized, and majo r conclusions are drawn. Risk characterization should be done in accordance with EPA’s science pol icy 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 ch aracterization section we re the developmental toxicity, reproductive toxici ty, neurotoxicity and cancer risk assessment guidelines ( 6 7 8 U.S. EPA 9 1991 , 1996 , 1998b , 2005b , 2005c ) and the National Research Council’s report Science and 10 Judgment in Risk A ssessment (NRC, 1994)

. 11 12 13 14 15 As with other sections of this framew ork, 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 ch aracterization of reproduc tive 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. 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 5.1. SUMMARY OF THE MAJOR CONCLUSION S IN LIFE STAGE-SPECIFIC RISK CHARACTERIZATION This summary includes a narrative of the majo r 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 deve lopment identified in th e hazard assessment and the associated exposure assessment. This nontec hnical 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 ga ps that could affect the respective major conclusions should be identified and described. Finally, the su mmary provides the qualitative and quantitative justification for the applicati on of life stage-specific adjustments for durationspecific health values (e.g., use of life stage-spec ific RfV for a specific du ration of exposure) if the assessment warrants it.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 79 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16 17 18

19 20 21 22 23 24 25 26 27 5.1.1. Hazard Characterization This section includes the integrative summ ary of information on the capacity of an environmental agent to cause adverse effects in laboratory animals and humans at different life stages. The qualitative descripti on is based both on the type of da ta 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, a nd MOA) into a WOE narrative. Tables 5-1 through 5-3 are not intended to be proscriptive bu t are provided to assist the preparation of the narrative.

5.1.2. Dose-Response Characterization The dose-response characterization focuse s on quantitative relationships between exposure (dose) and effects. Critical outcomes and life stages of concern from the hazard characterization are examined quantitatively and su mmarized in this section. For outputs of this analysis to be useful in benefits analysis, the endpoints that are quantifie d 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. Meth ods for assessing dose-response relationships often depend on assumptions used in the abse nce 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 narrat ive describing the basis for values used in exposure scenarios. If the values are ba sed on data, then the quality, purpose, and representativeness of the databa se should be described. Altern atively, if they are based on assumptions, the sources and general logic used to develop the assumptions should be described. The major factors thought to ac count for the greatest uncertain ty in the exposure assessment should be described and linked to in formation from sensitivity analyses or lack of particular data.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 80 DRAFT—DO NOT CITE OR QUOTE 1 Table 5-1. Issues Addressed in Hazard Characterization (Section 4.1.)

Toxicological Evidence What are the key toxicol ogical 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 c oncordance of effects? Are all studies supporting these findings discussed, and do any valid studies contradict these findings? Besides the developmental life st age 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 be tween animals and humans? If not, are there underlying biological reasons to explain these differences?This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 81 DRAFT—DO NOT CITE OR QUOTE 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 factor s, 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 bi ologic plausibility, internal and external consistency, and the infl uence of limitations of the design, data sources, and analytic methods? Are “negative” human studies (dat a) considered in the hazard characterization? Did included st udies 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 th at are also sup ported 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 st udies to humans at particular life stages?

1This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 82 DRAFT—DO NOT CITE OR QUOTE 1 2 Table 5-2. Issues Addressed in Dose-Response Characterization (Section 4.2.)

Nature and Extent of the Database: What data were used to de velop the dose-response curve? Would the results have been sign ificantly different if based on a different data set? Were there diffe rences 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 combinatio n? 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 do se-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 modelin g? 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?This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 83 DRAFT—DO NOT CITE OR QUOTE 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 av ailable to extrapolate across routes of exposure? Are data available from the same life stages as the expected exposed human populations? If not, are t oxicokinetic data available to extrapolate across life stages? What information was used to s upport duration adjustment and to calculate the human equivale nt 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?

Table 5-3. Issues Addressed in Exposure Characterization (Section 4.3.) 1

Pathways of Exposure What are the most significant path ways of environmental exposure? What are the likely routes of exposure?

Sources of Exposure What are the most significant sour ces 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 envi ronmental pathways for exposure? Populations Describe the groups assessed, incl uding parents before conception, and different developmental lif e stages (e.g., pregnant women, infants, young children, adolesce nts, highly exposed groups of children, and highly susceptib le groups of children).

Time Frame of Exposure Describe the time frame of exposur e, including pattern (continuous, intermittent) and duration of exposure (acute, short term, subchronic, or chronic).

