EPA/630/P-02/001F May 2003



# Framework for Cumulative Risk Assessment

Risk Assessm ent Forum U.S. Environm ental Protection Agency W a shington, DC 20460Disclaimer This docum ent has been reviewed in accordance with the U.S. Environm ental Protection Agency (EPA or the Agency) peer and adm i nistrative review policy. It has had extensive peer involve m e nt in develop m ent (including other Federal, State, and public involve m e nt), it has co m p leted the form al external technical peer review process, and it has been adm i nistratively reviewed under the auspices of the Agency Science Policy Council. The m e ntion of co mm e rcial products is for illustration only and in no way i m plies EPA endorse m e nt of these products.

iiTable of Contents
L i s t o f F i g ur e s
............................................................... v i
L i s t o f T e x t B o x e s
........................................................... v i i Acknowledgm ents

............................................................ i x F o r e w o r d ....................................................................x P r e f a c e
..................................................................... x i
A u th o r s , C o n tr i b u t o r s , an d R e v i e w e r s
............................................ x i i i List of Abbreviations and Acronym s
............................................. x v i
E x e c u t i v e S umm ary ......................................................... x v i i
1. INTRODUCTION ..........................................................1 1.1. Purpose and Scope of the Fram ework Report ..............................4 1.2. Intended Audience ...................................................6 1.3. Key Definitions in Cum u lative Risk Assessm ent ...........................6 1.4. The Cum u lative Risk Assessm ent as a Tool for a Variety of Users a n d P ur p o s e s .......................................................9 1.5. The Broader Decision-Making Context for Cum u lative Risk Assessm ent .......1 1 1.6. Organization of This Report ..........................................1 2
2. THE PLANNING, SCOPING, AND PROBLEM FORMULATION PHASE ...........1 4 2.1. Planning and Scoping ...............................................1 4 2.1.1. Defining the Purpose of the Assessm ent .........................1 7 2.1.2. Defining the Scope of Analysis and Products Needed ...............1 8 2.1.3. Agreeing on Participants, Roles, and Responsibilities ...............1 9 2.1.4. Agreeing on the Depth of the Assessm ent and the Analytical Ap p r o a c h ..................................................2 2 2.1.5. Agreeing on the Schedule and Resources Available ................2 2 2.1.6. Review of Lessons Learned ...................................2 2 2.2. Problem Form ulation, Conceptual Model, and Analysis Plan .................2 4 2.2.1. Problem Form ulation ........................................2 4 2.2.2. Developing the Conceptual Model ..............................2 5 2.2.3. Constructing the Analysis Plan .................................2 8 2.2.4. An Early Look at Uncertainty ..................................2 9 2.3. Ecological versus Hum an Health versus “Integrated” Cum u lative R i s k A s s e s s m e n t ...................................................3 0 2.4. The Final Step Before the Analysis Phase: Discussion of Possible Outcom es ....3 1

iii3. THE ANALYSIS PHASE ...................................................3 4 3.1. General Process ....................................................3 4 3.2. Available Methods and Approaches ....................................3 6 3.2.1. Exam ples of Increased Com p lexity of Cum u lative Risk Assessm ent ...3 7 3.2.2. Approaches for Predicting Risk of Multiple Stressors ...............4 3 3.2.2.1. Single stressor inform ation ............................4 4 3.2.2.2. Inform ation on stressor interactions and m u ltiple exposures ..........................................4 6 3.2.2.3. Decision indices .....................................4 8 3.2.2.4. Probabilistic approaches ..............................5 0 3.3. Areas of Com p lexity and Current Research ..............................5 0 3.3.1. Interactions Between Stressors and Other Factors ..................5 1 3.3.2. The Prom ise of Biom arkers and Biom onitoring ....................5 2 3.3.3. A Single Metric for Multiple Types of Hazard .....................5 4 3.3.3.1. Creating a comm on m e tric .............................5 5 3.3.3.2. General issues regarding a single m e tric ..................5 7 3.3.4. Qualitative Approaches .......................................5 8
4

. T H E R I S K C H A R A C T E R I Z A T I O N P H A S E ....................................5 9 4.1. Risk Description ...................................................6 1 4.2. Uncertainty Analysis ................................................6 3 4.2.1. Assum p tions in the Assessm ent ................................6 4 4.2.2. Uncertainty and Variability ...................................6 5 4.2.3. Uncertainty and Risk Addition .................................6 6 4.2.4. Other Cum u lative Risk Assessm ent Uncertainties .................6 7 4.3. Inform ation Provided by Cum u lative Risk Assessm ent .....................6 7 4.3.1. Making Sense of Multiple-Stressor Effects .......................6 7 4.3.2. Cum u lative Risk Assessm ents in a Public Health Context ............6 8 4.3.3. How the Scope and Purpose of the Assessm ent Affect Results ........6 9 4.3.4. Docum e nting Stakeholder Input ................................6 9 4.4. Using the Results of the Assessm ent ....................................6 9
5

. G L O S S A R Y ..............................................................7 2
R E F E R E N C E S ..............................................................7 5
APPENDIX A: RESEARCH AND DEVELOPMENT NEEDS ........................9 1
APPENDIX B: SELECT RESOURCES FOR EXPOSURE AND RISK ASSESSMENT ....9 4 B.1. Resources Relevant to Chem ical Exposures ..............................9 4 B.2. Resources Relevant to Exposures to Nonchem i cal Stressors .................9 6 APPENDIX C: SOME THOUGHTS ON BACKGROUND EXPOSURES ...............9 8

ivAPPENDIX D: EXAMPLES OF OUTLINES OF ANALYSIS PLANS .................1 0 0 D.1. Outline for Hum an Health Analysis Plan for Pesticides Under the 1996 Food Quality Protection Act (FQPA) ......................................1 0 0 D.2. Outline for Ecological Analysis Plan ..................................1 0 1
APPENDIX E: TOXICOLOGIC SIMILARITY—ORGANOPHOSPHORUS P E S T I C I D E S .........................................................1 0 2
A P P E N D I X F : O T H E R T Y P E S O F C U M U L A T I V E A S S E S S M E N T S .................1 0 5 F.1. Quality-of-Life Assessm ents .........................................1 0 5 F.2. Cum u lative Im pact Assessm ents ......................................1 0 7 F.3. Em pirically Derived Medical Models ..................................1 0 8 F.4. Risk Surrogates ...................................................1 0 9

vList of Figures

1-1. A chem ical- (or stressor-) focused assessm ent starts with a source and evaluates how the chem ical gets to various populations or ecological targets ........................1
1-2. Population-based assessm ents start with the receptors and determ ine which chem icals, s tr e s s o r s , o r o th e r r i s k f a c t o r s ar e a f f e c t i n g th e m ...............................2
1

- 3

. F r a m e w o rk f o r c um u l a t i v e r i s k a s s e s s m e n t ...................................1 3
2-1. The Planning, Scoping, and Problem Form ulation phase ........................1 5
2

- 2

. A n e x a m p l e o f a g e n e r i c c o n c e p tu a l m o d e l ...................................2 6
2-3. Specific conceptual m odel for a com p lex project, OAQPS’ National Scale Air T o x i c s A s s e s s m e n t ......................................................2 7
3

- 1

. T h e A n a l y s i s p h a s e .....................................................3 5
4

- 1

. T h e R i s k C h ar a c t e r i z a t i o n p h a s e ...........................................6 0

viList of Text Boxes
Exam ples of Cum u lative Risk Assessm ent Activities within EPA in 2002

............... x i x E P A ’ s R i s k A s s e s s m e n t G u i d e l i n e s ...............................................5 FQPA’s Term inology Interpretations ..............................................7
C um u l a t i v e R i s k A s s e s s m e n t F e a tur e s ............................................1 0
C o r e P r i n c i p l e s o f C o mm un i ty - B a s e d E n v i r o n m e n t a l P r o t e c t i o n ........................1 1
P o s s i b l e M an a g e m e n t G o a l s ....................................................1 7
E x a m p l e s o f C um u l a t i v e R i s k A s s e s s m e n t S c o p e s ...................................1 8
E x a m p l e s o f P o s s i b l e I n t e r e s t e d o r A f f e c t e d P art i e s ( S t a k e h o l d e r s ) ......................2 0 Guidelines for Stakeholder Involvem e nt ...........................................2 1
R e e d H o l d e rm an ’ s L e s s o n s L e arn e d ..............................................2 3
T h e S c i e n c e A dv i s o ry B o ar d ’ s D e s i r e d O u t p u t s f o r P r o b l e m F o rm u l a t i o n ................2 4
I m p o rt an t D e t a i l s f o r an A n a l y s i s P l an ............................................2 8
Cum u lative Risk Initiative (CRI) for Cook County (IL) and Lake County (IN) .............3 2 Scope of EPA’s National-Scale Assessm ent for Hazardous Air Pollutants ................3 6
T h e N a t i o n a l

- S c a l e A i r T o x i c s A s s e s s m e n t ........................................3 8
Exam ples of Exposure Models that Consider Tim e Aspects ............................4 0
T o x i c o l o g i c S i m i l ar i ty : T h e D i o x i n R e a s s e s s m e n t ...................................4 6 The Hazard Index .............................................................4 9
R i s k C h ar a c t e r i z a t i o n G u i d i n g P r i n c i p l e s ..........................................6 1
Som e Thoughts on Risk Characterization ..........................................6 2 Morgan and Henrion’s Ten Requirem e nts for Good Policy Analysis .....................6 3

viiThe Cum u lative Exposure Project ................................................6 5
T h e E ur o p e an E n v i r o n m e n t A g e n c y ’ s 1 2 L e s s o n s L e arn e d L a t e ........................7 1
Verm ont’s Quality-of

- Lif e Criteria ..............................................1 0 6
NEPA’s “Cum ulative Im pact” Def i nition .........................................1 0 7

viiiAcknow ledgments This U.S. Environm ental Protection Agency (EPA or the Agency) report has been developed under the auspices of EPA’s Risk Assessm ent Forum , a standing comm ittee of EPA scientists charged with developing risk assessm ent guidance for Agency-wide use. An interoffice Technical Panel chaired by Michael A. Callahan (Region 6) was comm i ssioned to write this report. Other m e m b ers of the Panel are Edward S. Bender (Office of Science Policy), George L. Bollweg (Region 5), Vicki L. Dellarco (Office of Pesticide Program s), Lynn A. Delpire (Office of Pollution Prevention and Toxics), Martin P. Halper (Office of Environm ental Justice), Richard C. Hertzberg (National Center for Environm ental Assessm ent), Elizabeth Lee Hofm ann (Office of Em ergency and Rem e dial Response), R. Craig Matthiessen (Chem i cal Em ergency Preparedness and Prevention Staff), Alexander McBride (Office of Solid W a ste), Deirdre L. Murphy (Office of Air Quality Planning and Standards), Henry C. Topper (Office of Pollution Prevention and Toxics), and W i nona Victery (Region 9). In addition, Carole Braverm an (Region 5), Loren Hall (Office of Civil Rights), and Denis R. Borum (Office of W a ter) participated for part of the duration of the panel. Steven M. Knott of the Risk Assessm ent Forum staff coordinated the project and also participated as a m e m b er of the panel. The Technical Panel would also like to thank Forum staff m e m b ers Lowell F. Sm ith, Marilyn D. Brower, and Crystal M. Sam u els for their assistance. Peer involvem e nt and peer review were provi ded by scientists from EPA, other Federal agencies, State agencies, academ ia, public interest groups, and the private sector; their nam e s are listed in the section titled “Authors, Contributors, and Reviewers.”

