EXTERNAL REVIEW DRAFT EPA/630/P-02/001A 

April 23, 2002 

Framework for Cumulative Risk Assessment


Risk Assessment Forum


U.S. Environmental Protection Agency


Washington, DC 20460

DISCLAIMER 

This document is in the process of being reviewed in accordance with U.S. 

Environmental Protection Agency’s peer and administrative review policy. It has had extensive 

peer involvement in development (including other Federal, State, and public involvement), but it 

has not yet completed the formal peer review process or administrative review process, so it 

should not be quoted or cited. The mention of commercial products is for illustration only and in 

no way implies EPA endorsement of these products. 

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Table of Contents 

List of Figures ............................................................... vi


List of Text Boxes ........................................................... vii


Acknowledgments ............................................................ ix


Foreword ................................................................... x


Preface ..................................................................... xi


Authors, Contributors, and Reviewers ............................................ xiii


List of Abbreviations and Acronyms ............................................. xvi


Executive Summary ......................................................... xviii


1. INTRODUCTION	 ........................................................... 1


1.1. Purpose and Scope of the Framework Report .............................. 5


1.2. Intended Audience ................................................... 6


1.3. Key Definitions in Cumulative Risk Assessment ........................... 6


1.4. The Cumulative Risk Assessment as a Tool for a Variety of Users and Purposes


............................................................... 10


1.5. The Broader Decision-Making Context for Cumulative Risk Assessment ....... 11


1.6. Organization of this report ........................................... 13


2. THE PLANNING, SCOPING, AND PROBLEM FORMULATION PHASE ........... 14


2.1. 	Planning and Scoping ............................................... 15


2.1.1. Defining the Purpose of the Assessment .......................... 16


2.1.2. Defining the Scope of Analysis and Products Needed ............... 17


2.1.3. Agreeing on participants, roles and responsibilities ................. 19


2.1.4. Agreeing on the Depth of the Assessment and the Analytical Approach


......................................................... 21


2.1.5. Agreement on the Resources Available and Schedule ............... 21


2.1.6. Review of Lessons Learned in Similar Studies ..................... 22


2.2. Problem Formulation, Conceptual Model, and Analysis Plan ................. 22


2.2.1. Problem Formulation ........................................ 23


2.2.2. Developing the Conceptual Model .............................. 23


2.2.3. Constructing the Analysis Plan ................................. 26


2.3. The Final Step Before the Analysis Phase: Discussion of Possible Outcomes .... 27


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3. 	THE ANALYSIS PHASE ................................................... 30


3.1. General Process .................................................... 31


3.2. Available Methods and Approaches .................................... 32


3.2.1. Examples of Increased Complexity of Cumulative Risk Assessment ... 32


3.2.2. Approaches for Predicting Risk of Multiple Stressors ............... 36


3.2.2.1. Single Stressor Information ............................ 37


3.2.2.2. Information on Stressor Interactions and Multiple Exposures


................................................... 40


3.2.2.3. Decision Indices ..................................... 42


3.2.2.4. Probabilistic Approaches .............................. 44


3.3. Areas of Complexity and Current Research ............................... 44


3.3.1. Interactions Between Stressors and Other Factors .................. 45


3.3.2. The Promise of Biomarkers and Biomonitoring .................... 46


3.3.3. A Single Metric for Multiple Types of Hazard ..................... 47


3.3.3.1. Creating a Common Metric ............................ 48


3.3.3.2. General Issues with a Single Metric ...................... 51


3.3.4. Qualitative approaches ....................................... 51


4. 	THE RISK CHARACTERIZATION PHASE .................................... 53


4.1. Risk Description .................................................... 54


4.2. Uncertainty Analysis ................................................ 56


4.2.1. Assumptions in the Assessment ................................ 57


4.2.2. Uncertainty and Variability .................................... 58


4.2.3. Uncertainty and Risk Addition ................................. 58


4.3. The Information Provided by Cumulative Risk Assessment .................. 59


4.3.1. Making Sense of Multiple Stressor Effects........................ 59


4.3.2. Cumulative Risk Assessments in a Public Health Context ............ 60


4.3.3. How Scope and Purpose of the Assessment Affect Results ........... 61


4.4. Using the Results of the Assessment .................................... 62


5. GLOSSARY .............................................................. 64


6. REFERENCES ............................................................ 66


APPENDIX A: RESEARCH AND DEVELOPMENT NEEDS ......................... 82


APPENDIX B: SELECTED RESOURCES FOR EXPOSURE AND RISK ASSESSMENT . 85


B.1. Resources Relevant to Chemical Exposures .............................. 85


B.2. Resources Relevant to Exposures to Non-Chemical Stressors ............... 86


APPENDIX C: SOME THOUGHTS ON BACKGROUND EXPOSURES ................ 89


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APPENDIX D: EXAMPLES OF ANALYSIS PLANS ................................ 91


D.1. Human Health Analysis Plan for Pesticides under FQPA ................... 91


D.2. Ecological Analysis Plan ............................................ 91


APPENDIX E: TOXICOLOGIC SIMILARITY: ORGANOPHOSPHORUS PESTICIDES ... 93


APPENDIX F: OTHER TYPES OF CUMULATIVE ASSESSMENTS .................. 96


F.1. Quality-of-Life Assessments ......................................... 96


F.2. Cumulative Impact Assessments ...................................... 97


F.3. Empirically-Derived Medical Models .................................. 98


F.4. Risk Surrogates .................................................... 99


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List of Figures 

1-1. Chemical or stressor focused assessment ..................................... 1


1-2. Population-based assessments .............................................. 2


1-3. Framework for cumulative risk assessment ................................... 13


2-1. The planning, scoping, and problem formulation phase ......................... 14


2-2. Generic conceptual model ................................................ 24


2-3. Specific conceptual model for a complex project, NATA ........................ 25


3-1. The analysis phase ...................................................... 30


4-1. The interpretation phase .................................................. 52


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List of Text Boxes 

Some Examples of Cumulative Risk Assessment Activities in EPA in Late 2001 .......... xx


EPA’s Risk Assessment Guidelines ................................................ 5


FQPA’s Terminology Interpretations ............................................... 8


Cumulative Risk Assessment Features ............................................. 9


The Core Principles of Community-Based Environmental Protection .................... 11


Possible Management Goals .................................................... 17


Examples of Different Cumulative Risk Assessment Scopes ........................... 18


Examples of Possible Interested or Affected Parties (Stakeholders) ...................... 19


Guidelines for Stakeholder Involvement ........................................... 20


Reed Holderman’s Lessons Learned .............................................. 22


Example: SAB’s Desired Outputs for Problem Formulation ........................... 23


Example: Cumulative Risk Initiative (CRI) for Cook Co., IL, and Lake Co., IN ............ 29


Example: Scope of EPA’s National-scale Assessment for Hazardous Air Pollutants ......... 31


Some Examples of Models which Consider Time Aspects ............................. 34


Example Using Toxicologic Independence: National-scale Air Toxics Assessment ......... 40


Example Using Toxicologic Similarity: The Dioxin Reassessment ...................... 42


Example Decision Index: The Hazard Index ........................................ 44


Risk Characterization Guiding Principles .......................................... 54


Some Thoughts on Risk Characterization .......................................... 56


Morgan and Henrion’s “Ten Commandments” for Good Policy Analysis ................. 57


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Uncertainty Analysis Example: The Cumulative Exposure Project ...................... 59


EEA’s Twelve Late Lessons Learned ............................................. 63


Vermont’s Quality of Life Criteria ............................................... 96


NEPA’s “Cumulative Impact” Definition .......................................... 97


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Acknowledgments 

This U.S. Environmental Protection Agency (EPA) report has been developed under the 

auspices of EPA’s Risk Assessment Forum, a standing committee of EPA scientists charged with 

developing risk assessment guidance for Agency-wide use. An interoffice technical panel 

chaired by Michael Callahan (Region 6) was commissioned to write this report. Other members 

of the panel are Edward S. Bender (Office of Science Policy), George L. Bollweg (Region 5), 

Vicki L. Dellarco (Office of Pesticides Programs), Lynn A. Delpire (Office of Pollution 

Prevention and Toxics), Martin P. Halper (Office of Environmental Justice), Richard C. 

Hertzberg (National Center for Environmental Assessment), Elizabeth Lee Hofmann (Office of 

Emergency and Remedial Response), R. Craig Matthiessen (Chemical Emergency Preparedness 

and Prevention Staff), Alexander McBride (Office of Solid Waste), Deirdre L. Murphy (Office of 

Air Quality Planning and Standards,), Henry C. Topper (Office of Pollution Prevention and 

Toxics), and Winona Victery (Region 9). In addition, Carole Braverman (Region 5), Loren Hall 

(Office of Civil Rights), and Denis R. Borum (Office of Water) participated for part of the 

duration of the panel. Steven M. Knott of the Risk Assessment Forum staff coordinated the 

project as well as participated as a member of the panel. The resulting document included peer 

involvement and peer review by scientists from EPA, other federal agencies, state agencies, 

academia, public interest groups, and the private sector. 

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Foreword 

Several reports have highlighted the importance of understanding the accumulation of 

risks from multiple environmental stressors. These include the National Research Council’s 

1994 report Science and Judgment in Risk Assessment and the 1997 report by the 

Presidential/Congressional Commission on Risk Assessment and Risk Management entitled Risk 

Assessment and Risk Management in Regulatory Decision-Making. In addition, legislation such 

as the Food Quality Protection Act of 1996, has directed the Environmental Protection Agency to 

move beyond single chemical assessments and to focus, in part, on the cumulative effects of 

chemical exposures occurring simultaneously. Further emphasizing the need for EPA to develop 

methods to assist consideration of cumulative risks are some of the cases filed with EPA under 

Title VI of the 1964 Civil Rights Act. 

The Superfund program began doing cumulative risk assessments at hazardous waste 

sites as early as the 1980s. More recently, in response to the increasing interest in cumulative 

risk, several other EPA programs have begun to explore approaches to cumulative risk 

assessment. In 1997, The EPA Science Policy Council issued a guidance on planning and 

scoping for cumulative risk assessments. More recently, the Office of Pesticide Programs has 

developed cumulative risk assessment guidance focused on implementing certain provisions of 

FQPA. In addition, the Office of Air Quality Planning and Standards is performing a nationalscale cumulative assessment of human health risks posed by outdoor air exposures to a set of 33 

priority urban air toxics. 

The EPA Science Policy Council has asked the Risk Assessment Forum to begin 

developing Agency-wide cumulative risk assessment guidance that builds from these ongoing 

activities. As a first step, a technical panel convened under the Risk Assessment Forum has been 

working to develop a Framework for Cumulative Risk Assessment. This document is the result 

of that technical panel’s efforts. Building from the Agency’s growing experiences, this 

Framework is intended to identify the basic elements of the cumulative risk assessment process. 

It should provide a flexible structure for the technical issues and define key terms associated with 

cumulative risk assessment. Further efforts and experience in the coming years should advance 

our knowledge beyond the Framework stage to a future set of Agency guidelines for cumulative 

risk assessment. 

William P. Wood, Ph.D.


Executive Director


Risk Assessment Forum


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Preface 

In the past several years, cumulative risk assessment, aggregate exposure assessment, and 

research on chemical mixtures has taken on increased importance. This is underscored by reports 

such as the National Research Council’s 1993 report Pesticides in the Diets of Infants and 

Children, (NRC, 1993) the 1994 NRC report Science and Judgment in Risk Assessment, (NRC, 

1994), the 1995 National Academy of Public Administration report Setting Priorities, Getting 

Results (NAPA, 1995), the 1997 report by the Presidential/Congressional Commission on Risk 

Assessment and Risk Management titled Risk Assessment and Risk Management in Regulatory 

Decision-Making (PCCRARM, 1997), and the EPA Science Advisory Board report Toward 

Integrated Environmental Decision-Making (USEPA, 2000a). There also have been several 

recent pieces of legislation that mandate the consideration of cumulative risk and variability 

factors in the risk characterization process. Specifically, the Food Quality Protection Act of 1996 

(FQPA) [PL 104-170, August 3, 1996] directs EPA in its assessments of pesticide safety to 

focus, in part, on the cumulative effects of pesticides that have a common mechanism of toxicity, 

considering aggregate dietary and non-occupational pathways of exposure. 

Assessment of cumulative risk through complex exposures is one of the high priorities of 

the Agency, especially in light of FQPA mandates, and is germane and of great interest to all 

program and regional offices. This area of research is also directly applicable to children’s risk 

issues. This Framework is meant to lay out broad areas where analysis might be conducted if 

needed. It does not suggest that cumulative risk assessment is a tool that should be used with 

every issue, nor does it suggest that when cumulative risk assessment is applied, that all areas of 

analysis outlined or discussed here must or even should be conducted in every assessment. The 

scope of the assessment will define the areas to be analyzed. In some areas discussed in this 

Framework, the methodology for doing the risk analysis may not yet exist. 

According to the expert panel report Safeguarding the Future: Credible Science, Credible 

Decisions (USEPA 1992a), a key role of science at EPA is to reduce uncertainties in 

environmental decision-making. The report points out that while many EPA programs have 

historically focused on chemical-specific impacts, methods to assess or control the effects of 

chemical mixtures and general stressors on human health and ecosystems remained to be 

developed. In Pesticides in the Diets of Infants and Children, (NRC, 1993) the NRC 

recommended that all exposures to pesticides – dietary and nondietary – need to be considered 

when evaluating the potential risks to infants and children. Estimates of total dietary exposure 

should be refined to consider intake of multiple pesticides with a common toxic effect. Further, 

the report identifies important differences in susceptibility with age. NRC in Science and 

Judgment in Risk Assessment (NRC, 1994) states that health risk assessments should generally 

consider all possible routes by which people at risk might be exposed, and recommends this 

approach universally in the assessment of hazardous air pollutants regulated by EPA under the 

Clean Air Act Amendments of 1990 [P.L. 101-549, November 15, 1990]. Regarding variability, 

the NRC Science and Judgment report recommended that EPA assess risks to infants and 

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children whenever it appears that their risks might be greater than those of adults. Public 

criticisms cited in this report include statements made by some experts that EPA does not appear 

to recognize the possibility of synergistic interactions when multiple chemical exposures occur, 

nor does it consider extreme variability among individuals in their responses to toxic substances. 

A related issue is the problem of how risks associated with multiple chemicals are to be 

combined. Finally, the FQPA [P.L.104-170, August 3, 1996], requires research on the influence 

of complex exposures on non-cancer human health effects of pesticides and other toxic 

substances. 

The issue of cumulative risk is also an important issue with the general public. In public 

meetings of Superfund stakeholders, held in late 1996 in San Francisco and Washington, DC, 

and in early 1998 in Atlanta, the issue of cumulative risk was raised several times in each session 

(USEPA 1996a, USEPA 1998a). 

Cumulative risk assessments will identify the need for many different kinds of data – 

some of them are not the data commonly used now for risk assessment – and often, cumulative 

risk assessment will demand large quantities of such data. Until data bases and data generation 

research can provide such data, for the near term, identification of critical data and research 

needs may be the primary result of many cumulative risk assessment endeavors. 

As of August 1, 2001, there were 19,533 pesticide products on the market (USEPA, 

2001a), and 79,120 existing chemicals on the TSCA inventory (USEPA, 2001b). Each year, an 

additional number of chemicals are added. Assessing the cumulative effect of these chemicals 

will be a great challenge to the Agency and may become the primary issue in the risk assessment 

field in the next ten years. 

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Authors, Contributors, and Reviewers 

Authors: 

EPA Risk Assessment Forum Cumulative Risk Technical Panel: 

Edward S. Bender, Office of Science Policy, ORD


George L. Bollweg, Air and Radiation Division, Region 5


Michael A. Callahan, Office of the Regional Administrator, Region 6 (Chair)


Vicki L. Dellarco, Office of Pesticides Programs, OPPTS


Lynn A. Delpire, Office of Pollution Prevention and Toxics, OPPTS


Martin P. Halper, Office of Environmental Justice, OECA


Richard C. Hertzberg, National Center for Environmental Assessment, ORD


Elizabeth Lee Hofmann, Office of Emergency and Remedial Response, OSWER


Steven M. Knott, Risk Assessment Forum, ORD


R. Craig Matthiessen, Chemical Emergency Preparedness and Prevention Staff, OSWER


Alexander McBride, Office of Solid Waste, OSWER


Deirdre L. Murphy, Office of Air Quality Planning and Standards, OAR


Henry C. Topper, Office of Pollution Prevention and Toxics, OPPTS


Winona Victery, Policy and Management Division, Region 9


Contributo rs and Rev iewers: 

EPA R eviewers: 

Donald G. Barnes, EPA Science Advisory Board


Michael Firestone, Office of Children’s Health Protection


Debra L. Forman, Region 3


Mark Madd aloni, Region 2


Elizabeth H. M argosches, Office of Po llution Prevention and T oxics 


Marian Olsen, Region 2


James Rowe, Office of Research and Development


Scott Schwenk, Office of Research and Development


Michae l Shapiro, O ffice of Solid W aste


Sally Shaver, Office of Air and Radiation


Margaret Stasikowski, Office of Pesticide Programs


Jeannette Wiltse, Office of Water


Jeffrey Yurk, Region 6


The following persons participated in peer involvement workshops held during 2001 to discuss and comment on the


draft Framework.


Federal Scientists’ Meeting, May 1, 2001: 

Michael A. Babich, Health Sciences Division, U.S. Consumer Product Safety Commission


Michael Buchman, Office of Response and Restoration, National Oceanic and Atmospheric Administration


Stephen Channe l, Department of the Air Fo rce, U.S. Depa rtment of Defense


Christopher T. DeRosa, Division of Toxicology, Agency for Toxic Substances and Disease Registry


Dennis Druck, A rmy Center for Health P romotion and P reventive Medicine , U.S. Departme nt of Defense


Frank H earl, Division of Respira tory Disease Studies, Na tional Institute for O ccupation al Safety and H ealth


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Keith Hodd inott, Army Center for Hea lth Promotion and P reventive Medicine , U.S. Departme nt of Defense


Steve Jones, Office of Regional Operations, Agency for Toxic Substances and Disease Registry


Brian Kaplan, Division of Health Assessment and Consultation, Agency for Toxic Substances and Disease Registry


Ralph Kodell, National Center for Toxicological Research, U.S. Food and Drug Administration


Dan Lew is, Health Effec ts Laborato ry Division, N ational Institute for Occup ational Safety a nd Hea lth


Margaret MacD onell, Argonne National Laboratory, U.S. Department of Energy


Mark McClanahan, National Center for Environmental Health, Centers for Disease Control and Prevention


Anita K. Meyer, H TRW Center of Expertise , U.S. Army Corps of Engineers


Moiz G. Mum taz, Division of Toxicology, Agency for Toxic Substances and Disease Registry


Leslie G. Rubin, Animal and Plant Health Inspection Service, U.S. Department of Agriculture


Antoinette Sebastian, Office of Community Planning and Development, Dept. of Housing and Urban Development


Scott D. Sudweeks, Div. of Health Assessment and Consultation, Agency for Toxic Substances and Disease Registry


Timothy Taylo r, Army Center for He alth Promotion and Preventive Me dicine, U.S. Depa rtment of Defense


John Wheeler, Division of Toxicology, Agency for Toxic Substances and Disease Registry


Jody Wirem an, Department o f the Air Force, U.S. De partment of Defense


States’ Meeting, May 3, 2001: 

Glen Andersen, National Conference of State Legislators


Ligia Mora-Applegate, Florida Department of Environmental Protection


Alex M . Barron, V irginia Dep artment of E nvironme ntal Quality


Sharon B axter, Office o f Pollution P revention, V irginia Dep artment of E nvironme ntal Quality


Joseph P. Brown, Office of Environmental Health Hazard Assessment, California Environmental Protection Agency


Michele F. Burgess, Georgia Department of Natural Resources


Perry Co hn, Enviro nmental H ealth Service , New Jers ey Depa rtment of H ealth


Linda J. Cullen, New Jersey Department of Environmental Protection


Susan Dempsey, Nebraska Department of Health and Human Services


Michael J. DiBartolomeis, Office of Environmental Health Hazard Assessment, California Env. Protection Agency


Michae l Ellenbeck er, Toxic s Use Re duction Institute , University of M assachusetts a t Lowell


George Hagevik, National Conference of State Legislators


Joann Held, Office of Air Quality, New Jersey Department of Environmental Protection


Bruce H ope, Or egon De partment o f Environm ental Quality


Tom Hornshaw, Toxicity Assessment Unit, Illinois Environmental Protection Agency


Paul B. Jiapizian, Maryland Department of the Environment


David R . Johnson, B ureau of E nvironme ntal Epide miology, Flo rida Dep artment of H ealth


Michael Juras, Community Right-to-Know, South Carolina Department of Health and Environmental Control


Kevin Kessler, Air and Waste Division, Wisconsin Department of Natural Resources


Rosanna Kroll, Health and Toxicology Section, Maryland Department of Environment


Charles Moore, Office of Environmental Management, South Carolina Department of Natural Resources


Rebecca Pottratz, Communication Specialist, Wisconsin Department of Natural Resources


John Ridgway, Environmental Justice Program, Washington State Department of Ecology


Kirpal S. S idhu, Enviro nmental Ep idemiolog y Division, M ichigan De partment o f Commu nity Health


Lawrence P. Sirinek, Division of Emergency and Remedial Response, Ohio Environmental Protection Agency


Alan Stern, Bureau for Risk Analysis, New Jersey Department of Environmental Protection


Chuck Str oebel, En vironmen tal Researc h Scientist, M innesota D epartmen t of Health


Barba ra S. Taylo r, Departm ent of Hea lth and Hu man Serv ices, We st Virginia B ureau for P ublic Hea lth


Mark W erner, W isconsin Div ision of Pub lic Health


Carol Rowan West, Office of Research and Standards, Massachusetts Department of Environmental Protection


Victor R . Wilford , Departm ent of Hea lth and Hu man Serv ices, We st Virginia B ureau for P ublic Hea lth


Stephen L. Wust, Drinking Water Bureau, New M exico Environment Department


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Public Meeting, August 22-23, 2001: 

Elizabeth Boa, American Chemistry Council, Inc.


Kenneth T. Bogen, Health and Ecological Assessment Division, Lawrence Livermore National Laboratory


James P. Butler, Environmental Assessment Division, Argonne National Laboratory


Douglas J. Crawford-Brown, Dept of Environmental Sciences and Engineering, University of North Carolina


Amy D. Kyle, School of Public Health, University of California-Berkeley


Norris McDonald, Center for Environment, Comm erce and Energy


Beth E. Mileson, Technology Sciences Group, Inc.


Stephen S . Olin, Risk Sc ience Institute, Inte rnational Life S ciences Institute


William R. Rhyne, H&R Technical Associates, Inc.


Jennifer Sas s, Health P rogram, N atural Reso urces De fense Cou ncil


Margo Schwab, S chool of P ublic Hea lth, Johns H opkins U niversity


Ken W. Sexton, Center for Environment and Health Policy, University of Minnesota (Chair)


Written Public Co mments: 

James M. Solyst, American Chemistry Council, Inc. 

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List of Abbreviations and Acronyms 

ACGIH - American Conference of Government Industrial Hygienists


AFS - AIRS Facility Subsystem


AIChE - American Institute of Chemical Engineers


AIHA - American Industrial Hygiene Association


AIRS - Aerometric Information Retrieval System


AMTIC - Ambient Monitoring Technology Information Center


APCA - American Crop Protection Association


APEX - Air Pollution EXposure model


ARE - Acute Reference Exposure


ATSDR - Agency for Toxic Substances and Disease Registry


CARES - Cumulative and Aggregate Risk Evaluation System


CBEP - Community-Based Environmental Protection


CEQ - Council for Environmental Quality


CFR - Code of Federal Regulations


CHIEF - Clearinghouse for Inventories and Emissions Factors


COHb - Carboxyhemoglobin


CRIA - Cumulative Risk Index Analysis


DALY - Disability-Adjusted Life Year


DOT - United States Department of Transportation


EPA - United States Environmental Protection Agency


FIFRA - Federal Insecticide, Fungicide, and Rodenticide Act


FQPA - Food Quality Protection Act


GAO - United States General Accounting Office


GIS - Geographical Information System


HAP - Hazardous Air Pollutant


HEC - Human Equivalent Concentration


HRS - Hazard Ranking System


HUD - United States Department of Housing and Urban Development


IED - Integrated Environmental Decision-making


ILSI - International Life Sciences Institute


LADD - Lifetime Average Daily Dose


LDP - Locational Data Policy


LLE - Loss of Life Expectancy


LOAEL - Lowest Observed Adverse Effect Level


MOE - Margin of Exposure


MSDS - Materials Safety Data Sheet


NAAQS - National Ambient Air Quality Standards


NAPA - National Academy of Public Administration


NATA - National Air Toxics Assessment


NEPA - National Environmental Policy Act


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List of Abbreviations and Acronyms (Continued) 

NHEXAS - National Human Exposure Assessment Survey


NIOSH - National Institute for Occupational Safety and Health


NOAEL - No Observed Adverse Effect Level


NRC - National Research Council


OAR - Office of Air and Radiation (EPA)


OECA - Office of Enforcement and Compliance Assurance (EPA)


OP - Organophosphorous


OPP - Office of Pesticide Programs (EPA)


OPPTS - Office of Prevention, Pesticides, and Toxic Substances (EPA)


ORD - Office of Research and Development (EPA)


OSWER - Office of Solid Waste and Emergency Response (EPA)


P.L. - Public Law


PAH - Polycyclic Aromatic Hydrocarbon


PCB - Polychlorinated Biphenyl


PCS - Permit Compliance System


PM-10 - Particulate Matter with diameter of 10 micrometers or less


pNEM - Probabilistic NAAQS Exposure Model


QALY - Quality-Adjusted Life Year


RfC - Reference Concentration


RfD - Reference Dose


SAB - Science Advisory Board


SAP - Scientific Advisory Panel


SAR - Structure-Activity Relationship


SCRAM - Support Center for Regulatory Air Models


SHEDS - Stochastic Human Exposure and Dose Simulation model


SPC - Science Policy Council 


TEAM - Total Exposure Assessment Methodology


TEMRAP - The European Multi-Hazard Risk Assessment Project


TIA - Transient Ischemic Attack


TRI - Toxic(s) Release Inventory


TRIM.Expo - Total Risk Integrated Methodology, Exposure Module


U.S.C. - United States Code


UF - Uncertainty Factor


USEPA - United States Environmental Protection Agency


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Executive Summary 

This report, “Framework for Cumulative Risk Assessment,” is the first step in a longterm effort to develop cumulative risk assessment guidelines. Its primary purpose is to offer a 

simple, flexible structure for conducting and evaluating cumulative risk assessment within EPA. 

Although this Framework report will serve as a foundation for development of future guidelines, 

it is neither a procedural guide nor a regulatory requirement within EPA and is expected to 

evolve with experience. This Framework report is intended to foster consistent approaches to 

cumulative risk assessment within EPA, identify key issues, and define terms used in these 

assessments. 

This Framework is meant to lay out broad areas where analysis might be conducted if 

needed. It does not suggest that cumulative risk assessment is a tool that should be used with 

every issue, nor does it suggest that when cumulative risk assessment is applied, that all areas of 

analysis outlined or discussed here must or even should be conducted in every assessment. The 

scope of the assessment will define the areas to be analyzed. In some areas discussed in this 

Framework, the methodology for doing the risk analysis may not yet exist. Appendix A includes 

a summary of areas where research is needed. 

In this report, “cumulative risk” means “the combined risks from aggregate exposures to 

multiple agents or stressors.” There are several key points which come from this definition of 

cumulative risk. First, cumulative risk involves multiple agents or stressors, which means that 

assessments involving a single chemical or stressor are not “cumulative risk assessments” under 

this definition. Second, there is no limitation that the “agents or stressors” be only chemicals. 

“Agents or stressors” may be chemicals, but they may also be biological agents, or physical 

agents, or even the absence of a necessity such as habitat. Third, this definition requires that the 

risks from multiple agents or stressors be combined. This does not necessarily mean “added,” 

but it means that some analysis needs to be conducted as to how the risks from the various agents 

or stressors interact. It also means that an assessment which covers a number of chemicals or 

other stressors, but which merely lists each chemical with a corresponding risk without 

consideration of the other chemicals present, is not an assessment of cumulative risk under this 

definition. 

Likewise, “cumulative risk assessment” in this Framework report means “an analysis, 

characterization, and possible quantification of the combined risks to health or the environment 

from multiple agents or stressors.” One key aspect of this definition is that a cumulative risk 

assessment need not necessarily be quantitative, so long as it meets the other requirements. 

The framework itself is conceptually similar to the approach used in both human health 

and ecological assessments, but it is distinctive in several areas. First, its focus on the combined 

effects of more than one agent or stressor makes it different from many assessments conducted 

today (which, if multiple stressors are evaluated, are usually evaluated individually and presented 

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as if the others were not present). Second, by the fact that multiple stressors are affecting the 

same population, there is increased focus on the specific populations potentially affected, rather 

than a focus on hypothetical receptors. Third, consideration of cumulative risk may generate 

interest in a wider variety of non-chemical stressors than traditional risk assessments. 

The framework describes three main phases to a cumulative risk assessment: (1) 

planning, scoping and problem formulation, (2) analysis, and (3) interpretation. In the planning, 

scoping and problem formulation phase, a team of risk managers, risk assessors, and other 

stakeholders establishes the goals, breadth, depth, and focus of the assessment. The end products 

of this phase are a conceptual model and an analysis plan. The conceptual model establishes the 

stressors to be evaluated, the health or environmental effects to be evaluated, and the 

relationships among various stressor exposures and potential effects. The analysis plan lays out 

the data needed, the approach to be taken, and the types of results expected during the analysis 

phase. 

The analysis phase includes developing profiles of exposure, considering interactions (if 

any) among stressors, and predicting risks to the population or populations assessed. It is in this 

phase that difficult technical issues are addressed and hopefully resolved, for example, issues 

relating to toxicity of mixtures, vulnerability of populations, or the interactions among stressors 

which may be chemical or non-chemical. The end product of this phase is an analysis of the risks 

associated with the multiple stressors to which the study population or populations are exposed. 

The third phase, interpretation, includes what is usually termed the “risk characterization” 

discussion in risk assessment, where the risk estimates are put into perspective in terms of their 

significance, the reliability of the estimates, and the overall confidence in the assessment. It is 

also in this phase that an evaluation is made of whether the assessment met the objectives and 

goals set forth in phase one. 

The discussion of cumulative risk in this Framework report takes a broad view of the 

topic, including many aspects of an assessment that might conceivably be conducted in the 

future, even though techniques may not currently exist to examine every question. It also 

includes aspects of cumulative risk which may be outside of EPA’s current legislative mandates, 

and where expertise outside of the Agency would be needed to address certain questions if they 

should arise. These aspects of cumulative risk are discussed here for the sake of technical 

completeness and not as a recommendation that EPA perform all possible aspects of a 

cumulative risk assessment in all EPA risk assessments – even all EPA cumulative risk 

assessments. 