Location of Exposure Discuss locations where child ren are being exposed (e.g

. , residence, school, outdoors). Activities Leading To Exposure Discuss activities that result in significant exposures (e.g., breastfeeding, mouthing, sports, a nd after-school employment).This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 84 DRAFT—DO NOT CITE OR QUOTE Exposure Characterization Describe the basis for the e xposure assessment, including any monitoring, modeling, or other analys es of exposure distributions. What are the key descriptors of exposure? Describe the range of exposures for the various categories of individuals (e.g., “average” indivi duals, the most highly exposed individuals, the general populat ion, children, aged, males, and pregnant or lactating females). How was the central tendency estima te developed? What factors or methods were used in developing this estimate? How was the high-end estimate devel oped? 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 e xposures 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 resu lts obtained and th e 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?

5.2. SUMMARY OF ALL THE VARIABIL ITY AND UNCERTA INTY ANALYSES 1 2 3 Determine whether different approaches us ed to estimate exposur e or health outcome provide similar risk estimates. Information from different sources can ca rry different kinds ofThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 85 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 7 8 9 10 11 variability and uncertainty. K nowledge of these sources of va riability and uncertainty are important when considering integration of the un certainties in the risk characterization. This knowledge can have an impact on de cisions that must be made a bout 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 asse ssments. Critical data gaps, de fined by the impact they have on the risk assessment, should be identified and described. These critical data gaps and the attendant research needs may provi de insight into future reducti ons 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?

5.3. RISK CONTEXT 12 13 14 15 16 17 18 19 20 21 The risk characterization must be presented in a context that relates to the original problem identified in the planning and scoping phas e of the framework. Risk assessment is an iterative process that grows in de pth and scope; this occurs in stag es, from screening for priority making, to preliminary estimation of risk, to fu ller examination in support complex regulatory decisions. If the statement of the problem evolve d during the analyses, this process needs to be summarized. The risk context of major conclusi ons 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 theThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 86 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 key conclusions and assumptions and a balanc e between confidence and uncertainty in the

assessment.

Table 5-5. Types Of Issues To Be Cons idered 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 characteris tics of the hazard to children (e.g

. , voluntary vs. involuntary, technol ogical vs. natural.)? ( Comment on findings, if any, from studies of risk perception that relate to this hazard or similar hazards.) How do life stage-specif ic risks compare? How does this risk compare with other risks in this regulatory program, or other similar risk s that EPA has evaluated? How can benefit analysis utilize the information derived from the risk characterization? Where appropriate, can this risk be compared wi th 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 c onclusions that merit discussion?

Other Information Is there other information that would be useful to the risk manager or the public in this situ ation that has not b een described above? 5This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 87 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6 6. SUMMARY AND IDENTIFICATION OF GAPS IN GUIDANCE FOR CHILDREN’S HEALTH RISK ASSESSMENT

This report summarizes the process for assess ing health risks resulting from children’s exposure to environmental agents using a phase d approach that include s problem formulation, analysis, and risk characterization. It utiliz es EPA documents that have outlined a similar approach ( U.S. EPA, 1998a , 2003a ) as well as the re port of a workshop (ILSI, 2003) that formed the basis for a children’s health risk assessment fr amework. 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 proce ss. In addition, the report refe rences appropriate guidelines, guidance documents, and other relevant reports and literature that can be drawn upon for more detailed information. 7 8 9 10 11 12 13 14 As indicated in this report, se veral EPA risk assessment guide lines relate to health risks from children’s exposures. The most relevant ar e the developmental toxicity risk assessment guidelines (U.S. EPA, 1991) that deal with the whole organi sm during development, but focus primarily on the effects of pren atal 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 15 16 17 (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. 19 20 21 22 23 24 25 The relevance of specific developmental outcom es 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 i ssue is considered in many of the risk assessments currently being generated across EPA. Ga ps identified in the document A Review of the Reference Dose 26 and Reference Concentration Processes regarding data needs and alternative approaches and strategies for developing testi ng guidelines are still necessary ( 27 U.S. EPA, 2002b , Section 5). In addition, there has not been a focused guidan ce document on dose-response assessment with developmental exposures, despite the fact that a good deal of re search and methods development on BMD 28 29 30 (U.S. EPA, 2000a) and pharmacokinetic modeling (e.g

. , Clewell et al. 2002a ; Ginsberg 31 et al. 2004b ) has been done using developmental data in animals and humans. 32This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 88 DRAFT—DO NOT CITE OR QUOTE 1 With regard to exposure assessment, there is very little guidance on approaches specific to children at different life stages, except for Child Specific Exposure Factor Handbook (U.S. 2 EPA, 2002a) and the guidance on selecting approp riate 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 child ren’s exposures. Data for exposure factors determinations for all the recommended age grou ps are limited or nonexistent for some exposure factors. 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

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22 23 24 25 26 27 Finally, one issue addressed briefly in this report is the integration of toxicity data and children’s exposure estimates, an issue for which essentia lly 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 biol ogical processes underlying development, MOA information, chemical-specific mechanisms, anatomical, physiological, and behavioral characteristics at different developmental life st ages 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 ris k. Some of these questions are: • How can adult biomonitoring da ta be applied to children? • How can biomonitoring data be inte rpreted to characterize exposure?