ixForew ord Several reports have highlighted the im portance of understanding the accum u lation of risks from m u ltiple environm ental stressors. Am ong these reports are the National Research Council’s 1994 Science and Judgment in Risk Assessment and the 1997 report by the Presidential/Congressional Comm i ssion on Risk Assessm ent and Risk Managem e nt, Risk Assessment and Risk Management in Regulatory Decision-Making

. In addition, legislation such as the Food Quality Protection Act of 1996 (FQPA), has directed the U.S. Environm ental Protection Agency (EPA, or the Agency) to m ove beyond single chem ical assessm ents and to focus, in part, on the cum u lative effects of chem ical exposures occurring sim u ltaneously. Som e of the cases filed with EPA under Title VI of the 1964 Civil Rights Act further em phasize the need for EPA to develop m e thods to assist consideration of cum u lative risks. The Superfund program began conducting cum u lative risk assessm ents at hazardous waste sites as early as the 1980s. More recently, in response to the increasing interest in cum u lative risk, several other EPA program s have begun to explore approaches to cum u lative risk assessm ent. In 1997, the EPA Science Policy Council issued a guidance on planning and scoping for cum u lative risk assessm ents. More recently, the Office of Pesticide Program s has developed cum u lative risk assessm ent guidance focused on im plem enting certain provisions of FQPA. In addition, the Office of Air Quality Planning and Standards is perform i ng a nationalscale cum u lative assessm ent of hum an 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 Assessm ent Forum to begin developing Agency-wide cum u lative risk assessm ent guidance that builds from these ongoing activities. As a first step, a technical panel convened under the Risk Assessm ent Forum has been working to develop a fram ework for cum u lative risk assessm ent. This docum ent is the result of that technical panel’s efforts. Building from the Agency’s growing experiences, this fram ework is intended to identify the basic elem ents of the cum u lative risk assessm ent process. It should provide a flexible structure for the technical issues and define key term s associated with cum u lative risk assessm ent. Further efforts and experience in the com i ng years should advance our knowledge beyond the fram ework stage to a future set of Agency guidelines for cum u lative risk assessm ent.

W illiam P. W ood, Ph.D. Executive Director Risk Assessm ent Forum

xPreface In the past several years, cum u lative risk assessm ent, aggregate exposure assessm ent, and research on chem ical m i xtures has taken on increased im portance, as evidenced by reports such as the National Research Council’s (NRC’s) Pesticides in the Diets of Infants and Children (NRC, 1993) and Science and Judgment in Risk Assessment (NRC, 1994), the National Academy of Public Adm i nistration’s Setting Priorities, Getting Results (NAPA, 1995), the Presidential/Congressional Comm i ssion on Risk Assessm ent and Risk Managem e nt’s Risk Assessment and Risk Management in Regulatory Decision-Making (PCCRARM, 1997), and the U.S. Environm ental Protection Agency’s (EPA’s or the Agency’s) Science Advisory Board Toward Integrated Environmental Decision-Making (USEPA, 2000a). In addition, recent legislation m andate s consideration of cu m u lative 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 assess m ent s of pesticide safety to focus, in part, on the cu m u lative effects of pesticides that have a co mm on m echanism of toxicity, considering aggre g ate dietary and nonoccupational pathways of exposure. Assessing cum u lative risk through com p lex exposures is one of the Agency’s high priorities, especially in light of FQPA m andates, and it is germ ane and of great interest to all program and regional offices. This area of research is also directly applicable to children’s risk issues. The fram ework presented in this docum ent is m eant to lay out broad areas where analysis m i ght be conducted if needed. It is not suggested that cum u lative risk assessm ent is a tool that should be used with every issue or that all areas of analysis outlined or discussed here m u st—or even should be—conducted in every such assessm ent. The scope of the assessm ent will define the areas to be analyzed. For som e areas discussed in this fram ework, the m e thodology for conducting the risk analysis m ay not yet exist. According to an expert panel report (USEPA, 1992a), a key role of science at EPA is to reduce uncertainties in the inform ation used for environm ental decision m a king. The report points out that although m any EPA program s have historically focused on chem ical-specific im pacts, m e thods to assess or control the effects of chem ical m i xtures and general stressors on hum an health and ecosystem s rem a ined to be developed. NRC (1993) has recomm e nded that all exposures to pesticides—dietary and nondietary—need to be considered when evaluating the potential risks to infants and children. Estim ates of total dietary exposure should be refined to consider intake of m u ltiple pesticides that have a comm on toxic effect. Further, the report identifies im portant differences in susceptibility with age. NRC (1994) has also stated that health risk assessm ents should generally consider all possible routes by which people at risk m i ght be exposed and recomm e nds this approach universally in the assessm ent of hazardous air pollutants regulated by EPA under the Clean Air Act Am endm ents of 1990 (P.L. 101-549, Novem b er 15, 1990).

xiRegarding variability, the NRC (1994) recomm e nds that EPA assess risks to infants and children whenever it appears that their risks m i ght be greater than those of adults. The report also encourages EPA to recognize the possibility of synergistic interactions when multiple chemical exposures occur, a n d to 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 co m b ined. EPA hopes to begin systematically addressing these issues in this framework. Finally, FQPA requires research on the influence of co m p lex exposures on noncancer hum an health effects of pesticides and other toxic substances.
Cum u lative risk is also an im portant issue with the general public. In public m eetings of Superfund stakeholders held in late 1996 in San Francisco and W a shington, DC, and in early 1998 in Atlanta, the issue of cum u lative risk wa s raised several tim es in each session (USEPA, 1996a, 1998a).
Cum u lative risk assessm ents will identif y the need f o r m any dif f e rent kinds of data—som e of which are not comm only used in current risk assessm ent—and they will of ten dem and large quantities of such data. Until such data can be provided, identif ication of critical inform ation and research needs m ay be the prim ary result of m any cum u lative risk assessm ent endeavors. As of August 1, 2001, there were 19,533 pesticide products on the m arket (USEPA, 2001a) and 79,120 existing chem icals on the Toxic Substances Control Act inventory (USEPA, 2001b). Each year, a num ber of chem icals are added. Assessing the cum u lative effect of these che m icals will be a great challenge to to the field of risk assessment and to the Agency.

xiiAuthors, Contributors, and Review ers Authors: EPA Risk Assessment Forum Cumulative Risk Technical Panel : Michael A. Callahan, Office of the Regional Adm i nistrator, Region 6 (Chair) Edward S. Bender, Office of Science Policy, ORD George L. Bollweg, Air and Radiation Division, Region 5 Vicki L. Dellarco, Office of Pesticide Program s, OPPTS Lynn A. Delpire, Office of Pollution Prevention and Toxics, OPPTS Martin P. Halper, Office of Environm ental Justice, OECA Richard C. Hertzberg, National Center for Environm ental Assessm ent, ORD Elizabeth Lee Hofm ann, Office of Em er gency and Rem e dial Response, OSW E R Steven M. Knott, Risk Assessm ent Forum , ORD R. Craig Matthiessen, Chem ical Em ergency Preparedness and Prevention Staff, OSW E R Alexander McBride, Office of Solid W a ste, OSW E R Deirdre L. Murphy, Office of Air Quality Planning and Standards, OAR Henry C. Topper, Office of Pollution Prevention and Toxics, OPPTS W i nona Victery, Policy and Managem e nt Division, Region 9
Contributors and Reviewers:
EPA Reviewers: Donald G. Barnes, EPA Science Advisory Board Michael Firestone, Office of Children’s Health Protection Debra L. Form an, Region 3 Audrey Galizia, Region 2 Mark Maddaloni, Region 2 Elizabeth H. Margosches, Office of Pollution Prevention and Toxics Marian Olsen, Region 2 Jam e s Rowe, Office of Research and Developm ent Scott Schwenk, Office of Research and Developm ent Michael Shapiro, Office of Solid W a ste Sally Shaver, Office of Air and Radiation Margaret Stasikowski, Office of Pesticide Program s Jeannette W iltse, Office of W a ter Jeffrey Yurk, Region 6 The following persons participated in peer involvem e nt workshops held during 2001 to discuss and comm e nt on the draft fram e work. Federal Scientists’ Meeting, May 1, 2001 : Michael A. Babich, Health Sciences Divisi on, U.S. Consum er Product Safety Comm i ssion Michael Buchm a n, Office of Response and Restorati on, National Oceanic and Atm o spheric Adm i nistration Stephen Channel, Departm e nt of the Ai r Force, U.S. Departm e nt of Defense Christopher T. DeRosa, Division of Toxicology, Ag ency for Toxic Substances and Disease Registry Dennis Druck, Arm yCenter for Health Prom otion a nd Preventive Medicine, U.S. Departm e nt of Defense Frank Hearl, Division of Respirator y Disease Studies, National Institute for Occupational Safety and Health Keith Hoddinott, Arm yCenter for Health Prom otion a nd Preventive Medicine, U.S. Departm e nt of Defense Steve Jones, Office of Regional Operations, Agen cy for Toxic Substances and Disease Registry
xiiiBrian Kaplan, Division of Health Assessm ent and Consultation, Agency for Toxic Substances and Disease Registry Ralph Kodell, National Center for Toxicological Research, U.S. Food and Drug Adm i nistration Dan Lewis, Health Effects Laboratory Division, National Institute for Occupational Safety and Health Margaret MacDonell, Argonne National Labor atory, U.S. Departm e nt of Energy Mark McClanahan, National Center for Environm ental Health, Centers for Disease Control and Prevention Anita K. Meyer, HTRW Center of Expertise , U.S. Arm yCorps of Engineers Moiz G. Mumt az, Division of Toxicology, Agen cy for Toxic Substances and Disease Registry Leslie G. Rubin, Anim al and Plant Health Insp ection Service, U.S. Departm e nt of Agriculture Antoinette Sebastian, Office of Comm unity Planning and Developm ent, Dept. of Housing and Urban Developm ent Scott D. Sudweeks, Div. of Health Assessm ent and Consu ltation, Agency for Toxic Substances and Disease Registry Tim o thy Taylor, Arm yCenter for Health Prom otion a nd Preventive Medicine, U.S. Departm e nt of Defense John W h eeler, Division of Toxicology, Agency for Toxic Substances and Disease Registry Jody W i rem a n, Departm e nt of the Air Force, U.S. Departm e nt of Defense States’ Meeting, May 3, 2001: George Hagevik, National Conferen ce of State Legislators (Moderator) Glen Andersen, National Conference of State Legislators Ligia Mora-Applegate, Florida Departm e nt of Environm ental Protection Alex M. Barron, Virginia Departm e nt of Environm ental Quality Sharon Baxter, Office of Pollution Prevention, Vi rginia Departm e nt of Environm ental Quality Joseph P. Brown, Office of Environm ental Health Hazar d Assessm ent, California Environm ental Protection Agency Michele F. Burgess, Georgia Departm e nt of Natural Resources Perry Cohn, Environm ental Health Service, New Jersey Departm e nt of Health Linda J. Cullen, New Jersey Departm e nt of Environm ental Protection Susan Dem p sey, Nebraska Departm e nt of Health and Hum a n Services Michael J. DiBartolom eis, Office of Environm ental Hea lth Hazard Assessm ent, California Env. Protection Agency Michael Ellenbecker, Toxics Use Reduction Institute, University of Massachusetts at Lowell Joann Held, Office of Air Quality, New Jersey Departm e nt of Environm ental Protection Bruce Hope, Oregon Departm e nt of Environm ental Quality Tom Hornshaw, Toxicity Assessm ent Unit, Illinois Environm ental Protection Agency Paul B. Jiapizian, Maryland Departm e nt of the Environm ent David R. Johnson, Bureau of Environm ental Epidem iology, Florida Departm e nt of Health Michael Juras, Comm unity Right-to-Know, South Carolin a Departm e nt of Health and Environm ental Control Kevin Kessler, Air and W a ste Division, W i sconsin Departm e nt of Natural Resources Rosanna Kroll, Health and Toxicology Sec tion, Maryland Departm e nt of Environm ent Charles Moore, Office of Environm ental Managem e nt , South Carolina Departm e nt of Natural Resources Rebecca Pottratz, Comm unication Specialist, W i sconsin Departm e nt of Natural Resources John Ridgway, Environm ental Justice Program , W a shington State Departm e nt of Ecology Kirpal S. Sidhu, Environm ental Epidem iology Divi sion, Michigan Departm e nt of Comm unity Health Lawrence P. Sirinek, Division of Em ergency and Rem e dial Response, Ohio Environm ental Protection Agency Alan Stern, Bureau for Risk Analysis, New Je rsey Departm e nt of Environm ental Protection Chuck Stroebel, Environm ental Research Sc ientist, Minnesota Departm e nt of Health Barbara S. Taylor, Departm e nt of Health and Hum a n Services, W e st Virginia Bureau for Public Health Mark W e rner, W i sconsin Division of Public Health Carol Rowan W e st, Office of Research and Standards, Massachusetts Departm e nt of Environm ental Protection Victor R. W ilford, Departm e nt of Health and Hum a n Services, W e st Virginia Bureau for Public Health Stephen L. W u st, Drinking W a ter Bureau, New Mexico Environm ent Departm e nt