EPA is currently engaged in activities which fall under various aspects of the cumulative 

risk assessment umbrella. Some of these activities are listed as illustrations in the box on the next 

page. The broad interpretation of cumulative risk in this Framework report allows these activities 

to be put into perspective relative to one another, and can illustrate how they fit together under 

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Some Example Cumulative Risk Assessment Activities within EPA in late 2001 

!	 The Superfund Program has updated its guidance on risk assessment to include planning and scoping for 

cumulative risk assessment and problem formulation for ecological risk assessments. The plan for the Office of 

Solid Waste’s Surface Impoundment Study includes both a conceptual model and an analytical plan, per the 

agency guidance on planning and scoping for cumulative risk. 

!	 The Office of Water is planning a watershed scale risk assessment involving multiple stressors in ecological risk. 

This approach was developed through a collaboration with external scientists and is now being field evaluated. 

!	 Several Regional Offices are evaluating cumulative hazards, exposures, and effects of toxic contaminants in 

urban environments. In Chicago (Region 5), citizens are concerned about the contribution of environmental 

stressors toward endpoints such as asthma and blood lead levels. In Baltimore (Region 3), a 

regional/OPPTS/community partnership tried to address the long term environmental and economic concerns in 

three neighborhoods that are adjacent to industrial facilities and tank farms. Region 6 (Dallas) is developing a 

geographic information system approach for planning and scoping cumulative risks. 

! The Food Quality Protection Act (FQPA) of 1996 requires the EPA to consider the cumulative effects to human 

health that can result from exposure to pesticides and other substances that have a common mechanism of toxicity. 

The Office of Pesticides Programs (OPP) has developed guidance for conducting cumulative risk assessments 

for pesticides, and has prepared a preliminary cumulative risk assessment for Organophosphorous pesticides. 

!	 The Office of Air and Radiation's air toxics program has a cumulative risk focus. Under the Integrated Urban 

Air Toxics Strategy (IUATS), OAR will be considering cumulative risks presented by exposures to air emissions 

of hazardous air pollutants from sources in the aggregate. Assessments will be performed both at the national 

scale - release of a national scale assessment for base year 1996 is planned for later this year - and at the urban or 

neighborhood scale. In partnership with ORD/NERL, the Office of Air Quality, Planning & Standards is 

developing the Total Risk Integrated Methodology (TRIM), a modular, modeling system for use in single or 

multi-media, single or multi-pathway, human health and ecological risk assessments of hazardous and criteria air 

pollutants at the neighborhood or city scale. The Agency’s guidance for planning and scoping of cumulative risk 

was used to develop a conceptual model and analysis plan for the national scale air toxics risk assessment. 

!	 The National Center for Environmental Assessment (ORD) has completed ecological risk assessment 

guidelines which support the cumulative risk assessment guidance. Five watershed case studies are being assessed 

to demonstrate the guidelines approach. Each of these cases deals with cumulative impacts of stressors (chemical, 

biological, and in some cases physical). In addition, NCEA has done a draft reassessment of dioxin and related 

compounds. 

!	 The Risk Assessment Forum has convened a technical panel to develop guidance for conducting cumulative risk 

assessments, of which this Framework is a first step. 

the framework. Individual Program Offices and Regions may have to make decisions affecting 

the scope, types of stressors, or methods used for their programs’ cumulative risk assessments, 

based on legislative mandates or other criteria. Nothing in this Framework report should be 

interpreted to mandate that cumulative risk assessment must be conducted, or must be conducted 

a certain way, for any specific case. Likewise, this Framework report is not an attempt to lay out 

protocols to address all the risks or considerations that are needed to adequately inform 

community decisions. Rather, this Framework report is an information document, focused on 

describing various aspects of cumulative risk, whether or not the methods or data currently exist 

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1 to adequately analyze or evaluate those aspects of the assessment. Because of the limitations of 

2 current science, cumulative risk assessments in the near future will not be able to adequately 

3 answer all questions posed by stakeholders or interested parties. This does not mean, however, 

4 that they can’t answer some of the questions asked; in fact, cumulative risk assessment may be 

5 the best tool available to address certain questions dealing with multiple stressor impacts. 

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1. INTRODUCTION 

During much of its early history, EPA focused its efforts on cleaning up the overt 

pollution problems of the 1960s and 1970s. Until EPA was established in 1970, relatively 

uncontrolled air emission, water effluents, and dumping of wastes had led to pollution of the 

environment that was easily detected by the five senses. The most effective and efficient way to 

approach these overt problems of the 1970s was to find the entry point of the pollution into the 

environment, and to keep it from entering the environment by controlling it there. Looking back, 

we see a strategy that moved to control stack emission, industrial and municipal effluents, 

pesticide application, land applications, burial of chemical wastes, and other “sources” of 

pollution. In addition, criteria and standards were established as goals for cleanup of the various 

environmental media. By the 1980s, this “command and control” strategy was well established in 

environmental laws and regulations, but was reaching the point of diminishing returns from a 

cost-benefit viewpoint. 

The development of risk assessment methodology during the 1970s and early 1980s 

closely followed the Agency’s strategy for control of pollution, since risk assessments were being 

used as one of the factors in EPA’s decision-making for regulations. The focus on sources led 

naturally to analysis of what types of pollutants were in effluents, air emissions, and waste sites. 

Figure 1-1. Chemical (or stressor) 

focused assessment starts with a source 

and evaluates how the chemical gets to 

various populations or ecological targets. 

Individual assessments may choose to 

pursue some or all pathways, media, or 

population segments. 

These were chemical, biological, and sometimes 

radiological agents. By the 1970s, the links between 

some chemicals and certain diseases such as cancer 

had been established through a series of bioassays, 

or in the cases of chemicals like vinyl chloride and 

asbestos, through epidemiological studies. New 

analytical techniques of the 1970s also made it 

possible to detect very minute concentrations of 

chemicals for the first time. The focus of the EPA 

strategy to control pollution (and the risk 

assessment methodology being used to partially 

support decisions) gradually leaned toward 

assessing and controlling the individual chemicals. 

Congressional legislation tended to underwrite this 

approach by focusing on controlling sources and 

even including lists of individual chemicals to be 

controlled. 

The risk assessment methodology of the 

1970s and early 1980s, for this reason, tended 

towards single chemical assessments (see Figure 1-

1). The 1983 National Research Council report Risk 

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Assessment in the Federal Government (NRC, 1983) was largely focused on the single chemical 

risk assessment approach when it spoke of the four parts of a risk assessment: hazard 

identification, dose-response assessment, exposure assessment, and risk characterization. EPA’s 

1986 Risk Assessment Guidelines (USEPA 1986a), with the exception of the mixtures guidelines 

(USEPA, 1986b), were also largely focused on single chemical assessment. 

Research conducted or sponsored by EPA in 

the early 1980s, however, was taking the first steps 

toward investigating a different type of risk 

assessment methodology, one that focused on the 

persons exposed, investigating the chemicals or 

stressors to which they were exposed, and 

consequent risks (Figure 1-2). This is in contrast to a 

focus on either a chemical, to investigate its 

environmental fate, exposed populations, and risks 

(Figure 1-1), or focus on a source to investigate its 

environmental releases, exposed populations, and 

risks. The goals of the population-focused approach1 

were much more useful to decision-makers who Figure 1-2. Population-based assessments were dealing with public health or ecological health start with the receptors, and determine questions, rather than controlling sources of what chemicals, stressors, or other risk pollution. factors are affecting them. 

The challenges posed by the populationbased assessment can be daunting, even if only a few of the stressors affecting a population are 

evaluated together (i.e., cumulatively). Taken to the extreme, Figure 1-2 represents a concept of 

“total risk” for the population or population segment being evaluated, with each chemical, 

biological, radiological, or other stressor2

 adding some fraction of the total risk. Looking at the 

problem from an individual stressor viewpoint, to do this type of assessment would require not 

1

 A chemical-focused assessment may look at several populations affected by exposure to the chemical, but not at other 

chemicals. A population-focused assessment looks at one population for perhaps many stressors, but not at other populations. 

Consequently, for traditional, chemical-focused assessments, we say we conduct a “risk assessments for a certain chemical.” In 

contrast, the essence of a cumulative risk assessment is that the assessment is conducted “for a certain population.” This 

difference is shown schematically by comparing figures 1-1 and 1-2. How the population is identified for a cumulative 

assessment is not addressed here. 

2 A stressor is a physical, chemical, biological, or other entity that can cause an adverse response in a human or other 

organism or ecosystem. A stressor can be exposure to a chemical, biological, or physical agent (e.g., radon), or it may be the lack 

of, or destruction of, some necessity such as a habitat. A socioeconomic stressor, for example, might be the lack of needed health 

care, which could lead to adverse effects. Harmful events, such as automobile crashes, could also be termed stressors. Obviously, 

calculating risks from different types of stressors can use widely different methods, including probabilistic estimates of disease 

via dose-response relationships, looking up rates in statistical tables of historical events, and other methods. 

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only evaluating each individual stressor, but also developing a way to add up all the risks among 

stressors across a population of individuals with different exposures and susceptibilities. In the 

early 1980s, the state of the science was unready for virtually any part of the methods for doing 

this type of assessment. 

But progress was being made toward developing a population-based methodology. 

Starting in the late 1970s, a group of EPA researchers and contractors began developing what 

would become the Total Exposure Assessment Methodology (TEAM) study (USEPA 1987). 

TEAM measured the concentrations of a number of chemicals simultaneously at the point of 

exposure. This led to a larger study, the National Human Exposure Assessment Survey 

(NHEXAS) in the 1990s (Sexton, et, al. 1995). Both TEAM and NHEXAS were populationbased exposure assessment approaches which developed analytical tools and methodologies to do 

this type of exposure assessment. 

Also in the early 1980s, some progress was being made toward the question of how to 

cumulatively consider the risks from different chemicals or stressors. The 1986 Risk Assessment 

Guidelines (USEPA, 1986a) included a guideline on chemical mixtures (USEPA, 1986b), which 

discussed how the risks from multiple chemicals could be evaluated as a whole. The work on this 

guidance has continued most recently with the Supplementary Guidance for Conducting Health 

Risk Assessment of Chemical Mixtures (USEPA, 2000e) which expands and supplements the 

1986 beginnings. 

About the same time the Agency made some progress on single chemical and chemical 

mixture risk assessment with the 1986 Guidelines, some different kinds of risk assessment 

problems began to catch the Agency’s attention. In 1986, eleven Chicago-area community 

groups joined together to file a petition under Section 21 of the Toxic Substances Control Act 

asking for a community assessment in Southeast Chicago. A series of community-based actions 

which started in 1982 and grew throughout the 1980s focused on disparities of risk among 

various population subgroups, calling specific attention to cumulative effects of pollution on 

minority subgroups (GAO, 1983; United Church of Christ, 1987). This series of communitybased actions, chronicled in the 1990 book Dumping in Dixie: Race, Class and Environmental 

Quality (Bullard, 1990) eventually became known as the Environmental Justice movement. The 

issues raised by the Environmental Justice movement were the basis of a 1994 Presidential 

Executive Order [Executive Order 12898, February 11, 1994] which told Agencies, among other 

things, that “Environmental human health analyses, whenever practicable and appropriate, shall 

identify multiple and cumulative exposures.” In the 1990s, Environmental Justice cases, 

including the cases which have been filed under Title VI of the 1964 Civil Rights Act, [P.L. 88-

352, July 2, 1964] have further emphasized the need for a cumulative human health risk 

assessment methodology. 

Even before Executive Order 12898 was issued, it was apparent that population-focused 

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assessments (like Figure 1-2) were going to be needed, in addition to the chemical- or stressorfocused assessments (like Figure 1-1), if EPA was going to be able to answer the questions and 

issues being raised by the public. Community spokespersons and other “stakeholders,” as well as 

scientific panels, were increasingly coming to the Agency with problems that demanded a multistressor approach (e.g., NRC 1994). Ecological problems, especially, were demanding a “placebased” context (such as the Chesapeake Bay watershed) in which the various populations within 

the area were looked at from a “total system” viewpoint. This place-based focus was a part of the 

1992 Framework for Ecological Risk Assessment (USEPA 1992b) and the 1998 Guidelines for 

Ecological Risk Assessment (USEPA 1998b). 

Although clearly addressing more than cumulative human health or ecological risk 

assessment, the National Environmental Policy Act of 1969 (NEPA) [P.L. 91-190, 42 U.S.C. 

4321-4347, January 1, 1970, as amended by P.L. 94-52, July 3, 1975, P.L. 94-83, August 9, 

1975, and P.L. 97-258, §4(b), Sept. 13, 1982], which was passed at about the same time EPA 

was established, requires assessments on the cumulative impacts of federal or federally-funded 

projects (such as roads, dams, power lines, military projects, and infrastructure development) on 

natural ecosystems, endangered species, habitats, and opportunities for public enjoyment and 

natural resource use. A primary concern for NEPA is “cumulative effects analysis,” defined as 

“the incremental impact of the action when added to other past, present, and reasonably 

foreseeable future actions . . . Cumulative impacts result from individually minor but 

collectively significant actions taking place over a period of time” (CEQ, 1997). Much of the 

NEPA cumulative effects analysis is qualitative, but risk assessments and cause-and-effect 

relationships are key parts of the analysis process for controversial projects. 

In 1997, the Agency issued a policy memo, Guidance on Cumulative Risk Assessment, 

Part 1: Planning and Scoping (USEPA, 1997a), which took the first formal step towards 

developing guidance and guidelines for cumulative risk assessment. 

By the first decade of the twenty-first century, cumulative risk assessment applications 

have become relatively common. These applications are not only for assessments of chemicals 

which operate by the same mode of action, as is mandated for the USEPA Pesticides Program, 

but also community based, population-based, assessments which may include more varied 

stressors than just chemicals alone. Much like the “place-based” ecological assessments, which 

may cover a wide variety of physical, chemical, and biological stressors, some communities have 

added human health and perhaps “quality of life” to the endpoints of interest in their place-based 

assessments. It is the demand for more sophisticated human health risk assessments that has 

driven the need for research into cumulative risk assessment, population-focused assessments, 

aggregate exposure assessment, and risk from chemical mixtures. 

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1.1. Purpose and Scope of the Framework Report 

An understanding of the finite purpose and scope of this Framework report is important. 

EPA and other organizations need detailed, comprehensive guidance on methods for evaluating 

cumulative risk. Before such detailed Agency-level guidance is developed on a relatively new 

field of risk assessment, it has been the recent policy of the Agency to first develop a simple 

framework as a foundation for later comprehensive guidance. This Framework for Cumulative 

Risk Assessment will emphasize chemical risks to human health in its discussion, but will do so 

in the context of the effects from a variety of stressors, including non-chemical stressors. Some 

important topics that could be 

characterized as “cumulative risk,” such as 

global climate change, are beyond the 

scope of this Framework report. 

With this background, the 

Framework has two simple purposes, one 

immediate and one longer term. As a 

broad outline of the assessment process, 

the Framework immediately offers a basic 

structure and provides starting principles 

for EPA’s cumulative risk assessments. 

The process described by the Framework 

report provides wide latitude for planning 

and conducting cumulative risk 

assessments in many diverse situations, 

each based on common principles 

discussed in the Framework report. The 

process also will help foster a consistent 

EPA approach for conducting and 

evaluating cumulative risk assessments, for 

identifying key issues, and for providing 

operational definitions for terms used in 

cumulative risk assessments. 

In the longer term, the Framework 

report offers the basic principles around 

which to organize a more definitive set of 

Cumulative Risk Assessment Guidance. 

With this in mind, this report does not 

provide substantive guidance on certain 

issues that are integral to the risk 

EPA’s Risk Assessment Guidelines 

Chemical Mixtures (USEPA 1986b)


Mutagenicity Risk Assessment (USEPA 1986c)


Carcinogen Risk Assessment (USEPA 1986d)


Developmental Toxicity Risk Assessment (USEPA 1991a)


Exposure Assessment (USEPA 1992c)


Reproductive Toxicity Risk Assessment (USEPA 1996b)


Proposed Carcinogen Risk Assessment (USEPA 1996c, 1999a,


1999b) 

Ecological Risk Assessment (USEPA 1998b) 

Neurotoxicity Risk Assessment (USEPA 1998c) 

Selected Policy and Guidance Documents 

Risk Assessment Guidance for Superfund (USEPA 1989a)


Locational Data Policy (USEPA 1991b)


Framework for Ecological Risk Assessment (USEPA 1992b)


Application of Refined Dispersion Models (USEPA 1993a)


Policy /Guidance for Risk Characterization (USEPA 1995ab)


Benchmark Dose (1995c, 2000b)


Cumulative Risk Planning and Scoping (USEPA 1997a)


Guiding Principles for Monte Carlo Analysis (USEPA 1997b)


Acute Inhalation Exposure (USEPA 1998d)


Chemical Emergency Risk Management (USEPA 1998e)


Draft Comparative Risk Framework (USEPA 1998f)


Aggregate Exposure and Risk (USEPA 1999g)


Community Involvement in Superfund RA (USEPA 1999c)


Guidance for Offsite Consequence Analysis (USEPA 1999d)


Guideline on Air Quality Models (USEPA 1999e)


Framework for Community Based Env. Prot. (USEPA 1999f)


Handbook for Risk Characterization (USEPA 2000c)


Handbook for Peer Review (USEPA 2000d)


Supplementary Guidance for Conducting Health Risk 


Assessment of Chemical Mixtures (USEPA 2000e) 

Cumulative Risk Assessment of Pesticide . . . Common 

Mechanism of Toxicity (USEPA, 2002a) 

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assessment process (see box at right and Appendix B for a listing of useful resources). These 

include specific analytical methods, techniques for analyzing and interpreting data, and guidance 

on issues influencing policy. Rather, on the basis of EPA experience and recommendations of 

peer reviewers, EPA has reserved discussion of these important aspects of cumulative risk 

assessment for future Guidance, which will be based on the risk assessment process described in 

this Framework report. 

This Framework report is meant to lay out broad areas where analysis might be conducted 

if needed. It does not suggest that cumulative risk assessment is a tool that should be used with 

every issue, nor does it suggest that when cumulative risk assessment is applied, that all areas of 

analysis outlined or discussed here must or even should be conducted in every assessment. The 

scope of the assessment should be defined in the planning and scoping stage (see section 2.1), 

and may include or exclude stressors or pathways as relevant to the particular context or 

application. In some areas discussed in this Framework report, the methodology for doing the 

risk analysis currently may not exist. 

1.2. Intended Audience 

This Framework report is primarily intended for EPA risk assessors, EPA risk managers, 

and other persons who either perform work under EPA contract or sponsorship or are subject to 

EPA regulations concerning risk assessments. The terminology and concepts described here also 

may be of assistance to other Federal, State, and local agencies as well as to members of the 

general public, including stakeholders, who are interested in cumulative risk assessment issues. 

The style and language used in this Framework report are chosen to be understood by as wide a 

variety of interested parties as possible, from the policy maker to the risk assessment scientist to 

the concerned non-scientist member of the general public. It is hoped that this Framework report 

will be the first step in developing a broad scientific consensus about cumulative risk assessment, 

and that further guidelines and guidance will build upon this foundation. 

1.3. Key Definitions in Cumulative Risk Assessment3 

In this Framework report, “cumulative risk” and “cumulative risk assessment” are defined 

as follows, assuming a defined population: 

3 In this section, a few basic definitions related to cumulative risk assessment will be discussed. For a glossary of 

terms, the reader is directed to Section 5. 

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Cumulative Risk: The combined risks from aggregate exposures4 to multiple agents or 

stressors. 

Cumulative risk assessment: An analysis, characterization, and possible quantification 

of the combined risks to health or the environment from multiple agents or stressors. 

There are several key points which come from this definition of cumulative risk. First, 

cumulative risk involves multiple agents or stressors, which means that assessments involving a 

single chemical or stressor are not “cumulative risks” under this definition. Second, there is no 

limitation that the “agents or stressors” be only chemicals. “Agents or stressors” may be 

chemicals, of course, but they may also be biological agents, or physical agents, or even the 

absence of a necessity such as habitat. Third, this definition requires that the risks from multiple 

agents or stressors be combined. This does not necessarily mean “added,” but it means that some 

analysis needs to be conducted as to if, and how, the effects or risks from the various agents or 

stressors interact. It also means that an assessment which covers a number of chemicals or other 

stressors, but which merely lists each chemical with a corresponding risk without consideration 

of the other chemicals present, is not an assessment of cumulative risk under this definition. 

The definition of cumulative risk assessment follows from the definition of cumulative 

risk, but again, there is a key point: cumulative risk assessments can be qualitative as well as 

quantitative. 

Some examples of types of cumulative risk assessments, and some examples of 

assessments we would not describe as “cumulative risk assessments,” are listed below. Each of 

these presupposes a defined individual or population5

: 

1. Single agent or stressor assessments. Risks can be added or accumulated over time 

for a single agent or stressor across sources, environmental pathways, or exposure routes. This 

is consistent with “aggregate risk” in the FQPA terminology in the box on the next page. 

Although this might conceivably be termed a cumulative risk assessment by some scientists, for 

clarity in this Framework report, such single-stressor assessments will be termed “aggregate risk 

assessments,” rather than “cumulative risk assessments.” Examples of this type of assessment 

might be a multi-source assessment of benzene risk in a community, or an assessment of 

individual risk to a specific pesticide from all uses combined. This type of assessment is not 

4 See the text box on the following page for a definition of aggregate exposure. 

5 Populations can be defined by geophysical boundaries, such as a watershed, geopolitical boundaries, such as city or 

county limits, or by cultural, racial, economic, or other criteria within a certain geographic boundary such as a neighborhood. The 

definition of a population needs to be clear enough so that it can be agreed upon whether any specific individual is included in or 

excluded from the population. 

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discussed in this Framework except to be 

referred to occasionally for clarity and 

contrast to cumulative risk assessments. 

2. Multiple stressor assessments. 

Exposures can be accumulated over time, 

pathways, sources, or routes for a number of 

agents or stressors. These stressors may cause 

the same effects (e.g., a number of 

carcinogenic chemicals or a number of 

threats to habitat loss), or a variety of effects. 

A risk assessment for multiple stressors may 

evaluate the risks of the stressors associated 

health effects or ecological impacts, one 

effect or impact at a time, or it may evaluate 

the combined risk from some or all the 

effects or impacts together. In either case, we 

will call these assessments cumulative risk 

assessments. 

FQPA’s Terminology Interpretations 

The Food Quality Protection Act of 1996 [P.L. 104-170] 

discusses the addition of exposure for a single chemical 

across sources, pathways, routes, and time as aggregate 

exposure. To be consistent with that terminology, the 

Agency has elected to speak of multiple source/pathway/ 

route single stressor exposures and risks as “aggregate 

exposures” and “aggregate risks.” The EPA Science 

Policy Council’s Cumulative Risk Subcommittee has 

developed the following working definitions for singlechemical or single-stressor situations: 

Aggregate exposure: The combined exposure of 

an individual (or defined population) to a specific agent or 

stressor via relevant routes, pathways, and sources. 

Aggregate risk: The risk resulting from aggregate 

exposure to a single agent or stressor. 

A multiple stressor cumulative risk assessment is distinct from a series of aggregate risk 

assessments as it includes consideration of any combined impact of the stressors including the 

potential for interactions among stressors (e.g., synergism or antagonism). One example of a 

multiple stressor, single effect cumulative risk assessment would be the combined risk to an 

individual or population from a series of pesticides all acting by the same mode of action and 

causing the same effect. 

Another example would be a dioxin assessment, where toxic equivalency factors (TEFs) 

are used to combine the toxicities of dozens of different congeners of chlorinated dibenzo-pdioxins and dibenzofurans, resulting in a single estimate of risk for a specific effect from the 

combination of congeners. 

Another example is a physician’s use of a model, derived empirically from 

epidemiological studies, to estimate the probability of a woman’s developing breast cancer over 

the next ten years. The “stressors” in the example of the breast cancer model are certain factors 

known to be correlated with that form of cancer, such as the woman’s age at first childbirth, age 

at menarche, having a previous biopsy with atypical hyperplasia, and others. This example shows 

that stressors may not necessarily be chemical stressors, nor do they all even need to be the same 

types of stressors. 

Another type of cumulative risk assessment that will be discussed in this report is the 

multiple stressor, multiple effects assessment. Again, stressors need not be limited to chemicals, 

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nor do they even have to be the same 

types of stressors to be included in this 

type of assessment. Nor do the effects 

have to be similar. For example, 

chemical, biological, radiological, other 

physical, and even psychological stressors 

can cause a variety of human health or 

ecological health effects. Assessing the 

risk for these situations is considerably 

more complex methodologically and 

computationally than the examples of 

aggregate risk assessments or singleeffect cumulative risk assessments given 

in the above paragraphs. 

As complex as this may sound, 

there are several examples of this type of 

assessment. Although these analytical 

approaches may start with the stressors 

and predict the risk of effects, more 

generally these types of assessments start 

with a defined geographical area or 

defined population and try to determine 

what stressors are important. 

For example, cumulative 

ecological risk assessments such as those 

that have been conducted in the Columbia 

River Basin and the Chesapeake Bay 

focus on a number of observed adverse 

Cumulative Risk Assessment Features 

While many different types of exposures, stressors and other 

factors can be included, the definition of cumulative risk might 

be better understood by contrasting the featured and optional 

considerations. By the definition given above for this Framework 

report, the following features are included: 

• multiple stressors 

•	 consideration of how the stressors act together, rather 

than individually 

•	 population focused assessment. Although this does not 

mean that the assessment must start with a population 

and work “backwards” toward the source, it does mean 

that the population needs to be defined and multiple 

stressors are assessed with regard to impact on that 

population, although not every individual will see the 

same (or all) effects. 

Additional layers of complexity, such as those listed below, may 

or may not be addressed: 

•	 multiple durations, pathways, sources, or routes of 

exposure. 

• multiple effects or impacts. 

•	 nonconventional stressors or risk factors (e.g., lifestyle, 

access to health care). These in general need continued 

research. 

• quantification of risks. 

conditions, then attempt to determine, among all of the possible stressors, which particular 

combination is responsible for the observed adverse conditions (Barnthouse, et al., 2000). 

The National Research Council, in its 1994 book Science and Judgment in Risk 

Assessment (NRC, 1994, appendix I), lays out the general mathematics for a quantitative 

approach to multiple stressor, multiple effect assessments. Recently, Bogen (2001) used this 

approach to quantify combined risk of cancer and noncancer endpoints induced by the chemical 

trichloroethylene (TCE), including quantitative characterization of associated interindividual 

variability and associated uncertainty (including uncertainty regarding mechanism of 

carcinogenic action). Technical hurdles involved in implementing this approach become those of 

defining the set of relevant (preferably independent) endpoints and of quantifying the likelihood 

of inducing each adverse health or ecotoxic response considered unacceptable as a function of the 

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endpoints. 

Another example of a type of multiple stressor, multiple effect assessment would be a 

cumulative community health risk assessment. 

We believe that the definition of cumulative risk used in this Framework report is 

consistent with the sense of most definitions of “cumulative” such as are included in NEPA or 

FQPA. A summary of the features and options of a cumulative risk assessment, by the definition 

used in this report, is given in the box on the previous page. 

1.4. The Cumulative Risk Assessment as a Tool for a Variety of Users and Purposes 

As discussed in the Introduction, the results of the assessment should reflect the purpose 

for doing the assessment. Information from cumulative risk assessments can also serve a variety 

of other purposes, however. Insights gained may also be used to partly meet regulatory 

mandates, to help identify targets for enforcement actions, or be considered when shaping policy 

and regulation. Assessments may also conceivably be used in the long term planning with regard 

to siting new sources of potential pollution in specific areas. Assessments also may be used for 

general educational purposes not directly related to an immediate decision on a course of action. 

Assessment results can also help guide priorities for voluntary or regulatory action, or to 

mobilize community efforts to address concerns. They can be done retrospectively (to determine 

past or current risks), prospectively (to assess the risks of, say, proposed facilities), or even 

creatively (to design a development plan for a community). As helpful as results may be in any of 

these other uses, however, some consideration must be given to the appropriateness of using the 

assessment for these purposes, given the objectives and scope of the assessment. 

Risk assessment, including cumulative risk assessment, is conceptually an analyticdeliberative process (NRC, 1996). It includes both analytic (i.e., rigorous, replicable methods, 

evaluated under the agreed protocols of an expert community) and deliberative (i.e., stakeholdervalue-and-judgment based) parts. Much of what is discussed in Chapter 2, the Planning and 

Problem Formulation Phase, is deliberative in nature, which means it depends on input from 

experts other than those who know how to do risk assessments. These include persons who are 

knowledgeable about a community and its values. Although much of Chapter 3, the Analysis 

Phase, is given over to the analytic process where risk assessment experts apply science to a 

problem, the deliberative aspect returns in Chapter 4, the Interpretation Phase, especially where 

risks of different types are being evaluated and combined. 

Cumulative risk assessment, because of this analytic-deliberative process, can be applied to a 

variety of different problems where analysis of the overall impacts of multiple sources, stressors, 

pathways, or routes is necessary. It can be used as a regulatory analysis tool, such as in reviewing 

the overall impact of several different pesticides that all act by the same mode of action (ILSI, 

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1999), or in NEPA analyses (CEQ, 1997). 

It can be used to analyze the overall 

impacts of permit decisions or the results 

of compliance with permits in a given 

community. 

Cumulative risk assessment can 

also be used in a community-based 

assessment approach, such as is outlined 

in EPA’s Framework for CommunityBased Environmental Protection 

(USEPA, 1999f). The CBEP approach 

The Core Principles of Community-Based 

Environmental Protection (CBEP) 

1. Focus on a definable geographic area. 

2. Work collaboratively with stakeholders. 

3. Assess the quality of all resources in a place. 

4. Integrate environmental, economic, and social objectives. 

5. Use the most appropriate tools. 

6. Monitor and redirect efforts through adaptive management. 

Source: U SEPA , 1999f 

(see box) encompasses both ecological and human health assessments. Cumulative risk 

assessment, being a population-based or place-based analytic-deliberative process, is ideal for 

CBEP-type applications. 

Cumulative risk assessment is also applied in ecological assessments. The definition of 

cumulative ecological risk assessment, as given in the EPA’s 1998 Guidelines for Ecological 

Risk Assessment is: A process that involves consideration of the aggregate ecological risk to the 

target entity caused by the accumulation of risk from multiple stressors (USEPA, 1998b). A 

recent Society of Environmental Toxicology and Chemistry publication (Foran and Ferenc, 1999) 

discusses multiple stressors in ecological risk assessment, and gives a good overview of the topic 

of cumulative ecological risk assessment. 