• How can data from children be inte rpreted 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 issu es and does not attempt to predict outcome or positions.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 89 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5

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35 36 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 impairme nt, or pathologic lesion that affects the performance of the whole organism or re duces 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 re sponse 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 molecula r level linking the targ et organ dose to the adverse effect.

Biomarker – A biological molecule or bi ochemical indicator of expos ure or biological changes resulting from exposures, or mark ers of risk or susceptibility. Biomonitoring – The assessment of human exposure to chemicals by the m easurement of the chemicals or their metabolites (b reakdown products) in human tissues or fluids such as blood or urine. Blood and urine levels re flect the amount of the chemical in the environment that actually gets into the body. Body Burden – The amount of a particular chemical, especially a po tentially 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 tissu e, 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 compar es subjects with the disease of interest (cases) to subjects wit hout the disease (controls). The groups are compared with respectThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 90 DRAFT—DO NOT CITE OR QUOTE 1 2

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37 38 to exposure history to ascertain whether they di ffer in the proportion expo sed to the chemical(s) under investigation. Case Report – A description of a person in a popul ation or study group identified as having a particular disease, health diso rder, or condition under investig ation, without a comparison made to a control.

Child –Conception to maturation of all organ sy stems, 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 re presentation of actual or predicted relationships between humans or ecological entities and the chemi cals 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 as sociation 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 th at make a toxic molecule less toxic.

Dose – The amount of a substance available for in teraction with metabolic processes or biologically significant recepto rs after crossing the outer boundary of an organism. Absorbed Dose is the amount crossing a spec ific 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 interacti on by any particular organ or cell. Internal Dose is a more general term denoting th e amount absorbed without respect to specific absorption barriers or exchange boundaries. Potential Dose is the amount ingested, inhale d, 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 relati onship between the magnitude of administered, applied, or internal dose and a specific biological response. Response can beThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 91 DRAFT—DO NOT CITE OR QUOTE 1 2

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33 34 35 36 37 38 expressed as measured or observed incidence, percent response in groups of subjects (or populations), or the probability of oc currence of a response in a population. Dose-Response Curve – A graphical representation of th e quantitative relationship between administered, applied, or internal dose of a chemical or agent, and a sp ecific 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 biologi cal pollutant after release into the environment. Environmental fate involves tempor al and spatial considerations of transport, transfer, storage, and transformation. Epidemiology – The study of the distribution and determin ants of health-relate d states or events in specified populations. Exposure – Contact made between a chemical, physic al, 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 th an 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 defin ition implies sufficient time for the chemical and its metabolites to clear the biological system before the subsequent exposure (i.e., non-cumulati ve toxicokinetics). Longer-Term Exposure is repeated exposure by the oral, derm al, or inhalation route for more than 30 days, up to approximately 10% of the lif e 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 fo r 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).This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 92 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 5 6

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9 10 11 12 13 14 15 16 17 18 19 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 pol lutant 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, a nd inferences that define a discrete situation where potential expos ures may occur. These may in clude the source, the exposed population, the time frame of exposure, microenvir onment(s), and activities. Scenarios are often created to aid exposure assesso rs 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 showi ng only effect levels for mortality or other extremely severe toxicity would not be su fficient 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 exposure, life stages, and su sceptible subpopulations. (See U.S. EPA, 2000b , pages 4-19.) 20

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27 28 29 30 31 32 33 34 35 36 37 38 39 40 Hazard Assessment – The process of determining whether exposure to an agent can cause an increase in the incidence of a par ticular 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 advers e health effects attributable to a specific environmental agent, the mechanisms by wh ich agents exert their toxic effects, and the associated dose, route, dura tion, and timing of exposure. Human Equivalent Concentration (HEC) or Dose (HED) – The human concentration (for inhalation exposure) or dose (for ot her routes of exposure) of an agent that is believed to induce the same magnitude of toxic effect as the expe rimental animal species concentration or dose. This adjustment may incorporate toxicokinetic information on the pa rticular 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 i ngests during some specifi c time period (units of mass/time). For inhalation, the intake rate is th e rate at which contamin ated air is inhaled. Factors that affect dermal exposur e are the amount of material th at comes into contact with the skin and the rate at which the contaminant is absorbed.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 93 DRAFT—DO NOT CITE OR QUOTE 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). 2 3

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38 39 Life Stage Approach – The comparison of exposure and effect data across different life stages from conception to old age. This approach provid es a temporal context in which to evaluate data for risk assessment. Longitudinal Study – An epidemiologic study comparing subj ect with an exposur e of interest to those without the exposure. These two cohorts are then followed over time to determine the differences in the rates of dis ease 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 incr eases in frequency or severity of adverse effects among the exposed population when compared w ith an appropriate control group. Margin of Exposure (MOE) – The ratio of the point of de parture (POD) over an exposure estimate (MOE = POD/Exposure).