Public Meeting, August 22-23, 2001:
xivKen W

. Sexton, Center for Environm ent and Hea lth Policy, University of Minnesota (Moderator) Elizabeth Boa, Am erican Chem istry Council, Inc. Kenneth T. Bogen, Health and Ecological Assessm ent Division, Lawrence Liverm ore National Laboratory Jam e s P. Butler, Environm ental Assessm ent Division, Argonne National Laboratory Douglas J. Crawford-Brown, Dept. of Environm ental Scie nces and Engineering, University of North Carolina Am y D. Kyle, School of Public Health , University of California-Berkeley Norris McDonald, Center for Environm ent, Comm e rce and Energy Beth E. Mileson, Technology Sciences Group, Inc. Stephen S. Olin, Risk Science Institute , International Life Sciences Institute W illiam R. Rhyne, H&R Technical Associates, Inc. Jennifer Sass, Health Program , Natural Resources Defense Council Margo Schwab, School of Public Health, Johns Hopkins University External Peer Review Workshop, June 4-5, 2002: Peter deFur, Environm ental Stewardshi p Concepts (Peer Review Panel Chair) Gail Charnley, Health Risk Strategies Robert W

. Collin, University of Oregon David F. Goldsm ith, George W a shington University Dale B. Hattis, Clark University Joann Held, New Jersey Departm e nt of Environm ental Protection Paul A. Locke, Johns Hopkins University Margaret M. MacDonell, Argonne National La boratories, U.S. Departm e nt of Energy Pavel Muller, ToxProbe, Inc. P. Barry Ryan, Em ory University Jennifer Sass, Natural Resources Defense Council Paul M. Schlosser, CIIT Centers for Health Research Curtis C. Travis, Quest Technologies Written Public Comments:
Jam e s M. Solyst, Am erican Chem istry Council, Inc. Andy Lawrence, U.S. Departm e nt of Energy Joe J. Mayhew, Am erican Chem istry Council, Inc.

xvList of Abbreviations and Acronyms
APEX - Air Pollution EXposure m odel ATSDR - Agency for Toxic Substances and Disease Registry CARES - Cum u lative and Aggregate Risk Evaluation System CBEP - Comm unity-Based Environm ental Protection DALY - Disability-Adjusted Lif e Year EPA - U.S. Environm ental Protection Agency FQPA - Food Quality Protection Act GIS - Geographical Inform ation System HAP - Hazardous Air Pollutant HEC - Hum an Equivalent Concentration HRS - Hazard Ranking System HUD - U.S. Departm e nt of Housing and Urban Developm ent IED - Integrated Environm ental Decision-m a king ILSI - International Lif e Sciences Institute LADD - Lifetim e Average Daily Dose LLE - Loss of Life Expectancy LOAEL - Lowest-Observed-Adverse-Effect Level MSDS - Materials Safety Data Sheet NAAQS - National Am bient Air Quality Standards NATA

- National Air Toxics Assessm ent NEPA - National Environm ental Policy Act NHEXAS - National Hum an Exposure Assessm ent Survey NOAEL - No-Observed-Adverse-Effect Level NRC - National Research Council OAR - Office of Air and Radiation (EPA) OP - Organophosphorous OPP - Office of Pesticide Program s (EPA) OPPTS

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

- Office of Research and Developm ent (EPA) PAH - Polycyclic Arom atic Hydrocarbon PCB - Polychlorinated Biphenyl pNEM - Probabilistic NAAQS Exposure Model QALY - Quality-Adjusted Lif e Year RfC - Reference Concentration RfD - Reference Dose SAB - Science Advisory Board SHEDS - Stochastic Hum an Exposure and Dose Sim u lation m odel TEAM - Total Exposure Assessm ent Methodology TEF - Toxicity Equivalence Factor

xviExecutive Summary This report, Framework for Cumulative Risk Assessment , is the first step in a long-term effort to develop cum u lative risk assessm ent guidelines. Its prim ary purpose is to offer a sim p le, flexible structure for conducting and evaluating cum u lative risk assessm ent within the U.S. Environm ental Protection Agency (EPA, or the Agency). Although this fram ework report will serve as a foundation for developing future guidelines, it is neither a procedural guide nor a regulatory requirem e nt within EPA, and it is expected to evolve with experience. This report is intended to f o ster consistent approaches to cum u lative risk assessm ent within EPA, identif y key issues, and define term s used in these assessm ents. This fram ework is m eant to lay out broad areas where analysis m i ght be conducted if needed. It does not suggest that cum u lative risk assessm ent is a tool that should be used with every issue, nor does it suggest that when cum u lative risk assessm ent is applied, that all areas of analysis outlined or discussed here m u st—or even should be—conducted in every assessm ent. The scope of the assessm ent will def i ne the areas to be analyzed. In som e areas discussed in this fram ework, the m e thodology for doing the risk analysis m ay not yet exist. Appendix A includes a summ ary of areas where research is needed. In this report, “cum u lative risk” m eans “the com b ined risks from aggregate exposures to m

u ltiple agents or stressors.” Several key points can be derived f r om this def i nition of cum u lative risk. First, cum u lative risk involves m u ltiple agents or stressors, which m eans that assessm ents involving a single chem ical or stressor are not “cum u lative risk assessm ents” under this definition. Second, there is no lim itation that the “agents or stressors” be only chem icals; they m ay be, but they m ay also be biological or physical agents or an activity that, directly or indirectly, alters or causes the loss of a necessity such as habitat. Third, this definition requires that the risks from m u ltiple agents or stressors be com b ined. This does not necessarily m e an that the risks should be “added,” but rather that som e analysis should be conducted to determ ine how the risks from the various agents or stressors interact. It also m eans that an assessm ent that covers a num ber of chem icals or other stressors but that m e rely lists each chem ical with a corresponding risk without consideration of the other chem icals present is not an assessm ent of cum u lative risk under this definition.
“Cum ulative risk assessm ent” in this report m eans “an analysis, characterization, and possible quantif ication of the com b ined risks to health or the environm ent f r om m u ltiple agents or stressors.” One key aspect of this definition is that a cum u lative risk assessm ent need not necessarily be quantitative, so long as it m eets the other requirem e nts. The fram ework itself is conceptually sim ilar to the approach used in both hum an health and ecological assessm ents, but it is distinctive in several areas. First, its focus on the com b ined effects of m o re than one agent or stressor m a kes it different from m any assessm ents conducted today, in which, if m u ltiple stressors are evaluated, they are usually evaluated individually and presented as if the others were not present. Second, because m u ltiple stressors are affecting the sam e population, there is increased focus on the specific populations potentially affected rather
xviithan on hypothetical receptors. Third, consideration of cum u lative risk m ay generate interest in a wider variety of nonchem i cal stressors than do traditional risk assessm ents. The fram ework describes three m a in phases to a cum u lative risk assessm ent: (1) planning, scoping, and problem form ulation, (2) anal ysis, and (3) risk characterization. In the first phase, a team of risk m anagers, risk assessors, and other stakeholders establishes the goals, breadth, depth, and focus of the assessm ent. The end products of this phase are a conceptual m odel and an analysis plan. The conceptual m odel establishes the stressors to be evaluated, the health or environm ental effects to be evaluated, and the relationships am ong 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) am ong stressors, and predicting risks to the population or populations assessed. It is in this phase that dif f i cult technical issues such as the toxicity of m i xtures, the vulnerability of populations, or the interactions am ong stressors that m ay be chem ical or nonchem i cal are addressed and, hopefully resolved. The end product of this phase is an analysis of the risks associated with the m u ltiple stressors to which the study population or populations are exposed. The third phase, risk characterization (interpretation), puts the risk estim ates into perspective in term s of their signif i cance, the reliability of the estim ates, and the overall confidence in the assessm ent. It is also in this phase that an evaluation is m a de of whether the assessm ent m e t the objectives and goals set forth in phase one. The discussion of cum u lative risk in this fram ework report takes a broad view of the topic and includes m any aspects of an assessm ent that m i ght conceivably be conducted in the future, even though techniques m ay not currently exist to exam ine every question. It also includes aspects of cum u lative risk that m ay be outside of EPA’s current legislative m andates and where expertise outside of the Agency would be needed to address certain questions if they should arise. These aspects are discussed here for the sake of technical com p leteness and not as a recomm e ndation that EPA perform all possible aspects of a cum u lative risk assessm ent in all its risk assessm ents—even all its cum u lative risk assessm ents. This fram ework m ay, however, provide an opportunity for the Agency to start to integrate the requirem e nts of its various legislative m andates, at least in the area of risk assessm ent. EPA is currently engaged in activities that fall under various aspects of the cum u lative risk assessm ent um brella. Som e of these activities are listed as illustrations in the box on the next page. The broad interpretation of cum u lative risk in this fram ework report allows these activities to be put into perspective relative to one another and can illustrate how the activities f i t together under the fram ework. Individual Progr am Offices and Regions m ay have to m a ke decisions that affect the scope, types of stressors, or m e thods used for their program s’ cum u lative risk assessm ents, based on legislative m andates or other criteria. Nothing in this report should be