When should a cumulative risk assessment be done? Recognizing that the scope and 

nature of a cumulative risk assessment may range from a very limited qualitative assessment of a 

local situation, to a comprehensive assessment of the cumulative risk patterns for a large 

community, to a national assessment conducted within one of EPA’s programs, the simple 

answer is that one should be conducted whenever the combined impact of multiple stressors 

needs to be considered. Only experience with these assessments over a period of time will 

provide the wisdom needed to develop practical guidelines on this question. 

1.5. The Broader Decision-Making Context for Cumulative Risk Assessment 

Cumulative risk assessments may be used to form hypotheses that could be tested, but it 

is more likely that these assessments will be used as decision-making tools. Decisions can be at 

a wide variety of levels, from a neighborhood group evaluating ways to improve or safeguard 

their health and environment, to a Federal official weighing options for action at a much broader 

geographical level. Although the decision-making method is beyond the scope of this Framework 

report, such decisions usually involve more than the basic science and analysis that make up the 

“scientific” part of risk assessment. Robert T. Clemen, in his book Making Hard Decisions notes 

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that in one type of decision-making approach (called decision analysis): 

Managers and policy makers frequently complain that analytical procedures from 

management science and operations research ignore subjective judgments. Such 

procedures often purport to generate “optimal” actions on the basis of purely objective 

inputs. But the decision-analysis approach allows the inclusion of subjective judgments. 

In fact, decision analysis requires personal judgments: they are important ingredients for 

making good decisions. (Clemen, 1996, page 5) 

Regardless of the type of decision being made or the decision-making approach, a 

cumulative risk assessment’s analytic part is not the decision-making vehicle in itself. That is, 

“cranking out the numbers” will not be the sole basis for a decision. Although in some cases, the 

estimated risks can weigh heavily in the decision, understanding the risk estimate is but one 

factor in a broader decision-making process including risk management components such as 

technical feasibility, economic costs and benefits, political realities, and other factors. The U.S. 

EPA’s Science Advisory Board (SAB) in their August, 2000, publication Toward Integrated 

Environmental Decision-Making (USEPA, 2000a), constructed a framework for what it termed 

Integrated Environmental Decision-making (IED). The SAB noted that “The IED Framework 

recognizes that risks often are experienced simultaneously and are cumulative. . .”. It speaks of 

risk assessments in a very broad way, including human health effects, ecological effects, and 

quality-of-life effects. The first phase and part of the second phase of the IED, “Problem 

Formulation” and “Analysis and Decision-making” essentially correspond to the three phases we 

discuss in this Framework for Cumulative Risk Assessment. Decision-making, and the SAB’s 

third phase, “Implementation and Performance Evaluation,” are beyond the scope of this 

Framework report. 

The SAB’s report (USEPA, 2000a) gives a good insight into the broader context for 

cumulative risk assessment, and some of the aspects of the analytic-deliberative parts of the 

assessment. The analytical-deliberative process will be discussed more in Chapters 2 through 4, 

as these phases of the cumulative risk assessment process are examined. 

The 1996 book Understanding Risk (NRC, 1996) also provided much information on the 

analytic-deliberative aspects of a risk assessment, and devoted a great deal of discussion to risk 

characterization. Needless to say, it is very important to apply cumulative risk assessment in the 

context of the decision or decisions to be made. This is most efficiently done by early and 

continued attention to the “risk characterization” step in the risk assessment process (NRC, 1996; 

USEPA, 2000c). The box in section 4.1 summarizes some of the points made in Understanding 

Risk. 

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Figure 1-3. Framework for Cumulative Risk Assessment 

1.6. Organization of this report 

Figure 1-3 shows the basic structure of this Framework for Cumulative Risk Assessment. 

Each of the three general process steps are described in detail in later chapters. The Framework is 

organized to follow the outline in Figure 1-3, namely (a) a planning, scoping, and problem 

formulation phase (Chapter 2), (b) an analysis phase (Chapter 3), and (c) an interpretation phase, 

where the risk characterization is completed (Chapter 4). Chapter 5 is a glossary of terms, 

followed by References in Chapter 6. Additional information on selected resources and 

cumulative risk related topics are provided in the appendices. 

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Figure 2-1. The Planning, Scoping, and Problem Formulation Phase. 

2. THE PLANNING, SCOPING, AND PROBLEM FORMULATION PHASE 

The first step in any risk assessment process is to define the problem to be assessed. This 

step has been called “problem formulation” in the Framework for Ecological Risk Assessment 

(USEPA, 1992b), the NRC book Understanding Risk (NRC, 1996), Toward Integrated 

Environmental Decision-Making (USEPA, 2000a) and elsewhere (e.g., USEPA, 1997a). It is a 

phase where, according to NRC, “public officials, scientists, and interested and affected parties 

clarify the nature of the choices to be considered, the attendant hazards and risks, and the 

knowledge needed to inform the choices” (NRC, 1996) . 

Planning and Scoping of the assessment are often thought of as being part of the Problem 

Formulation phase, although the 1997 Planning and Scoping guidance treats Planning and 

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Scoping as a separate activity before problem formulation begins (USEPA, 1997a). Whether it is 

considered a separate phase or not, it takes place at the very start of the process of doing a 

cumulative risk assessment. For convenience, this section incorporates both Planning and 

Scoping and Problem Formulation into a single phase. 

2.1. Planning and Scoping 

Risk assessments are conducted within some context, that is, they are usually conducted 

because of a regulatory requirement, a community need, a health crisis, or some other “driving 

force.” This context generates individuals or groups with interest in having the assessment done, 

and there are several summary articles or books available about the challenges of successful 

participation by these interested parties (e.g., Chess and Purcell, 1999; Frewer, 1999; Thomas, 

1995). They may be public officials, risk experts, community leaders, or any number of others. 

Planning and scoping begins with a dialogue among these interested parties. 

Among these interested parties, there will be a person or a group of people charged with 

making decisions about how a risk may be mitigated, avoided, or reduced. For the sake of 

simplicity, we will call this person or group the “decision maker,” or “risk manager6

,” and for 

ease of discussion, will discuss the risk manager as if it were a single person. 

During planning and scoping, risk experts (including those involved in assessing risk 

such as ecologists, toxicologists, chemists, along with other technical experts such as economists 

and engineers) and decision makers work together as a team, informed by stakeholder input, to 

develop the rationale and scope for the risk assessment and characterization. 

As part of the initial discussions concerning the need for a risk assessment, other 

“interested and affected parties” besides the risk manager and risk assessor may help define 

purpose, scope, and approach. This “risk assessment planning team” seeks agreement through 

extensive dialogue and discussion on what analytical and deliberative steps need to be taken, and 

by whom, by when, and why (USEPA, 2000a). The SAB’s report Toward Integrated 

Environmental Decision-Making explains some of the roles of the various participants on the risk 

assessment planning team during the Planning and Problem Formulation phase: 

“Scientists play an important role in [this phase] by collecting, analyzing, and presenting 

data in such a way that all parties can appreciate the type and magnitude of the problem(s) 

under discussion. This activity will generally involve all four parts of risk assessment, 

including assessment of exposures experienced by special populations and/or ecological 

resources. Planning, scoping, and screening -- including selection of endpoints of 

6

 We will use the term “risk management”to include actions that the risk assessment team recommends or implements 

that are not taken by the risk assessment team, per se. These include actions to address the problems taken by others outside the 

process, who may not be identified until the analysis is underway or complete. 

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concern -- also requires explicit input of societal values and stakeholder participation. 

For instance, while some of the ecological endpoints may be chosen because of their role 

in a valued ecosystem, there may also be ecological endpoints chosen because of their 

direct significance to society. Examples of the latter include both economically important 

species and ‘charismatic’ species. Similarly, in integrated decision-making, judgments 

may have to be made about diverse health endpoints, such as cancer risks in the general 

population and the risk of reproductive/developmental risks in children. While scientists 

can help characterize such risks, they are not uniquely qualified to set priorities among 

them and broader deliberation is essential. Finally, decision-makers also play an 

important role during problem formulation; in addition to bringing the scientific and other 

resources of the Agency to bear on the problem, they also should help to identify the 

range of potential decisions and viable management options, while examining economic, 

political, or other constraints on those options. Decision-makers also serve as managers 

of the overall process.” (USEPA, 2000a) 

Another role of the risk assessment planning team is documentation. The activities of the 

following sections are important, and should be documented by the team for several reasons. 

Written records can be referred to by assessors and people at public meetings. They can also help 

prepare for responding to comments, and begin establishing a peer-review record for any later 

decisions or plans that need to be peer reviewed (USEPA, 2000d). The risk assessment planning 

team should consider whether or not the overall project is to be peer reviewed, and if so, what 

type of peer review will be conducted. The team should plan and execute the peer review at the 

appropriate time. A peer review by an independent review group will not only help establish the 

validity of the science, but can also provide neutral comments on some of the interpretations of 

the assessment. 

In some cases, it may be useful for the stakeholders to appoint a “point person” to serve 

as point of contact for communications. This is not to imply that stakeholders must speak with a 

single voice (which is not likely in any case), but that they have at least one person to help 

facilitate interactions and identify available technical resources and other sources of information. 

The Agency or stakeholders may also consider a public web site for the project. A variety of 

resources can be posted, including cumulative risk tools and databases, project-related news, list 

of experts, glossary, reports, related links, etc. An online discussion forum could also be 

included on the web site as a more interactive way of exchanging information with stakeholders. 

Finally, while including stakeholders in the risk assessment process, a regulatory agency 

like EPA needs to balance stakeholder participation with the Agency’s need to retain the ability 

to carry out its responsibility to protect public health and the environment. For this reason, EPA 

will usually need to set some reasonable boundaries around the process to ensure that progress is 

being made in a timely and efficient fashion. 

2.1.1. Defining the Purpose of the Assessment 

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As discussed in section 1.5 above, the risk assessment should be developed to inform the 

risk management decision by constructing an appropriate, decision-relevant risk characterization. 

After the risk assessment planning team is assembled, the dialogue between the decision maker 

and risk experts begins with a discussion on risk management objectives and information needed 

to manage risks in the particular situation. The manager and assessment planning team must 

discuss any regulatory or legal basis for the risk assessment, and what kind of information is 

needed to satisfy such requirements. If interested and affected parties are part of the risk 

assessment planning team, it is especially important that the entire team agree on the purpose of 

the assessment, since a differing sense of purpose among the team will lead to problems later. 

The purpose and risk management objectives guide the risk assessment strategy (see box for 

some possible management goals from which risk management objectives can be derived, e.g., in 

terms of key participants, data sources, selection of assessment endpoints, approach, and the 

schedule for developing the assessment). 

The previous discussion follows the 

typical situation where the risk manager is 

presented as an independent decision-maker, 

such as a senior official in a regulatory agency 

who is responsible for establishing permit 

conditions for a facility of some type. There 

are situations, however, where the risk 

manager may be one of the interested parties, 

such as a local citizens’ board. For example, 

the risk assessment may indicate that 

mitigation of risks may not be significantly 

affected by any permit decisions but will 

depend instead on local zoning decisions or on 

decisions which affect traffic patterns in a 

community. This is one of the reasons why, in 

the final step in the planning and problem 

formulation phase, the discussion of possible 

outcomes (discussed in section 2.3), is so 

important. 

Possible Management Goals 

The goals of risk management are varied. They may be risk 

related, aiming to: 

• Reduce or eliminate risks from exposure to hazardous 

substances. 

• Reduce the incidence of an adverse effect. 

• Reduce the rate of habitat loss. 

They may be economic, aiming to: 

•Reduce the risk without causing job loss. 

•Reduce the risk without reducing property values. 

They may involve public values, aiming to: 

• Protect the most sensitive population. 

• Protect children. 

• Preserve a species from extinction. 

Source: Presidential/Congressional Commission, 1997 

2.1.2. Defining the Scope of Analysis and Products Needed 

Scoping a cumulative risk assessment effort involves defining the elements that will or 

will not be included in the risk assessment7

 (USEPA, 1997a). These include the stressors, 

sources, pathways, routes, and populations to be evaluated. As illustrated by the examples in the 

text box (next page), the scope of a cumulative risk assessment may be narrow or broad. Initially, 

7 An assessment which looks at all stressors over a period of time for a specific population would be a “total risk” 

assessment, which is difficult to perform given our current methods. 

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the risk assessment planning team needs to 

select the kind of risk information, exposure 

scenarios and assessment issues that need to 

be covered. These should be directly linked 

to the risk-related questions being asked 

when establishing the purpose. Limitations in 

scope can be geographical (such as political 

or ecological boundaries), environmental 

(such as assessing only certain media), 

demographic (such as assessing only risks to 

children or asthmatics), statutory, or by using 

other criteria such as data limitations. The 

issue of “background” exposures to stressors 

should be discussed and agreements reached 

(see Appendix C). An adequate assessment 

scope should make it clear what’s included 

and what’s excluded from the assessment. 

Care must be taken to reconcile the 

Examples of Different 


Cumulative Risk Assessment Scopes


• Health risks associated with the aggregate exposure (via 

all pathways and routes) to insecticides acting by a 

common mode of action. 

• Human health risks associated with outdoor inhalation 

exposures of the general population to 33 priority air 

pollutants nationwide. 

• Human health risks associated with exposure via all 

routes to all pollutants present or being released from a 

hazardous waste site. 

• Human health risks, for a specific neighborhood, 

associated with exposure via all routes to all pollutants 

present or being released from a set of adjacent sources, 

including several industries, two hazardous waste sites, 

traffic, and a municipal landfill. 

limitations of scope with the list of questions to be answered in the statement of purpose. If, for 

example, data limitations preclude the addressing of certain of the questions outlined in the 

purpose, the list of questions to be addressed should be modified and the risk assessment 

planning team agree to the narrower scope of the assessment. 

Reasons for choosing the particular scope of the assessment, and how it will address the 

questions posed in the purpose statement, should be stated explicitly. Defining the scope of the 

assessment should include details on the limitations of resources, limitations of data, the impact 

of risk elements on the risk estimate (i.e., some pathways may be seen as having negligible 

impact on the risks related to the questions being addressed), and limitations of the methods 

available. In cases where an element of risk is likely to be important, but no valid data are 

available, the assessor must highlight this deficiency or use judgment or assumed values to 

approximate the missing data. Such judgments and approximations should be clearly 

documented, and explained to the manager in the risk characterization. 

Once the elements (sources, stressors, populations, etc.) have been identified through 

brainstorming with all participants, the participants should discuss the need for and availability of 

technical information and how such information may affect the overall uncertainty of the 

assessment. Using input from the risk assessor, the risk assessment planning team must 

determine what elements will and will not (or, can and cannot) be included in the risk 

assessment. Some of the stakeholder concerns may not be suitable for analysis by risk 

assessment, so other expertise and evaluation may be required to provide this additional analysis. 

Information gathered at this stage is preliminary and may be modified during the analysis phase. 

Identification of potential stressors, populations to be assessed, and potential effects are all part 

of the scoping process, and help define the method of approach. 

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As examples of some of these scoping elements, stressors can include physical (including 

radiological) stressors or chemical or biological agents that may cause an adverse effect. The 

sources of the stressors can be human activities in sectors of society (e.g., manufacturing, 

transportation, agriculture, land development), personal human activities (e.g., smoking, diet, and 

other “lifestyle activities”) or natural phenomena (e.g., forest fires, floods). Stressors that are not 

physical, chemical, or biological, such as economic or other quality-of-life stressors may also be 

identified, but good techniques for including the effect these have on risk currently may not exist. 

Possible population elements to be assessed usually focus on the entities that are at risk, 

e.g., populations, communities, ecosystem functions, or vulnerable subpopulations such as 

persons with certain diseases, or persons at vulnerable life stages, such as children. The more 

specifically these can be defined, the more focused the analysis can be. This will be helpful in 

interpreting the results of the assessment. 

2.1.3. Agreeing on participants, roles and responsibilities 

The risk assessment planning team will usually recommend others who should participate 

in the assessment’s planning, scoping, and risk analysis phase. Depending on the schedule, 

approach, and level of effort envisioned for the risk assessment, there may be no additional 

participants, or there may be many. Assessments will usually require substantial technical 

expertise in the analytic portions of the assessment. Some of the fields of science that may be 

necessary or helpful include toxicology, epidemiology, ecology, risk assessment, exposure 

assessment, fate and transport modeling (e.g., indoor and outdoor air, surface and drinking 

water), computer science (including geographical information systems [GIS]), chemistry, 

biology, various engineering fields (e.g., chemical, mechanical, industrial, civil), economics, 

sociology, and others. 

For the deliberative portions of the 

assessment, there can be a number of 

stakeholders and other interested parties that 

should be considered for participation. The 

box at the right lists some examples to choose 

from among interested or affected parties for 

the deliberative portions of the assessment. 

For community-based assessments, in 

particular, it is important that community 

involvement be sought and encouraged. The 

Presidential/Congressional Commission on 

Risk Assessment and Risk Management 

[hereafter, the “Commission”] (1997) suggests 

the following questions to identify potential 

Examples of Possible Interested or 

Affected Parties (Stakeholders) 

(adapted from USEPA 1999b) 

State governments Affected industry 

Tribal governments Civic organizations 

Local governments Business owners 

Community groups Trade associations 

Grassroots organizations Labor unions 

Environmental groups Public health groups 

Consumer rights groups Academic institutions 

Religious groups Impacted citizens 

Civil rights groups Other federal agencies 

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interested or affected parties (stakeholders): 

• “Who might be affected by the risk management decision? (This includes not only 

groups that already know or believe they are affected, but also groups that may be 

affected but as yet do not know it.) 

• “Who has information and expertise that might be helpful? 

• “Who has been involved in similar risk situations before? 

• “Who has expressed interest in being involved in similar decisions before? 

• “Who might be reasonably angered 

if not included?” 

It has become increasingly recognized 

as important that stakeholders be involved in 

risk assessment (e.g., NRC 1996, 

Presidential/Congressional Commission. . . 

1997, USEPA 1996a, 1997a, 1998a, 1999c, 

1999f, 2000a). The Commission suggested 

guidelines for stakeholder involvement (see 

box at right). 

There are several issues concerning 

the stakeholders’ capacity to participate that 

should not be overlooked by the risk 

assessment planning team. First, some 

stakeholders may need training to be able to 

participate in technical and risk management 

discussions. Second, as noted in the box at 

right, some stakeholders may require 

incentives such as travel funds or lodging at 

sites of meetings outside the area where they 

live. The risk assessment planning team, 

along with the potential source of funds for 

such incentives, should decide to what extent, 

if any, such incentives can be provided, based 

on the scope, level of effort, and financial 

constraints of the risk assessment project. 

Guidelines for Stakeholder Involvement 

• Regulatory agencies or other organizations considering 

stakeholder involvement should be clear about the extent 

to which they are willing or able to respond to stakeholder 

involvement before they undertake such efforts. If a 

decision is not negotiable, don’t waste stakeholders’ time. 

• The goals of stakeholder involvement should be 

clarified at the outset and stakeholders should be involved 

early in the decision-making process. Don’t make saving 

money the sole criterion for success or expect stakeholder 

involvement to end controversy. 

• Stakeholder involvement efforts should attempt to 

engage all potentially affected parties and solicit a diversity 

of perspectives. It may be necessary to provide appropriate 

incentives to encourage stakeholder participation. 

• Stakeholders must be willing to negotiate and should be 

flexible. They must be prepared to listen to and learn from 

diverse viewpoints. Where possible, empower 

stakeholders to make decisions, including providing them 

with the opportunity to obtain technical assistance. 

• Stakeholders should be given credit for their roles in a 

decision, and how stakeholder input was used should be 

explained. If stakeholder suggestions were not used, 

explain why. 

• The nature, extent, and complexity of stakeholder 

involvement should be appropriate to the scope and impact 

of a decision and the potential of the decision to generate 

controversy. 

Source: Presidential/Congressional Commission on Risk 

Assessment and Risk Management, 1997 

Roles and responsibilities for technical and non-technical participants (i.e., ground rules 

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for participants) should also be proposed by the planning team, depending upon the schedule, 

approach, and level of effort that is envisioned for the risk assessment. There will be several key 

points in the risk assessment process where stakeholder input will be critical. Some of these are 

the agreements on purpose, scope, and approach. Each project should define and agree upon a list 

of critical points for stakeholder input. The team may even decide to break stakeholders out into 

several subgroups, with specific tasks such as (1) to understand the technical information and 

report back to the larger group; (2) to elevate and clarify stakeholder issues as needed; or (3) to 

provide information and facts to their peers and the analysts. 

Sometimes citizens choose not to participate because they feel they will not influence the 

outcome, the issue is too complex or technical, the effort is too great, or because the decision 

process is unclear (USEPA, 2001c). Moreover, despite increased emphasis on stakeholder 

participation, there are instances where it may not be appropriate for large scale stakeholder 

involvement. EPA (as the decision maker) must determine whether, and to what degree, 

stakeholder involvement in a cumulative risk decision will be useful and what objectives it may 

accomplish. There is a continuum of objectives that may apply to individual cases, from 

exchanging information on one end, through obtaining stakeholder recommendations, to 

developing agreements for joint activities at the other end (USEPA, 1998g). 

Much of the activities and data needed for cumulative risk assessment overlap the 

jurisdiction of EPA, other public health agencies, and academia. The most successful future 

cumulative risk assessments are likely to be those where cooperation among organizations 

(Federal, State, private, environmental, academic, etc.) leads to use of the best data and tools for 

the various parts of the assessment. 

2.1.4. Agreeing on the Depth of the Assessment and the Analytical Approach 

The analysis approach (discussed further in section 2.2.3 and chapter 3) may fall 

anywhere on a continuum from relatively unsophisticated methods which rely heavily on default 

(and often conservative) assumptions, and consequently have greater uncertainty, to increasingly 

refined assessments in which data are substituted for assumptions and uncertainty is reduced. 

Some of the factors that go into deciding on the approach include the level of uncertainty in the 

risk estimates that is acceptable to the participants, the intended use and audience for the 

assessment, the time and money resources available, and the amount, quality and accessibility of 

data. In making the decision on approach, there will need to be an understanding of both the 

level of effort necessary for conducting the assessment selected, with an insight to alternatives, 

and the features and limitations of the selected approach, in comparison to other approaches. 

2.1.5. Agreement on the Resources Available and Schedule 

Schedule and resources are often interrelated. They may also affect whether the work is 

performed in-house by the organization or team desiring the assessment, or by contractor or other 

external source. The need to meet external deadlines or coordinate with schedules of other 

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organizations may become an overriding factor in defining what will be prepared. Assessments 

requiring short-term, low budget efforts, or preliminary screening assessments, may not have the 

scope, time or resources where extensive stakeholder involvement is necessary or beneficial. For 

assessments, especially those where there is extensive stakeholder involvement, a budget and 

time schedule should be developed and known by all participants. 

2.1.6. Review of Lessons Learned in 

Similar Studies 

Much time and effort can be saved by 

taking the advice of those who have been 

through this process – or similar processes – 

before. Risk assessment reports will often have 

a review chapter of “lessons learned” (or, “if I 

had to do this over again, this time I would . . 

.”). We have tried to include some of the 

discussion of recent Agency experiences as 

examples to illustrate parts of this Framework 

report. In addition, the reader is encouraged to 

find similar advice in other reports (e.g., Lesson 

Learned on Planning and Scoping for 

Environmental Risk Assessments, USEPA, 

2002b). EPA’s Office of Water has conducted 

several watershed studies over the past decade 

and has compiled a web page with lessons 

learned (USEPA, 2001d). One of the lists from 

that source is in the box at right, but there are 

many others. Even though the studies were not 

all cumulative risk studies, much of the wisdom 

gained is relevant. 

2.2. Problem Formulation, Conceptual 

Model, and Analysis Plan 

One outcome of the problem 

formulation phase is a conceptual model that is 

intended to identify relevant stressors, sources, 

pathways, exposure routes, receptors, and 

effects, and to identify relationships among 

them. The conceptual model serves as a basis 

for the analysis plan, which is used to focus the 

analysis phase of the assessment. These three 

components are discussed in the sections 

Reed Holderman's Lessons Learned 

(California Coastal Conservancy, Santa Ynez Watershed) 

1. Be sure that [the project] is needed, and if it is, build 

community support for it before proceeding. 

2. Invite everyone into the process and ask political leaders 

to select the steering committee. Otherwise, people will 

ask, “Who appointed you?” 

3. Don't be presumptuous. On the Santa Ynez River, we 

assumed everybody would appreciate a well thought out 

scope of work, budget, and schedule. Wrong. They said it 

only proved that the whole thing was a set-up. Next time, 

let [the whole planning team] figure it out! 

4. When the majority of stakeholders tell you that they 

want to deal with their issue first, believe them. I remain 

convinced that our failure to sustain interest in the Santa 

Ynez River plan was primarily because we were not 

willing to assist the County in carrying out its proposed 

channel clearing activities in the Lompoc valley as a 

separate and distinct project. 

5. Do whatever you can to break down barriers and 

perceptions people have of each other. Be creative. 

Family BBQs, softball games, and parties have done 

wonders to improve relationships among stakeholders and 

build trust. 

6. Maintain constant communication among stakeholders 

throughout the process – and especially in the beginning – 

to pass information along, answer questions, or deal with 

rumors. Whether it's through regular meetings, 

newsletters, web sites, phone trees, or all four, good 

communication is a must. 

7. And finally, line up your money and in-kind services in 

advance of starting your [assessment] project, or else two 

bad things will happen: (a) your stakeholders will buy into 

a process and scope of work only to find out they can't 

afford it; and (b) you will spend more time looking for 

cash than participating in the planning process. Either 

way, you lose. 

[Source: Lessons Learned Web page (USEPA, 2001d)] 

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below. 

The Science Advisory Board in their report Toward Integrated Environmental DecisionMaking (USEPA, 2000a) suggests a list of desired outputs from the Problem Formulation part of 

an environmental decision-making exercise. Although this is not precisely the same as a risk 

assessment, many of the points they list have applicability to risk assessment, also. The SAB 

suggests these should not only be left to the visual presentation of the Conceptual Model 

Diagram, but should also be explained in narrative form. Some of the SAB’s recommended 

outputs, included here as an example, are listed in the box below. Not all of these would 

necessarily be applicable to a given risk assessment, depending on the scope. 

Example: SAB’s Desired Outputs for Problem Formulation 

! The initial goals for the decision-making exercise, including environmental goals to be achieved


! Which environmental problems/stressors/systems will be included and which will not, and the reasons for these decisions


! The health, ecological, and quality-of-life effects of concern


! The spatial, temporal, and organizational dimensions of the problem


! Relevant data and models, and possible approaches to data analysis


! Scoping of the uncertainties involved and research needed to significantly reduce critical uncertainties


! Initial review of the range of options available to reduce risks, considering likely economic, political, or other constraints


! The endpoints upon which the condition of the ecological, human health, or societal systems ultimately will be judged


! The types of factors that will be considered when reaching a decision


From Toward Integrated Environmental Decision-Making (USEPA, 2000a) 

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12 2.2.1. Problem Formulation.


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14 Problem formulation is a systematic planning step that identifies the major factors to be


15 considered in a particular assessment. It is linked to the regulatory and policy context of the


16 assessment. Problem formulation is an iterative process within which the risk assessor develops


17 preliminary hypotheses about why adverse effects might occur or have occurred. It provides the


18 foundation for the technical approach of the assessment. The outcome of the problem


19 formulation process is a conceptual model that describes the relationship between the stressors,


20 the population exposed, and the assessment endpoints that will be addressed in the risk


21 assessment.


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23 2.2.2. Developing the Conceptual Model


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25 A conceptual model includes both a written description and a visual representation of


26 actual or predicted relationships between humans (or populations, population segments) or


27 ecological entities and the chemicals or other stressors to which they may be exposed. 


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Figure 2-2. An example of a generic conceptual model (adapted from USEPA, 2002a). 

Conceptual models represent many relationships, and may describe primary, secondary, 

or tertiary exposure pathways. The model is developed by the risk assessor and may include input 

from other experts (including stakeholders). The model narrative needs to distinguish – to the 

extent possible – between what is known or determined, and what is assumed. Also, it needs to 

include a discussion of uncertainties in the formulation of the assessment and state how the 

assessment is cumulative, i.e., for which sources, stressors/agents, pathways/exposure routes, 

receptors/populations, and endpoints. In some cases, conceptual models will be submitted for 

peer review. A general conceptual model is illustrated in Figure 2-2. The conceptual model 

includes factors and endpoints which may not be analyzed in the risk assessment, but may be 

evaluated in the overall decision-making process. 

The conceptual model and the associated narrative show the basic rationale for the 

decisions made in pursuing a particular course of action in a cumulative risk assessment. It 

provides a record of decisions for future reference during risk analysis, characterization, and 

communication of the risk management decision. It is also valuable as a risk communication tool 

both internally within the Agency and externally in interactions with the public. The 

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Figure 2-3. Specific conceptual model for a complex project, OAQPS’ National Scale Air Toxics Assessment 

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conceptual model provides a scientific or technical work product that includes: (1) the scientific 

rationale for the selection of the stressors, sources, receptors, exposed populations, exposure or 

environmental pathways, endpoints or effects, (2) the scientific, technical, economic, or 

sociologic basis for the construction of the conceptual model; and (3) the scientific implications 

of additional data gathering. Figure 2-3 is an example of a conceptual model from the National 

Air Toxics Assessment8

. 

It is not inconceivable, given the deliberative nature of the process of developing a 

conceptual model, that more than one model will be considered as alternatives. If the team 

decides to ultimately use more than one model, and to evaluate each as part of hypothesis testing, 

a careful consideration of time and monetary resources needs to be made, as well as a very 

careful consideration of how the results will be interpreted (see section 2.3). 

2.2.3. Constructing the Analysis Plan 

The analysis plan is the final stage of planning and scoping before the risk assessment. 

The analysis plan is discussed in the Ecological Risk Assessment Guidelines (USEPA, 1998b), 

Section 3.5. The analysis plan describes how hypotheses about the relationships among the 

sources, stressors, exposure conditions, populations, and adverse effects, presented in the 

conceptual model and narrative, will be considered during the risk analysis phase of the 

assessment. The plan includes the rationale for which relationships (referred to as “risk 

hypotheses” in the Guidelines for Ecological Risk Assessment) are addressed, methods, models, 

and a discussion of data gaps and uncertainties. It also may include a comparison between the 

level of confidence needed for the management decision with that expected from alternative 

analyses in order to determine data needs and evaluate which analytical approach is best. In 

some cases, a phased, or tiered, risk assessment approach can facilitate management decisions, 

particularly in cases involving minimal data sets. 