Mechanism of Action – The complete sequence of biol ogical events (i.e., including toxicokinetic and toxicodynamic events) from expos ure to the chemical to the ultimate cellular and molecular consequences of chemical exposure that are required in or der to produce the toxic effect. However, events that are coincident but not required to produce th e toxic outcome are not included.

Media – see Exposure Media. Meta-Analysis – Any systematic method that uses statistica l analysis to integrate the data from a number of independent studies.

Mode of Action – The sequence of key event(s) (i.e., toxicokinetics and to xicodynamics) after chemical exposure upon which the toxic outcome depend.

Model – A mathematical function with parameters th at 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, st atistical or empirical models selected for particular numerical properties are fitted to da ta; 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 ca rries higher confiden ce 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 freque ncy or severity of adve rse effect between theThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 94 DRAFT—DO NOT CITE OR QUOTE 1 2

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36 37 38 39 exposed population and its appropri ate 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 re sult 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 abso rption 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 ne ar 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 mode l (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 th e pathological onset of a disease. Reference Concentration (RfC) – An estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposur e to the human population (including sensitive subgroups) that is likely to be wit hout an appreciable risk of dele terious 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 spanni ng 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 eff ects during a lifetime. It can be derived from a NOAEL, a LOAEL, or a benchmark dose, with uncer tainty factors generally applied to reflect limitations of the data used. It is generally us ed in U.S. EPA’s non-cance r health assessments. Reference Value (RfV) – An estimation of an exposure for (a given duration) to the human population (including susceptible subgr oups) that is likely to be w ithout an appreciable risk of adverse effects over a lifetime. It is derive d from a BMDL, a NOAEL, a LOAEL, or another suitable POD, with uncertainty/variability factors a pplied to reflect limitations of the data used.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 95 DRAFT—DO NOT CITE OR QUOTE 1 2

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24 25 26 27 28 29 (Durations include acute, short term, longer term, a nd chronic and are defined individually in this glossary.) Risk (in the context of human health) – The probability of advers e 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 e nvironmental agents (hazard char acterization), the dose-response relationship (dose-response asse ssment), and the extent of hu man exposure to those agents (exposure assessment). The product of the risk assessment is a stat ement regarding the probability that populations or individuals so ex posed 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 a ny 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 engineer ing implications together with risk-related information in order to develop, analyze, a nd 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 ch emical structure and biol ogical activity. It is based on the premise that the biological fate a nd activity of a chemical (i.e., whether it is absorbed, metabolized, or bioaccumulated and whet her 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 cont acted 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 analys is can provide a quantitative ranking of the model inputs based on their relative contributions to model output variability and uncertainty (U.S. EPA 30 2001a)

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35 36 37 38 Short-Term Exposure – Repeated exposure by the oral, derm al, 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 expre ssed in units of proportion (of a population) affected per mg/kg/day, is genera lly reserved for use in the low-dose region of the dose-response relationship, i.e., for exposures corresponding to risk s less than 1 in 100.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 96 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4

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–The origin of an agent for the purposes of an exposure assessment.

Source-to-Dose Model

–An approach where an environmenta l 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 m odulate normal functions of the organism or induce an adverse response (e.g

. , agent, lack of food, drought). Superfund – Federal authority, established by the Comprehensive Environmental Response, 11 Compensation, and Liability Act (CERCLA) (U.S. 96 th Congress, 1980) to respond directly to releases or threatened releases of hazardous s ubstances that may endange r health or welfare. 12 13

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33 34 35 36 37 Susceptibility – Increased likelihood of an adverse eff ect 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., child ren 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-speci fic, 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 bi ological 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 lead ing to a toxic response to an environmental agent (sometimes referred to as pharmacodynamics, also MOA. Toxicokinetics (TK) – The determination and quantificati on of the time course of absorption, distribution, metabolism, and excretion of chemicals (sometimes referred to as pharmacokinetics).