xviiiExamples of Cumulative Risk Asse ssment Activities w i thin EPA in 2002

! The Superfund Program has updated its guidance on risk assessm ent to include planning and scoping for cum u lative risk assessm ent and problem form ulati on for ecological risk assessm ents. The plan for the Office of Solid Waste’s Surface Im poundm ent Study includes both a conceptual m odel and an analytical plan, per the agency guidance on planning and scoping for cum u lative risk.

! The Office of Wateris planning a watershed-scale risk assessm ent involving m u ltiple stressors in ecological risk. This approach was developed thr ough a collaboration with external scientists and is now being field evaluated.

! Several Regional Offices are evaluating cum u lative hazards, exposures, and effects of toxic contam inants in urban environm ents. In Chicago ( Region 5 ), citizens are concerned about the contribution of environm ental stressors to endpoi nts such as asthm aand blood lead levels. In Baltim ore ( Region 3 ), a regional /Office of Prevention, Pesticides, and Toxic Substances /comm unity partnership tried to address the long-term e nvironm ental and econom ic concerns in three neighborhoods that are adjacent to industrial facilities and tank farm s. Region 6 (Dallas) is developing a geographic inform ation system approach for planning and scoping cum u lative risks.

! The Food Quality Protection Act of 1996 requires that EPA consider the cum u lative effects to hum an health that can result from exposure to pesticides and other substances that have a comm on m echanism of toxicity. The Office of Pesticide Programs has developed guidance for conducting cum u lative risk assessm ents for pesticides and has prepared a prelim inary cum u lative risk assessm ent for organophosphorous pesticides.

! The Office of Air and Radiation’s (OAR’s) air toxics program has a cum u lative risk focus. Under the Integrated Urban Air Toxics Strategy, OAR will be considering cum u lative risks presented by exposures to air em issions of hazardous air pollutant s from sources in the aggregate. Assessm ents will be perform ed at both the national scale (a nationa l-scale assessm ent for base year 1996 was com p leted in 2002) and at the urban or neighborhood scale. In partnership with the Office of Research and Development (ORD) and the National Exposure Research Laboratory , the Office of Air Quality Planning and Standards is developing the Total Risk Inte grated Methodology (TRIM), a m odular, m odeling system for use in single or m u ltim edia, single or m u ltipathway hum an health and ecological risk assessm ents of hazardous and criteria air po llutants at the neighborhood or city scale. The Agency’s guidance for planning and scoping cum u lative risk was used to develop a conceptual m odel and analysis plan for the national-scale air toxics risk assessm ent.

! ORD’s National Center for Environmental Assessment(NCEA) has com p leted ecological risk assessm ent guidelines that support the cum u lative risk assessm ent guidance. Five watershed case studies are being assessed to dem onstrate the guide lines approach. Each of these cases deals with cum u lative im pacts of stressors (chem i cal, biological , and, in som e cases, physical). In addition, NCEA has prepared a draft reassessm ent of dioxin and related com pounds.

! The Risk Assessment Forum convened a technical panel to develop guidance for conducting cum u lative risk assessm ents, of which this fram e work is a first step.

xixinterpreted as m andating that a cu m u lative risk assess m ent be conducted or be conducted in a certain way for any specific case. Likewise, this report is not an attem p t to lay out protocols to address all the risks or considerations that are needed to adequately inform comm unity decisions. Rather, it is an inform ation docum ent, focused on describing various aspects of cum u lative risk whether or not the methods or data currentlyexist to adequately analyze or evaluate those aspects of the assessment

. Because of the lim itations of current science, cum u lative risk assessm ents done in the near future will not be able to adequately answer all the questions posed by stakeholders or interested parties. This does not m ean, however, that they cannot answer some of the questions; in fact, cum u lative risk assessm ent m ay be the best tool available to address certain questions dealing with m u ltiple-stressor im pacts.

xx1. INTRODUCTION During m u ch of its early history, the U.S. Environm ental Protection Agency (EPA, or the Agency) focused its efforts on cleaning up the overt pollution problem s of the 1960s and 1970s. Until the Agency was established, in 1970, relatively uncontrolled air em issions, water effluents, and dum ped wastes had led to pollution of the environm ent that was easily detected by the five senses. The m o st effective and efficient way of approaching these overt problem s of the 1970s was to find the entry point of the pollutant into the environm ent and to control it at that point. Looking back, we see a strategy that m oved to control stack em issions, industrial and m unicipal effluents, pesticide application, land applications , burial of chem ical wastes, and other “sources” of pollution. In addition, criteria and standards were established as goals for cleaning up the various environm ental m e dia. By the 1980s, this “comm and and control” strategy was well established in environm ental laws and regulations but was reaching the point of dim i nishing returns from a cost-benefit viewpoint. The developm ent of risk assessm ent m e thodology during the 1970s and early 1980s

Figure 1-1. A chemical- (or stressor-) focused assessment starts w i th a source and evaluates howthe chemical gets to various populations or ecological targets. Individual assessm ents m ay pursue som e or all pathways, m e dia, or population segm ents. closely followed the Agency’s strategy for control of pollution, because risk assessm ents were being used as a factor in EPA’s regulatory decision m a king. The focus on sources led naturally to analyses of what types of pollutants were in effluents, air em issions, and waste sites and the detection of chem ical, biological, and—som etim es —radiological agents. By the 1970s, the link between som e chem icals and certain diseases such as cancer had been established through a series of bioassays or, in the case of chem icals such as vinyl chloride and asbestos, through epidem iological studies. New analytical techniques also m a de it possible for the first tim e to detect very m i nute concentrations of chem icals. The focus of the EPA strategy to control pollution (and the risk assessm ent m e thodology being used to partially support decisions) gradually leaned toward assessing and controlling the individual chem icals. Congressional legislation tended to underwrite this approach by focusing on controlling sources and even including lists of individual chem icals to be controlled. The risk assessm ent m e thodology of the 1970s and early 1980s, therefore, tended toward single-chem ical assessm ents (Figure 1-1). A National Research Council (NRC) report (NRC, 1983) was focused largely on the single-chem ical risk assessm ent approach when it spoke of the four parts of a Federal risk assessm ent: hazard identification, dose-response assessm ent,

1exposure assessm ent, and risk characterization. EPA’s 1986 risk assessm ent guidelines (USEPA, 1986a), with the exception of the m i xtures guidelines (USEPA, 1986b), also focused largely on single-chem ical assessm ent. However, research conducted or sponsored by EPA in the early 1980s was taking the first steps toward investigating a different type of risk assessm ent m e thodology, one that focused on identifying the persons exposed, investigating the chem icals or stressors to which they were exposed, and determ ining consequent risks (Figure 1-2). This approach differs from those that focus on either a che m ical (and investigates the che m ical environm ental fate, exposed populations, and risks [Figure 1-1]) or a source (and investigates environm ental releases from that source, exposed populations, and risks). The goals of the population-focused approach 1 w e r e mu c hmo r e Figure 1-2. Population-based assessments start w i th the receptors and determine w h ich chemicals, stressors, or other risk factors are affecting them. useful to decisionm akers who were dealing with public health or ecological health questions rather than controlling sources of pollution. The challenges posed by the population-based assessm ent can be daunting, even if only a few of the stressors affecting a population are ev aluated together (i.e., cum u latively). Taken to the extrem e, Figure 1-2 represents a concept of “total risk” for the population or population segm ent being evaluated, with each chem ical , biological, radiological, or other stressor 2 adding som e fraction of the total risk. Looking at the problem from an individual stressor viewpoint, to do this type of assessm ent would require not only evaluating each individual stressor, but also developing a way to add up all the risks am ong stressors across a population of individuals with

1 A chem ical-focused assessm ent m a y look at several populations affected by exposure to the chem ical but not at other chem icals. A population-focused assessm ent looks at one population for perhaps m a ny stressors but not at other populations. Consequently, for traditional, ch em ical-focused assessm ents, we say we conduct a “risk assessm ents for a certain chem ical.” In contrast, the esse nce of a cum u lative risk assessm ent is that the assessm ent is conducted “for a certain population.” This difference is shown schem a tically by com p aring Figures 1-1 and 1-2. How the population is identified for a cum u lative assessm ent is not addressed here.