The analysis plan provides a synopsis of measures that will be used to evaluate risk 

hypotheses (as shown in Appendix D) . The plan is strongest when it contains explicit 

statements for how measures were selected, what adverse effect (or assessment endpoint) they 

are intended to evaluate, and which analyses they support. Uncertainties associated with selected 

measures and analyses and plans for addressing them should be included in the plan when 

possible. The analysis plan can be a brief summary of what the key components of the risk 

assessment are and how each component will be measured or calculated. 

As in the conceptual model, the economic or societal importance, complexity, data and 

resources available will determine the degree of sophistication and detail needed in the analysis 

plan. Key data gaps should be identified. It should also include thoughts about how to fill the 

information needs in the near-term using existing information, in the mid-term by conducting 

8 NATA is the technical support component of EPA’s National Air Toxics Program [see 64FR38706-38740 (“National 

Air Toxics Program: Integrated Urban Strategy”) or USEPA, 2001e. 

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tests with currently available test methods to provide data on the agent(s) of interest, and over the 

long-term to develop better, more realistic understandings of exposure and effects and more 

realistic test methods to evaluate agents of concern. The plan should explain how measures were 

selected, what they are intended to evaluate, and which analyses they support. Uncertainties 

associated with selected measures and analyses, and plans for addressing them, should also be 

explicitly stated. 

The analysis plan should include (where feasible) milestones for completion of the risk 

assessment. The plan may be revisited and revised periodically. Such revisions may be 

anticipated, if new information is acquired, to refine hypotheses of exposure and toxicity, to 

modify the risk hypotheses addressed, or to compare public concerns with the projected risk 

management options. 

2.3. The Final Step Before the Analysis Phase: Discussion of Possible Outcomes 

It is useful for the entire team to hold some preliminary discussions, before the analytical 

efforts of the assessment are started, about the various possibilities of the cumulative risk 

assessment results and their implications. Given that statutory mandates, regulations, property 

rights, or due process may constrain or define most or all acceptability criteria, what conclusions 

of the team will be associated with various results or risk levels? For example, for a risk 

assessment team with members from the community, industry, and the local and other 

government entities, what would happen if the assessment shows risk levels to be “low”? Would 

members accept this? Conversely, if “unacceptable” risks are determined, will all team members 

accept the results and their possible responsibility to do something about that risk? Do team 

members understand the limitations of the information to be generated? 

Discussions like these will help determine if the assessment can really address the 

questions of the team. If not, the assessment may not be worth doing as planned. If members of 

the team will not accept the possibility of a range of results of the analysis, then it is important to 

reopen the entire planning and scoping discussion before anything is done in the analysis phase, 

since the planning and scoping phase has not been satisfactorily completed. Although it is not 

necessary to have unanimity among stakeholders on the plan before proceeding, knowing where 

some of the potential disagreements may occur after the Analysis and Interpretation phases are 

started allows the stakeholders as a group to plan beforehand for how such disagreements will be 

addressed, should they occur. 

As an example, the Baltimore Community Environmental Partnership Air Committee 

Technical Report (USEPA, 2000f) is a case study where the stakeholders thought they had 

agreement on roles, responsibilities and approach, only to find that the group acrimoniously 

splintered after the analysis results came back. The Baltimore report contains valuable lessons 

learned in the area of stakeholder disagreements and agendas, and can provide some insight for 

planning teams. 

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Finally, discussions just prior to the analysis phase may lead to an assessment very 

different from the one originally envisioned. The CRI case study (box, next page) is one where 

the original plan was to do a quantitative cumulative risk assessment, but because of the lack of 

some critical information, the scope was changed. This led to an assessment that, while not as 

broad as originally planned – and not even directly calculating risk – had better stakeholder buyin with a better chance of success of providing useful information. 

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Example: Cumulative Risk Initiative (CRI) for Cook Co., IL and Lake Co., IN 

(formerly Chicago Cumulative Risk Initiative, CCRI) 

CRI BACKGROUND AND O VERVIEW 

In 1995 the Chicago Legal Clinic and 11 Chicago-area community advocacy groups filed a petition under the Toxic 

Substances Control Act (TSCA) requesting that the USEPA Administrator prohibit or further regulate the emissions from 

eight proposed or constructed incinerators in the Chicago metropolitan area and Northwest Indiana. The petitioners 

believed that neither current statutes nor local siting laws adequately address cumulative impacts of multiple sources of 

toxic pollutants in a geographic area. They requested that the Administrator restrict emissions of dioxins, furans, mercury, 

lead and cadmium from these sources. In May 1996 the petition was withdrawn in response to a USEPA offer to 

participate in an investigation of multimedia pollutant impacts in Cook County, Illinois and Lake County, Indiana. This 

effort became CRI. CRI is an attempt to investigate cumulative loadings and hazards from pollutant sources, develop 

community-based activities to help address these concerns, and use analytic results to help prioritize use of regulatory 

agency resources. USEPA and the petitioners agreed to a four phase project: (1) Environmental Loadings Profile (EPA 

747-R-1-002); (2) Petitioner Risk Workshop (completed); (3) Hazard Screening Assessment (peer review draft available 

Jan. 2002); and (4) Risk-Hazard Management Response (pending). 

HAZARD SCREENING ASSESSMENT 

The CRI Hazard Screening Assessment was authored primarily by Argonne National Laboratory with input from local, 

state and federal participants. Reflecting stakeholder deliberations, the Report focuses on cumulative hazard (not “risk” as 

typically defined by USEPA) associated with noncriteria air pollutants (“air toxics”) in the two county study area. It relies 

on “off-the-shelf” air pollutant information, including USEPA’s Toxics Release Inventory, Cumulative Exposure Project, 

Regional Air Pollutant Inventory Development System, and outdoor air monitoring data. Emission estimates are “toxicity 

weighted”, while modeled/monitored outdoor air pollutant concentrations are compared with reference values to develop 

hazard index-like ratios. The ratios or toxicity weighted emission estimates are used to derive indicators of cumulative 

hazard, then mapped over study area locations. To identify geographic areas where potentially elevated hazards and 

individuals with potentially greater susceptibility are collocated, another part of the study assembles pollutant hazard 

information and data on existing human disease rates and indicators. 

PRELIMINARY LESSONS LEARNED 

1. A major planning/scoping/problem formulation effort by a broad group of stakeholders narrowed the scope of the CRI 

Hazard Screening Assessment and seemed to increase stakeholder “buy-in” with the process. This was valuable given the 

complexity, expense, effort, time requirement and difficulty encountered in addressing even the narrowed scope. 

2. Large data gaps make risk and hazard assessment of environmentally-relevant chemical exposures highly uncertain, even 

for single agents. Expanded assessments that address cumulative risk considerations (e.g. mixtures; developmental toxicity; 

non-chemical agents) are a better match for real-world circumstances but require acknowledgment of even more 

uncertainty. 

3. Obtaining and managing input from a large group of technical stakeholders is cumbersome and time-consuming, but that 

group’s perspective and expertise greatly improved the CRI assessment. 

4. Given that the NRC’s 1983 four-step “framework” required several years for broad use and acceptance in the U.S., the 

greater complexity of cumulative risk (for CRI, cumulative hazard) assessment suggests an equally long period may be 

needed for terminology standardization, refinement of approaches and development of consensus methods. 

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Figure 3.1. The Analysis Phase 

3. THE ANALYSIS PHASE 

The Analysis Phase is primarily an analytic process where risk experts apply risk 

assessment approaches to evaluating the problem at hand9

. The risk assessment paradigm most 

widely used by risk assessors during the past two decades was first documented by the National 

Research Council (NRC, 1983). It consists of four parts: hazard identification, dose-response 

assessment, exposure assessment, and risk characterization. This paradigm was developed when 

almost all risk assessments were being conducted on single chemicals. Nevertheless, it is a useful 

place to start when considering cumulative risks. As a prerequisite, assessors considering 

cumulative risk assessments should be familiar with the 1983 NRC risk paradigm, as well as the 

various EPA risk assessment guidelines (see text box in section 1.1). 

9 Although the Analysis Phase is primarily an analytic process with heavy emphasis on the role of the scientist, risk 

assessor, or other technical expert, other stakeholders can be involved in various ways as agreed upon before the Analysis Phase 

begins. Some roles stakeholders might have in the Analysis Phase include (1) suggesting sources of data, or providing data for 

the assessment; (2) helping clarify issues identified during Problem Formulation; (3) working alongside the risk assessment 

experts to see what data and assumptions are being used and why, and to better understand how the risk assessment process 

works; and (4) suggesting alternate scenarios that may reflect more realistic exposure conditions in the community. A variety of 

roles for stakeholders in the Analysis Phase can be proposed and adapted for the particular circumstances of the individual case, 

assuming that the roles can be agreed upon by the team. 

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In both single and multiple stressor risk assessments, the analyst will look at hazard and 

dose response relevant to the stressor(s) of interest, and perform an analysis of exposure(s) to 

those stressor(s). This chapter begins with a basic discussion of this general process and its basic 

ingredients (section 3.1). The second part of this chapter (section 3.2) discusses some of the 

situations arising in cumulative risk assessment, methods currently available for addressing them, 

steps in the process, and some limitations to these methods. Finally, section 3.3 identifies areas 

of ongoing work particularly relevant to cumulative risk assessment. 

3.1. General Process 

In developing the conceptual model and analysis plan (see section 2.2), the scope of the 

assessment was specified (see example in box at right). Some of the aspects of scope include 

stressors, sources, pathways and media, exposure routes, populations and subpopulations, 

endpoints, and measures. 

The analysis plan should specify how data, modeling or assumptions will be obtained, 

performed or defined for all of the details 

concerning the characterization of exposure 

for the defined set of stressors, to the 

defined population and subpopulations. 

Additionally, the analysis plan specifies the 

strategy for obtaining and considering 

hazard and dose-response information for 

these stressors. And, the plan will specify 

the method for combining the exposure 

information with the hazard and doseresponse information to generate risk 

estimates or measures. As the risk analysis 

is refined, it may be appropriate to revisit 

and refine the exposure, hazard and doseresponse information in an iterative 

fashion. 

In the integration of exposure, 

hazard and dose-response information for a 

cumulative risk assessment, several aspects 

of the assessment may be particularly 

important. These include multiple stressor 

hazard, dose-response and exposure issues, 

exposure time or duration related issues, 

vulnerability or susceptibility of the study 

Example: Scope of EPA’s national scale assessment 

for hazardous air pollutants (also see Figure 2-3): 

stressors 33 priority urban HAPs 

sources	 major industrial, small “area”, 

mobile (on- and off-road), & extrinsic

“background” in air 

pathways/media	 outdoor air, indoor air 

microenvironments 

routes inhalation 

subpopulations general population only 

endpoints	 cancers, developmental, CNS, kidney,

liver, respiratory effects 

metrics	 for cancer: distribution of high-end

cancer risk estimates, predicted

percent of population within predicted

cancer risk ranges, predicted number

of cancer cases, HAP-specific and 

cumulative 

for other effects: distribution of 

estimated hazard index values and 

estimated percent of population within

specified ranges of index values 

population, along with the influencing factors, and subpopulations with special exposures. These 

items are discussed in the following section, along with the currently recognized methods for 

evaluating the toxicity or risk associated with mixtures. 

The area of identifying and assessing risk to susceptible subpopulations has an increased 

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profile in cumulative risk assessments. A variety of factors may be influential in affecting 

population susceptibility. The extent to which these can be considered will be heavily dependent 

on existing knowledge and available information. Section 3.2 discusses available methods for 

identifying and estimating risk or hazard to susceptible or vulnerable subpopulations. Section 

3.3 discusses areas of complexity and on-going work. 

3.2. Available Methods and Approaches 

There are many aspects of traditional risk assessment methodology which apply to 

cumulative risk assessment. Predicting cumulative risk of multiple stressors, however, has 

required the development of additional specific methods or approaches. Additionally, there are 

some aspects of risk assessment, while common to both single-stressor and multiple-stressor 

assessments, that may increase in complexity or significance, in a cumulative risk assessment. 

Together they frame the methodological issues pertinent to the discussion of cumulative risk 

assessment. 

While these aspects common to single-stressor assessment may be many (e.g., the added 

dimension of multiple stressors influences consideration of stressor sources, routes of exposure, 

environmental media/pathways, and other factors), several examples are raised here. As one 

example, the assessment of the dose-response relationship and corresponding characterization of 

exposures in terms of duration, timing relevant to life stage and exposure history gains an 

additional dimension with the need to consider this in some way cumulatively. The 

consideration of population susceptibility or vulnerability, as recommended in the Agency’s 

policy and guidance on Risk Characterization (USEPA 1995a, 1995b, 2000c), also increases in 

complexity. A third example of a complicating aspect in cumulative risk assessment is the 

consideration of subpopulations with particularly distinctive exposures. These examples are 

further discussed in section 3.2.1. 

Although it is beyond the scope of this Framework report to describe all risk methods in 

detail, Appendix B lists a variety of resources relevant to various exposure assessment methods. 

Relatively speaking, there is a great deal of information on assessing human and environmental 

exposures to chemical stressors, some information on biological and radiological stressors, but 

relatively little information on many other types of stressors. 

The most prominent aspect of cumulative risk assessment is often the prediction of the 

combined effects of multiple stressors. Past and current activities in the development of 

approaches for predicting risk of multiple stressors include the Agency’s Guidelines for the 

Health Risk Assessment of Chemical Mixtures (USEPA, 1986b) and Supplementary Guidance for 

Conducting Health Risk Assessment of Chemical Mixtures (USEPA, 2000e). Concepts, 

approaches, or methods described in these documents or elsewhere are discussed in section 3.2.2, 

with clarification of their applicability, limitations and notable points regarding interpretation of 

the results they produce. 

3.2.1. Examples of Increased Complexity of Cumulative Risk Assessment. 

Three examples of the potential for increased complexity of cumulative risk assessment 

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compared to single stressor risk assessment are described here, and related to: 1) time related 

aspects, 2) vulnerability or susceptibility, and 3) subpopulations with special or particularly 

distinctive exposures. All three of these aspects are relevant in single stressor assessments, but 

have the potential to be more complicated in multiple stressor assessments. 

Time related aspects. The issue of repeated exposures to a single stressor or exposures 

to multiple stressors that may vary in time dimensions may have implications with regard to 

susceptibility, which, consequently, has implications regarding the dose-response relationship. 

Traditionally in dose-response assessment, for many stressors and effects there is an inherent 

presumption that it is the cumulative exposure (combination of intensity and duration) to which 

the organism responds. Thus dose-response assessments based on one pattern of exposure (e.g., 

6 hours per day, 5 days per week over a lifetime) are routinely applied to the assessment of risk 

associated with a variety of patterns of exposure. 

In the case of linear carcinogens, this cumulative exposure assumption has been carried as 

an explicit assumption in the risk assessment step. Regardless of the details of the exposure 

circumstances for the study on which the cancer potency was based, it is assumed that there is a 

linear relationship between amounts of exposure and associated cancer risk. For non-linear 

carcinogens 10, and conceivably for linear carcinogens, if data indicate deviation from the 

assumption that cancer risk is proportional to lifetime dose, the details and sequence of exposure 

may be important, both in developing the dose-response relationship and in predicting risk 

associated with exposures of interest. 

As some chemicals may have the ability to affect an organism’s response to other 

chemicals, consideration of the time sequence of exposure may take on an additional layer of 

complexity in multiple chemical cumulative risk assessments. For example, persons with 

relevant past exposures might have increased susceptibility to the effects of a particular chemical 

due to a previous exposure to the same – or a second – chemical. 

These considerations suggest that for cumulative risk assessment, chemical exposures 

need to be characterized in terms of which other chemicals are present, and when. As noted in the 

ILSI Framework for Cumulative Risk Assessment (ILSI, 1999): “Data collected specifically to 

support a cumulative exposure assessment should conserve the covariance and dependency 

structures associated with the chemicals of concern.” It is important to note, however, that the 

detail to which exposures are characterized should be closely tied to the detail of information 

available in the dose-response assessment, since a lack of corresponding detail in the doseresponse assessment can pose a limitation on the interpretation and usefulness of detailed 

exposure estimates. 

Cumulative risk assessment can present challenges in matching exposure estimates with 

dose-response relationships. Ideally, the dose-response assessment will indicate if the time 

sequence for the chemical(s) or stressors of interest in the assessment is important for risk 

estimation. In cumulative assessments involving chemicals where time sequence of exposure is 

important, it may be necessary to characterize the details and sequence of exposure to the 

10 The draft cancer guidelines (USEPA, 1999l) explicitly recognize the potential for non-linear dose response. It is 

only in the case where non-linear response is modeled that time sequence of exposure can be considered in the risk assessment. 

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1 exposed population (see text box, previous page), so there will be a match in not only the form, 

but also the assumptions between the dose-response relationship and the exposure/dose estimate. 

3 

2 

Some Examples of Exposure Models which Consider Time Aspects 

Calendex (Novigen Sciences, Inc), integrates different pathways (e.g., dietary – food and water – and 

residential) and routes (oral, dermal, inhalation) of exposure using a calendar-based probabilistic approach . 

One of the important factors of this approach is it provides estimates of risk which reflect aggregate and 

cumulative exposure to discrete individuals with exposure pathways and routes appropriately linked for the 

scenarios being assessed. Calendex also allows one to estimate exposure pre- and post use of a chemical, as 

well as during degradation periods. Calendar based assessments maintain the integrity of the individual by 

capturing: the location of the exposed individual, the time of year in which he or she was exposed, and the 

patterns of ex posure. C alendex also allows for a va riety of time-brea kout optio ns for the analysis o f exposure . 

APEX - The Air P ollution Exp osure (AP EX) m odel is base d on the pN EM p robabilistic N ational Am bient Air 

Quality Stand ards mod el (pNE M) for ca rbon mo noxide (J ohnson, et al., 2000). T his model m imics the basic 

abilities of the pNEM /CO model; it calculates the distributions of human exposure to selected airborne 

pollutants within a selected study area as a function of time. As a dose model (for CO), it calculates the 

pollutant dose within the body, specifically summarized by the blood carboxyhemoglobin (COHb) 

concentration. APEX is a cohort-m icroenviro nmen t exposure model in tha t it combines d aily activity diaries to 

form a composite year-long activity pattern, which represent specific popula tion coho rts and are tracked as they 

move from one microenvironment to another. A cohort consists of a sub set of the pop ulation that is exp ected to 

have som ewhat similar ac tivity (and hence exposure ) patterns; they ar e formed by comb ining demo graphic 

groups and geographic locations (districts). Once each cohort has been modeled and its relative size determined, 

an exposure distribution for the entire population can be assembled. A microenvironment is a description of 

the immediate surroundings of an individual that serves as an indicator of exposure (e.g., inside a residence, 

school or car, outdo ors, etc.). AP EX has b een deve loped as o ne of the inhala tion expos ure mod els accessible in 

the Exposure Event Module of the Total Risk Integrated Methodology (TRIM.Expo) for assessment of 

exposures to either criteria or hazardous air pollutants (USEPA, 1999j) 

Other models include the LifeLine Model, developed under a cooperative agreement between EPA/O PP and 

Hampshire Research Institute (Hampshire Research Institute, 1999, 2000); the Stochastic Human Exposure and 

Dose Simulation Model (SHE DS), under development by EPA’s Office of Research and Developm ent 

(Zartarian, et al., 2000), and the Cumulative and Aggregate Risk Evaluation System (CARES), under 

development by member companies of the American Crop P rotection Association (APCA, 1999) along with the 

Residential Exposure Year (RExY) model being developed by Infoscientific.com. 

4 Vulnerability. One of the concepts that can be used in risk assessments (both for human


5 health and ecological assessments) is that of vulnerability of the population or ecosystem. 


6 Vulnerability has been a common topic in socioeconomic and environmental studies. The


7 European Commission’s TEMRAP (The European Multi-Hazard Risk Assessment Project),


8 studying vulnerability to natural disasters such as floods, windstorms, fires, earthquakes, and


9 others, defines “vulnerability” as “the intrinsic predisposition of an exposed element [organism,


10 population, or ecologically valuable entity] to be at risk of suffering losses (life, health, cultural


11 or economic) upon the occurrence of an event of [a specific] intensity” (European Commission,


12 2000, bracketed material added). 


13


14 Vulnerability of a population places them at increased risk of adverse effect, and may be


15 an important factor in deciding which stressors are important in doing a cumulative risk


16 assessment. The Agency’s risk characterization policy and guidance (USEPA, 2000c) touches on


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this concept by recommending that risk assessments “address or provide descriptions of [risk to] 

... important subgroups of the population, such as highly exposed or highly susceptible groups”. 

Further, the Agency’s guidance on planning and scoping for cumulative risk assessments 

(USEPA, 1995b) recognizes the importance of “defining the characteristics of the population at 

risk, which include individuals or sensitive subgroups which may be highly susceptible to risks 

from stressors or groups of stressors due to their age, gender, disease history, size or 

developmental stage”. That guidance also recognizes the potential importance of other social, 

economic, behavioral or psychological stressors that may contribute to adverse health effects 

(e.g., existing health condition, anxiety, nutritional status, crime and congestion). These same 

concepts may also be discussed as a group in terms of “population vulnerability.” The various 

ways in which a population may be vulnerable are discussed below in four categories: 

susceptibility, differential exposure, differential preparedness, and differential ability to recover. 

The first of these is susceptibility. Susceptible individuals within a population have a 

different or more pronounced dose-response relationship when confronted with a stressor. 

Reasons for susceptibility may be related to any number of sensitivity factors, including life stage 

(e.g., children or the elderly may be more susceptible), genetic polymorphisms (e.g., genetic 

susceptibilities which occur in a small but significant percentage of the population), or existing 

disease state (e.g., asthmatics). In addition, susceptibility may be related to the conditions of 

exposures (e.g., prior exposures leading to the development of sensitization reactions, or having 

had exposures which compromise the immune system). Confronted with equal concentrations of 

a chemical for equal durations, for example, a biologically susceptible individual may show 

effects while the typical individual within the population would not. Although we generally do 

not have a lot of data available on this topic, susceptibilities or sensitivities may also exist among 

races or genders. 

The second category of vulnerability is differential exposure. While it is obvious by 

examining a dose-response curve that two individuals at different exposure levels may have a 

different likelihood of effects, this also extends to differences in historical exposure, body 

burden, and background exposure, which are sometimes overlooked in an assessment. 

The third category of vulnerability is differential preparedness to withstand the insult of 

the stressor, and the fourth is the differential ability to recover from the effects of the stressor. 

These last two are linked to what kind of coping systems and resources an individual, population, 

or community has. Preparedness or recovery is often a crucial factor in ecological assessments. In 

human health assessments, lack of access to health care, income differences, unemployment, or 

lack of insurance, for example, may affect a community’s ability to prepare for or recover from a 

stressor. One aspect of differential ability to recover is illustrated by differing survival rates for 

the same disease (e.g., Lantz, et. al 1998). 

Cumulative risk assessments may be uniquely suited to addressing the issues related to 

vulnerability. In order to do that, however, there needs to be some relationship between the 

factors discussed above and changes in risk. At the current state of the science, many of these 

factors have not been extensively developed beyond correlations between mortality rates and 

several socioeconomic factors such as income (e.g., Lynch, et al. 1998). Susceptibility has had 

much more development than the other factors, and current approaches implemented by EPA and 

others to address risk of noncancer endpoints routinely employ a 10-fold factor to address 

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heterogeneity in sensitivity. Variability with regard to susceptibility was discussed in detail by 

NRC (1994), and the current state of knowledge concerning epidemiologically based (e.g., 

oncogene-specific) risk factors provides empirical data upon which at least crude estimates of the 

magnitude of heterogeneity in susceptibility to toxic response can be based. Much research in 

this area, however, remains to be done. 

Subpopulations with Special Exposures. Certain subpopulations can be highly exposed 

to stressors based on geographic proximity to sources of these stressors, coincident direct or 

indirect occupational exposures, their activity patterns, or a combination of these factors. The 

Agency’s Risk Characterization policy and guidance (USEPA, 2000c) includes recognition of the 

need for risk information to include as available, information on highly-exposed subgroups. 

Accordingly, risk assessments, including those that are cumulative, may need to include special 

emphasis on identifying and evaluating these subpopulations. 

Subpopulations at risk of high exposure due to geographic proximity could include 

workers at a facility which is a source of a stressor or residents near such sources. Specific 

examples might be people living downwind from a coal burning power plant, those near and 

using a polluted water body (for example, for fishing or recreation), or along roadways with high 

levels of vehicular traffic. Occupational exposures may be either direct (occurring in the 

workplace) or indirect (occurring at home). Indirect occupational exposures include those 

experienced by family members of those occupationally exposed, who may be exposed to 

occupational chemicals brought into the house by the worker (e.g., on clothing). Thus, workers 

or family members may be subject to greater exposures than others in the population without this 

additional burden. 

Examples of subpopulations at high exposure due to activity patterns may include people 

who exercise heavily in polluted air, recreational or subsistence fishers or hunters who consume 

large quantities of fish or game, farmers or others who get a large percentage of their food from a 

location near a source of pollution and live in areas with high pesticide use, individuals with long 

commutes in automobiles, or children (because they consume a larger amount of food, drink, and 

air relative to their body weight, and because of additional exposure routes such as incidental soil 

ingestion). Additionally, some subpopulations may be affected by the combined impact of high 

geographic exposure and high exposure activity patterns (e.g., runners who run along heavily 

traveled roadways, and those who fish for food in heavily polluted urban rivers). 

It is important to recognize that some heavily exposed populations may also be 

particularly vulnerable or susceptible to the effects associated with the stressors of concern. 

Examples of those who could be particularly vulnerable to certain stressors include children 

during certain stages of development, people with chronic respiratory problems, the elderly, and 

those economically disadvantaged without access to medical care. A cumulative risk assessment 

may need to take into account potential combinations of high exposure and high vulnerability, 

but few, if any, methods are available and accepted today to address the combined effects of 

exposure and vulnerability. This is an important area for further research and methods 

development. 

3.2.2. Approaches for Predicting Risk of Multiple Stressors. 

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Combination toxicology (Carpy, et al., 2000) is the study of the toxicity of mixtures. In 

such studies, one may either measure the mixture toxicity directly (whole mixture toxicity), or 

one may develop an estimate of the combined toxicity from information on the multiple 

component stressors acting in concert with each other. If evaluated using its component 

chemicals, the mixture toxicity data set should only be treated as a snapshot of a 

multidimensional dose-response relationship, because the joint toxicity and interactions can 

change with changes in exposure route, duration, relative proportions of the components, or the 

effect being tracked. The application of such a data set to a specific situation then requires careful 

matching of the test mixture composition and exposure conditions to those of the target situation. 

In whole mixture toxicity, once the mixture toxicity is known, a risk evaluation can be done on 

the mixture using the 1983 NRC risk assessment paradigm. On the other hand, component based 

mixture assessments are rarely evaluated using the strict NRC paradigm, because the exposure 

and toxicity information must be compatible, requiring some iteration to obtain toxicity 

information that is relevant to the actual exposure estimates (USEPA, 2000e). 

To address concerns over health risks from multi-chemical exposures, EPA issued 

Guidelines for Health Risk from Exposure to Chemical Mixtures in 1986 (USEPA, 1986b). 

Those Guidelines described broad concepts related to mixtures exposure and toxicity and 

included few specific procedures. In 1989, EPA published guidance for the Superfund program 

on hazardous waste that gave practical steps for conducting a mixtures risk assessment (USEPA, 

1989a). Also in 1989, EPA published the revised document on the use of Toxicity Equivalence 

Factors for characterizing health risks of the class of toxicologically similar chemicals that 

included the dibenzodioxins and dibenzofurans (USEPA, 1989b). In 1990, EPA published a 

Technical Support Document to provide more detailed information on toxicity of whole mixtures 

and on toxicologic interactions (e.g., synergism) between chemicals in a two-chemical mixture 

(USEPA, 1990a). Whole mixture assessments, toxicologic independence and similarity, and risk 

methods using toxicologic interactions are discussed at length in the recent Supplementary 

Guidance for Conducting Health Risk Assessment of Chemical Mixtures (USEPA, 2000e). 

Risk assessment on mixtures usually involves substantial uncertainty. If the mixture is 

treated as a single complex substance, these uncertainties range from inexact descriptions of 

exposure to inadequate toxicity information. When viewed as a collection of a few component 

chemicals, the uncertainties also include the generally poor understanding of the magnitude and 

nature of toxicologic interactions, especially those interactions involving three or more 

chemicals. Because of these uncertainties, the assessment of health risk from chemical mixtures 

should include a thorough discussion of all assumptions and the identification when possible of 

the major sources of uncertainty. 

3.2.2.1. Single Stressor Information. 

Assessments which evaluate the risk from a single stressor do not fall into the category of 

cumulative risk assessments by the definition given in Section 1.3, whether these single-stressor 

assessments address a single (dominant) endpoint or multiple endpoints, or whether the 

exposures are simple or complex (e.g., multi-source, multi-pathway, multi-route exposure). Some 

of them may be termed “aggregate risk assessments” by extension of the FQPA terminology. 

They can, however, provide useful information for cumulative assessments. 

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A cumulative risk assessment considers the joint impact of multiple stressors. Studies on 

individual stressors can, however, provide informative qualitative information for multi-stressor 

assessments, particularly regarding hazard identification. The collection of single stressor effects 

can indicate the variety of types of adverse effects likely to result from the stressor combination, 

though perhaps not the magnitude or extent of the effects. Factors affecting population 

susceptibility to the individual chemicals are also likely to be important with the combined 

exposure. To go further in terms of quantitative risk assessment requires consideration of the 

potential for joint toxicity. For most exposure situations, hazard and dose-response studies of all 

of the joint effects from the multiple stressors will not be available, so that conclusions will have 

to be based at least partly on the single stressor information. 

Exposure assessments for single stressors also need further consideration before they can 

be used to characterize long term cumulative exposure to all the stressors by all pathways. 

Transport and environmental transformation of a chemical can be influenced by presence of other 

chemicals. Consequently, both the exposure levels and the relative proportions of chemicals at 

future times may not correspond well to present measurements of a combination of chemicals 

unless these influences are taken into account. In addition, exposure to one stressor may 

influence the uptake of a second stressor. For example, a nonchemical stressor that increases 

ventilation rate will increase the inhalation uptake of airborne chemicals. 

Toxicologic independence. Two situations allow plausible approximations of the joint 

exposure-response relationship using only the single stressor information: toxicologic 

independence and toxicologic similarity (USEPA 2000e). In the case of toxicologic 

independence, if the toxicity modes of action are biologically independent, then as long as there 

are no pre-toxicity interactions (e.g., metabolic inhibition, influence on uptake), the single 

stressor information is sufficient to approximate the joint exposure-response relationship. When 

the effects from two or more stressors are different, the cumulative response, if toxicologically 

independent, is merely all the single stressor responses, as if the other stressors were not present. 