Toxification

–Metabolic conversion of a potentially t oxic substance to a pr oduct 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 differe nt 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 evaluate d. Variability can beThis document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 97 DRAFT—DO NOT CITE OR QUOTE 1 2 3

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20 21 22 23 24 better characterized with more da ta but it cannot be reduced or el iminated. 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 experi mental 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 fr om data obtained in a study with less-than-lifetime exposure (i.e., extrapola ting 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 tr ue heterogeneity or divers ity. 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. Th is may be due to differences in exposure (i.e

. , different people drinking differe nt amounts of water and having di fferent body weights, different exposure frequencies, and differe nt exposure durations) as well as differences in response (e.g., genetic differences in resistance to a chemical dos e). Those inherent differences are referred to as variability. Differences among individuals in a population are referred to as interindividual variability; differences for one in dividual over time is referred to as intraindivi dual variability. Vulnerability – A matrix of physical, chemical, biol ogical, social, and cultural factors which result in certain communities and sub-populati ons being more susceptible to environmental toxins, being more exposed to toxins, or havi ng compromised ability to cope with and/or recover from such exposure. Four types of vulne rability are considered with regard to a life stage approach: susceptibility or sensitivity, di fferential exposure, differential preparedness, and differential ability to recover (NEJAC, 2004)

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26 27 28 Weight of Evidence (WOE) – An approach requiring a critical evaluation of the entire body of available data for consistency a nd biological plausibility. Poten tially relevant studies should be judged for quality and studies of high quality given much more weight than those of lower quality. (See U.S. EPA, 2000b , pages 4-11-12.) 29 30This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 98 DRAFT—DO NOT CITE OR QUOTE 1 2 3 4 REFERENCES 12

Adams, J; Barone, S Jr; LaMantia, A; Philen, R; Rice, D; Spear, L; Susser, E. (2000) Workshop summary to identify critical windows of exposure for children’s hea lth: Neurobehavioral workgroup. Environmental Health Perspectives 108(Suppl 3):535-544. Available online at http://ehp.niehs.nih.gov/members/2000/suppl-3/535- 5 544adams/adams-full.html 6 7 8 9 10 Allen, B; Gentry, R; Shipp, A; Van Landingham, C. (1998) Calculation of benchmark doses for reproductive and developmental toxicity observed after exposure to isopropanol. Regulatory Toxicology and Pharmacology 28(1), 38-44. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=PubMed&cmd=Retriev e&list_uids=9784431&dopt=Citation 11 12 13 14 15 Andersen, ME; Meek, ME; Boorman, GA; Brusick, DJ; Cohen, SM; Dragan, YP; Frederick, CB; Goodman, JI; Hard,GC; O'Flaherty, EJ; Robinson, DE. (2000) Lessons learned in applying the U.S. EPA proposed cancer guidelines to specific compounds. Toxicol Sci 53:159-172. Available online at http://toxsci.oxfordjournals.org/cgi/reprint/53/2/159 16 17 18 19 Andersen, ME; Dennison, JE. (2001) Mode of action and tissue dosimetry in current and future risk assessments. Sci Total Environ 274:3-14. Available online at: http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=PubMed&cmd=Retriev e&list_uids=11453304&dopt=Citation 20 21 22 23 Anderson, LM; Diwan, BA; Fear, NT; Roman, E. (2000) Cr itical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models. Environmental Health Perspectives 108(Suppl 3):573-594. Available online at http://ehp.niehs.nih.gov/members/2000/suppl-3/573- 24 594anderson/anderson-full.html 25 26 27 28 29 Ashani, Y; Pistinner, S. (2004) Estimation of the upper limit of human butyrylcholinesterase dose required for protection against organophosphates toxicity: a mathematica lly based toxicokinetic model. Toxicological Sciences 77:358-367. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14600276& 30 query_hl=13 31 32 33 34 35 Barnes, DG; Daston, GP; Evans, JS; Jarabek, AM; Kavl ock, RJ; Kimmel, CA; Park, C; Spitzer, HL. (1995) Benchmark dose workshop: criteria for use of benchmark dose to estimate a reference dose. Regulatory Toxicology and Pharmacology 21:296-3 06. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7644719&q 36 uery_hl=25 37 38 39 40 41 Barr, M, Jr; DeSesso, JM; Lau, CS; Osmond, C; Ozanne, SE; Sadler, TW; Simmons, RA; Sonawane, BR. (2000) Workshop to identify critical windows of exposure for child ren's health: Cardiovascular and Endocrine Work Group summary. Environmental Health Perspectives 108(Suppl 3):569-572. Available online at http://ehp.niehs.nih.gov/members/200 0/suppl-3/569-571barr/barr-full.html 42 43 44 45 Barton, H. (2005) Computational pharmacokinetics during developmental windows of susceptibility. Journal of Toxicology and Environmental Health, Part A: 68(11-12):889-900. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16020183& 46 query_hl=8 47 48 49 50 51 Beck, BD; Mattuck, RL; Bowers, TS; Cohen, JT; O'Flah erty, E. (2001) The development of a stochastic physiologically based pharmacokinetic model for lead. The Science of the Total Environment 274:15-19. Available online at