2 A stressor is a physical, chem ical, biological, or ot her entity that can cause an adverse response in a hum an or other organism or ecosystem

. Exposure to a chem ical, biological, or physical agent (e.g., radon) can be a stressor, as can the lack of, or destru ction of, som e necessity, such as a habitat. The stressor m a y not cause harm directly, but it m a y m a ke the target m o re vulnerable to harm by other stressors. A socioeconom ic stressor, for exam ple, m i ght be the lack of needed health care, which could lead to adverse effects. Harm ful events, such as autom obile crashes, could also be term ed stressors. O bviously, calculating risks from different types of stressors can use widely differing m e thods, including probabilistic estim ates of disease via dose-response relationships or looking up rates in statistical tables of historical events, am ong others. 2different exposures and susceptibilities. In the early 1980s, the state of the science was unready for virtually any part of the m e thods for doing this type of assessm ent. But progress was being m a de toward developing a population-based m e thodology. Starting in the late 1970s, a group of EPA res earchers and contractors began developing what would becom e the Total Exposure Assessm ent Methodology (TEAM) study (USEPA, 1987). TEAM m easured the concentrations of a num ber of chem icals sim u ltaneously at the point of exposure. This project led to a larger study, the National Hum an Exposure Assessm ent Survey (NHEXAS) in the 1990s (Sexton et al., 1995). Both TEAM and NHEXAS developed analytical tools and m e thodologies to do population-based exposure assessm ents. Som e progress was also being m a de in the early 1980s on the question of how to cum u latively consider the risks from different chem icals or stressors. EPA’s 1986 risk assessm ent guidelines (USEPA, 1986a) included a guideline on chem ical m i xtures (USEPA, 1986b), which discussed how the risks from m u ltiple chem icals could be evaluated as a whole. W o rk on this guidance has continued m o st recently with Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures (USEPA, 2000e), which expands and supplem ents the 1986 effort. As progress was being m a de on single che m ical and che m ical m i xture risk assessment with the 1986 guidelines, so m e different kinds of risk assess m ent proble m s began to catch the Agency’s attention. In 1986, 11 Chicago-area co mm unity groups joined to file a petition under Section 21 of the Toxic Substances Control Act, asking for a community assessment in Southeast Chicago. A series of co mm unity-based actions that started in 1982 and grew throughout the 1980s focused on disparities of risk a m ong various population subgroups, calling specific attention to cu m u lative effects of pollution on minority subgroups (GAO, 1983; United Church of Christ, 1987). This series of community-based actions, chronicled by Bullard (1990), eventually beca m e known as the movement. The issues raised by the movement were the basis of a 1994 Presidential Executive Order (Executive Order 12898, February 11, 1994), which told federal agencies, among other things, to consider multiple and cumulative exposures whenever practicable and appropriate. In the 1990s, Environmental Justice cases, including the cases 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 assess m ent m e thodology.
I t was apparent that in addition to chemical- or stressor-focused assessments (as shown in Figure 1-1), population-focused assessments (as shown in Figure 1-2) would be needed if EPA was going to be able to answer the questions and issues being raised by the public. Co mm unity spokespersons and other stakeholders, as well as scientific panels, were increasingly co m i ng to the Agency with proble m s that demanded a multi-stressor approach (e.g., NRC 1994). Ecological proble m s in particular were demanding a “place-based” context (such as the Chesapeake Bay watershed) in which the various populations within the area were looked at from a “total syste m ” viewpoint. This place- based focus was part of Framework

3for Ecological Risk Assessment (USEPA, 1992b) and Guidelines for Ecological Risk Assessment (USEPA, 1998b). Although clearly addressing m o re than cum u lative hum an health or ecological risk assessm ent, the National Environm ental Policy Act of 1969 (NEPA) (P.L. 91-190, 42 U.S.C. 4321-4347, January 1, 1970, as am ended 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 sam e tim e EPA was established, requires assessm ents on the cum u lative im pacts of federal or federally funded projects (such as roads, dam s , power lines, m ilitary projects, and inf r astructure developm ent) on natural ecosystem s, endangered species, habitats, and opportunities for public enjoym ent and natural resource use. A prim ary concern for NEPA is “cum u lative effects analysis,” defined as “the increm ental im pact of the action when added to other past, present, and reasonably foreseeable future actions

. . . . Cum u lative im pacts result from individually m i nor but collectively significant actions taking place over a period of tim e” (CEQ, 1997). Much of the NEPA cum u lative ef f ects analysis is qualitative, but risk assessm ents and cause-and-ef f ect relationships are key parts of the analysis process for controversial projects. In 1997, the Agency issued a policy m e m o, Guidance on Cumulative Risk Assessment, Part 1: Planning and Scoping (USEPA, 1997a), which took the first form al step toward developing guidance and guidelines for cum u lative risk assessm ent. Cum u lative risk assessm ent applications have becom e relatively comm on, not only for assessm ents of chem icals that operate by the sam e m ode of action, as m andated for the EPA’s pesticides program , but also for comm unity-based, population-based, assessm ents that m ay include m o re varied stressors than just chem icals alone. Much like the “place-based” ecological assessm ents, which m ay cover a wide variety of physical, chem ical, and biological stressors, som e comm unities have added hum an health and perhaps “quality of life” to the endpoints of interest in their place-based assessm ents. The dem and for m o re sophisticated hum an health risk assessm ents has driven the need for research into cum u lative risk assessm ent, populationfocused assessm ents, aggregate exposure assessm ent, and risk from chem ical m i xtures. 1.1. Purpose and Scope of the Framew ork Report An understanding of the finite purpose and scope of this fram ework report is im portant. EPA and other organizations need detailed, com p rehensive guidance on m e thods for evaluating cum u lative risk. Before such detailed Agency-level guidance is developed on a relatively new field of risk assessm ent, it has been the recent policy of the Agency to first develop a sim p le fram ework as a foundation for later com p rehensive guidance. This Framework for Cumulative Risk Assessment em phasizes chem ical risks to hum an health in its discussion and also in the context of the effects from a variety of stressors, including nonchem i cal stressors. Som e im portant topics that could be characterized as “cum u lative risk,” such as global clim ate change, are beyond the scope of this report.

4Given this background, the fram ework has two sim p le purposes, one imm e diate and one longer term

. As a broad outline of the assessm ent process, the fram ework imm e diately offers a basic structure and provides starting principles for EPA’s cum u lative risk assessm ents. The process described by the report provides wide latitude for planning and conducting cum u lative risk assessm ents in m any diverse situations, each based on comm on principles discussed in the report. The process also will help f o ster a consistent EPA approach for conducting and evaluating cum u lative risk assessm ents, for identifying key issues, and for providing operational def i nitions f o r term s used in cum u lative risk assessm ents. In the longer term , the fram ework report offers the basic principles around which to organize a m o re def i nitive set of cum u lative risk assessm ent guidance. W ith this in m i nd, this report does not provide substantive guidance on certain issues that are integral to the risk assessm ent process (see box on this page and Appendix B for a listing of useful resources). These issues include specific analytical m e thods, techniques for analyzing and interpreting data, and guidance on issues influencing policy. Rather, on the basis of EPA experience and the recomm e ndations of peer reviewers, EPA has reserved discussion EPA’s Risk Assessment Guidelines
Chem ical m i xtures (USEPA, 1986b) Mutagenicity risk assessm ent (USEPA, 1986c) Carcinogen risk assessm ent (USEPA, 1986d) Developm ental toxicity risk assessm ent (USEPA, 1991a) Exposure assessm ent (USEPA, 1992c) Reproductive toxicity risk assessm ent (USEPA, 1996b) Proposed carcinogen risk assessm ent (USEPA, 1996c,

1999a, b) Ecological risk assessm ent (USEPA, 1998b) Neurotoxicity risk assessm ent (USEPA, 1998c) Selected Policy and Guidance Documents
Risk assessm ent guidance for superfund (USEPA, 1989a) Locational data policy (USEPA, 1991b) Fram ework for ecological risk assessm ent (USEPA, 1992b) Application of refined dispersion m odels (USEPA, 1993a) Policy/guidance for risk characterization

(USEPA, 1995a, b) Benchm ark dose (USEPA, 1995c, 2000b) Cum u lative risk planning and scoping (USEPA, 1997a) Guiding principles for Monte Carlo analysis

(USEPA, 1997b) Acute inhalation exposure (USEPA, 1998d) Chem ical em ergency risk m a nagem e nt (USEPA, 1998e) Draft com p arative risk fram e work (USEPA, 1998f) Aggregate exposure and risk (USEPA, 1999g) Comm unity involvem e nt in Superfund risk assessm ent (USEPA, 1999c) Guidance for offsite consequence analysis (USEPA, 1999d) Guideline on air quality m odels (USEPA, 1999e) Fram ework for comm unity-based environm ental protection (USEPA, 1999f) Handbook for risk characterization (USEPA, 2000c) Handbook for peer review (USEPA, 2000d) Supplem entary guidance for conducting health risk

assessm ent of chem ical m i xtures (USEPA, 2000e) Cum u lative risk assessm ent of pesticide . . . comm o n m echanism of toxicity (USEPA, 2002a)

of

these im portant aspects of cum u lative risk assessm ent f o r f u ture guidance, which will be based on the risk assessm ent process described in this fram ework report. This report lays out broad areas where analysis m i ght be conducted if needed. It does not suggest that cum u lative risk assessm ent is a tool that should be used with every issue, nor does it suggest that when cum u lative risk assessm ent is applied, all areas of analysis outlined or

5discussed here m u st or even should be conducted in every assessm ent. The scope of the assessm ent should be defined in the planning and scoping stage (see Section 2.1) and m ay include or exclude stressors or pathways as relevant to the particular context or application. In som e areas discussed in this report, the m e thodology for doing the risk analysis m a y not yet exist. Following com p letion of this f r am ework report, EPA plans to initiate developm ent of a m o re detailed guidance docum ent. As a f i rst step in this process, EPA will oversee the preparation of a num ber of case studies and issue papers on select topics. In addition, the Agency plans to hold workshops to further evaluate those issues. Following these activities, EPA will begin draf ting the m o re detailed guidance in the f o rm of Guidelines for Cumulative Risk Assessment. At this tim e, the Agency does not have a def i nite schedule f o r these activities.
1.2. Intended Audience This fram ework report is prim arily intended for EPA risk assessors, EPA risk m anagers, and other persons who either perform work under EPA contract or sponsorship or are subject to EPA regulations concerning risk assessm ents. Th e term inology and concepts described here also m ay be of assistance to other Federal, State, and local agencies as well as to m e m b ers of the general public, including stakeholders, who are interested in cum u lative risk assessm ent issues. The style and language used in this report were chosen so as to be understandable by as wide a variety of interested parties as possible, from the policy m a ker to the risk assessm ent scientist to the concerned nonscientist m e m b er of the general public. It is hoped that this report will be the first step in developing a broad scientific consensus about cum u lative risk assessm ent, and that further guidelines and guidance will build upon this foundation.
1.3. Key Definitions in Cumulative Risk Assessment 3 In this report, “cum u lative risk” and “cum u lative risk assessm ent” are defined as follows, assum i ng a defined population:
Cumulative risk: The com b ined risks from aggregate exposures 4 to m u ltiple agents or stressors. Cumulative risk assessment: An analysis, characterization, and possible quantification of

the com b ined risks to health or the environm ent f r om m u ltiple agents or stressors.

3 In this section, a few basic definitions related to cum u lative risk assessm ent are discussed. For a glossary of term s, the reader is directed to Chapter 5.