For example, joint but low exposure to heat (causing minor elevated heart rate) and toluene 

(causing minor hearing loss) would be expected to cause both the minor heart rate elevation and 

minor hearing loss, but to the same extent as expected for each stressor alone. If each stressor is 

below its toxicity threshold, then for stressors exhibiting toxicologic independence, there will be 

no estimated cumulative response, because the set of individual responses is then a collection of 

zeros. 

When the single stressor and cumulative toxicities are each represented by a frequency or 

probability for affected individuals, also termed a probabilistic risk, then independence means 

that “response addition,” as defined in the Agency’s Supplementary Guidance for Conducting 

Heath Risk Assessment of Chemical Mixtures (USEPA 2000e), can be applied for each adverse 

effect that the stressors have in common. When all the single stressor risks are low, the joint risk 

of a common effect under response addition can be approximated by the simple sum of the single 

stressor risks. For example, if reproductive toxicity is the general effect common to the multiple 

chemicals, the cumulative risk of reproductive effects (at low single chemical risk levels) is 

approximately the sum of the single chemical reproductive risks. Risk addition under 

independence places no constraints on the individual chemical dose-response curves. 

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Toxicologic Similarity. In the second situation, the stressors are grouped according to 

the common mode of action for each effect of concern determined in the planning and scoping 

phase (USEPA, 2002a). For all effects caused by that mode of action, “dose addition” (USEPA, 

2000e) can be applied to the stressor group. Thus far, this approach has only been used with 

combinations of toxicologically similar chemicals, not with combinations of chemicals with 

other kinds of stressors such as radiation, physical factors or health status. With similar 

chemicals, each chemical exposure is converted into the equivalent exposure level of one of the 

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An Example using Toxicological Independence: National-Scale Air Toxics Assessment 

The National-Scale Air Toxics Assessment, which is based on 1996 emissions data, provides results that are


useful in understanding the quality of air and its possible effect on human health nationwide. The assessment


includes 32 air toxics (a subset of EPA's list of 188 air toxics) and also diesel particulate matter (which is used


as a surrogate measure for diesel exhaust). Specifically, the assessment consists of 4 steps that will produce


nationwide estimates of: (1) the release of these pollutants into the air from various sources; (2) the


concentra tion of these co mpound s in the air; (3) the e xposure o f populatio ns to this air; and (4 ) the risk of bo th


cancer and non-cancer health effects resulting from this exposure.


Purpose: The results of the national-scale assessment will provide important information to help EPA continue


to develo p and imp lement vario us aspects o f the national air to xics progra m. They w ill not be used directly to


regulate sources of air toxics emissions. While regulatory priority setting will be informed by this and future


national assessments, risk-based regulations will be based on more refined and source-specific data and


assessment tools. More specifically, the assessment results will help to: identify air toxics of greatest potential


concern; characterize the relative contributions to air toxics concentrations and population exposures of different


types of air toxic s emissions so urces (e.g., ma jor, mob ile) and set prio rities for the collec tion of add itional air


toxics data a nd researc h to impro ve estimates o f air toxics conc entrations and their potential p ublic health


impacts. Important additional data collection activities will include upgraded emission inventory information,


ambient air toxics monitoring, and information on adverse effects to health and the environment; establish a


baseline for tracking trends over time in modeled ambient concentrations of air toxics; and establish a baseline


for measurin g progress toward m eeting goals fo r inhalation risk re duction from ambient air to xics. 


The Four Steps: The national-scale assessment includes the following four major steps for assessing air toxics


across the co ntiguous U nited States (a lso Puerto Rico and the Virgin Islan ds). 


(1) Compiling a 1996 national emissions inventory of air toxics emissions from outdoor sources. The types of


emissions sources in the inventory include major stationary sources (e.g., large waste incinerators and factories),


area and o ther source s (e.g.,dry clean ers, small man ufacturers, wildfire s), and both onroad and nonro ad mob ile


sources (e.g ., cars, trucks, bo ats). EPA made so me mod ifications to the 1 996 N ational To xics Inventor y to


prepare the emissions for computer modeling.


(2) Estimating 1996 ambient concentrations based on the 1996 emissions as input to an air dispersion model


(the ASP EN mo del). As pa rt of this mode ling exercise, E PA com pared estim ated amb ient concen trations to


available ambient air toxics monitoring data to evaluate model performance.


(3) Estimating 1996 population exposures based on a screening-level inhalation exposure model (HAPEM4)


and the estimated ambient concentrations (from the ASPEN model) as input to the exposure model. Estimating


exposure is a key step in determining potential health risk. People move around from one location to another,


outside to inside, etc., so exposure isn't the same as concentration at a static site. People also breathe at different


rates depending on their activity levels, so the amount of air they take in varies. For these reasons, the average


concentration of a pollutant that people breathe (i.e., exposure concentration) may be significantly higher or


lower than the concentra tion at a fixed lo cation (i.e., amb ient concen tration). 


(4) Characterizing 1996 potential public health risks due to inhalation of air toxics. This includes both cancer


and noncancer effects, using available information on air toxics health effects, current EPA risk assessment and


risk characterization guidelines, and estimated population exposures. Using the toxicological independence


formula and the default assumption of additivity of risks (USEPA 1986b, 2000e), this assessment combines


cancer risk e stimates by sum ming them fo r certain weigh t of evidence groupings, a nd also acr oss all group ings. 


For non-cancer effects, the assessment assumes dose additivity, and aggregates or sums hazard quotients for


individual air to xics that affect the sa me organ or organ syste m (USE PA 20 00e), in this ca se comb ining air


toxics that act as respiratory irritants.


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chemicals, called the index chemical. The joint toxicity or risk from the combined exposure is 

then estimated by determining the effects or risk for that equivalent exposure level using the 

dose-response information for the index chemical. For example, with the dioxins and furans (see 

text box, next page), each congener exposure level is converted into its equivalent exposure as 

the index chemical, 2,3,7,8-TCDD (USEPA, 1989b). 

Although the assumption itself is not complicated, the decision to assume toxicologic 

similarity can be complicated, depending on the level of assessment decided in the planning and 

scoping phase and described in the analysis plan. The implementation used in Superfund 

assessments (USEPA 1989a, Part D) is a rough approximation to dose addition where a Hazard 

Index is determined whenever chemicals have a common target organ. The implementation by 

the Office of Pesticide Programs in support of FQPA (USEPA, 2002a) is much more extensive 

and requires knowledge of modes of action in order to calculate the Relative Potency Factors 

(RPFs) for the effect of concern (see example in Appendix E). The Toxicity Equivalence Factor 

(TEF) method used for the dioxins is a special case of the RPF method (see Appendix E); it 

requires the most toxicologic similarity because the similarity applies to every toxic effect by any 

type of exposure (USEPA, 2000e). 

Single stressor information can also be used with dissimilar chemicals to gauge the 

potential for toxicologic interaction. For example, chemicals with long whole body half lives, or 

long tissue residence times, have the potential to be present in those tissues at the same time. 

Such overlapping exposures can result in a higher effective tissue dose, altered tissue doses 

caused by toxicokinetic interactions, or altered toxicity from interacting toxic mechanisms. When 

a careful evaluation indicates no internal dose overlap, including metabolites, the single 

exposures might be considered independently. 

3.2.2.2. Information on Stressor Interactions and Multiple Exposures. 

One important simplification that has been common in the assessment of single stressors 

has been the separate evaluation of many of the key steps. That is, simplifying assumptions have 

often been made regarding many characteristics of exposure (e.g., continuous vs. intermittent, 

variations in magnitude) . For a given exposure route, for example, only one dose-response curve 

may be used for the bounding case of setting a cleanup or action level of exposure, and also the 

predictive case of estimating existing risk. These simplifying assumptions allow the doseresponse step to be performed in isolation from the exposure assessment step, with the two steps 

executed in either order. For health-protective action levels, one may use bounds, such as the 

upper bounds on toxic potency and exposure and lower bounds on the resulting acceptable 

exposure level. Such bounds may be much easier to calculate, but may be more difficult to 

interpret in terms of the uncertainties, likelihood and closeness to the best or central estimate. 

The incorporation of multiple chemicals, other stressors, and multiple exposure 

conditions obviously complicates the assessment and the use of simplifying assumptions. In 

cumulative assessments, performing the exposure and dose-response steps of the risk assessment 

paradigm separately is an approximation that obviously invokes a simplifying assumption. If the 

dose response data do not represent the same conditions as the exposure being assessed, an 

extrapolation has to be made, which introduces additional uncertainty that must be clearly stated. 

Joint or cumulative toxicity depends on the total dose or exposure, relative exposure levels, 

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An Example using Toxicologic Similarity: The Dioxin Reassessment 

Scientists from the Environ mental Pro tection Age ncy (EPA ), other Fed eral agencie s and the gen eral scientific 

commu nity have bee n involved in a compr ehensive rea ssessment of d ioxin expo sure and hu man health e ffects 

since 199 1 (USE PA, 20 02c). T he final dioxin re assessment w ill consist of three p arts. Part 1: Estimating 

Exposure to Dioxin-Like Compounds will include four volumes that focus on sources, levels of dioxin-like 

compo unds in enviro nmental me dia, and hum an expos ures. Part 2: Human Health Assessment Document for 

2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds will consist of two volumes that include 

information on critical hum an health end points, mod e of action, p harmaco kinetics, dose -response, a nd TE Fs. 

Part 3: Integrated Summary and Risk Characterization for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and 

Related Compounds will be a stand-alone document. In this summary and characterization, key findings 

pertinent to understanding the potential hazards and risks of dioxins are described and integrated, including a 

discussion o f all important as sumptions a nd uncerta inties. 

2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin) is highly toxic to many animal species producing a variety of 

cancer and noncancer effects. Other 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins and dibenzo furans, 

and coplanar polychlorinated biphenyls (PCBs), exhibit similar effects albeit at different doses and with different 

degrees o f confidence in the databa se. The sim ilarities in toxicity betw een specie s and acro ss different diox in 

congene rs stem from a commo n mode o f action via initial bind ing to the aryl hyd rocarbo n (Ah) rece ptor. This 

commo n mode o f action is supp orted by co nsistency in effects ev ident from d ata from mu ltiple congen ers. This 

has led to an international sc ientific consensu s that it is prudent sc ience polic y to use the con cept of toxic 

equivalency factors (TEFs) to sum the contributions of individual PCDD, PCD F, and coplanar PCB congeners 

with dioxin-like activity (van den Berg, et al., 1998). The data supportive of dioxin-like toxicity, both cancer and 

noncancer, are strongest for those congeners that are the major contributors to the risk to human populations. In 

addressing receptor-m ediated re sponses re sulting from co mplex mix tures of diox in-like congen ers, this 

assessment has provided a basis for the use of integrated measures of dose, such as average body burden, as more 

appropriate default metrics than daily intake. The Agency recognizes, however, that the final choice of an 

appropriate dose metric may depend on the endpoint under evaluation. 

In this study, 2,3,7,8-tetrachlorodibenzo-p-dioxin was chosen as the index chemical, and the other dibenzo-pdioxins and dibenzofurans, and coplanar polychlorinated biphenyl doses were adjusted to 2,3,7,8-TCDD 

equivalent toxicities so the doses could be added. 

and the many characteristics of exposure (e.g., duration, continuous vs. intermittent presence, 

route, co-occurrence with other chemicals), and in many cases the complexities introduced by 

multiple stressors will not allow use of some of the common simplifying assumptions of singlestressor assessments. For example, toxicologic interactions have been shown to change using the 

same doses but with a reversal of the sequence of exposure (i.e., chemical B then A instead of A 

then B), so that the exposure and dose-response steps must be compatible and performed 

together. 

Nonchemical stressors can also cause toxicologic interactions. Biological stressors, like 

their chemical counterparts, can interact with chemical exposures and change the overall risk in 

non-additive ways. Ototoxic chemicals, such as toluene, can damage the auditory system and 

have been shown to potentiate the effects of a physical stressor, noise, on hearing loss (Morata, et 

al., 1997; Morata, 2000). 

Toxicity and interaction data for the exposure-response relationship for the mixture of 

interest that covers the full range of exposures is usually impossible because of limits on cost and 

other resources. More feasible approaches to cumulative risk characterization, beyond that with 

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various simplifying assumptions, then require close matching of the exposure and dose-response 

steps to minimize the data requirements. In many cases, screening level ranking may be the only 

practical assessment. In some cases, there will be sufficient information for some quantitative 

evaluation of cumulative health risks that reflect both the complex exposures and toxicologic 

interactions. The issues for these cases are now presented along with their main research 

implications, starting with the simplest case where only chemical interactions are considered. 

“Joint chemical toxicity” means the outcome of exposure to multiple chemicals that 

includes the single chemical effects along with any toxicologic interactions. Chemical 

interactions can be divided into two major categories: those resulting from toxicokinetic and 

those resulting from toxicodynamic modes of action (USEPA, 2000e). Toxicokinetic modes of 

interaction involve alterations in metabolism or disposition of the toxic chemicals, for example, 

by the induction or inhibition of enzymes involved in xenobiotic activation and detoxification. 

Toxicodynamic modes of interaction include those processes that affect a tissue’s response or 

susceptibility to toxic injury. A simplifying observation is that most interactions seem to involve 

pharmacokinetics. Unfortunately, most studies of toxicologic interaction to date have only 

involved two chemicals, and few have quantified the magnitude of the interaction or its 

dependence on exposure conditions. 

Toxicologic interactions are commonly described with terms such as synergism and 

antagonism. These terms are only marginally useful, in part because the underlying toxicological 

concepts are only defined for two-chemical mixtures, while most environmental and 

occupational exposures are to mixtures of many more chemicals. Further, the mathematical 

characterizations of synergism and antagonism are inextricably linked to the prevailing definition 

of "no interaction," instead of some intrinsic toxicological property (Hertzberg and MacDonell, 

2002). The U.S. EPA has selected “dose addition” as the primary no-interaction definition for 

mixture risk assessment, so that synergism would represent observed toxic effects that exceed 

those predicted from dose addition (USEPA, 2000e). The EPA mixture risk guidance also 

describes a modified Hazard Index that incorporates evidence of pairwise toxicologic interactions 

but notes that the pairwise evidence may be specific to the exposure conditions of the study. The 

guidance further encourages development of full biomathematical models for the joint toxicity, 

such as those based on pharmacokinetics, so that qualitative interaction labels such as synergism 

are replaced by quantitative estimates of mixture response that directly reflect the actual 

environmental exposure levels. 

3.2.2.3. Decision Indices. 

The complexities with cumulative risk assessment include the frequent need to combine 

pieces of information that differ widely from each other. Exposure data for some stressors may 

be only as time-weighted averages, while others reflect daily human activity patterns. Toxicity 

data for some chemicals may allow estimation of probabilistic risk for one endpoint, while only 

providing qualitative descriptions of other endpoints. It is possible to develop the risk 

characterization using the original information in a high dimensional matrix, but such a summary 

will be difficult to evaluate and communicate. One approach to diverse multivariate data used 

successfully for weather forecasting is the decision index, with examples such as the smog index, 

the pollen count, and the mold index commonly used to assist in public and personal decisions 

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about environmental exposure. A similar approach can be taken for cumulative risk assessment 

(Hertzberg, 2000). 

The advantage of a decision index is 

the simplicity in converting highly 

multivariate technical information into a 

single number. The most common example 

used for cumulative health risk is the Hazard 

Index (HI) for mixture risk (see box at right). 

Although specific for a single affected target 

organ, each HI reflects multiple studies of 

multiple chemicals, often involving multiple 

test animal species and test exposures, and 

highly varied measures of toxicity. 

The main disadvantage of a simple 

index is that the uncertainties in its 

calculation are largely hidden. Another key 

disadvantage is in quantifying what are often 

Example Decision Index: The Hazard Index 

The Hazard Index for oral exposure is implemented by 

Superfund assessors by the formula: 

HI = sum[ HQj ] = sum[ Ej/RfDj ] 

where Ej

 and RfDj

 are the daily exposure and Reference 

Dose of chemical j. 

The RfD is itself a kind of decision index in that it reflects 

a dose that is selected to be sufficiently low that any toxic 

effects are judged highly unlikely. All available doseresponse data, on all effects, are considered in determining 

each RfD. Uncertainties in the RfD will differ across the 

chemicals, making the uncertainty in HI difficult to 

characterize. 

scientific judgments. For example, the Hazard Index implemented under Superfund (USEPA, 

1989a) is a number whose decision threshold is usually given as 1.0, so that when the HI is 

greater than 1, additional action is indicated. The actual value of HI is not that informative; HI=6 

is not necessarily twice as bad as HI=3. 

One alternative for addressing multiple effects is to recast these qualitative judgments in 

terms of severity categories or levels of concern, and then use statistical methods such as 

categorical regression that use only the ordering of the severity scores, but not their actual values. 

The result is not a risk of a particular toxic effect, but rather a risk of exceeding a certain 

minimum toxic severity level, or level of minimal concern (Hertzberg, 1989; Guth, et al., 1993). 

In the best situations, such as the EPA interaction-based Hazard Index (USEPA, 2000e), the 

decision index formula is modular so that component pieces can be evaluated separately for 

accuracy, and so that improvements in one area can be easily incorporated to give an improved 

index. 

Another example of a decision index with more overt display of its diverse parts is the 

Hazard Ranking System (HRS), a formula developed for characterizing the relative hazards of a 

particular waste site. These hazards were highly diverse, including corrosivity, explosivity, 

toxicity and soil conditions. As with the HI, different uncertainties in the components make the 

uncertainty of the HRS index difficult to describe. Instead of merely presenting the index as a 

number, a high dimensional graphical presentation could be used such as the star plots of 

multivariate data (Chambers, et al., 1983; Hertzberg, 2000), where each arm of the star represents 

one of the sub-indices. While this approach shows the relative contribution of each factor, it 

again hides the uncertainties of the factors as well as of the HRS index itself. 

Hybrid methods also have been used for complex risk assessments that combine 

judgment with numerical descriptions of risk or dose-response. The EPA interaction-based 

Hazard Index (USEPA, 2000e) and the mixture risk approaches of the Agency for Toxic 

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Substances and Disease Registry (Hansen, et al., 1998) both include a judgmental weight of 

evidence (WOE) score to reflect the strength of evidence for toxicologic interactions and 

relevance to human health risk. The ATSDR WOE is used in communicating risks and 

intervention options, while the EPA WOE is used to calculate a modified Hazard Index. A 

slightly different approach is the Integral Search System data base program for combinations of 

carcinogens (Woo et al., 1994) by which available studies on pairwise interactions of 

carcinogenicity are used to modify the risk range of the combination from that predicted by 

response addition (USEPA, 2000e). In all these cases, scientific judgment is used to alter the risk 

description or quantitative estimate, but only in terms of an approximate risk interval or a 

decision threshold. 

3.2.2.4. Probabilistic Approaches. 

The recent report by Bogen (2001) illustrates an alternative probabilistic approach to 

noncancer endpoints, in which methods used for integrated quantitative treatment of uncertainty 

and variability are made consistent with those used for probabilistic assessment of cancer risk. 

This report addresses many issues concerning the implementation of probabilistic methods for 

noncancer endpoints, and cites a number of related references (e.g., Lewis, 1993; Dourson et al., 

1994; Slob and Pieters, 1998). 

Any approach to cumulative risk assessment needs to carefully define the set of relevant 

endpoints. Precisely how this is done has important logical and practical implications for how 

the cumulative risk may be calculated and interpreted. For example, the risk of inducing a given 

endpoint may differ among different people in a population at risk for some endpoints, (e.g., 

cancer conditional on all carcinogen exposures), but may be unaffected by interindividual 

variability (e.g., in exposure or susceptibility) for other endpoints (such as ecological or aesthetic 

effects). Defining the latter risks in terms of individual risk per se will thus complicate 

calculating cumulative risk if a probabilistic approach to cumulative risk assessment is used, and 

perhaps if other approaches are used as well. 

In contrast, the probabilistic approach to cumulative risk assessment may be facilitated by 

defining the risk of a given endpoint in terms of population risk, i.e., in terms of the predicted 

number of cases of that endpoint. Alternatively (or additionally), similar simplification can be 

achieved for all heterogeneous endpoints by defining the risk of that endpoint only with respect 

to those persons in the population at risk who are reasonably maximally exposed (e.g., 

individuals adjacent to a proposed source), or to those persons who will incur the greatest 

increased risk (e.g., children or other members of a sensitive subpopulation who might be located 

adjacent to a proposed source). 

3.3. Areas of Complexity and Current Research 

One reason for the somewhat limited availability of cumulative risk assessments may be 

the accompanying complexity that arises in various aspects of the assessment. Some of this is 

discussed in the previous section, along with currently available methods specific to human 

health risk assessment. In this section, some areas where research is ongoing are discussed, and 

some existing methods for quantitatively assessing multiple types of risk or hazard using a single 

metric are described. 

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3.3.1. Interactions Between Stressors and Other Factors. 

In identifying and characterizing susceptible subpopulations, it may be important to 

consider a variety of factors such as current physical and mental health status and past exposure 

histories, which may exacerbate the effects of the stressors of interest. Economic considerations 

such as economic status, community property values, source of income, level of income, and 

standard of living may also affect susceptibility and exposure of subpopulations to certain other 

stressors. Risks associated with chemical or biological stressors may be significantly affected by 

“vulnerability factors” such as lack of health care or genetic predisposition to some diseases and 

effects. Community traditions and beliefs may affect activity patterns and behaviors and therefore 

affect exposure to stressors as well as the risk management options deemed acceptable. 

Depending on the scope of the assessment and the stressors included, “lifestyle factors” such as 

smoking habits, nutritional habits and others may be important to susceptibility. 

In what could be characterized as an exploration of how somewhat abstract factors may 

affect susceptibility, the Agency for Toxic Substances and Disease Registry (ATSDR) held an 

expert panel workshop in 1995 on the subject of psychological responses to hazardous substances 

(ATSDR, 1995). In this report, the panel noted that there is “a significant lack of information” 

about how often communities near hazardous waste sites or spills suffer chronic stress reactions, 

but that psychological stress causes both psychological changes that can be measured by selfreports and objective tests, as well as physical changes such as increased blood pressure, heart 

rate, and biochemical parameters such as changes in stress hormones. Assessing the levels of 

stress, and their potential contribution to risk, is difficult for a variety of reasons. The report notes 

that “unlike the damage and injuries caused by a natural disaster, many toxic substances are 

invisible to the senses.... In the face of no external cues and uncertain circumstances, each person 

affected by a hazardous exposure develops their own beliefs about the nature of the resultant 

harm. These beliefs are based on the facts available to them, pre-existing opinions, cultural 

factors, sensory cues, and the beliefs of leaders and others in the community. . . . Unlike a natural 

disaster, which hits and has a low point after which recovery can begin, the response to a 

hazardous waste site can take 12 to 20 years.” 

Although the ATSDR report indicates that stress related to hazardous chemicals in the 

community can show measurable physical effects, they stopped short of saying that long-term 

health effects from this stress can be converted to risk estimates at this time. One of the questions 

the panel was asked to address was, “Given what is known regarding the psychology of stress, 

are there interactions between chronic stress and exposure to neurotoxicants that could shift the 

dose-response curve for neurotoxins?” The panel concluded: 

“A methodology does not exist that would allow for discrimination between stress or 

neurotoxicant-mediated effects in community-based studies. . . . Experimental animal 

data exist to suggest that stress levels can modulate a toxic response; however, the 

question of specificity remains. Given that stress can induce or unmask a latent effect of 

a toxicant, there is the possibility that chronic stress could alter basal levels of 

neurofunctioning and shift the threshold for neurotoxicity. Indeed, one may find a shift in 

the dose response to a neurotoxicant; however, a specific effect of the neurotoxicant 

needs to be examined in greater detail than the generalized non-specific endpoints. 

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Detecting such a shift would require the knowledge of toxicant-specific biological 

mechanisms of actions, which most often are not known.” (ATSDR, 1995, page 30) 

The ATSDR report made many suggestions for research to fill data gaps in this area, and 

scientists may make significant progress in this area in the coming years. 

Another group of factors which may influence the risk to health or the environment, 

whose evaluation may require a different approach from the traditional NRC risk paradigm, is the 

group of “quality-of-life” issues. Although a cumulative human health or ecological health risk 

assessment is not a cumulative impact analysis such as is conducted under NEPA, changes in 

quality-of-life factors may affect the vulnerability of a population to health or ecological risks, 

and consequently may be part of the considerations in a cumulative risk assessment. Since few, if 

any, established and accepted relationships are currently available quantitatively linking qualityof-life factors and health or ecological risk, this is an area in which further research may prove 

valuable. 

To evaluate the effects on human or ecological health from these types of stressors, a 

more deliberative approach (in the analytical-deliberative process) is needed than is used in, say, 

cancer risk analysis. EPA’s Guidebook to Comparing Risks and Setting Environmental Priorities 

(USEPA, 1993b) suggests a six-step process that may help characterize quality-of-life factors, 

some of which may be relevant to the assessment (e.g., in considering population susceptibility). 

An example of a set of quality-of-life criteria, and their descriptions, developed by the State of 

Vermont’s Agency of Natural Resources (State of Vermont, 1991) is provided in Appendix F. 

Quality-of-life issues can encompass much more than the criteria mentioned in Appendix 

F as an example. Some human health or ecological cumulative risk assessments may consider 

quality-of-life factors as having a role in susceptibility to the stressors being assessed. 

3.3.2. The Promise of Biomarkers and Biomonitoring. 

There are a variety of measures that are inherently cumulative. These include biomarkers 

(they give the full effect or full exposure, regardless of source) and measures of the incidence and 

prevalence of disease in a community. The latter give an indication of the total effect of multiple 

sources of exposure. In light of our understanding of the multifactorial basis of disease, a public 

health approach that says “regardless of the cause, a community has x level of disease” can be 

informative. Such statistics can be compared across geographical areas that have different 

sources or different groups that have different levels of vulnerability. The approach is based 

strongly in the field of epidemiology. Indeed, the most often heard critique of epidemiology – 

that it is the prevalence or incidence of disease documented as a function of the combined effect 

of many exposures (over time and/or space), is exactly what makes it so well suited for 

cumulative risk assessment. It is likely that epidemiological concepts will figure prominently in 

cumulative risk assessment, both in identifying the underlying vulnerability of a population and 

by generating hypotheses regarding the determination of relative contributions of multiple 

stressors. 

Sources of data include cross sectional analyses that determine prevalence levels, as well 

as basic surveillance techniques. With respect to the latter, The Pew Environmental Health 

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Commission (http://pewenvirohealth.jhsph.edu/html/home/home.html then click on “reports”) 

has recently completed a series of reports that document the extent of national and state level 

resources for chronic disease surveillance. Reports focus on the type of surveillance systems 

needed, as well as the status of registries for birth defects and asthma. Health Track 

(http://health-track.org/ and http://healthyamericans.org/) is the outgrowth of that research, and is 

devoted to tracking and monitoring of chronic disease that would help communities begin to 

identify patterns of health problems. 

Biomarkers are inherently cumulative risk measures. Using biological measurements – 

biomarkers – to determine prior exposures (biomarkers of exposure) or the current health status 

of individuals (biomarkers of effect) holds some promise for cumulative risk assessments of the 

future. Use of biomarkers for a group of chemicals or stressors which act upon individuals in the 

same way can give the assessor a picture of where an individual currently falls on the continuum 

from exposure to effects, making it much easier to predict risks if additional exposure occurs. 

A few biomarkers (or even a single one) can possibly represent exposure to a suite of 

chemicals. Although this reduces the analytical burden and simplifies the process of estimating 

cumulative risk, the approach loses some of the advantages of single-chemical assessment 

(especially being able to quickly discern the importance of different pathways and routes of 

exposure contributing to the risk). 

Biomarkers may be the approach of choice in the future, but the state-of-the-science is not 

developed enough to make this practicable today in an assessment with large numbers of diverse 

stressors (although it may be possible to do this for more simple cases). Currently, biomarker 

development is not at the stage where they can be widely applied. For example, information on 

the cumulative risks in a local population of a group of chemicals that are toxic to the liver might 

be provided by selective liver function tests, but causal inferences would have to take account of 

many other factors that may affect liver function. Likewise, body burden data for chlorinated 

dioxins and related compounds may show that exposure has occurred, but assumptions would 

need to be made as to the pathways, route, and timing of exposures, as well as scenarios 

developed for future exposures if risks are to be estimated. 

One of the benefits of this approach, the development of data which show the actual 

current exposure and risk status of a population, is also its major impediment: it can require 

extensive (or for humans, possibly invasive) monitoring. This can be not only costly, but 

difficult to obtain. This approach uses primarily measurement methods, and also can develop 

statements of probability of adverse effects of additional incremental exposures. This approach 

holds great promise for simplification of a cumulative risk assessment, but few methods exist at 

this time for applying this approach in a cumulative assessment. The main drawback of the 

biomarker approach, at least for a regulatory agency like EPA, is that a decision to act to reduce 

risk is often dependent on separation of contributions from exposure pathways so that effective 

policies can be determined. 

3.3.3. A Single Metric for Multiple Types of Hazard. 

The most complex cumulative risk assessments will evaluate both multiple exposures 

(potentially, multiple sources, stressors, pathways and durations) and multiple effects. Ideally 

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this evaluation would provide projections regarding the potential for a particular complex 

exposure to cause particular effects to different physiological systems, and also provide an 

integration of these projections into a qualitative characterization of overall potential impact to 

human health. Some applications have attempted this via approaches which range from treating 

the assessment as a number of multi-stressor, single effect assessments, where the risks from the 

various effects are combined or characterized at the final step, to those that are more integrated 

throughout. 

For example, cumulative ecological risk assessments such as those that have been 

conducted in the Columbia River Basin and the Chesapeake Bay focused on a number of 

observed adverse conditions, then determined, among all of the possible stressors, which 

particular combination was most influential in creating the observed adverse conditions. 

Stressors such as overharvesting of natural resources, modification of natural hydrology, land use 

change, point-source and non-point-source pollution, including toxic chemicals, and presence of 

exotic species are analyzed, with the goal of the assessment being to design effective restoration 

strategies to eliminate or ameliorate the conditions (Barnthouse, et al., 2000). 

If it is considered desirable to the assessment, an important cumulative risk assessment 

activity may be determining how (if at all possible) to combine risks from different effects – or 

the even more problematic disparate measures of risk – and present them in an integrated 

manner. Depending on the purpose and risk management objectives (see section 2.1.1), some 

cumulative risk assessments may employ some sort of single, common metric to describe overall 

risk. 

One, but certainly not the only, approach to simplifying this problem is to collapse this 

“n-dimensional matrix” of hazards and risks into a few or even a single measure (Murray, 1994). 

However, this requires converting the various measures of risk to a common metric or otherwise 

translating them into a common scale or index. Some methods for combining disparate measures 

of risk are briefly described below. 