12 All references are hyperlinked to the online document when available. Due to copyright regulations, there may be links to sites where the document is available for purchase. Note that links may change over time.This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 99 DRAFT—DO NOT CITE OR QUOTE http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11453291& 1 query_hl=27 2 3 4 5 Beckman, DA; Feuston, M. (2003) Landmarks in the development of the female reproductive system. Birth Defects Research Part B: Developmental and Reproductive Toxicology 68(2):137-143. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12866705& 6 query_hl=23 7 8 9 10 Besunder, JB; Reed, MD; Blumer, JL. (1988a) Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part I) . Clin. 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Environmental Health Perspectives 110:A333-337. Available online at http://ehp.niehs.nih.gov/members/2002/1 10pA333-A337clewell/clewell-full.html 41 42 43 44 Clewell, HJ, III; Andersen, ME; Barton, HA. (2002a) A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment. Environ Health Perspect 110(1):85-93. Available online at http://ehp.niehs.nih.gov/members/2002/110p85-93clewell/clewell-full.html 45 46 47 48 49 Clewell, HJ; Teeguarden, J; McDonald, T; Sarangapani, R; Lawrence, G; Covington, T; Gentry, R; Shipp, A. (2002b) Review and evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Crit. Rev. Toxicol 32:329-389. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12389868& 50 query_hl=38 51 52 53 54 55 Clewell, RA; Merrill, EA; Yu , KO; Mahle, DA; Sterner, TR; Fisher, JW; Gearhart, JM. 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(2001) Toward a biologically based dose-response model for developmental toxicity of 5-fluorouracil in the rat: a mathematical construct. Toxicol Sci 59(1):49-58. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11134543& 25 query_hl=142 26 27 28 29 30 Shuey, DL; Lau, C; Logsdon, TR; Zucker, RM; Elstein, KH; Narotsky, MG; Setzer, RW; Kavlock, RJ; Rogers, JM. (1994) Biologically based dose-response modeling in developmental toxicology: biochemical and cellular sequelae of 5-fluorouracil exposure in the developing rat. Toxicol Appl Pharmacol 126(1):129-44. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8184423&q 31 uery_hl=144 32 33 34 35 36 37 Slikker, W, Jr; Andersen, ME; Bogdanffy, MS; Bus, JS; Cohen, SD; Conolly, RB; David, RM; Doerrer, NG; Dorman, DC; Gaylor, DW; Hattis, D; Rogers, JM; Woodr ow, SR; Swenberg, JA; Wallace, K. (2004a) Dosedependent transitions in mechanisms of toxicity. Toxicology and Applied Pharmacology 201:203-225. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15582645& 38 query_hl=146 39 40 41 42 43 44 Slikker, W, Jr; Andersen, ME; Bogdanffy, MS; Bus, JS; Cohen, SD; Conolly, RB; David, RM; Doerrer, NG; Dorman, DC; Gaylor, DW; Hattis, D; Ro gers, JM; Setzer, RW; Swenberg, JA; Wallace, K. (2004b) Dose-dependent transitions in mechanisms of toxicity: case studies. Toxi cology and Applied Pharmacology 201: 226-294. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15582646& 45 query_hl=148 46 47 48 49 Spearow, JL; Doemeny, P; Sera, R; Le ffler, R; Barkley, M. (1999) Genetic variation in susceptibility to endocrine disruption by estrogen in mice. Science 285(5431):1259-61. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10455051& 50 query_hl=150 51 52 53 54 Spearow, JL; O'Henley, P; Doemeny, P; Sera, R; Leffler, R; Sofos, T; Bark ley, M. (2001) Genetic variation in physiological sensitivity to estrogen in mice. APMIS 109(5):356-64. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11478683& 55 query_hl=152 56This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 106 DRAFT—DO NOT CITE OR QUOTE 1 2 U.S. 96 th Congress. (1980) Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Public Law 96-510. 42 U.S.C. 9601 et seq. Available online at http://www.epa.gov/superfund/action/law/cercla.htm 3 4 5 U.S. 104 th Congress. (1996a) Food Quality Protection Act (FQPA). P.L. 104-170. Available online at http://www.epa.gov/opppsps1/fqpa/ 6 7 8 U.S. 104 th Congress. (1996b) Safe Drinking Water Act (SDWA) Amendments. P.L. 104-182. Available online at http://www.epa.gov/safe water/sdwa/text.html 9 10 11 U.S. EPA (Environmental Protection Agency). (1991) Guidelines for developmental toxicity risk assessment. Federal Register 56(234):63798-63826. Available online at http://www.epa.g ov/ncea/raf/pdfs/devtox.pdf 12 13 14 U.S. EPA (Environmental Protection Agency). (1992) Guidelines for exposure assessment. Risk Assessment Forum, Washington, DC; 600Z-92/001. Available online at http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=15263 15 16 17 18 19 U.S. EPA (Environmental Protection Agency). (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Office of Research and Development, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Offi ce, Research Triangle Park, NC. EPA/600/8-90/066F. Available online at http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993 20 21 22 U.S. EPA (Environmental Protection Agency). (1995a) Policy on evaluating health risks to children. Office of the Administrator, Washington, DC. Available online at http://www.epa.gov/osa/spc/htm/memohlth.htm 23 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 http://cfpub.epa.gov/ncea/cfm/ recordisplay.cfm?deid=40957