4 See the box on the next page for a definition of aggr egate exposure. Som e references (e.g., Berglund et al., 2001) refer to this type of total exposure over tim e fo r a single stressor as “cum ulative exposure.” To avoid confusion, we have not used the term “cum ulative exposure” in this report. 6Several key points arise from this definition of cum u lative risk. First, cum u lative risk involves m u ltiple agents or stressors, which m eans that assessm ents involving a single chem ical or stressor are not “cum u lative risk assessm ent” under this definition. Second, there is no lim itation that the “agents or stressors” be only chem icals. “Agents or stressors” m ay be chem icals, of course, but they m ay also be biological or physical agents or even the absence of a necessity such as habitat. Third, this definition requires that the risks from m

u ltiple agents or stressors be com b ined. This does not necessarily m ean that they be “added,” but rather that som e analysis should be conducted on if and how the effects or risks from the various agents or stressors interact. It also m eans that an assessm ent that covers a num ber of FQPA’s Terminology Interpretations The Food Quality Protection Act of 1996 [P.L

. 104-170] discusses the addition of exposure for a single chem ical across sources, pathways, routes, and tim e as aggregate exposure. To be consistent with that term inology, the Agency has elected to speak of m

u ltiple source/pathway/route single-stressor exposures and risks as “aggregate exposures” and “aggregate risks.” The EPA Science Policy Council’s Cum u lative Risk Subcomm ittee has developed the following working definitions for single-chem ical or single-stressor situations: Aggregate exposure: The com b ined 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.

chem icals or other stressors but that m e rely lists each chem ical with a corresponding risk without consideration of the other chem icals present is not an assessm ent of cum u lative risk under this definition. The definition of cum u lative risk assessm ent follows from the definition of cum u lative risk, but again there is a key point: cum u lative risk assessm ents can be qualitative as well as quantitative.
Som e exam ples of cum u lative risk assessm ents as well as assessm ents that would not be considered as cum u lative risk assessm ents are listed below. Each exam ple presupposes a defined individual or population 5 : 1. Single-agent or -stressor assessment. Risks can be added or accum u lated over tim e for a single agent or stressor across sources, environm ental pathways, or exposure routes. This concept is consistent with “aggregate risk” in the term inology of the Food Quality Protection Act of 1996 (FQPA), shown in the box on this page. Although this type of assessm ent m i ght conceivably be term ed a cum u lative risk assessm ent by som e scientists, in this fram ework report such single-stressor assessm ents are term ed “aggregate risk assessm ents.” Exam ples m i ght be a m

u ltisource assessm ent of benzene risk in a comm unity or an assessm ent of individual risk to a

5 Populations can be defined by geophysical boundaries , such as a watershed, or geopolitical boundaries, such as city or county lim its, or by cultural, racial, ec onom ic, or other criteria within a certain geographic boundary such as a neighborhood. The definition of a population n eeds to be clear enough so that it can be agreed upon whether any specific individual is included in or excluded from the population. 7specific pesticide from all uses com b ined. This type of assessm ent is not discussed in this report except to be referred to occasionally for clarity and contrast to cum u lative risk assessm ents. There are several publications that discuss aggregate exposure and risk assessm ent in detail (e.g., ILSI, 1998, 2001; USEPA, 1999g).
2. Multiple-stressor assessment

. Exposures can be accum u lated over tim e, pathways, sources, or routes for a num ber of agents or stressors. These stressors m ay cause the sam e effects (e.g., a num ber of carcinogenic chem icals or a num ber of threats to habitat loss) or a variety of ef f ects. A risk assessm ent f o r m u ltiple stressors m ay evaluate the risks of the stressors, associated health effects or ecological im pacts one effect or im pact at a tim e or it m ay evaluate the com b ined risk from som e or all the effects or im pacts; in either case, it is considered to be a cum u lative risk assessm ent. A m u ltiple-stressor cum u lative risk assessm ent is distinct f r om a series of aggregate risk assessm ents because it considers any com b ined im pact of the stressors, including the potential for interactions am ong stressors (e.g., synergism or antagonism ). One exam ple of a m u ltiple

stressor, single-effect cum u lative risk assessm ent would be the com b ined risk to an individual or population from a series of pesticides acting by the sam e m ode of action and causing the sam e effect. Another exam ple would be a dioxin assessm en t, where toxicity equivalency factors (TEFs) are used to com b ine the toxicities of dozens of different congeners of chlorinated dibenzo-p-dioxins and dibenzofurans, resulting ina single estim ate of risk for a specific effect from the com b ination of congeners (Eadon et al., 1986; Barnes et al., 1991). Another exam ple is a physician’s use of a m odel derived em pirically from epidem iological studies to estim ate the probability of a wom an’s developing breast cancer over the next 10 years. The “stressors” in the exam ple of the breast cancer m odel are those risk factors known to be correlated with that form of cancer, such as the wom an’s age at first childbirth, age at m e narche, or having a prev ious biopsy with atypical hyperplasia. This exam ple shows that stressors m ay not necessarily be chem ical stressors, nor do they even need to be the sam e types of stressors. These m odels (discussed further in Appendix F) are in som e ways quite different from the predictive risk assessm ents generally done for regulatory and other purposes. Another type of cum u lative risk assessm ent discussed in this report is the m u ltiple

stressor, m u ltiple-ef f ects assessm ent. Again, stressors need not be lim ited to chem icals, nor do they even have to be the sam e types of stressors or have sim ilar effects to be included in this type of assessm ent. For exam ple, chem ical, biol ogical, radiological, and other physical and even psychological stressors can cause a variety of hum an health or ecological health effects. Assessing the risk for these situations is considerably m o re com p lex m e thodologically and com putationally than for the exam ples of aggregate risk assessm ents or single-effect cum u lative risk assessm ents given in the above paragraphs.

8As com p lex as this m ay sound, there are several exam ples of this type of assessm ent. Although these analytical approaches m ay start with the stressors and predict the risk of effects, m o re generally these types of assessm ents start with a defined geographical area or defined population (e.g., a population dam a ged in som e endpoint or due to a reduction in a resource value) and try to determ ine what stressors are im portant.
For exam ple, cum u lative ecological risk assessm ents such as those that have been conducted in the Colum b ia River Basin and the Chesapeake Bay focus on a num ber of observed adverse conditions, then attem p t to determ ine, am ong all of the possible stressors, which particular com b ination is responsible for the observed adverse conditions (Barnthouse et al., 2000). NRC (1994, Appendix I) lays out the general m a them atics for a quantitative approach to m

u ltiple-stressor, m u ltiple-effect assessm ents. Recently, Bogen (2001) used this approach to quantify com b ined risk of cancer and noncancer endpoints induced by the chem ical trichloroethylene (TCE), including quantitative ch aracterization of associated interindividual variability and associated uncertainty (including uncertainty regarding m echanism of carcinogenic action). Technical hurdles invol ved in im plem enting this approach include defining the set of relevant (preferably inde pendent) endpoints and quantifying the likelihood of inducing each adverse health or ecotoxic response considered unacceptable as a function of the endpoints. Another exam ple of a type of m u ltiple-stressor, m u ltiple-ef f ect assessm ent would be a cum u lative comm unity health risk assessm ent.
W e believe that the definition of cum u lative risk used in this fram ework report is consistent with the sense of m o st definitions of “cum u lative,” such as are included in NEPA or FQPA. A summ ary of the f eatures and options of a cum u lative risk assessm ent, by the def i nition used in this report, is given in the box on the next page.
1.4. The Cumulative Risk Assessment as a Tool for a Variety of Users and Purposes As discussed in the introduction of this report, the results of an assessm ent should reflect the purpose for conducting the assessm ent. However, inform ation from cum u lative risk assessm ents can also serve a variety of other purposes. Insights gained m ay also be used to partly m eet regulatory m andates and to help identify targets for enforcem ent actions, or they m ay be considered when shaping policy and regulation. Assessm ents m ay conceivably be used in long-term planning with regard to siting new sources of potential pollution in specific areas. Assessm ents also m ay be used for general educational purposes not directly related to an imm e diate decision on a course of action. Assessm ent results can help guide priorities for voluntary or regulatory action or m obilize comm unityefforts to address concerns. They can be conducted retrospectively (to determ ine past or current risks), prospectively (to assess the risks of, say, proposed facilities), or even creatively (to design a developm ent plan for a comm unity). As helpful as results m ay be in any of these other uses, however, som e consideration should be

9given to the appropriateness of using the assessm ent for these purposes, given the objectives and scope of the assessm ent. Risk analysis, including cum u lative risk analysis, is conceptually an analytic-deliberative process (NRC, 1996). The analytic com ponent includes rigorous, replicable m e thods that are evaluated under the agreed protocols of an expert comm unity; the deliberative com ponent is based on stakeholder value and judgm ent. Much of what is discussed in Chapter 2, “The Planning, Scoping, and Problem Form ulation Phase,” is deliberative in nature, which m eans it depends on input from experts other than those who know how to do risk assessm ents, including persons who are knowledgeable about a comm unity and its values. Although m u ch of Chapter 3, “The Analysis Phase,” is given over to the analytic process, where risk assessm ent experts apply science to a problem , the deliberative aspect returns in Chapter 4, “The Risk Characterization Phase,” especially where risks of different types are being evaluated and com b ined.Because of this analyticdeliberative process, the cum u lative risk assessm ent can be applied to a variety of Cumulative Risk Assessment Features Although m a ny different types of exposures, stressors and other factors can be included, the definition of cum u lative risk m i ght be better understood by contrasting the featured and optional considerations. By the definition given above for this Fram ework report, the following features are included:

• M ultiple stressors.

• C onsideration of how the stressors act together rather

than individually.

• P opulation-focused assessm ent. Although this does

not m ean that the assessm ent m u st start with a population and work “backwards” toward the source, it does m ean that the population needs to be defined, and m u ltiple stressors are assessed with regard to im pact on that population, although not every individual will see the sam e (or all) effects. Additional layers of com p lexity, such as those listed below, m a y or m a y not be addressed:

• M ultiple durations, pathways, sources, or routes of

exposure.

• M ultiple effects or im pacts.

• N onconventional stressors or risk factors (e.g.,

lifestyle, access to health care). These in general need continued research.

• Q uantification of risks.

dif f e rent problem s where analysis of the overall im pacts of m u ltiple sources, stressors, pathways, or routes is necessary. It can be used as a regulatory analysis tool, such as in reviewing the overall im pact of several different pesticides that act by the sam e m ode of action (ILSI, 1999) or in NEPA analyses (CEQ, 1997). It can be used to analyze the overall im pacts of perm it decisions or the results of com p liance with perm its in a given comm unity.
Cum u lative risk assessm ent can also be used in a comm unity-based assessm ent approach, as outlined in USEPA (1999f). The comm unity-based environm ental protection (CBEP) approach (see box on next page) encom p asses both ecological and hum an health assessm ents. Cum u lative risk assessm ent, being a population-based or place-based analytic-deliberative process, is ideal for CBEP-type applications.