3.3.3.1. Creating a Common Metric. 

As discussed earlier in this chapter, there are several different theoretical approaches to 

cumulative risk assessment. Some of these require synthesizing a risk estimate (or risk 

indication) by “adding up” risks for different parts of the risk picture. Actual mathematical 

addition, of course, requires a “common denominator,” or a common metric. Frequently used 

common metrics are risk, money, time, and effort. Finding a common metric for dissimilar risks 

(cancer vs. non-cancer, human vs. ecological, etc.) is not strictly an analytic process, since some 

judgments must be made as to how to link two or more separate scales of risks. These judgments 

often involve subjective values, and because of this, it is a deliberative process. 

As an example of combining different effects into a common metric and the consequent 

judgment needed to achieve a common metric, the EPA Office of Pollution Prevention and 

Toxics in 1999 released its CD-ROM called “Risk-Screening Environmental Indicators Model, 

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Version 1.0" (USEPA, 1999i)11. In this model, emissions for both carcinogens and noncarcinogens are weighted by a toxicity factor so that they can be combined in a risk-based 

screening “score” for a particular geographic area. The scale for this weight for carcinogens is 

related to the unit risk factor, and the weight for the non-carcinogens is based on the RfD. 

According to the authors, it is possible to relate these two scales by making a judgment as to how 

they relate. They note that in their case, “when combining cancer and noncancer endpoints, it is 

assumed that exposure at the RfD is equivalent to a 2.5 x 10-4 cancer risk” (Bouwes and Hassur, 

1998; USEPA, 1998h). 

Obviously, as Bouwes and Hassur acknowledge, equating an HQ value of 1.0 (i.e., 

exposure is at the RfD) with a cancer risk of 2.5 x 10-4 is a judgment that is outside the strictly 

analytic part of an assessment; the equating of the two points in the respective scales represents a 

value judgment and as such can be debated. Therefore, this particular part of the assessment is 

deliberative in nature. In most cases, construction of a single scale for different types of 

endpoints will involve comparative risk, a field where different types of risks or endpoints are 

ranked, compared, or converted to a scale based on the judgments and values of the persons 

doing the assessments (USEPA, 1993b, 1998f, 1999j). 

There have been some attempts to allow for transparent and quantitative incorporation of 

values into a common metric. One example flows from the suggestion that “time is the unit of 

measure for the burden of disease”; whether the disease results in disability or premature 

mortality (Murray, 1994). Based on this premise, economic analyses of the costs and benefits of 

disease intervention strategies have used Quality Adjusted Life Years (QALYs) and Disability 

Adjusted Life Years (DALYs) as the metrics for the adverse effects of disease. These metrics are 

intended to reflect the years of life spent in disease states (considering the variation in severity of 

effects) and the years of life lost due to premature mortality resulting from disease as a surrogate 

measure for risk from a variety of different types of effect. Even if this conversion of effects into 

QALYs or DALYs were successful, for diseases that result in periods of morbidity and disability 

(but not death), weighting factors (based on judgments) are used to equate time spent in various 

disease states with years lost to mortality. In this way, dissimilar adverse effects can be 

combined to provide a single measure of disease burden. However, it should be noted that 

aggregation of effects in this manner obscures the meaning of the final measure. QALYs and 

DALYs do not represent an actual shortening of the lifespan but are indicators of the overall 

degradation of well-being that results from various disease states. Therefore, QALYs and 

DALYs may be best suited for ranking and comparative analyses. 

Experience with applying such measures as QALYs and DALYs to environmental risk 

problems is extremely limited. Some very early methods development work has been initiated 

which explores the use of QALYs for combining microbial and disinfection by-product risks 

(USEPA, 1998f). However, some concerns have been raised about the adequacy of such 

measures, especially when integrated with economic information for decision making USEPA, 

2000g). Further methods development work is needed to improve the utility of QALYs and 

DALYs for environmental risk assessments; especially with respect to the incorporation of 

uncertainty (USEPA, 1999j). 

11 As of this writing, EPA has RSEI version 2.0 in beta test. Details are at www.epa.gov/oppt/env_ind/beta_test.htm. 

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Categorical regression may provide another tool for combining disparate effects using a 

common metric. In this approach, adverse effects are assigned to severity categories (again, a 

judgment making the process deliberative) and the ordered categories are regressed against 

increasing dose (Teuschler et al., 1999). The use of categorical regression as a tool for 

combining disparate effects has definite limits on interpretation of the results. Since the toxicities 

are only represented by categories, and judgment is used to place the observed response into a 

severity category, the results are rather coarse. But because the analysis is almost totally 

empirical, that is, no low-dose extrapolation is required, the results can still be quite useful. 

EPA has also used decision indices (see section 3.2.2.3) based on dissimilar measures, 

and while they do not produce risk estimates, the indices can still prove useful. The approach 

involves developing a composite score – or index – from measures of various risk dimensions . 

Various environmental risk indices have been developed and applied to ranking and comparative 

analyses. Often, these indices employ surrogate measures for risk rather than using actual 

calculations of the probability of adverse effects. One such index is the Hazard Ranking System 

(HRS) [47 Fed. Reg. 31219, dated July 16, 1982, and amended 55 Fed. Reg. 51532, dated 

December 14, 1990], used to place uncontrolled waste sites on the National Priorities List (NPL) 

for Superfund. This index is based on the likelihood of off-site movement of waste, the toxicity 

of the waste, and the people and sensitive environments that may be affected. It also uses 

corrosivity, toxicity, fire hazard and other factors, all scored and combined into one numerical 

indicator of overall hazard potential. Such an approach for a composite index has been suggested 

for communication of cumulative risk (Hertzberg, 2000). 

Fischhoff et al. (1984) provided an example of this approach as applied to the evaluation 

of energy technologies. In this case, disparate risks are assigned a score from a fixed scale (e.g., 

from 0, representing no risk, to 100, representing the worst risk for that dimension). The scores 

are then weighted to reflect value judgments about the importance of the various risk dimensions 

and the composite score is calculated by summing the individual weighted scores. Again, the 

aggregation of dissimilar adverse effects obscures the meaning of the final score making it more 

appropriate for ranking and comparative analyses. 

Recently, EPA has been working on several index-based approaches to dealing with 

cumulative risk issues. EPA Region III and the Office of Research and Development have been 

jointly working to develop a Potential Risk Indexing System (USEPA, 1993c, 1995d, 1997c). 

This index also uses a vulnerability index, and gauges the overall well-being of a locale and 

various subpopulations. Again, the volume and toxicity of released stressors serve as surrogate 

measures of risk in developing this index. 

Combining diverse effects and risk using either common metrics or indices each have 

pros and cons. A weakness of the index approach is that information is “lost,” and the meaning 

of the final score can be obscured, by aggregating dissimilar information. One strength, however, 

is common to both approaches. Both techniques have the ability to incorporate social values in 

an explicit and quantitative manner in the risk assessment. For example, in the derivation of 

DALYs, weights can be used to reflect the different social roles people play as they age (Murray, 

1994). In the composite scores developed by Fischhoff (1984), public concern was incorporated 

as an adverse effect. This is an important feature for methods that will be applied to cumulative 

risk assessments, especially for communities. Given that cumulative assessments have a 

community/population focus, the ability to incorporate social values in an overall assessment of 

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well-being will be critical. 

3.3.3.2. General Issues with a Single Metric. 

As described above, each approach to portraying the results of a cumulative risk 

assessment has desirable and undesirable features. While common metrics and indices can 

incorporate social values in an explicit and quantitative manner, the meaning of the final measure 

can be obscured by aggregation of dissimilar effects. The abstract meaning of the final measure 

could lead to difficulties when communicating the results of the cumulative risk assessment to 

the public. Graphical and mapping techniques do not necessarily overcome such problems with 

communication. While these techniques may avoid some of the problems associated with the 

mathematical aggregation of dissimilar effects, it can be difficult to accurately describe the 

information that a graphic is intended to convey. 

Because we have relatively little experience in combining different types of risk, a key 

issue is the need for methods development in this area. The approaches described above indicate 

a beginning. Additional exploratory work is needed, however, to further develop existing 

methods and to find additional methods that are flexible, can incorporate social values, are easy 

to communicate, and provide an integrated portrayal of the overall well-being of a community 

and its various subpopulations. 

3.3.4. Qualitative approaches. 

There will be cases where cumulative risk cannot be quantified in any meaningful or 

reliable way. Qualitative approaches can be valuable for cumulative risk assessment and, in the 

near-term, may be the only practical way to address many of the complexities involved. 

Qualitative approaches may be used as a way to overcome the complexity and data deficiencies 

that hinder quantitative approaches. In many assessments, risk may not be a quantifiable 

variable. 

For these cases, there may be qualitative approaches that provide some insight. Broad 

indicators related to exposure in complex ways (e.g., production volumes, emissions inventories, 

environmental concentrations, etc.) and indicators of toxicity can be communicated using 

geographic information systems. Displaying complex multi-dimensional matrices in a map can 

help visualize locations of areas with multiple stressors. Furthermore, geographically based 

measures of hazard are potentially useful cumulative measures – although they do not provide 

information on the risks, the locations of hazards can be used as an indicator of cumulative 

exposures, thus risks from all of the potential chemicals associated with that site. The 

environmental justice literature has used this approach. 

Quantitative results might eventually be reduced to a more qualitative scale (High, 

Medium or Low), or the qualitative results could provide “comments” tacked to the quantitative 

results. The assessment might simply raise “red flags” associated with specific issues (e.g. 

density of emitters in a community; presence of minority populations; special exposure 

pathways; etc); a high number of such flags would indicate unacceptable cumulative risk, even if 

this isn’t quantified. This approach has been used in the European Union, and their experience 

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[ref needed] in using qualitative methods for permitting suggests that “qualitative” is not 

“irrational”. Other relevant tools include expert judgment techniques, focus groups, opinion 

surveys, citizen juries, alternative dispute resolution, and others. 

Figure 4.1. The Interpretation and Risk Characterization Phase. 

4. THE RISK CHARACTERIZATION PHASE 

The last phase of cumulative risk assessment, Risk Characterization, integrates and 

interprets the results of the Analysis phase and addresses the problem(s) formulated in the 

Planning and Scoping phase. It should describe the qualitative and/or quantitative risk 

assessment results; list the important assumptions, limitations and uncertainties associated with 

those results; and discuss the ultimate use of the analytic-deliberative outcomes. Given the 

complexity of cumulative risk issues and the need for clarity and transparency in risk 

characterization, such 'full disclosure' presents a major communication challenge. 

As in the Analysis Phase, there is a substantial analytical component of the Interpretation 

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Phase, but there is also a considerable need for deliberation. At a minimum, stakeholders in this 

phase should (1) understand the outcome of the cumulative risk assessment; (2) ask questions 

about how best to frame the interpretation; (3) confirm that the cumulative risk assessment met 

the goals set in the Problem Formulation, or if not, why not. As in the previous phase, the 

stakeholders’ role is only limited by what is proposed and agreed upon in the individual case 

being assessed. 

Risk estimation in a cumulative risk assessment will involve some combination of risks, 

either risks from various stressors causing similar effects, or risks from various stressors causing 

different types of effects. The stressors may be similar or widely different. Combinations of many 

types of stressors with different endpoints in a single assessment will quickly cause the risk 

estimation step to become very complex and difficult. 

Because of its potential complexity, and because in some cases cumulative risk 

assessments will be dealing with “uncharted territory” methodologically, it is very important that 

the planning, conduct, analysis, and characterization of a cumulative risk assessment be 

transparent. As stated by OMB (OMB, 

2002), the "benefit of transparency is that 

the public will be able to assess how much 

an agency's analytic result hinges on the 

specific analytic choices made by the 

agency." The process, methodology, data, 

assumptions, and selection among alternate 

interpretations must be very carefully 

documented and very clearly stated. This is 

noted again in the next section. 

4.1. Risk Description 

The ultimate product in the risk 

assessment process is the risk 

characterization, in which the information 

from all the steps is integrated and an 

overall conclusion about risk is synthesized 

that is complete, informative, and useful for 

decision-makers. The nature of the risk 

characterization will depend on the 

information available, the regulatory 

application of the risk information, and the 

resources (including time) available. It is 

important to identify and discuss all major 

issues associated with determining the 

nature and extent of the risk. Further, the 

EPA Administrator’s March 1995 Policy for 

Risk Characterization (U.S. EPA, 1995a) 

specifies that a risk characterization “be 

prepared in a manner that is clear, 

Risk Characterization Guiding Principles 

Regarding information content and uncertainty aspects: 

�� The risk characterization integrates the information from the 

exposure and dose-response assessments, using a combina tion 

of qualitative information, quantitative information, and 

information regarding uncertainties. 

�� The risk characterization includes a discussion of uncertainty 

and variability. 

�� Well-balanced risk characterizations present risk conclusions 

and information regarding the strengths and limitations of the 

assessment for other risk assessors, EPA decision-makers, and 

the public. 

Regarding risk descriptors: 

�� Information about the distribution of individual exposures is 

important to communicating the results of a risk assessment. 

�� Information abou t population exposure leads to another 

important way to describe risk. 

�� Information about the distribution of exposure an d risk for 

different subgroups of the population are important components 

of a risk assessment. 

�� Situation-specific information adds perspective on possible 

future events or regulatory options. 

�� An evaluation of the uncertainty in the risk descriptors is an 

important component of the uncertainty discussion in the 

assessment. 

Source: USEPA, 1995b. 

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transparent, reasonable, and consistent with other risk characterizations of similar scope prepared 

across programs in the Agency.” In short, estimates of health risk are to be presented in the 

context of uncertainties and limitations in the data and methodology. 

The 1995 Guidance for Risk Characterization (USEPA, 1995b) lists several guiding 

principles for defining risk characterization in the context of risk assessment (see text box), both 

with respect to information content and uncertainty aspects and with respect to descriptions of 

risk. EPA has recently published a handbook on risk characterization (USEPA, 2000c). 

Risk assessments are intended to address or provide descriptions of risk to one or more of 

the following: (1) individuals exposed at average levels and those in the high-end portions of 

the risk distribution; (2) the exposed population as a whole; and (3) important subgroups of the 

population such as highly susceptible groups or individuals (e.g., children), if known. Risk 

predictions for sensitive subpopulations are a subset of population risks. Sensitive 

subpopulations consist of a specific set of individuals who are particularly susceptible to adverse 

health effects because of physiological (e.g., age, gender, pre-existing conditions), 

socioeconomic (e.g., nutrition), or demographic variables, or significantly greater levels of 

exposure (USEPA, 1992a). Subpopulations can be defined using age, race, gender, and other 

factors. If enough information is available, a quantitative risk estimate for a subpopulation can 

be developed. If not, then any qualitative information about subpopulations gathered during 

hazard identification should be summarized as part of the risk characterization. 

The 1996 book Understanding Risk (NRC, 1996) devoted a great deal of discussion to risk 

characterization. Risk characterization is most efficiently conducted by early and continued 

attention to the “risk characterization” step in the risk assessment process (NRC, 1996; USEPA, 

2000c). The box on the following page summarizes some of the points made in Understanding 

Risk. 

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Some Thoughts on Risk Characterization 

The NRC book Understanding Risk (NRC, 1996) has and character of uncertainty. . .


risk characterization as its primary focus. In their


conclusions, NRC states: Getting the right science. The analysis has addressed


the significant risk-related concerns of public officials 

1. Risk characterization should be a decision-driven and the spectrum of interested and affected parties, such 

activity, directed towards informing choices and solving as risks to health, economic well-being, and ecological


problems. The view of risk characterization as a and social values, with analytic priorities having been


translation or summary is seriously deficient. . .. Risk set so as to emphasize the issues most relevant to the


characterization should not be an activity added at the decision.


end of risk analysis; rather, its needs should largely


determine the scope and nature of risk analysis. Getting the right participation. The analytic-deliberative


process has had sufficiently broad participation to 

2. Coping with a risk situation requires a broad ensure that the important, decision-relevant information 

understanding of the relevant losses, harms, or enters the process, that all important perspectives are 

consequences to the interested and affected parties. A considered, and that the parties’ legitimate concerns


risk characterization must address what the interested about inclusiveness and openness are met.


and affected parties believe to be at risk in the particular


situation, and it must incorporate their perspectives and Getting the participation right. The analytic-


specialized knowledge. deliberative process satisfies the decision makers and


interested and affected parties that it is responsive to 

3. Risk characterization is the outcome of an analytic- their needs: that their information, viewpoints, and 

deliberative process. . . . Analysis and deliberation can concerns have been adequately represented and taken 

be thought of as two complementary approaches to into account; that they have been adequately consulted; 

gaining knowledge about the world, forming and that their participation has been able to affect the 

understandings on the basis of knowledge, and reaching way risk problems are defined and understood. 

agreement among people. 

Developing an accurate, balanced, and informative 

4. The analytic-deliberative process leading to a risk synthesis. The risk characterization presents the state of 

characterization should include early and explicit knowledge, uncertainty, and disagreement about the risk 

attention to problem formulation. situation to reflect the range of relevant knowledge and 

perspectives and satisfies the parties to a decision that 

5. The analytic-deliberative process should be mutual they have been adequately informed within the limits of 

and recursive. . . . A recurring criticism of risk available knowledge.


characterization is that the underlying analysis failed to


pay adequate attention to questions of central concern to 6. Those responsible for a risk characterization should


some of the interested and affected parties. This is not begin by developing a diagnosis of the decision


so much a failure of analysis as a failure to integrate it situation so that they can better match the analytic-


with broadly based deliberation: the analysis was not deliberative process leading to the characterization to


framed by adequate understanding about what should be the needs of the decision, particularly in terms of level


analyzed. . . . Structuring an effective analytic- and intensity of effort and presentation of parties. . . .


deliberative process for informing a risk decision is not a Diagnosis of risk decision situations should follow eight


matter for a recipe. Every step involves judgment, and steps: (1) diagnose the kinds of risk and the state of


the right choices are situation dependent. Still, it is knowledge, (2) describe the legal mandate, (3) describe


possible to identify objectives that also serve as criteria the purpose of the risk decision, (4) describe the affected


for judging success: parties and anticipate public reactions, (5) estimate


resource needs and timetable, (6) plan for organizational 

Getting the science right. The underlying analysis meets needs, (7) develop a preliminary process design, and (8)


high scientific standards in terms of measurement, summarize and discuss the diagnosis with the


analytic methods, data bases used, plausibility of responsible organization.


assumptions, and respectfulness of both the magnitude


1 

2 

3 

4 4.2. Uncertainty Analysis 

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In their 1990 book Uncertainty: A Guide to Dealing with Uncertainty in Quantitative 

Risk and Policy Analysis, Morgan and Henrion (1990) note that historically, the most common 

approach to uncertainty in policy analysis (including in risk assessment) has been to ignore it. In 

a section titled “Why Consider Uncertainty?” they advance three primary reasons, all of which 

are especially relevant to an analytic-deliberative process such as cumulative risk assessment. 

They suggest that it is important to worry about uncertainty: 

•	 “when one is performing an analysis in which people’s attitude toward risk is likely to be 

important, for example, when people display significant risk aversion; 

•	 “when one is performing an analysis in which uncertain information from different 

sources must be combined. The precision of each source should help determine its 

weighting in the combination; and 

•	 “when a decision must be made about whether to expend resources to acquire additional 

information. In general, the greater the uncertainty, the greater the expected value of 

additional information.” 

Morgan and Henrion provide 

“ten commandments” for good policy 

analysis, and although all are 

commendable, and several have been 

discussed elsewhere in this Framework 

report, we should look more closely at 

numbers 6-8 in the box at right for 

some insight into uncertainty analysis. 

There are many resources available 

which talk in detail about how to 

perform uncertainty analysis (e.g., 

USEPA, 1997b, Morgan and Henrion, 

1990). While detailed instruction on 

how to perform uncertainty analysis is 

beyond the scope of this Framework 

Morgan & Henrion’s “Ten Commandments” 

for Good Policy Analysis 

1. Do your homework with literature, experts, and users. 

2. Let the problem drive the analysis. 

3. Make the analysis as simple as possible, but no simpler. 

4. Identify all significant assumptions. 

5. Be explicit about decision criteria and policy strategies. 

6. Be explicit about uncertainties. 

7. Perform systematic sensitivity and uncertainty analysis. 

8. Iteratively refine the problem statement and the analysis. 

9. Document clearly and completely. 

10. Expose the work to peer review. 

Source: Morgan and Henrion, 1990. 

report, we believe that a discussion of some general principles is in order. 

4.2.1. Assumptions in the Assessment 

Cumulative risk assessment will typically be used in a decision-making process to help 

inform the decision-maker(s). For this reason, it is important that the decision makers be made 

explicitly aware of any assumptions that may significantly affect the conclusions of the analysis 

(item #6 in the box above). Morgan and Henrion suggest that these assumptions include: 

• the main policy concerns, issues, or decisions that prompted the assessment; 

• the evaluation criteria to be used to define issues of concern or options; 

•	 the scope and boundaries of the assessment, and ways in which alternate selections might 

influence the conclusions reached; 

• soft or intangible issues that are ignored or inadequately dealt with in the quantitative 

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analysis (e.g., intrinsic value of wilderness, equity of distribution of risks and benefits); 

• approximations introduced by the level of aggregation or by level of detail in models; 

• value judgments and tradeoffs; and 

•	 the objective function used, including methods of combining ratings on multiple criteria 

(or combining risk scales). [adapted from Morgan and Henrion, 1990] 

Identifying significant assumptions can often highlight “soft” uncertainties that are not 

easily quantified, and are therefore often left out of a quantitative uncertainty analysis. 

Nevertheless, these “soft” assumptions can often contribute more to the overall uncertainty of the 

assessment than the factors more easily quantified. 

In item #7 in Morgan and Henrion’s “ten commandments,” they list three types of 

uncertainty that analysts should explicitly include: 

•	 uncertainty about technical, scientific, economic, and political quantities (e.g., quantities 

like rate constants often lend themselves to quantitative uncertainty estimates relatively 

easily); 

•	 uncertainty about the appropriate functional form of technical, scientific, economic, and 

political models (e.g., are the models used, such as dose-response models, biologically 

sound?); 

•	 disagreements among experts about the values of quantities or the functional form of 

models (e.g., different health scientists using different forms of dose-response models). 

In Item #8 in the box on the previous page, Morgan and Henrion suggest that an assessor 

needs to find out which assumptions and uncertainties may significantly alter the conclusions, 

and that process can be conducted using sensitivity and uncertainty analysis. Techniques for these 

include: 

•	 deterministic, one-at-a-time analysis of each factor, holding all others constant at nominal 

values; 

• deterministic joint analysis, changing the values of more than one factor at a time; 

•	 parametric analysis, moving one or a few inputs across reasonably selected ranges to 

observe the shape of the response; and 

•	 probabilistic analysis, using correlation, rank correlation, regression, or other means to 

examine how much of the uncertainty in the conclusions is attributable to which inputs. 

Finally, Morgan and Henrion answer the question of why we should consider uncertainty 

analysis with the following point. “Policy analysts have a professional and ethical responsibility 

to present not just “answers” but also a clear and explicit statement of the implications and 

limitations of their work. Attempts to fully characterize and deal with important associated 

uncertainties help them to execute this responsibility better.” (Morgan and Henrion, 1990) 

4.2.2. Uncertainty and Variability 

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In their 1994 report Science and Judgment in Risk Assessment (NRC, 1994), the National 

Research Council noted a clear difference between uncertainty and variability, and recommended 

that the distinction between these two be maintained: 

“A distinction between uncertainty (i.e., degree of potential error) and inter-individual 

variability (i.e., population heterogeneity) is generally required if the resulting 

quantitative risk characterization is to be optimally useful for regulatory purposes, 

particularly insofar as risk characterizations are treated quantitatively. The distinction 

between uncertainty and individual variability ought to be maintained rigorously at the 

level of separate risk-assessment components (e.g., ambient concentration, uptake, and 

potency) as well as at the level of an integrated risk characterization.” (NRC, 1994, page 

242) 

Variability and uncertainty have been treated separately and distinctly in single-chemical 

assessments such as the assessment of trichloroethylene in ground water at Beale Air Force Base 

in California (Bogen, 2001). The treatment of variability and uncertainty will be an important 

issue in cumulative risk assessments, also, although at the time of this writing there are no good 

examples available of an elegant treatment of this issue for cumulative risk. 

4.2.3. Uncertainty and Risk Addition 

Calculating individual stressor risks, 

and then combining them, presents largely the 

same challenges as combination toxicology, 

but also adds some statistical stumbling 

blocks. Toxicity addition, independence, 

synergism, or antagonism still need to be 

evaluated, but since risk estimates for various 

stressors are often presented as values on the 

same numeric scale (e.g., as cancer 

probabilities), cancer risks are often just 

added together. 

Since most cancer slope factors are 

not “most probable estimates,” but 95% upper 

confidence levels, adding traditional risk 

levels can cause the resulting sum to 

overestimate a 95% upper confidence level 

risk for a mixture. There have been several 

recent papers discussing this problem and 

Uncertainty Analysis Example: 

The Cumulative Exposure Project 

EPA’s Cumulative Exposure Project (CEP), completed in 

1998, modeled 1990 outdoor concentrations of hazardous 

air pollutants (HAPs) across the United States, which were 

combined with unit risk estimates to estimate the potential 

increase in excess cancer risk from multiple HAPs. The 

cancer risks of different HAPs were assumed to be additive 

and were summed across pollutants in each census tract to 

estimate a total cancer risk in each census tract. 

Consideration of some specific uncertainties, including 

underestimation of ambient concentrations, combining 

upper 95% confidence bound potency estimates, and 

changes to potency estimates, found that cancer risk may 

be underestimated by 15% or overestimated by 40-50%. 

Other unanalyzed uncertainties could make these under- or 

overestimates larger. 

Source: Woodruff, et al., 2000 

how it may effect the resulting estimates. Kodell and Chen (1994) looked at several binary 

mixtures and calculated that the summation of individual upper 95% confidence intervals for 

chlorobenzene and hexachlorobenzene would overestimate the upper-bound risk of a binary 

mixture of these compounds by 2-6%, while for chlorobenzene and trichloroethylene, the 

overestimate would be in the range of 12-15%. Seed, et al. (1994) noted that, “in most cases, the 

magnitude of the difference in cancer risk estimates calculated by [Kodell and Chen’s] various 

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methods will be greatest for mixtures of eqipotent compounds. However, even for mixtures of 

equipotent compounds, the differences in joint risk estimated by summing the upper 95% 

confidence levels. . .are not great.” After analyzing four cases, Cogliano (1997) concluded that 

“as the number of risk estimates increases, their sum becomes increasingly improbable, but not 

misleading.” For example, in adding 20 different cancer risk estimates based on a 95% upper 

bound, the resulting sum of the upper bounds was no more than 2.2 times the true upper bound. 

Cogliano goes on to suggest that, for certain cases not involving synergistic or antagonistic 

interactions, “depending on the number of carcinogens and the shape of the underlying risk 

distributions, division by a factor of 2 can be sufficient to convert a sum of upper bounds into a 

plausible upper bound for the overall risk” (Cogliano, 1997). 

The assumption of toxicologic independence (see section 3.2.2) may not be a bad 

assumption if other evidence supports it, but it should be addressed in the assessment if used 

(i.e., if risks are added). Although there are some scientists who believe that toxicologic 

interactions are of minor consequence at concentrations observed in the environment (see 

discussion in USEPA, 2000e), the scientific evidence for such an assumption has not been firmly 

established. 

Notwithstanding the statistical limitations of adding traditional risk estimates, and the 

implicit assumption that the toxicities will be additive12 (i.e., no interactions such as synergism or 

antagonism occur), the numerical ease for combining risks in this way may make it the most 

popular method for approximating cumulative risks in the short term, at least at a screening level 

of assessment. 

4.3. The Information Provided by Cumulative Risk Assessment 

It is important to clarify how cumulative risk assessment and this Framework report relate 

to community assessments and community decision making. Certainly, the Agency’s Risk 

Characterization Handbook (USEPA, 2000c) emphasizes that whatever information is imparted, 

it be transparent, clear, consistent, and reasonable. For example, if it is known that the results of a 

particular cumulative risk assessment will be severely limited because of a lack of data or 

available methods, it may be advisable to start with a screening analysis to set priorities for a 

subsequent more detailed, focused study. In simple terms, what can a cumulative risk assessment 

tell us, and what can’t it tell us? 

4.3.1. Making Sense of Multiple Stressor Effects 

The information provided by cumulative risk assessment is only a portion of the 

information that communities and governments need to make informed decisions about risks. 

There are almost always a multitude of factors that affect health in a community (e.g., crime, 

drugs, health care access, vehicle safety, climate, infectious disease, diet. . .), some of which may 

not have been considered within the scope of any given cumulative risk assessment. Community 

decision-making will typically take risks to the environment into account, as well as 

12 At risk levels often seen with pollutant concentrations observed in the environment, the combined risks calculated assuming 

“response additi vity” (that is, each component acts as if the other were not present) are app roximate ly the same a s with dos e additivity (USEPA, 

2000e). 

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consideration about historical and cultural values, and questions of fairness and distribution of 

risks. The methodology is not currently available to understand how these factors (or stressors) 

may affect cumulative health risk. 

Additionally, benefits that may be associated with chemical or other stressor exposures – 

benefits such as jobs and useful products or services – may be important contexts for decisions 

on the risks considered in cumulative risk assessments. 

This Framework report is not an attempt to lay out protocols to address all the risks or 

considerations that are needed to adequately inform community decisions. Rather, it is focused 

on describing various aspects of cumulative risk, whether or not the methods or data currently 

exist to adequately analyze or evaluate those aspects of the assessment. The Framework report 

devotes considerable time to a discussion of improving the methods for a single part of the 

broader picture -- characterizing health risks associated with exposures to multiple chemicals via 

multiple routes. Because of the limitations of the current state of the science, cumulative risk 

assessments in the near future will not be able to adequately answer all questions posed by 

stakeholders or interested parties. This does not mean, however, that they can’t be useful in 

providing insights to some of the questions asked; in fact, cumulative risk assessment may be the 

best tool available to address certain questions dealing with multiple stressor impacts. 

4.3.2. Cumulative Risk Assessments in a Public Health Context 

The public, in a variety of forms, continually draws attention to health statistics, asking 

for clarification of the relationship between environmental pollution (and risk assessments 

concerning it) and public health. It is important to clarify that to draw relationships between 

environmental pollutant exposures and disease incidence, a body of epidemiological study is 

necessary, and trying to “work backwards” from health statistics to risk factors requires full 

knowledge of the risk factors associated with the relevant disease(s). 

Health statistics, including death rates and incidence of various diseases, illustrate the 

impact of a variety of risk factors (e.g., smoking as well as environmental pollutants) and risk 

reduction factors (e.g., exercise and good nutrition, as well as pollution control measures). 