. 27 28 29 30 U.S. EPA (Environmental Protection Agency). (1996) Guide lines for reproductive toxicity risk assessment. Risk Assessment Forum, Washington, DC; 630/R-96/0009. Available online at http://cfpub.epa.gov/ncea/raf/ recordisplay.cfm?deid=2838 31 32 33 34 U.S. EPA (Environmental Protection Agency). (1997a) Guid ance on cumulative risk assessment. Part 1: Planning and scoping. Office of the Administrator, Washington, DC. Available online at http://epa.gov/osa/spc/htm/cumrisk2.htm 35 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 http://www.epa.gov/ncea/raf/montecar.pdf 39 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. Available online at http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=12186 43 44 45 U.S. EPA (Environmental Protection Agency). (1998a) Guid elines for ecological risk assessment. Federal Register 63(93):26846-26924. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=36512 46 47 48 49 U.S. EPA (Environmental Protection Agency). (1998b) Guidelines for neurotoxicity risk assessment. Federal Register 63(93):26926-26954. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=4555 50 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 http://cfpub.epa.gov/ncea/raf/ recordisplay.cfm?deid=55007 54 55This document is a draft for review purposes only and does not constitute Agency policy. 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 Devel opment, Washington, DC; EPA/630/R-98/004. Available online at http://cfpub2.ep a.gov/ncea/cfm/recordis play.cfm?deid=12487 3 4 5 U.S. EPA (Environmental Protection Agency) (1999b) Toxicological review for ethylene glycol monobutyl ether. Available online at http://www.epa.gov/iris/to xreviews/0500-tr.pdf 6 7 8 9 U.S. EPA (Environmental Protection Agency). (2000a) Benchmark dose technical guidance document (external review draft). Risk Assessment Forum, Washingt on, DC; EPA/630/R-00/001. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=4727 10 11 12 13 14 U.S. EPA (Environmental Protection Ag ency). (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 http://cfpub.epa.gov/ncea/cfm/ recordisplay.cfm?deid=20867 15 16 17 18 U.S. EPA (Environmental Protection Agency). (2000c) Sc ience policy handbook: risk characterization. Science Policy Council, Washington, DC; EPA/100/B/00/002. Available online at http://www.epa.gov/osa/spc/htm/rchandbk.pdf 19 20 21 22 U.S. EPA. (Environmental Protection Agency). (2000d) Stra tegy for research on environmental risks to children. Office of Research and Development, Washington , DC; EPA/600/R-00/068. Available online at http://www.epa.gov/ncea/pd fs/strat4resrch.pdf 23 24 25 26 U.S. EPA (Environmental Protection Agency). (2000e) Gu idelines for preparing econo mic analyses. Office of the Administrator, Washington DC; EPA/240-R-00-003. Available online at http://yosemite.epa.gov/ee/epa/eed.nsf/webpages/Guidelines.html 27 28 29 30 31 U.S. EPA (Environmental Protection Agency). (2001a) Risk assessment guidance for Superfund: process for conducting probabilistic risk assessments. Volume 3, Pa rt A. Office of Solid Waste and Emergency Response, Washington, DC; EPA/540/R-02/002. Available online at http://www.epa.gov/oswer/riskassessment/rags3a/index.htm 32 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 http://www.epa.gov/oswer/riskassessment/ragsd/index.htm 37 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 http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=8298 41 42 43 44 U.S. EPA (Environmental Protection Agency). (2002a) Child -specific exposure factor handbook (interim report). Office of Research and Developmen t, National Center for Environmental Assessment, Washington, DC; EPA/600/P/00/002B. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=36528 45 46 47 48 U.S. EPA (Environmental Protection Agency). (2002b) A re view of the reference dose and reference concentration processes. Risk Assessment Forum, Washington, DC; EPA/630/P-02/002F. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=36836 49 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 online at http://www.epa.gov/oppfead1/trac/science/determ.pdf