10Cum u lative risk assessm ents are also applicable in ecological assessm ents. EPA’s definition of cum u lative ecological risk assessm ent is a process that involves consideration of the aggregate ecological risk to the target entity caused by the accum u lation of

risk f r om m u ltiple stressors (USEPA, 1998b). A report by Foran and Ferenc (1999) discusses m u ltiple stressors in ecological risk assessm ent and gives a good overview of the topic of cum u lative ecological risk assessm ent.
Wh en should a cum u lative risk Core Principles of Community-Based Environmental Protection
1. Focus on a definable geographic area. 2. W o rk collaboratively with stakeholders. 3. Assess the quality of all resources in a place. 4. Integrate environm ental, econom ic, and social objectives. 5. Use the m o st appropriate tools. 6. Monitor and redirect efforts through adaptive m a nagem e nt. Source: USEPA, 1999f

assessm ent be done? Recognizing that the scope and nature of a cum u lative risk assessm ent m ay range from a very lim ited qualitative assessm ent of a local situation, to a com p rehensive assessm ent of the cum u lative risk patterns f o r a large comm unity, to a national assessm ent conducted within one of EPA’s program s, the sim p le answer is that one should be conducted whenever the com b ined im pact of m u ltiple stressors should be considered. Only experience with these assessm ents over a period of tim e will provide the wisdom needed to develop practical guidelines on this question.
1.5. The Broader Decision-Making Context for Cumulative Risk Assessment
Cum u lative risk assessm ents m ay be used to form hypotheses that can be tested, but it is m o re likely that these assessm ents will be used as decision-m a king tools. The levels of decision m a king m ay vary widely, from a neighborhood gr oup evaluating ways to im prove or safeguard its health and environm ent to a Federal official weighing options for action at a m u ch broader geographical level. Although the decision-m a king m e thod is beyond the scope of this report, such decisions usually involve m o re than the basic science and analysis that m a ke up the “scientific” part of risk assessm ent. Clem en (1996) notes that in one type of decision-m a king approach (called decision analysis): Managers and policy m a kers frequently com p lain that analytical procedures from m anagem e nt science and operations research ignore subjective judgm ents. Such procedures often purport to generate “optim al” actions on the basis of purely objective inputs. But the decision-analysis approach allows the inclusion of subjective judgm ents. In fact, decision analysis requires personal judgm ents: they are im portant ingredients for m a king good decisions. Regardless of the type of decision being m a de or the decision-m a king approach, a cum u lative risk assessm ent’s analytic com ponent is not the decision-m a king vehicle in itself. That is, “cranking out the num bers” will not be the sole basis for a decision. Although in som e cases the estim ated risks can weigh heavily in the decision, understanding the risk estim ate is but 11one factor in a broader decision-m a king process that includes risk m anagem e nt com ponents such as technical feasibility, econom ic costs and benefits, political realities, and other analyses usually associated with the field of policy analysis (e.g., OMB, 2000; Freem an, 1999; Hattis and Gobel, 1994; Ashford et al., 1981). EPA’s Science Advisory Board (SAB) (USEPA, 2000a) has constructed a fram ework for what it term s integrated environm ental decision m a king. The SAB noted that “The IED Fram ework recognizes that risks often are experienced sim u ltaneously and are cum u lative

. . . . ” It speaks of risk assessm ents in a very broad way and includes hum an health effects, ecological ef

f ects, and quality-of

- lif e ef f ects. The f i rst phase (“Problem Form ulation”) and part of the second phase (“Analysis and Decision-m a king”) of the IED essentially correspond to the three phases discussed in this fram ework report. Decision m a king—and the SAB’s third phase, “Im p lem e ntation and Perform ance Evaluation,” are beyond the scope of this report. The SAB report gives a good insight into the broader context for cum u lative risk assessm ent and som e of the aspects of the analy tic-deliberative parts of the assessm ent. The analytical-deliberative process is discussed m o re in Chapters 2 through 4 of this report as these phases of the cum u lative risk assessm ent process are exam ined. NRC (1996) also provides m u ch inform ation on the analytic-deliberative aspects of a risk assessm ent and devotes a great deal of discussion to risk characterization. Needless to say, it is very im portant to apply cum u lative risk assessm ent in the context of the decision or decisions to be m a de. This is m o st efficiently done by early and continued attention to the “risk characterization” step in the risk assessm ent process (NRC, 1996; USEPA, 2000c). The box in Section 4.1 summ arizes som e of the points m a de in the NRC report

. 1.6. Organiz ation of This Report Figure 1-3 shows the basic structure of this report. Each of the three general process steps are described in detail in later chapters. The f r am ework is organized to f o llow the outline in Figure 1-3, nam e ly (a) a planning, scoping, and problem form ulation phase (Chapter 2), (b) an analysis phase (Chapter 3), and (c) a risk characterization phase, where the interpretation of findings and explanation of the results are com p leted (Chapter 4). Chapter 5 is a glossary of term s, followed by references in Chapter 6. Additional inform ation on selected resources and cum u lative risk related topics are provided in the appendices.

12

# Planning, Scoping, and Problem Formulation

Analysis

Interpretation and Risk Characteri z a tion

Figure 1-3. Framew ork for cumulative risk assessment.

132. THE PLANNING, SCOPING, AND PROBLEM FORMULATION PHASE The first step in any risk assessm ent process is to define the problem to be assessed. This step has been called “problem form ulation” (for exam ple, USEPA, 1992b, 1997a, 2000a; NRC, 1996). It is a phase where “public officials, scien tists, 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). The planning and scoping of an assessm ent are often thought to be part of the problem form ulation phase, although EPA guidance (U SEPA, 1997a) treats planning and scoping as activities that take place before problem form ulation begins. Wh ether they are considered a separate phase or not, they take place at the very beginning of a cum u lative risk assessm ent. For convenience, this chapter incorporates planni ng, scoping, and problem form ulation into a single phase (see Figure 2-1).
2.1. Planning and Scoping Risk assessm ents are conducted within som e context, that is, they are usually conducted because of a regulatory requirem e nt, a comm unity need, a health crisis, or som e other driving force. This context generates individuals or groups with interest in having the assessm ent done; several summ ary articles or books discuss the challenges of successful participation by these interested parties (e.g., Chess and Purcell, 1999; Frewer, 1999; Thom as, 1995). These parties m ay include public officials, risk experts, community leaders, or any num ber of others, including those, if any, who are legally m andated to be pa rt of the process. Planning and scoping begins with a dialogue am ong these individuals or groups.
Am ong these interested parties will be a person or a group of people charged with m a king decisions about how a risk m a y be m itigated, avoided, or reduced. For the sake of sim p licity, we call this person or group the “decisionm aker,” or “risk m anager 6 ,” and for ease of discussion will discuss the risk m anager as if he or she were a single person. During planning and scoping, risk experts (i ncluding those involved in assessing risk, such as ecologists, toxicologists, chem ists, and other technical experts such as econom ists and engineers), and decisionm akers work together as a team , inform ed by stakeholder input, to develop the rationale and scope for the risk assessm ent and characterization.

6 W e use the term “ r isk m a nagem e nt” to include actions that the risk assessm ent team recomm e nds or im plem ents that are not taken by the risk assessm ent team , per se. These include actions to address the problem s taken by others outside the process who m a y not be id entified until the analysis is underway or com p lete. 14Pl a n ni n g , Sc op i n g, a n d P r ob lem F o rm ul ation

An al y s is

I n terp retatio n an d Ris k C h ar acteriz atio n Pl a n ni n g , Sc op i n g, a n d P r ob lem F o rm ul ation

An al y s is

I n terp retatio n an d Ris k C h ar acteriz atio n

P l anni ng and Sc o p i n g

- P ur po s e - App ro a c h

- S c op e - R e s o ur c e s

- P articip ants

- P as t Exp e ri ences Prob lem For m u l at ion Con ceptu al Mo del

- S ou r ces - R ece p tor s - S tr e s s o rs - E ndpo i nt s

- P a t hwa y s/ Ro ut e s An al y s is P l an

- M eth o ds

- D ata G aps

- M od els

- Un certain ties

Di sc ussi on o f P o ssibl e O u tc o m e s

Figure 2-1. The Planning, Scoping, and Problem Formulation phase.
As part of the initial discussions concerning the need f o r a risk assessm ent, other “interested and affected parties” besides the risk m anager and risk assessor m ay help define purpose, scope, and approach. This “risk assessm ent planning team ” seeks agreem ent through extensive dialogue and discussion on what analytical and deliberative steps need to be taken and by whom , when, and why (USEPA, 2000a). USEPA (2000a) explains som e of the roles of the various participants on the risk assessm ent planning team during the planning and problem form ulation phase: Scientists play an im portant role in [this phase] by collecting, analyzing, and presenting data in such a way that all parties can appreciate the type and m a gnitude of the problem (s) under discussion. This activity will generally involve all four parts of risk assessm ent, including assessm ent of exposures

15experienced by special populations and/ or ecological resources. Planning, scoping, and screening—including selec tion of endpoints of concern—also requires explicit input of societal values and stakeholder participation. For instance, while som e of the ecological endpoints m ay be chosen because of their role in a valued ecosystem , there m ay also be ecological endpoints chosen because of their direct significance to society. Exam ples of the latter include both econom ically im portant species and ‘charism atic’ species. Sim ilarly, in integrated decision-m a king, judgm ents m ay have to be m a de about diverse health endpoints, such as cancer risks in the general population and the risk of reproductive/developm ental risks in children. Wh ile scientists can help characterize such risks, they are not uniquely qualif ied to set priorities am ong them and broader deliberation is essential. Finally, decision-m a kers also play an im portant role during problem form ulation; 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 m anagem e nt options, while exam ining econom ic, political, or other constraints on those options. Decisionm a kers also serve as m anagers of the overall process. (USEPA, 2000a) Another role of the risk assessm ent planning team is docum entation. The activities discussed in the following sections are im portant and should be docum ented by the team for several reasons. Wr itten records can be referred to by assessors and attendees at public m eetings. They can also help in responding to comm e nts and in establishing a record for any later decisions or plans that need to be peer revi ewed (USEPA, 2000d). The risk assessm ent 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 tim e. A peer review by an independent review group will help not only to establish the validity of the science, but it can also provide neutral comm e nts on som e of the interpretations of the assessm ent.
In som e cases, it m ay be useful for the stakeholders to appoint a “point person” to serve as the contact for comm unications. This is not to im ply that stakeholders m u st 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 inform ation. The Agency or stakeholders m ay also consider a public W e b site for the project. A variety of resources can be posted, including cum u lative risk tools and databases, project-related news, list of experts, glossary, reports, and related li nks. An online discussion forum could also be included on the W e b site as a m o re interactive way of exchanging inform ation with stakeholders. Finally, while including stakeholders in the risk assessm ent process, a regulatory agency such as EPA should balance stakeholder participation with the Agency’s need to retain the ability to carry out its responsibility to protect public health and the environm ent. For this reason, EPA will usually need to set som e reasonable boundaries around the process to ensure that progress is being m a de in a tim ely and efficient fashion.