Indeed, population health statistics are reflective of all risk and risk reduction factors in a 

population’s history-to-date. Even the best cumulative risk assessment given today’s state of the 

science would fall short of being able to include an evaluation of the magnitude and interactions 

of all stressors and effects. At best, the risk estimates of a cumulative risk assessment will reflect 

some of the risks which may be reflected in community health statistics. With rare exceptions13, 

cumulative risk assessment estimates would not be expected to match exactly with community 

health statistics, even for specific health endpoints such as specific cancers. 

4.3.3. How Scope and Purpose of the Assessment Affect Results 

13 It is conceivable that high risks to rare specific effects could be comparable between a risk assessment and 

community health statistics given current state of the art. To be sure this is not coincidental, a substantial effort to match risk 

assessment scenarios with actual histories or exposures would have to be made. 

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Historically, the Agency’s risk assessments have focused on assessing the risks from 

environmental pollutants to public health or the environment, usually for the purposes of 

prioritizing risk management activities or triggering regulatory action. Given the need for public 

health protective decisions, traditional risk assessment tools usually focus on predicting high 

ends of the risk distribution. Also, the traditional tools are not designed to predict risk of diseases 

other than cancer. Additionally, the many environmental pollutants comprise only some of the 

categories of risks to public health. While quite adequate for their original purpose, when the 

results of these types of assessments are viewed from another perspective, such as a community 

concerned about the cumulative health impacts of five industrial and commercial facilities within 

a two block area, they may not be useful. 

The Agency is doing more place-based human health and ecological assessments (i.e., 

compared to source- or media-specific assessments) than in the past, but it will be some time 

before place-based assessments become commonplace. Consistent with good practices for 

planning and scoping, these often may be driven by specific risk management needs. To the 

extent there are parties that were outside the process, their desired objectives and purpose may 

differ from those for which the assessment was designed. For this reason, users of cumulative 

risk assessments are advised to carefully study the scope and purpose of the assessment at hand, 

as well as the analysis plan and resulting characterization, in order to determine whether it is 

suitable (or partly suitable) to answer questions outside its stated objectives and purpose. 

4.4. Using the Results of the Assessment 

Once the results of an assessment are in hand, the assessment participants will usually 

focus primarily on the use of those results. The intended use of the assessment was considered at 

the beginning, in the Problem Formulation Phase, both to plan the assessment work and to set the 

stage for what possible actions might be taken at this point.. A detailed discussion of the use of 

the results of a cumulative risk assessment is beyond the scope of this document, but in deciding 

on a course of action, other considerations will need to be taken into account along with the 

results of the cumulative risk assessment. 

If the goals of a cumulative risk analysis are to estimate the risk from multi-chemical and 

multi pathway exposure to individuals living within a geographical area of concern, then an 

important objective in presenting the results is to identify the major risk contributors in order to 

understand the sources, pathways, and stressors which contribute most to that overall risk. The 

results of a cumulative risk assessment provide an additional tool for the risk manager, one that 

permits a more complete accounting and more explicit analysis to target follow-up risk 

mitigation strategies toward those stressors which most contribute to the population’s risk. 

If action to mitigate or prevent risk is the goal of the stakeholders, then options for action 

discussed in the planning of the assessment can be re-evaluated in light of the results of the 

assessment. Some of the issues after re-evaluating the action alternatives might include: “Is 

regulatory authority available to address concerns or are voluntary actions better suited to address 

the risks?” or “Can the concerns be addressed by the stakeholders involved in the assessment or 

are the options for mitigation and prevention beyond the scope of their control?” In the latter 

case, for example, siting issues are usually decided locally and may be within the authority of the 

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participants of a local assessment. In contrast, 

risk from mobile sources or acid rain are likely 

to require action beyond the scope of a single 

local community. In that case, taking action 

will require working with other communities 

and is likely to take more time. Discussion of 

the options available for addressing results of 

a risk assessment will help to keep 

expectations in line with possibilities. 

In taking action – or not taking action – 

after a cumulative risk assessment has been 

interpreted, the team may benefit from lessons 

learned by others, just as in the planning, 

scoping, and problem formulation phase. The 

European Environment Agency (EEA) in early 

2002 released an extensive study of twelve 

classic case studies in human and 

environmental health protection, and the 

lessons learned from them (EEA, 2001). The 

report is available on the internet and should 

be “food for thought” for any group 

contemplating protective actions, but 

particularly for community assessments. 

Twelve of the EEA’s “late lessons learned” are 

reproduced in the box at right. 

Finally, it is important to keep in mind 

that the results of the risk assessment will be 

EEA’s 12 Late Lessons Learned 

- Acknowledge and respond to ignorance, as well as 

uncertainty and risk, in technology appraisal and public 

policy-making. 

- Provide adequate long-term environmental and health 

monitoring and research into early warnings. 

- Identify and work to reduce blind spots and gaps in 

scientific knowledge. 

- Identify and reduce interdisciplinary obstacles to 

learning. 

- Ensure that real world conditions are adequately 

accounted for in regulatory appraisal. 

- Systematically scrutinize the claimed justifications and 

benefits alongside the potential risks. 

- Evaluate a range of alternative options for meeting needs 

alongside the option under appraisal, and promote more 

robust, diverse and adaptable technologies so as to 

minimize the costs of surprises and maximize the benefits 

of innovation. 

- Ensure use of "lay" and local knowledge, as well as 

relevant specialist expertise in the appraisal. 

- Take full account of the assumptions and values of 

different social groups. 

- Maintain regulatory independence from interested parties 

while retaining an inclusive approach to information and 

opinion gathering. 

- Identify and reduce institutional obstacles to learning and 

action. 

- Avoid "paralysis by analysis" by acting to reduce 

potential harm when there are reasonable grounds for 

concern. 

Source: EEA, 2001 

only one of the factors that will need to be considered in making a decision on action to address 

the risk. Risk information can make an important and valued contribution to the decisionmaking process, but risk information, by itself, can not determine the decision. Factors such as 

the availability of resources for change, fairness and other community values, politics, business 

and employment considerations, quality of life issues, or concern for future generations will also 

influence any decision made. In the siting example mentioned above, the assessment may 

determine that the new facility does not significantly increase risk to the community and a 

decision not to site the facility might still be made on the basis of a quality of life issue unrelated 

to risk. Or, in contrast, a community may decide that the economic and employment benefits 

outweigh the risks associated with the siting. Other risk factors not considered in the assessment 

may also enter into the decision-making process. This can include both the environmental risks 

not covered in the cumulative risk assessment as well as the non-environmental risks that may 

affect a community. With limited resources, a community may use all available risk information 

to most effectively target its resources. 

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5. GLOSSARY 

Adverse effect - A biochemical change, functional impairment, or pathological lesion that either 

singly or in combination adversely affects the performance of the whole organism or reduces an 

organism’s ability to respond to an additional environmental challenge. 

Agent - a chemical, radiological, mineralogical, or biological entity that may cause deleterious 

effects in an organism after the organism is exposed to it. 

Aggregate exposure - The combined exposure of an individual (or defined population) to a 

specific agent or stressor via relevant routes, pathways, and sources. 

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

Benchmark dose (BMD) - The dose producing a predetermined, altered response for an effect. 

A BMD10, for example, would be calculated based on a benchmark response of 10%. 

Benchmark response (BMR) - A predetermined level of altered response or risk at which the 

benchmark dose is calculated. Typically, the BMRs used are 1%, 5%, or 10%. 

Conceptual model - Both a written description and a visual representation of actual or predicted 

relationships between humans or ecological entities and the chemicals or other stressors to which 

they may be exposed. 

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

Cumulative risk assessment - An analysis, characterization, and possible quantification of the 

combined risks to health or the environment from multiple agents or stressors. 

Dose additivity - In a mixture, when each chemical behaves as a concentration or dilution of 

every other chemical. The response of the combination of chemicals is the response expected 

from the equivalent dose of an index chemical (the chemical selected as a basis for 

standardization of toxicity of components in a mixture). The equivalent dose is the sum of 

component doses scaled by their toxic potency relative to the index chemical. For example, for 

chlorinated dibenzodioxins (CDDs), 2,3,7,8-TCDD is selected as the index chemical, and other 

CDD concentrations are adjusted for their potency relative to 2,3,7,8-TCDD, then treated as if 

they were 2,3,7,8-TCDD “equivalents.” 

Dose-response relationship - A relationship between (1) the dose, either “administered dose” or 

absorbed dose, and (2) the extent of toxic injury produced by that chemical or agent. Response 

can be expressed either as the severity of injury or proportion of exposed subjects affected. 

Endpoint - An observable or measurable biological or chemical event used as an index of the 

effect of a stressor on a cell, tissue, organ, organism, etc. 

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Lowest observed adverse effect level (LOAEL) - The lowest dose or exposure level in a study 

which there is a statistically or biologically significant increase in the frequency or severity of an 

adverse effect in the exposed population as compared with an appropriate, unexposed control 

group. 

Model - A mathematical representation of a natural system intended to mimic the behavior of the 

real system, allowing description of empirical data and predictions about untested states of the 

system. Use of models is usually facilitated by computer programming of the mathematics and 

construction of a convenient input and output format. 

No observed adverse effect level (NOAEL) - An exposure level at which there are no 

statistically or biologically significant increases in the frequency or severity of adverse effects 

between the exposed population and its appropriate control; some effects may be produced at this 

level, but they are not considered to be adverse or precursors to adverse effects. In an experiment 

with several NOAELs, the common usage of the term NOAEL is the highest exposure without 

adverse effects. 

Ototoxic stressor - A stressor which causes damage to the ear or the sense of hearing. 

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

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

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

a lifetime. 

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

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

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

Response additivity - In a mixture, when the toxic response (rate, incidence, risk, or probability 

of effects) from the combination is equal to the conditional sum of component responses as 

defined by the formula for the sum of independent event probabilities. For two chemical 

mixtures, for example, the body’s response to the first chemical is the same whether or not the 

second chemical is present. 

Risk - Absolute risk: The probability of injury, disease, or death under specific circumstances. In 

quantitative terms, risk is expressed in values ranging from zero (representing the certainty that 

there is no chance of harm), to one (representing the certainty that harm will occur). Incremental 

risk: The probability of injury, disease, or death under specific circumstances, relative to the 

background probability. In quantitative terms, risk is expressed in values ranging from zero 

(representing the certainty that the probability of harm is no greater than the background 

probability), to one (representing the certainty that harm will occur). 

Stakeholder - An interested or affected party in an ongoing or contemplated project (usually 

involving a group or team planning the project, analyzing one or more problems, and making 

decisions for possible actions based on the interpretation of that analysis). 

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1 Stressor - Any physical, chemical, or biological entity that can induce an adverse response. 

2 Stressors may also be the lack of an essential entity, such as a habitat. 

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6. REFERENCES 

ACGIH, 1998. Threshold Limit Values for Chemical Substances and Physical Agents. 

American Conference of Government Industrial Hygienists, Cincinnati, OH. 

AIChE, 1992. Guidelines for Hazard Evaluation Procedures, 2nd Edition with Worked 

Examples. Center for Chemical Process Safety, American Institute of Chemical Engineers, New 

York, NY. 

AIChE, 1996. Guidelines for Use of Vapor Cloud Dispersion Models, 2nd Ed. Center for 

Chemical Process Safety, American Institute of Chemical Engineers, New York, NY. 

AIHA, 2000. Emergency Response Planning Guidelines Series. Emergency Response Planning 

Guidelines Committee, American Industrial Hygiene Association, Fairfax, VA. 

Albert, Roy E., 1999. Unifying the standard setting process for carcinogens and non-carcinogens. 

Applied Occupational and Environmental Hygiene 14:742-747 

Albert, Roy E., Joellen Lewtas, Stephen C. Nesnow, Todd W. Thorslund, and Elizabeth L. 

Anderson, 1983. Comparative potency method for cancer risk assessment application to diesel 

particulate emissions. Risk Analysis 3:101-117 

American Heart Association, 2000. Stroke Risk Factors. Internet: www.americanheart.org. 

Andersen, Melvin E., M. Elizabeth Meeks, Gary A. Boorman, David J. Brusick, Samuel M. 

Cohen, Yvonne P. Dragan, Clay B. Frederick, Jay I. Goodman, Gordon C. Hard, Ellen J. 

O’Flaherty, and Denise E. Robinson, 2000. Lessons learned in applying the U.S. EPA proposed 

cancer guidelines to specific compounds. Toxicological Sciences 53:159-172 

APCA, 1999. “Cumulative & Aggregate Risk Evaluation System: CARES. Conceptual Model.” 

American Crop Protection Association. Washington, DC. Internet: www.alphacares.org/ 

ATSDR, 1995. Report of the Expert Panel Workshop on the Psychological Responses to 

Hazardous Substances. Agency for Toxic Substances and Disease Registry, U.S. Department of 

Health and Human Services. Atlanta, Georgia. Internet: www.atsdr.cdc.gov/HEC/PRHS/ 

Barnes, Donald G., Ann Alford-Stevens, Linda Birnbaum, Frederick W. Kutz, William Wood, 

and Dorothy Patton, 1991. Toxic equivalency factors for PCBs? Quality Assurance 1:70-81. 

Barnes, Donald G. and Michael L. Dourson, 1988. Reference dose (RfD): description and use in 

health risk assessments. Regulatory Toxicology and Pharmacology 8:471-486. 

Barnthouse, Lawrence W., David R. Marmorek, and Calvin N. Peters, 2000. Assessment of 

multiple stresses at regional scales. In: Multiple Stressors in Ecological Risk and Impact 

Assessment: Approaches to Risk Estimation. (Ferenc and Foran, Eds.) Society of Environmental 

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EPA/630/R-95/001F 

USEPA, 1998d. “Methods for Exposure-Response Analysis for Acute Inhalation Exposure to 

Chemicals: Development of the Acute Reference Exposure.” Review Draft. Office of Research 

and Development, U.S. Environmental Protection Agency. Washington, DC. EPA/600/R-98/051 

USEPA, 1998e. “General Guidance for Risk Management Programs (40 CFR Part 68).” 

Chemical Emergency Preparedness and Prevention Office, Office of Solid Waste and Emergency 

Response, U.S. Environmental Protection Agency, Washington, DC. EPA 550-B-98-003 

USEPA, 1998f. “Comparative Risk Framework: Methodology and Case Study.” SAB Review 

Draft dated November 9, 1998. National Center for Environmental Assessment, Office of 

Research and Development, U.S. Environmental Protection Agency. Cincinnati, OH. 

USEPA, 1998g. “Report of the Common Sense Initiative Council’s Stakeholder Involvement 

Work Group.” Common Sense Initiative Council, U.S. Environmental Protection Agency. 

Washington, DC. 

USEPA, 1998h. “An SAB Report: Review of Disproportionate Impact Methodologies.” Science 

Advisory Board, U.S. Environmental Protection Agency. Washington, DC. EPA-SAB-IHEC-99-

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007 

USEPA, 1998i. “Handbook for Air Toxics Emission Inventory Development, Volume I: 

Stationary Sources.” Office of Air Quality Planning and Standards, Office of Air and Radiation, 

U.S. Environmental Protection Agency. Research Triangle Park, NC. EPA-454/B-98-002 

USEPA, 1998j. “Human Health Risk Assessment Protocol for Hazardous Waste Combustion 

Facilities.” Peer Review Draft. Office of Solid Waste and Emergency Response, U.S. 

Environmental Protection Agency. Washington, DC. EPA530-D-98-001 Internet: 

www.epa.gov/epaoswer/hazwaste/combust/riskvol.htm 

USEPA, 1998k. “A Common Mechanism of Action: The Organophosphate Pesticides.” 

Scientific Advisory Panel, United States Environmental Protection Agency. Washington, DC. 

Internet: http://www.epa.gov/scipoly/sap/1998/march/comec.htm 

USEPA, 1999a. “Guidelines for Carcinogen Risk Assessment.” Review draft dated July, 1999. 

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

Agency. Washington, DC. NCEA-F-0644 

USEPA, 1999b. “Review of Revised Sections of the Proposed Guidelines for Carcinogen Risk 

Assessment.” Science Advisory Board, U.S. Environmental Protection Agency. Washington, DC. 

EPA-SAB-EC-99-015 

USEPA, 1999c. “Risk Assessment Guidance for Superfund: Volume 1 - Human Health 

Evaluation Manual. Supplement to Part A: Community Involvement in Superfund Risk 

Assessments.” Office of Solid Waste and Emergency Response, United States Environmental 

Protection Agency. Washington, DC. EPA 540-R-98-042/PB99-963303 

USEPA, 1999d. “Risk Management Program Guidance for Offsite Consequence Analysis.” 

Chemical Emergency Preparedness and Prevention Office, Office of Solid Waste and Emergency 

Response, U.S. Environmental Protection Agency, Washington, DC. EPA 550-B-99-009 

USEPA, 1999e. “Guideline on Air Quality Models.” Office of Air Quality Planning and 

Standards, Office of Air and Radiation, U.S. Environmental Protection Agency. Research 

Triangle Park, NC. 40CFR Ch. I (7-1-99 Edition), Appendix W to Part 51, Pages 390-481 

USEPA, 1999f. “EPA’s Framework for Community-Based Environmental Protection.” Office of 

Policy/Office of Reinvention, U.S. Environmental Protection Agency, Washington, DC. EPA 

237-K-00-001 

USEPA, 1999g. “Guidance for Performing Aggregate Exposure and Risk Assessments.” Office 

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

Protection Agency. Washington, DC. Item 6043, dated October 29, 1999. Available on the 

internet at: http://www.epa.gov/fedrgstr/EPA-PEST/1999/November/Day-10/6043.pdf 

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USEPA, 1999h. “Total Risk Integrated Methodology, TRIM.Expo.: Technical Support 

Document.” External Review Draft. Office of Air Quality Planning and Standards, Office of Air 

and Radiation, U.S. Environmental Protection Agency. Research Triangle Park, NC. EPA453/D-99-001 

USEPA, 1999i. “Risk-Screening Environmental Indicators: 1988-1997 TRI Data ‘Air-Only’ 

Model.” Office of Pollution Prevention and Toxic Substances, Office of Prevention, Pesticides, 

and Toxic Substances, U.S. Environmental Protection Agency. Washington, DC. CD-ROM 

Version 1.0, dated July 6, 1999. (Version 2.0 is now in beta-testing.) 

USEPA, 1999j. “An SAB Report on the National Center for Environmental Assessment’s 

Comparative Risk Framework Methodology.” Science Advisory Board, U.S. Environmental 

Protection Agency. Washington, DC. EPA-SAB-DWC-99-016 

USEPA, 1999k. “Handbook for Criteria Pollutant Inventory Development: A Beginner’s Guide 

for Point and Area Sources.” Office of Air Quality Planning and Standards, Office of Air and 

Radiation, U.S. Environmental Protection Agency. Research Triangle Park, NC. EPA-454/R-99-

USEPA, 1999l. “Federal Guidance Report No. 13: Cancer Risk Coefficients for Environmental 

Exposure to Radionuclides.” Office of Air and Radiation, U.S. Environmental Protection 

Agency. Washington, DC. EPA-402-R-99-001 

USEPA, 1999m. “Guidance for Identifying Pesticide Chemicals and Other Substances that Have 

a Common Mechanism of Toxicity;” Office of Pesticide Programs, Office of Prevention, 

Pesticides, and Toxic Substances, United States Environmental Protection Agency. Washington, 

D.C. Internet: http://www.epa.gov/fedrgstr/EPA_PEST/1999/February/Day_05/ 

USEPA, 2000a. “Toward Integrated Environmental Decision-Making.” Science Advisory Board, 

U.S. Environmental Protection Agency. Washington, DC. EPA-SAB-EC-00-011 

USEPA, 2000b. “Benchmark Dose Technical Guidance Document” Draft report. Risk 

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

Agency. Washington, DC. EPA/630/R-00/001 

USEPA, 2000c. “Science Policy Council Handbook: Risk Characterization.” Science Policy 

Council, U.S. Environmental Protection Agency. Washington, DC. EPA 100-B-00-002 

USEPA, 2000d. “Science Policy Council Handbook: Peer Review.” 2nd Edition. Science Policy 

Council, U.S. Environmental Protection Agency. Washington, DC. EPA 100-B-00-001 

USEPA, 2000e. “Supplementary Guidance for Conducting Health Risk Assessment of Chemical 

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Mixtures.” Risk Assessment Forum, Office of Research and Development, U.S. Environmental 

Protection Agency. Washington, DC. EPA/630/R-00/002 

USEPA, 2000f. “Baltimore Community Environmental Partnership Air Committee Technical 

Report. Community Risk-Based Air Screening: A Case Study in Baltimore, MD.” Office of 

Pollution Prevention and Toxics, Office of Prevention, Pesticides, and Toxic Substances, U.S. 

Environmental Protection Agency. Washington, DC. EPA 744-R-00-005 

USEPA, 2000g. “Handbook for Non-Cancer Health Effects Valuation.” Non-Cancer Health 

Effects Valuation Subcommittee of the EPA Social Science Discussion Group, Science Policy 

Council, U.S. Environmental Protection Agency. Washington, DC. Dated November, 2000. 

USEPA, 2000h. “AP-42: Compilation of Air Pollutant Emission Factors, Volume II: Mobile 

Sources.” Office of Transportation and Air Quality, Office of Air and Radiation. Washington, 

DC. EPA AP-42, Volume II Internet: www.epa.gov/otaq/ap42.htm 

USEPA, 2000i. “Catalog of Hazardous and Solid Waste Publications.” 13th Edition. Office of 

Solid Waste and Emergency Response, U.S. Environmental Protection Agency. Washington, DC. 

EPA530-B-00-001 Internet: www.epa.gov/epaoswer/osw/catalog.htm 

USEPA, 2000j. “Guide to Field Storage of Biosolids, Appendix A: Odor Characterization, 

Assessment and Sampling.” Office of Wastewater Management, Office of Water, U.S. 

Environmental Protection Agency. Washington, DC. EPA/832-B-00-007 Internet: 

www.epa.gov/owm/bio/fsguide/ 

USEPA, 2001a. Personal communication. Debby Sisco,. Biological and Economic Analysis 

Division, Office of Pesticide Programs, Office of Prevention, Pesticides, and Toxic Substances, 

U.S. Environmental Protection Agency. Washington, DC. August 1, 2001 

USEPA, 2001b. Personal communication. Anna Koutlakis, Office of Prevention, Pesticides, and 

Toxic Substances, U.S. Environmental Protection Agency. Washington, DC. August 1, 2001 

USEPA, 2001c. “Stakeholder Involvement & Public Participation at the U.S. EPA: Lessons 

Learned, Barriers, & Innovative Approaches.” Office of Policy, Economics and Innovation, U.S. 

Environmental Protection Agency. Washington, DC. EPA-100-R-00-040. 

USEPA, 2001d. “Top 10 Watershed Lessons Learned.” Office of Wetlands, Oceans and 

Watersheds, Office of Water, U.S. Environmental Protection Agency. Washington, DC. Internet: 

http://www.epa.gov/owow/watersheds/lessons/index.html 

USEPA, 2001e. “National-Scale Air Toxics Assessment for 1996.” SAB Review Draft. Office of 

Air Quality, Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection 

Agency. Washington, DC. EPA-453-R-01-003 

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USEPA, 2002a. “Guidance on Cumulative Risk Assessment of Pesticide Chemicals that Have a 

Common Mechanism of Toxicity.” Office of Pesticide Programs, Office of Prevention, 

Pesticides, and Toxic Substances, U.S. Environmental Protection Agency. Washington, DC. 

January 14, 2002. Internet: http://www.epa.gov/pesticides/trac/science/cumulative_guidance.pdf 

USEPA, 2002b. “Lesson Learned on Planning and Scoping for Environmental Risk 

Assessments.” Science Policy Council, U.S. Environmental Protection Agency. Washington, 

DC. January, 2002. Internet: http://www.epa.gov/ORD/spc/2cumrisk.htm. 

USEPA, 2002c. “Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo 

-p-Dioxin (TCDD) and Related Compounds.” National Center for Environmental Assessment, 

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

[to be published] 

van den Berg, Martin, Linda Birnbaum, Albertus T.C. Bosveld, Björn Brunström, Philip Cook, 

Mark Feeley, John P. Giesy, Annika Hanberg, Ryuichi Hasegawa, Sean W. Kennedy, Timothy 

Kubiak,John Christian Larsen, F.X. Rolaf van Leeuwen, A.K. Djien Liem, Cynthia Nolt, Richard 

E. Peterson, Lorenz Poellinger, Stephen Safe, Dieter Schrenk, Donald Tillitt, Mats Tysklind, 

Maged Younes, Fredrik Wærn, and Tim Zacharewski, 1998. Toxic equivalency factors (TEFs) 

for PCBs, PCDDs, PCDFs for humans and wildlife. Environmental Health Perspectives 

106:775-792 

WHO, 1983. “Guidelines on Studies in Environmental Epidemiology.” Environmental Health 

Criteria 27. International Programme on Chemical Safety. World Health Organization. Geneva. 

EHC 27 

Woodruff, Tracey J., Jane Caldwell, Vincent J. Cogliano, and Daniel A. Axelrad, 2000. 

Estimating cancer risk from outdoor concentrations of hazardous air pollutants in 1990. 

Environmental Research Section A 82:194-206 

Yang, Raymond S.H., 2001. “Application of Computer Modeling to Simple or Complex 

Mixtures,” presented at Application of Technology to Chemical Mixture Research Conference, 

January 9-11, 2001, Fort Collins, CO. 

Zartarian, Valerie G., Halûk Özkaynak, Janet M. Burke, Maria J. Zufall, Marc L. Rigas, and 

Edwin J. Furtaw, Jr, 2000. “A Modeling Framework for Estimating Children’s Residential 

Exposure and Dose to Chlorpyrifos via Dermal Residue Contact and Non-Dietary Ingestion.” 

Environmental Health Perspectives 108:505-514 

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APPENDIX A: RESEARCH AND DEVELOPMENT NEEDS 

The Framework for Cumulative Risk Assessment is intended to provide a basic structure 

for the issues and define key terms and concepts. In some cases, the concepts introduced in the 

Framework report require the application of knowledge and methods that are not currently 

available. The following is a discussion of the needed areas of research and methods 

development, highlighted within the Framework report, that may be most important to an 

evaluation of cumulative risks. This is not intended to be a comprehensive listing of cumulative 

risk assessment research needs. 

EPA and other scientists are currently investigating the use of similar approaches for 

cancer and noncancer assessments. Although we will not discuss this research need here, it 

would be useful to cumulative risk assessment to have similar approaches, and it is a topic of 

current discussion within scientific circles (e.g., Albert, 1999). 

Understanding the Timing of Exposure and its Relationship to Effects 

A key concept in the definition of cumulative risk is that it represents an accumulation of 

risk over time. However, unlike the traditional approach to risk assessment where exposure 

events are summed and averaged over a period of time, cumulative risk assessment will involve 

developing an understanding of how the sequence and timing of exposures influence the ultimate 

risk of effects. For example, for multiple stressors, it is important to understand how prior 

exposures to one or several stressors influence the risks from subsequent exposures to the same 

or different stressors. In addition, it is important to understand the implications of these 

exposures occurring during critical periods of an individual’s life (e.g., important periods of 

development or periods of disease). Several exposure models are under development which 

recognize the need to understand the timing of various exposure events (e.g., Calendex, APEX, 

Lifeline, SHEDS, and CARES/RExY). 

In addition to gaining a better understanding of the sequence and timing of exposures and 

their relationship to effects, it is important to understand how acute, non-lethal exposures from 

accidents contribute to chronic or long-term effects. 

Understanding the Composition and Toxicity of Mixtures 

Chemical mixtures can change or degrade over time and space making the assessment of 

exposure a particular challenge. For cumulative risk assessment, the composition of the mixture 

at the point of contact with the receptor needs to be well characterized. Both measurement 

techniques (at the receptor) and predictive models are applicable in this characterization. 

EPA’s Guidance for the Health Risk Assessment of Chemical Mixtures (USEPA, 2000e) 

presents approaches for combining the toxicities of multiple chemical stressors. These 

approaches necessarily involve a number of simplifying assumptions when the mixtures are 

complex. Although the current methods provide a valuable resource for assessing cumulative 

risks, future cumulative risk assessment will need a more complete understanding of the 

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interactions among chemicals in complex mixtures. Some current research efforts are seeking to 

identify toxicologic principles of joint action that are applicable to mixtures involving many 

chemicals. 

Applying the Risk Factor Approach to Environmental Health Risks 

The risk factor approach has been used in the medical profession to predict the chances of 

individuals developing various diseases. It has proved to be a useful approach not only in 

assessing certain cumulative risks, but also in communicating with patients. In this approach, 

characteristics of a population (e.g., age, ethnicity, personal habits, genetic polymorphisms, prior 

diseases, etc.) are correlated with the incidence of disease. For some diseases (e.g., breast cancer, 

coronary artery disease, stroke) these correlations are well established. However, there are 

substantial data gaps in terms of the role played by exposures to environmental stressors in the 

development of human disease, and correlations of environmental exposures with disease 

outcomes are generally not available. 

Using Biomarkers and Biomonitoring 

The use of biomarkers of exposure or effect holds a great deal of promise for cumulative 

risk assessment. This approach can provide a method to assess stressors in groups. Currently, 

however, this approach is not practicable when considering a large number of diverse stressors, 

since appropriate biomarkers for many types of stressors have not yet been developed. 

Considering Hazards Presented by Non-Chemical Stressors 

Cumulative risk assessment could encompass the interactions of chemical stressors with 

biological stressors, radiological stressors, other physical stressors, socioeconomic stressors and 

lifestyle conditions. In trying to assess all these different types of stressors, it is helpful to 

determine what types of effects the stressors produce, and then to try to group stressors by like 

effects. Ideally, one would like to know the mechanism or mode of action by which various 

stressors cause effects to allow a more refined grouping. Currently, however, there are few 

methods to understand how these disparate stressors interact to result in risk. 

Considering Psychological Stress as Part of Cumulative Risk 

Psychological stress causes both psychological and physiological changes that can be 

measured. Assessing levels of stress and their potential contribution to risk, however, is difficult 

for a variety of reasons. The Agency for Toxic Substances and Disease Registry (ATSDR) began 

the process of identifying research needs in this area through an expert panel workshop held in 

1995. 

Considering All Aspects of Vulnerability 

The issue of the vulnerability of a population can be thought of as having four 

components: susceptibility of individuals, differential exposures, differential preparedness to 

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withstand the insult, and differential ability to recover from effects. Traditional risk assessment 

may consider one or more of these categories but rarely are all considered. The overall 

consideration of all four categories may be more important in cumulative risk assessment than in 

traditional one-chemical assessments. A cumulative risk assessment, for example, may need to 

consider potential combinations of high exposure and high vulnerability across stressors. 

Methods development work is needed in this area. 