. 53 54This document is a draft for review purposes only and does not constitute Agency policy. 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 http://cfpub.epa.gov/ncea/raf/ recordisplay.cfm?deid=54944 3 4 5 6 7 U.S. EPA (Environmental Protection Agency). (2003b) Gu idance on selecting the appropriate age groups for assessing childhood exposures to environmental contamin ants. (external review draft). Risk Assessment Forum, Washington, DC; EPA/630/P-03/003A. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=429113 8 9 10 11 U.S. EPA (Environmental Protection Agency). (2003c) Huma n health research strategy . Office of Research and Development, Washington, DC; EPA/600/R-02/050. Available online at http://www.epa.gov/nheerl/humanhealth/HHRS_final_web.pdf 12 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 http://yosemite.epa.gov/ee/epa/eed.nsf/webpages/HandbookChildrensHealthValuation.html 17 18 19 U.S. EPA (Environmental Protection Agency) (2003f) Toxicological review of xylenes (EPA 635/R-03/001). Available online at http://www.epa.gov/iris/to xreviews/0270-tr.pdf 20 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 http://cfpub.epa.gov/ncea/cfm/r ecordisplay.cfm?deid=135427 25 26 27 28 U.S. EPA (Environmental Protection Agency). (2005b) Guide lines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC. EPA/630/P-R-03/001B.003. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=439797 29 30 31 32 U.S. EPA (Environmental Protection Agency). (2005c) S upplemental guidance for asse ssing cancer susceptibility from early-life exposure to carcin ogens. Risk Assessment Forum, Washington, DC; EPA/630600/R-03/003F. Available online at http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=439798 33 34 35 36 U.S. EPA (Environmental Protection Agency) (2005d) Revi ew of the National Ambient Air Quality Standards for Particulate Matter: Policy Assessment of Scientific and Technical Information, OAQPS Staff Paper (EPA-452/R-05- 005). Available online at http://www.epa.gov/ttn/naaqs/standards/pm/s_pm_cr_sp.html 37 38 39 40 U.S. EPA (Environmental Protection Agency) (2005e) Ai r quality criteria for ozone and related photochemical oxidants (Second external review draft) (E PA/600/R-05/004aB). Available online at http://cfpub.epa.gov/ncea/cfm/r ecordisplay.cfm?deid=137307 41 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, EPA/630/P-03/003F. Available online at http://cfpub2.epa.gov/ncea/cfm/ recordisplay.cfm?deid=146583 45 46 47 U.S. FDA (Food and Drug Administration). (1997) Food and drug administration modernization act. PL 105-115. Available online at http://www.fda.gov/cder/guidance/105-115.htm 48 49 50 U.S. FDA (Food and Drug Administrati on). (2002) Best pharmaceu ticals for children act. PL 107-109. Available online at http://www.fda.gov/opacom/la ws/pharmkids/contents.html 51 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 Drug Evaluation and Research (CDER). Available online at http://www.fda.gov/cder/ guidance/3816dft.PDF 55 56This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 109 DRAFT—DO NOT CITE OR QUOTE 1 U.S. FDA (Food and Drug Administration). (2003b) Pediatri c research equity act. PL 108 -155. Available online at http://www.fda.gov/opacom/laws/prea.html 2 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 http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14745989& 7 query_hl=163 8 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 document (EHC). Available online at http://www.who.int/ipcs/publications/ehc/provisional_outline/en/ 12 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 http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12866702& 16 query_hl=160 17 18 19 20 Zoetis, T; Hurtt, ME. (200 3b) Species comparison of lung developm ent. Birth Defects Research Part B: Developmental and Reproductive Toxicology 68(2):121-124. Available online at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12866703& 21 query_hl=158 22 23 24 25 Zoetis, T; Walls, I. (ed.) (2003) Princi ples and practices for direct dosing of pre-weaning mammals in toxicity testing and research. Risk Science Institute, Washington, DC: ILSI Press. Available online at http://www.ilsi.org/publications /pubslist.cfm?publicationid=520 26 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 http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12866701& 31 query_hl=155 32 33This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 110 DRAFT—DO NOT CITE OR QUOTE 1 2 APPENDIX 1. HAZARD CHARACTERIZAT ION – 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, andlimitations considered for life stagespecific data?This document is a draft for review purposes only and does not constitute Agency policy. 03/01/06 111 DRAFT—DO NOT CITE OR QUOTE Topic/Subject (Section) Study Type General Questions Life-Stage Specific Questions

► Was the study conducted in accordance with g ood laboratory practices? ► Were life stage -specific studies conducted in acco rdance 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?This document is a draft for review purposes only and does not constitute Agency policy. 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?This document is a draft for review purposes only and does not constitute Agency policy. 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 sta g e-s p ecific differencesThis document is a draft for review purposes only and does not constitute Agency policy. 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 st age-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 oruncertainty 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 determ ine critical windows of exposure (Selevan et al. 2000) ? If so,This document is a draft for review purposes only and does not constitute Agency policy. 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 broadscreening 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?This document is a draft for review purposes only and does not constitute Agency policy. 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 h azards indicate the need for follow-up studies to better define uncertainties, e.g

. , for the specific assessment question and issues?