Methods for Combining Different Types of Risk 

Another key concept in the definition of cumulative risk assessment is that it represents 

the combined risk from multiple stressors. This implies that, in some cases, it may be necessary 

to combine disparate measures of risk (i.e., different types of effects) to simplify the expression 

of cumulative risks. There have been some attempts to collapse complex arrays of risk into a few 

or even a single measure. These approaches have involved the use of common metrics (e.g., 

Quality Adjusted Life Years, Disability Adjusted Life Years, Loss of Life Expectancy, etc.), 

indices (e.g., Hazard Ranking System, etc.), and the categorization of effects (e.g., as for 

categorical regression). Alternatively, Geographic Information Systems (GIS) and mapping 

techniques can be used to graphically portray integrated information on risks without 

mathematically combining disparate measures. Much methods development work remains to be 

completed in each of these areas. 

Development of Default Values for Cumulative Risk Assessments 

Just as conventional risk assessments use a series of default values for screening or other 

applications, it may be necessary to investigate whether certain defaults need to be established 

specifically for cumulative risk assessments. 

Development of Case Studies and Issue Papers on Specific Cumulative Risk Topics 

The more detailed technical issues and methodologies should be developed as a series of 

issues papers that would augment the Framework report. The level of detail would, of course, 

vary depending on the topic, and may include the generic material from other guidance 

documents. The issues papers (or white papers) should also include details on additional 

approaches to cumulative risk assessment that are currently being explored (including screeninglevel analyses, place-based assessments, comparative risk assessments, NEPA cumulative effects 

analyses, and hazard assessments). In addition, the issues papers could include summaries of 

case studies of cumulative risk projects that would extend the Framework from theoretical to 

practical approaches and applications. 

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APPENDIX B: SELECTED RESOURCES FOR EXPOSURE AND RISK ASSESSMENT 

B.1. Resources Relevant to Chemical Exposures 

EPA Guidelines: 

Most of EPA’s general guidelines are listed in the text box in section 1.1, page 5. 

Air-related sources and activities: 

EPA’s Clearinghouse for Inventories and Emission Factors (CHIEF) website 

(www.epa.gov/ttn/chief/) is an excellent starting place that has many of the relevant 

documents on methods and data for constructing emissions inventories available for 

download. These include Handbook for Criteria Pollutant Inventory Development: A 

Beginner’s Guide for Point and Area Sources (USEPA, 1999k), Handbook for Air Toxics 

Emission Inventory Development, Volume I: Stationary Sources (USEPA, 1998i),and 

Compilation of Air Pollutant Emission Factors (for both stationary and mobile sources) 

(USEPA, 1995e, 1996d, 1997d, 2000h), as well as many other documents and software. 

EPA’s Support Center for Regulatory Air Models (SCRAM) website 

(www.epa.gov/ttn/scram/) provides extensive information on the models discussed in 

Guideline on Air Quality Models (USEPA, 1999e), including downloadable software and 

users guides for many of the models. 

The Ambient Monitoring Technology Information Center (AMTIC) website 

(www.epa.gov/ttn/amtic/) contains information on monitoring programs, monitoring 

methods, and other monitoring-related information. 

The umbrella website for all three of the above is the Technology Transfer Network 

(www.epa.gov/ttn/), which also has other useful information and links in addition to those 

noted above. 

Sources to land, and waste-related activities: 

The EPA Office of Solid Waste and Emergency Response has published an extensive 

catalog summarizing their publications (USEPA, 2000i). They have also published a 

“peer review draft” document called Human Health Risk Assessment Protocol for 

Hazardous Waste Combustion Facilities (USEPA, 1998j) which deals with how to assess 

risks from hazardous waste incinerators. These reports are available on-line. 

Chemical accidents, transportation-related spills: 

There are several steps in assessing an accidental chemical release exposure. The typical 

analytical steps in an overall accidental chemical release risk assessment are process 

analysis, likelihood or frequency of accidents, source term modeling, dispersion or 

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consequence modeling, and the exposure assessment. 

� The process analysis is a formal, systematic analysis of the process where a 

chemical is handled to determine the probabilities and consequences of acute, 

catastrophic failures of engineered systems leading to an accidental release of the 

chemical. This analysis is often called a Process Hazards Analysis (PHA). 

Several formal PHA evaluation techniques are available including “What-If,” 

“Failure Mode and Effect Analysis,” “Event-Tree”, and “Fault-Tree” analysis 

(USEPA 1998e, AIChE, 1992). 

� The likelihood or frequency of accidents step is an evaluation of each of the 

scenarios uncovered in the process analysis step for likelihood or frequency of 

occurrence. 

� Source term modeling, which estimates the amount or rate of release in case of 

accident, is performed once the failure scenarios are determined. A wide variety of 

published calculation methods or models are available (USEPA 1998e, USEPA 

1999d) to determine the source terms for an accidental chemical release. 

� Dispersion or consequence modeling is performed once the source terms (rate and 

duration of the release) are known. A wide variety of dispersion and consequence 

modeling tools, ranging from simple screening models to sophisticated and 

complex computer applications, are available for this step (USEPA 1999d, AIChE 

1996, USEPA 1993a). In addition to the source terms generated above, several 

other data elements are needed, such as physical/chemical properties (e.g., 

whether the vapor cloud is heavier than air or water reactive), meteorological 

conditions (e.g., wind speed and direction, temperature, humidity), and terrain 

surrounding the facility (e.g., buildings or valleys that may channel or disperse a 

vapor cloud). Physical/chemical properties can be found in chemical reference 

texts such as Kirk-Othmer’s Encyclopedia of Chemical Technology (Kroschwitz 

and Howe-Grant, 1994), Perry’s Chemical Engineers’ Handbook (Perry, et al., 

1997), on Material Safety Data Sheets (MSDS)14, or in the Guidance for Offsite 

Consequence Analysis (USEPA 1999d). Meteorological conditions are often 

collected on-site or at local airports. Information about terrain can be collected 

from topological maps or by visual inspection. Guidance on all these parameters is 

available in USEPA 1999d. 

The final step in a chemical accident exposure analysis is the exposure assessment. The 

exposure assessment is related to, and builds from, the dispersion or consequence 

modeling step. The dispersion or consequence modeling depends on a health endpoint 

and the exposure level related to that endpoint. Besides lethality, concentrations for 

certain health effects (e.g., odor thresholds, eye irritation) are available for several 

14 There are many searchable MSDS data bases on-line that can be located with most search engines. 

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common toxic substances (NIOSH 1997, ACGIH 1998, AIHA 2000). 

B.2. Resources Relevant to Exposures to Non-Chemical Stressors 

Biological stressors: 

The ILSI Risk Science Institute recently published a workshop report entitled “Revised 

Framework for Microbial Risk Assessment” (ILSI, 2000), which looks at methods for 

assessing risks to microorganisms such as Cryptosporidium, which has caused disease 

outbreaks when it contaminates drinking water. The methodology is superficially similar 

to a risk assessment conducted for a chemical pollutant, but only at the most general 

level. How exposure is characterized, for example, includes many differences from 

environmental chemical exposure assessment. Under “characterization of exposure,” for 

example, the framework includes (1) pathogen characterization, (2) pathogen occurrence, 

(3) exposure analysis, and finally developing (4) an exposure profile. 

Radiological stressors: 

EPA’s Office of Air and Radiation maintains a web page at 

http://www.epa.gov/radiation/assessment/. This page provides (or cites) much of the 

needed documentation for performing risk assessments for radionuclides. This includes 

the Radiation Exposure and Risk Assessment Manual (RERAM) (USEPA, 1996e) and 

several Federal Guidance Reports (USEPA, 1988, 1993d, 1999l). 

Noise, vibration, and congestion: 

The U.S. Department of Housing and Urban Development has issued The Noise 

Guidebook (HUD, 1991), which implements the existing noise regulations [24 CFR 51-

B] and includes the HUD Noise Assessment Guidelines. (The Guidebook is available in 

hard copy only.) 

The Federal Railroad Administration has developed a manual called High-Speed Ground 

Transportation Noise and Vibration Impact Assessment (DOT, 1998) which provides the 

theory, equations, and applications of noise and vibration analysis for high-speed 

railroads. Much of the theory and information is also applicable to other noise and 

vibration problems. Appendix A of the DOT Guide is a general discussion of noise 

concepts, with references. The Guide is available on-line. 

The National Institute of Occupational Health and Safety has done much research on the 

interaction of noise with chemical exposures (Morata, 2000). 

Odor: 

EPA’s Office of Wastewater Management has issued a report called Guide to Field 

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Storage of Biosolids (USEPA, 2000j) which contains an appendix on “Odor 

Characterization, Assessment, and Sampling.” Odor assessment is an analyticdeliberative process, involving both science-based analytical methods and more 

subjective analysis. The appendix of the Guide discusses sensory characterization of 

odors (character, intensity, pervasiveness, quantity), some practical options for assessing 

odors in a community, and the chemistry of odors (including range of odor thresholds). It 

also discusses odor sample collection and analysis, and has several dozen references for 

further information. This report is available on-line. 

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APPENDIX C: SOME THOUGHTS ON BACKGROUND EXPOSURES 

When looking at aggregate exposures or cumulative risks of citizens, “background 

exposures” to specific chemicals are no less “real” exposures than the pollution usually studied 

for regulatory purposes. Whereas in historical single-chemical assessments conducted for 

limiting pollution, background sources of the chemical were often irrelevant to the questions 

being asked of the assessment (or ignored as having negligible effect on risk), background 

sources are rarely irrelevant with cumulative risk assessments15. 

Background concentrations can be categorized as either naturally-occurring, that is, 

chemicals which are naturally present in the environment before it was influenced by humans, or 

anthropogenic, that is, present in the environment due to historical human-made sources. 

Naturally-occurring background chemicals may be either localized or ubiquitous. Anthropogenic 

background sources can be either localized from a point source, or generalized from unidentified 

sources or non-point sources. 

Assessments of morbidity incidence and death rates, market basket surveys, and pesticide 

residue surveys also provide information which can be reflective of background chemical 

concentrations as well as overt pollution. Background issues extend across all media, beyond 

regulated sources, and beyond direct exposure. Many chemicals are naturally present in the 

environment (e.g., soils, water, vegetation and other biota) and are consequently part of dietary, 

dermal and inhalation exposures. In some cases, naturally-occurring substances may occur at 

levels that exceed health-based or risk-based regulatory standards (e.g., drinking water 

standards), or other levels established to protect human health and the environment. Since 

cumulative risk assessments are population based, exposures due to naturally-occurring 

background concentrations should typically be considered to be of importance. 

There are several important issues related to natural or anthropogenic background 

concentrations in cumulative risk assessment. First, if the risks posed by “background” 

concentrations of certain chemicals are significant (and some may approach or exceed health 

reference levels), their exclusion from the cumulative risk estimates and characterization may 

seriously distort the portion of the total estimated risk thought to be posed to the population by a 

specific evaluated source. A second issue is the problem of whether background chemical 

exposures can be clearly distinguished from specific source-related chemicals, and how to 

quantify these exposures. It may be important in a cumulative risk assessment to estimate 

background exposures separately from specific source-related exposures, so that the risk assessor 

15 The word “background” is often used to describe exposures to chemicals or other stressors that derive from sources 

other than the sources being assessed. For example, in the Agency’s assessment of residual risk associated with hazardous air 

pollutant emissions from particular categories of sources that remain after the implementation of technology-based controls, 

“background” is defined as all hazardous air pollutant exposures (via inhalation or other routes) not associated with the source(s) 

being assessed. At a Superfund site, “background contamination” refers to contamination that is not related to the site release of 

chemicals, as defined by Comprehensive, Environmental Response, Compensation and Liability Act (CERCLA).[P.L. 96-510, 

December 11, 1980, as amended by P.L. 98-802, August 23, 1983, and P.L. 99-499, October 17, 1986] Such focusing or 

segregation in a risk assessment can be useful to decisions involving pollution sources covered by particular statutory authorities, 

but it is typical of a chemically-focused assessment rather than a population-focused assessment such as a cumulative risk 

assessment. 

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can provide the community with a more complete picture of both total and known source-related 

risks. This also provides a clearer, more complete picture for making risk management 

decisions. Finally, there may be problems in identifying representative geographic areas for 

determining “background levels” for comparison. 

Finally, background exposures for a community or population may also include both 

voluntary and involuntary exposures, and subsequent risks. Involuntary exposures are associated 

with the naturally-occurring or anthropogenic background concentrations described above. 

Voluntary exposures, such as are associated with lifestyle decisions, are exposures due to 

activities such as smoking, consuming char-grilled meats with PAHs, or other choice-based 

exposures, and may also sometimes be defined in the assessment as “background” exposures if 

they are not assessed directly in the cumulative risk assessment. 

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APPENDIX D: EXAMPLES OF ANALYSIS PLANS 

D.1. Human Health Analysis Plan for Pesticides under FQPA 

Risk management /regulatory goal: Protection of the general human population and susceptible 

subpopulations to adverse effects from exposure to pesticide “X” under the 1996 Food Quality 

Protection Act (FQPA) 

Assessment endpoints: 

- human or animal health status of exposed versus unexposed populations/cohorts/dose 

groups 

Measures of Effects: 

- general types of toxicological effects grouped according to acute, subchronic, and 

chronic exposure durations 

- organ-specific toxicity such as reproductive effects, developmental effects, 

neurotoxicity, developmental neurotoxicity, immunotoxicity, hepatotoxicity, 

pulmonary effects, cardiovascular effects, etc. 

- general classes of toxic effects such as carcinogenicity, mutagenicity 

Measures of Exposure: 

- monitoring of food, water, residential, occupational exposures, etc. (direct or surrogate) 

- monitoring of biological fluids or biomarkers (blood, urine, DNA or other 

macromolecules) 

What Can and Cannot be Done Based on Planning and Scoping 

- pathways and relationships to be evaluated 

- resource restraints 

- milestones for completion of risk assessment 

Methods for Conducting Risk Analysis 

- RfD 

- Margin of Exposure (MOE) 

- probabilistic risk assessment based on dose-response or exposure parameters 

- quotients (e.g., ratio of exposure level to toxicity threshold) 

- narrative discussions 

- other considerations (e.g., mechanisms of action, toxicokinetic models, timing of dose, 

sensitive population characteristics) 

Data Needs and Uncertainties 

D.2. Ecological Analysis Plan 

Risk management/regulatory goal: Viable, self-sustaining coho salmon population that supports 

a subsistence and sport fishery. 

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Assessment endpoints: Coho salmon breeding success, fry survival, and adult return rates. 

Measures of Effects: 

- egg and fry response to low dissolved oxygen 

- adult behavior in response to obstacles 

- spawning behavior and egg survival with changes in sedimentation 

- population data over time in relation to fish passage 

Measures of Ecosystem and Receptor Characteristics: 

- water temperature, water velocity, and physical obstructions 

- abundance and distributions of suitable breeding substrate 

- abundance and distribution of suitable food sources for fry 

- feeding, resting, and breeding behavior 

- natural reproduction, growth, and mortality rates 

Measures of Exposure: 

- number of hydroelectric dams and associated ease of fish passage 

- toxic chemical concentrations in water, sediment, and fish tissue 

- nutrient and dissolved oxygen levels in ambient waters 

- riparian cover, sediment loading, and water temperature 

What Can and Cannot be Done Based on Planning and Scoping 

- pathways and relationships to be evaluated 

- resource restraints 

- milestones for completion of risk assessment 

Methods for Conducting Risk Analysis 

- quotients 

- narrative discussions 

- stressor-response curves with probabilities 

Data Needs and Uncertainties 

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APPENDIX E: TOXICOLOGIC SIMILARITY: ORGANOPHOSPHORUS PESTICIDES 

The Food Quality Protection Act of 1996 (FQPA) requires that EPA reassess pesticide tolerances 

(legal limits for residues in food) that were in effect as of August 1996. As part of the 

reassessment, EPA must consider available information concerning the cumulative effects on 

human health resulting from exposure to multiple chemicals that have a common mechanism of 

toxicity. In this context, pesticides are determined to have a common mechanism of toxicity if 

they produce the same toxic effect, in the same organ or tissue, and by essentially the same 

sequence of major biochemical events (USEPA, 1999m). 

Shortly after enactment of FQPA, EPA began developing new methods and tools that would 

allow the consideration of combined risks from exposure to several pesticides via several 

pathways and routes of exposure. Actual data sets for organophosphorous pesticides were used 

in pilot analyses to test these methods. The methods and pilot analyses were subjected to peer 

review through the FIFRA Scientific Advisory Panel (SAP) to ensure the use of sound science. 

As part of this ongoing effort, on December 28, 2001 EPA’s Office of Pesticide Programs (OPP) 

announced the availability of the Preliminary Organophosphorus Cumulative Risk Assessment 

[66FR67249-67250]. The risk assessment is available electronically at: 

http://www.epa.gov/pesticides/cumulative. In preparing the cumulative risk assessment for the 

organophosphorous (OP) pesticides, OPP followed 5 major steps. 

1. Selection of the specific pesticides, pesticide uses, pathways and routes of exposure to include 

in the quantitative analysis. 

The selection of the specific OP pesticides began with identifying a “common mechanism 

group.” This was accomplished following the Guidance For Identifying Pesticide 

Chemicals And Other Substances That Have A Common Mechanism Of Toxicity 

(available at http://www.epa.gov/pesticides/trac/science). All 39 registered OP pesticides 

share inhibition of acetylcholinesterase as a common mechanism for causing adverse 

effects (USEPA, 1998k). 

The common mechanism group was further refined to reflect current use patterns and 

information on the detection of residues from USDA’s Pesticide Data Program. This 

resulted in the following recommendations for quantitative analysis: include 22 OP 

pesticides for the food pathway of exposure; 24 OPs for the water pathway and 10 OPs 

for residential exposures were identified based on use patterns and their individual 

assessments. 

2. Dose-response analysis for toxic potencies, relative contribution from each OP, and selection 

of an index chemical to use as the point of reference in the dose-response analysis. 

To determine the combined risk from multiple OP pesticides, EPA used the Relative 

Potency Factor (RPF) approach [for additional examples of comparative potency 

approaches, also see Albert, et al., 1983; Lewtas, 1985, Lewtas, 1988]. The index 

chemical was selected based on the quality of the dose-response data. Then the relative 

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potency of each OP pesticide was estimated by taking the ratio of its toxic potency to that 

of the index chemical. 

In selecting studies for evaluating toxic potencies, EPA used relative potency factors and 

points of departure developed from cholinesterase inhibition in rats exposed to pesticides 

for 21 days or more. This practice was adopted to reflect cholinesterase inhibition at a 

point in the treatment schedule at which a steady state had been achieved. OPP elected to 

use data reflecting a steady state in the interest of producing relative potency factors that 

are reproducible and reflect less uncertainty due to rapidly changing time-sensitive 

measures of cholinesterase. 

Also, EPA considered that people generally have had some level of prior exposure to OP 

pesticides. Further, the effects of exposure can persist for several days to weeks. 

Therefore, people may be more vulnerable to subsequent exposures to OP pesticides than 

might be predicted by not considering these prior exposures. 

3. Estimation of the risks associated with all pertinent pathways of exposure in a manner that is 

both realistic and reflective of variability due to differences in location, time, and demographic 

characteristics of exposed groups. 

Evaluation of the OP pesticide use profiles allowed for the identification of exposure 

scenarios that may overlap, co-occur, or vary between chemicals. In addition, the use 

profiles allowed for the identification of populations of potential concern. Based on this 

analysis, EPA considered exposure to OP pesticides in food to be uniform across the 

nation (i.e., there are no significant differences in food exposure due to time of year or 

geographic location). For the residential and drinking water pathways of exposure, EPA 

divided the nation into 12 regions for assessment. This allowed for the consideration of 

such factors as the location of vulnerable surface watersheds and region specific pest 

pressures. To estimate risks, EPA used a calendar based computer model titled Calendex. 

This model integrates the various pathways of exposure while simultaneously 

incorporating the time dimensions of the data. The model produces a detailed profile of 

the potential exposure to individuals across a calendar year. 

4. Identification of the significant contributors to risk. 

Although interpretation of the preliminary organophosphorous cumulative risk 

assessment is ongoing, there are some early indications concerning contribution to risk. 

The drinking water pathway for exposure does not appear to be a major contributor to the 

total cumulative risk. Residential exposure appears to be a contributor to risk, 

particularly inhalation exposures from certain no-pest strips and crack and crevice 

treatments. Childhood exposure from mouthing hands also appears to be a contributor 

but there is a great deal of uncertainty associated with the estimates. 

5. Characterization of the confidence in the results and the uncertainties encountered. 

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1 In addition to some uncertainties noted above, EPA identified many areas for additional 

2 analysis including: sensitivity analyses on input parameters, verification of residential 

3 use patterns, closer examination of the tails of the food consumption distribution, and 

4 evaluation of the effect of assumptions about residue concentrations in baby foods. 

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APPENDIX F: OTHER TYPES OF CUMULATIVE ASSESSMENTS 

There are several other types of cumulative assessments that are related to the types of 

human health and ecological cumulative assessments done by the Agency. It is beyond the scope 

of this Framework to discuss these in detail, but a short explanation of several other types of 

cumulative assessments are given in this appendix. 

F.1. Quality-of-Life Assessments 

One type of assessment which 

resembles a cumulative risk assessment, but 

whose evaluation may require a different 

approach from the traditional NRC risk 

paradigm, is the quality-of-life assessment. 

These assessments define “harm” to an 

individual or community broadly, then 

evaluate the importance of the various threats 

of harm to a set of “quality-of-life” criteria 

(see box at right). These assessments do not 

usually attempt to predict probability that the 

harm will occur (as would a cumulative risk 

assessment), but rather aim to apply the 

community’s values to deal with the most 

important perceived threats. 

Although a quality-of-life assessment 

is not a risk assessment in most cases, changes 

in quality-of-life factors may affect the 

vulnerability of a population to health or 

ecological risks, and consequently may be part 

of the considerations in a cumulative risk 

assessment. Since few, if any, established and 

accepted relationships are currently available 

quantitatively linking quality-of-life factors 

and health or ecological risk, this is an area in 

which further research may prove valuable. 

To evaluate the effects on human or 

ecological health from these types of impacts, 

a more deliberative approach (in the 

analytical-deliberative process) is needed than 

is used in, say, cancer risk analysis. To help 

Vermont’s Quality of Life Criteria 

Impacts on Aesthetics: Reduced visibility, noise, odors, 

dust and other unpleasant sensations, and visual impact 

from degradation of natural or agricultural landscapes. 

Economic Well-Being: Higher out-of-pocket expenses to 

fix, replace, or buy items or services (e.g., higher waste 

disposal fees, cost of replacing a well, higher housing 

costs), lower income or higher taxes paid because of 

environmental problems, and health-care costs and lost 

productivity caused by environmental problems. 

Fairness: Unequal distribution of costs and benefits (e.g., 

costs and benefits may be economic, health, aesthetic). 

Future Generations: Shifting the costs (e.g., economic, 

health risks, environmental damage) of today’s activities to 

people not yet able to vote or not born yet. 

Peace of Mind: Feeling threatened by possible hazards in 

air or drinking water, or potentially risky structures of 

facilities (e.g., waste sites, power lines, nuclear plants), and 

heightened stress caused by urbanization, traffic, etc. 

Recreation: Loss of access to recreational lands (public 

and private), and degraded quality of recreation experience 

(e.g., spoiled wilderness, fished-out streams). 

Sense of Community: Rapid growth in population or 

number of structures, or development that changes the 

appearance and feel of a town; loss of mutual respect, 

cooperation, ability, or willingness to solve problems 

together; individual liberty exercised at the expense of the 

individual; the loss of Vermont’s landscape and the 

connection between the people and the land. 

Source: State of Vermont, 1991 

better characterize these impacts, EPA’s Guidebook to Comparing Risks and Setting 

Environmental Priorities (USEPA, 1993b) suggests a six-step process in Quality-of-Life 

Analysis: 

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1. Identify impacts and determine the values of the community. 

2. Identify and define evaluative criteria. 

3. Collect and analyze data on impacts. 

4. Characterize impacts for all problem areas. 

5. Present findings and rank problem areas for quality-of-life impacts. 

6. Analyze future environmental conditions and risk management considerations. 

Quality-of-Life impacts are determined by analyzing a set of criteria developed for each 

community, depending on what they value. Stressors are those things that threaten to degrade the 

quality-of-life criteria for that community. An example of a set of quality-of-life criteria, and 

their descriptions, is in the box on the previous page. These criteria were developed by the State 

of Vermont’s Agency of Natural Resources (State of Vermont, 1991). Vermont’s experience in 

evaluating these criteria was described as a qualitative description of harm, or in their terms, 

“risk:” 

“Because most of these seven criteria are intangible, they are extremely difficult to 

measure or quantify. The Quality-of-Life Work Group described how each problem area 

affects each criterion and how widespread or intense the effects are. Although these nonquantitative descriptions of risk often lack precision and scientific objectivity, they focus 

attention on specific critical issues and thus are useful tools for comparing the problems 

systematically and consistently.” (State of Vermont, 1991) 

Quality-of-life issues can encompass much more than the criteria used here as an 

example. Ultimately, such an analysis may introduce much additional complexity into the 

analysis. There may, for instance, be feedback loops not easily evaluated (e.g., loss of property 

value, aesthetics, etc., tend to negatively affect the socioeconomic system, which in turn tends to 

increase rates of crime, traffic accidents, and communicable-pathogen transmission, all 

ultimately reflecting on overall community 

health or ecological risk). Some cumulative 

risk assessments may consequently include 

quality-of-life impacts as indirect measures of 

health effects if sufficient links can be 

established between the two. 

F.2. Cumulative Impact Assessments 

The National Environmental Policy 

Act (NEPA) has certain requirements for 

“cumulative impacts” assessment (see box at 

right), which looks at various stressors 

leading to a variety of impacts or effects on 

the environment. Although the Council on 

NEPA’s “Cumulative Impact” Definition 

CEQ Regulation 1508 for Implementing the National 

Environmental Policy Act of 1969 [P.L. 91-190, 42 U.S.C. 

4321-4347, January 1, 1970, as amended by P.L. 94-52, 

July 3, 1975, P.L. 94-83, August 9, 1975, and P.L. 97-258, 

§4(b), Sept. 13, 1982] defines “cumulative impact” as “the 

impact on the environment which results from the 

incremental impact of the action when added to other past, 

present, and reasonably foreseeable future actions 

regardless of what agency (Federal or non-Federal) or 

person undertakes such other actions. Cumulative impacts 

can result from individually minor but collectively 

significant actions taking place over a period of time.” 

Source: CEQ, 1997 

Environmental Quality’s guidelines for cumulative impact analysis (CEQ, 1997) take a primarily 

qualitative approach to the analysis, this is a multiple stressor, multiple effect assessment. 

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The projects or actions that NEPA addresses can be viewed as sources of stressors. 

Environmental impact assessment under NEPA contains a description of the affected 

environment that contains four types of information: (1) data on the status of important natural, 

cultural, social, or economic resources and systems; (2) data that characterize important 

environmental or social stress factors; (3) a description of pertinent regulations, administrative 

standards, and development plans; and (4) data on environmental and socioeconomic trends. 

Health effects on populations and susceptible individuals are part of the affected environment as 

considered by the NEPA cumulative effects analysis, but the NEPA analysis may also consider 

effects on historic and archaeological resources, socioeconomic factors like employment, human 

community structure, and quality of life changes. Although there is not always a clear 

relationship between these NEPA cumulative impacts and effects relevant to human health, the 

NEPA methods and tools for cumulative impact analysis may be useful for cumulative risk 

assessments. For example, cumulative impact analysis begins with an extensive scoping process 

and relies on conceptual models to plan the analysis. NEPA effects data may help risk assessors 

identify susceptible subpopulations, environmental pathways, or exposure patterns. 

EPA’s Region VI has developed a system called the Cumulative Risk Index Analysis 

(CRIA), primarily for NEPA-type assessments (Osowski, et al., 2001). The CRIA contains some 

90 criteria to evaluate the health of an area and its ecosystem/human populations. These criteria 

help evaluate factors as diverse as human health, ecosystem health, and environmental justice 

considerations. Each criterion, which leads to an indexing of 1-5, has been through the 

deliberative process, peer review, and is well documented. 

We also acknowledge that other Federal Agencies have been preparing “cumulative risk 

analyses” for various purposes related to their own mission as part of environmental impact 

statements (e.g., NOAA, 1999). 

F.3. Empirically-Derived Medical Models 

The medical profession has long used empirically-derived models to predict the chances 

of particular health effects in individual patients. In this approach, the characteristics of 

individuals within the population are correlated with the incidence of specific diseases or effects. 

For example, the risk factors for stroke are: increasing age, heredity (family history) and race, 

prior stroke, high blood pressure, cigarette smoking, diabetes mellitus, carotid and other artery 

disease, heart disease, transient ischemic attacks (TIAs), high red blood cell count, sickle cell 

anemia, socioeconomic factors, excessive alcohol consumption, and certain types of drug abuse 

(American Heart Association, 2000). Each of these risk factors can be correlated with stroke 

incidence, and then the risk of stroke from various combinations of these factors can be explored. 

In this way, the analysis is “cumulative,” but “risk factors” are not always synonymous with 

“stressors.” 

Physicians use models containing effect-specific risk factors to advise patients of the 

probabilities of future effects (e.g., stroke, breast cancer) based on their medical history. 

Although the medical data upon which these factors are based have been well developed for 

many effects in humans, there are substantial data gaps remaining in terms of the role played by 

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exposures to many chemicals in the environment in the development of human disease. This 

approach may be built on links between risk factors and effects for better studied stressors, but 

may be limited or nonexistent for less robust health effects data bases. Although this approach 

may some day be applicable to human health and environmental risk assessment such as EPA 

conducts, at present the data and methods are not available. 

F.4. Risk Surrogates 

Geographic Information Systems (GIS) and related mapping techniques (e.g., 

Environmental Defense, 2001) appear to hold some promise as tools for presenting integrated 

information concerning cumulative risks without mathematically combining disparate measures. 

Considerable methods development work remains to be completed. 

Not all statements of probability of harm are expressed as probabilities of specific health 

effects. Bernard Cohen, in his Catalog of Risks Extended and Updated (Cohen, 1991), uses 

mortality ratios to derive “loss of life expectancy” (LLE) estimates for a wide variety of riskrelated activities. For example, workers in all occupations have a 60 day LLE as a result of 

working, but workers in agriculture have a 320 day LLE, construction workers a 227 day LLE, 

etc., as a result of their particular occupation. These types of statements are empirically derived, 

probability-based statements of harm that do not use “probability of adverse health effect” as the 

basis for the risk statement. For estimates such as LLEs, one could theoretically add up the 

various activities and the corresponding LLEs in days to estimate a cumulative risk in terms of 

loss of life expectancy. These “other” types of risk-surrogate probability statements could 

conceivably be used in cumulative risk assessment, although there is apparently no methodology 

currently being used to do so. 

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