161 7 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 2.1.1. Defining the Purpose of the Assessment As discussed in Section 1.5 above, the risk assessment should be developed to inform the risk management decision by constructing an appropriate, d ecision-relevant risk characterization. After the risk assessment planning team is assembled, the dialogue between the decisionmaker and risk experts begins with a discussion of risk management objectives and information needed to manage risks in the particular situation. The manager and assessment pl anning team should 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 because a differing sense of purpose among the team will lead to problems later on. The purpose and risk m anage m ent objectives guide the risk assess m ent strategy (see box below for some possible management goals from wh ich 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 assess m ent). Other p o ssible m anage m ent goals include identifying options for control or abate m ent of hazards or risk s , where decisions can then be m ade after considering costs and benefits of the various risk m anage m ent option s
. The previous discussion follows the typical situation where the risk manager is presented as an independent decisionmaker, 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 outside the Agency, such as a local citizens’ board. For example, mitigation of risks may not be significantly affected by any Agency or State permit decisions but will depend instead on local zoning decisions or on decisions that affect traffic patterns in a community. This is one of the reasons why the discussion of possible outcomes (discussed in Section 2.3) the final step in the planning and problem formulation phase is so important.2.1.2. Defining the Scope of Analysis and Products Needed Scoping a cum u lative risk assessm ent effort involves defining the elem ents that will or will not be included in the risk assessm ent 7 (USEPA, 1997a). These include the stressors, sources, pathways, routes, populations, and eff ects or assessm ent endpoints to be evaluated. As illustrated by the exam ples in the adjacent text box, the scope of a cum u lative risk assessm ent m ay be narrow or broad. Initially, the risk assessm ent planning team should select the kind of risk inform ation, exposure scenarios, and assessm ent issues that need to be covered. These should be directly linked to the risk-related questions being asked when establishing the purpose. Scope can be lim ited geographically (e.g., by political or ecological boundaries), environm entally (e.g., by assessing only certain m e dia), dem ographically (e.g., by assessing only risks to children or asthm a tics), legally (e.g., by statute or regulation), or by lack of m e thods or data in certain areas. The issue of background exposures to stressors should be discussed and agreem ents reached (see Appendix C). An adequate assessm ent scope should m a ke it clear what is included in and what is excluded from the assessm ent. Care should Examples of Cumulative Risk Assessment Scopes

• H ealth risks associated with the aggregate

exposure (via all pathways and routes) to insecticides acting by a comm on m ode of action.

• H um an health risks associated with outdoor

inhalation exposures of the general population to 33 priority air pollutants nationwide or via all routes to all pollutants present or being released from a hazardous waste site.

• H um an health and ecological risks associated with

m

u ltiple stressors resulting from developing a site or corridor of land for transportation, infrastructure, or a stationary facility.

• H um an 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 m unicipal landfill.

be taken to reconcile the lim itations of the scope w ith the list of questions to be answered in the statem ent of purpose. If, for exam ple, data lim itations preclude addressing certain questions outlined in the purpose, the list of questions should be m odified and the risk assessm ent planning team agree to the narrower scope of the assessm ent. Defining the scope of an assessm ent is a process that can include both analytical and deliberative aspects. The reasons for choosing the particular scope of the assessm ent and the m anner in which the assessm ent will address the questions posed in the purpose statem ent should be stated explicitly. Defining the scope of the assessm ent should include details on the lim itations of resources, lim itations of data, the im pact of risk elem ents on the risk estim ate (i.e., som e pathways m ay be seen as having negligible im pact on the risks related to the questions being addressed), and lim itations of the m e thods available. In cases where an elem ent of risk is likely

7 An assessm ent that looks at all stressors over a pe riod of tim e for a specific population would be a “total risk” assessm ent, which is difficult to perform with our current m e thods. 18to be im portant but no valid data are available, the risk assessors highlight this deficiency or use judgm ent or assum e d values to approxim a te the m i ssing data. Such judgm ents and approxim a tions should be clearly docum ented and explained to the m anager in the risk characterization. Once the elem ents (sources, stressors, populations, etc.) have been identified by brainstorm ing with all the participants, the participants should discuss the need for and availability of technical inf o rm ation and how such inf o rm ation m i ght af f ect the overall uncertainty of the assessm ent. Using input from the risk assessor, the risk assessm ent planning team should determ ine what elem ents will and will not (or can and cannot) be included in the risk assessm ent. Som e of the stakeholder concerns m ay not be suitable for analysis by risk assessm ent, so other expertise and evaluation m ay be required to provide this additional analysis. Inform ation gathered at this stage is prelim inary and m ay be m odified 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 m e thod of approach. Stressors can include physical (including radi ological) stressors or chem ical or biological agents that m ay cause an adverse ef f ect. The sources of the stressors can be hum an activities in sectors of society (e.g., m anufacturing, transportation, agriculture, land developm ent), personal activities (e.g., sm oking, diet, and other lifestyle activities), or natural phenom ena (e.g., forest fires, floods). Stressors that are not physical, ch em ical, or biological, such as econom ic or other quality-of-life stressors, m ay also be identified, but good techniques for including the effect these have on risk currently m ay not exist. Population elem ents are usually entities that are at risk, for exam ple, comm unities, portions of ecosystem functions (e.g., those species that provide food for others within the food chain), or vulnerable subpopulations such as persons with certain diseases or persons at vulnerable life stages, such as children. The m o re specifically these can be defined, the m o re f o cused the analysis can be. This will be helpf u l in interpreting the results of the assessm ent. 2.1.3. Agreeing on Participants, Roles, and Responsibilities The risk assessm ent planning team will usually recomm e nd other groups or individuals who should participate in the assessm ent planning, scoping, and risk analysis phase. Depending on the schedule, approach, and level of effort envisioned for the risk assessm ent, there m a y be no additional participants or there m ay be m any. The analytic portions of the assessm ent will usually require substantial technical expertise. Som e disciplines that m ay be pertinent include toxicology, epidem iology, ecology, exposure assessm ent, fate and transport m odeling (e.g., indoor and outdoor air, surface and drinking wate r), com puter science (including geographical inform ation system s [GISs]), chem istry, biol ogy, various engineering fields (e.g., chem ical, m echanical, industrial, civil), econom ics, sociology, and others.

19For the deliberative portions of the assessm ent, it m ay be that a num ber of stakeholders and other interested parties should be considered for participation (see box for exam ples). For comm unity-based assessm ents, in particular, it is im portant that comm unity involvem e nt be sought and encouraged. The Presidential/Congressional Comm i ssion on Risk Assessm ent and Risk Managem e nt (PCCRARM, 1997) suggests the following questions to identify potential interested or affected parties (stakeholders):

• Who m i ght be affected by the risk m anagem e nt decision? (This includes not only groups that already know or believe they are affected, but also Examples of Possible Interested or Affected Parties (Stakeholders) State governm e nts Affected industry Tribal governm e nts Civic organizations Local governm e nts Business owners Comm unity groups Trade associations Grassroots organizations Labor unions Environm ental groups Public health groups Consum er rights groups Academ ic institutions Religious groups Outdoors clubs Fishers and hunters Im pacted citizens Civil rights groups Other federal agencies Source: Adapted from USEPA, 1999b

groups that m ay be affected but as yet do not know it.)

• Who has inform ation and expertise that m i ght be helpful?

• Who has been involved in sim ilar risk situations before?

• Who has expressed interest in being involved in sim ilar decisions before?

• Who m i ght be reasonably angered if not included? The im portance of involving stakeholders in risk assessm ent is being increasingly recognized (e.g., NRC 1996; PCCRARM, 1997; USEPA 1996a, 1997a, 1998a, 1999c, 1999f, 2000a). The Comm i ssion’s suggested guidelines for stakeholder involvem e nt are shown in the box on the next page. There are several issues concerning the stakeholders’ capacity to participate that should not be overlooked by the risk assessm ent planning team

. First, som e stakeholders m ay need training to be able to participate in technical and risk m anagem e nt discussions. Second, as noted in the box on the next page, som e stakeholders m ay require incentives such as travel funds or lodging at sites of m eetings outside the area where they live. The risk assessm ent planning team , along with the potential source of funds for such in centives, 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 assessm ent project. The roles and responsibilities of technical and nontechnical participants (i.e., ground rules for participants) should also be proposed by the planning team , depending on the schedule, approach, and level of ef f o rt that is envisioned f o r the risk assessm ent. There will be several key

20Guidelines for Stakeholder Involvement

• R egulatory agencies or other organizations

considering stakeholder involvem e nt should be clear about the extent to which they are willing or able to respond to stakeholder involvem e nt before they undertake such efforts. If a decision is not negotiable, do not waste stakeholders’ tim e.

• T he goals of stakeholder involvem e nt should be

clarified at the outset and stakeholders should be involved early in the decision-m a king process. Do not m a ke saving m oney the sole criterion for success or expect stakeholder involvem e nt to end controversy.

• Stakeholder involvem e nt efforts should attem p t to engage all potentially affected parties and solicit a diversity of perspectives. It m a y be necessary to provide appropriate incentives to encourage stakeholder participation.

• S takeholders m u st be willing to negotiate and should be flexible. They m u st be prepared to listen to and learn from diverse viewpoints. W h ere possible, em power stakeholders to m a ke decisions, including providing them with the opportunity to obtain technical assistance.

• S takeholders should be given credit for their roles

in a decision, and how their input was used should be explained. If stakeholder suggestions were not used, explain why.

• T he nature, extent, and com p lexity of stakeholder involvem e nt should be appropriate to the scope and im pact of a decision and the potential of the decision to generate controversy. Source: Presidential/Congressional Comm i ssion on Risk Assessm ent and Risk Managem e nt, 1997 points in the risk assessm ent process where stakeholder input will be critical, such as agreem ent on purpose, scope, and approach. Each project should define and approve a list of critical points for stakeholder input. The team m ay even decide to assign stakeholders to subgroups that have specific tasks, such as understanding the technical inform ation and reporting back to the larger group, elevating and clarifying stakeholder issues as needed, or providing inform ation and facts to their peers and to the analysts.
Som e tim es citizens choose not to participate because they feel that they will not influence the outcom e , that the issue is too com p lex or technical, or that the effort is too great or because the decision process is unclear (USEPA, 2001c). Moreover, despite the increased em phasis on stakeholderparticipation, there are instances where largescale stakeholder involvem e nt m ay not be appropriate. EPA (as the decisionm aker) should determ ine whether, and to what degree, stakeholder involvem e nt in a cum u lative risk decision will be usef ul and what objectives it m ay accom p lish. There is a continuum of objectives that m ay apply to individual cases, from exchanging inform ation on one end, through obtaining stakeholder recomm e ndations, to developing agreem ents f o r joint activities at the other end (USEPA, 1998g). Many of the activities and m u ch of the data needed for cum u lative risk assessm ent draw upon broad expertise, experience, and legal m andates found not only in EPA, but in other public health agencies and academ ia. The m o st successful cum u lative risk assessm ents will likely be those where cooperation am ong organizations (Federal, State, private, environm ental, academ ic, etc.) leads to use of the best data and tools for the various parts of the assessm ent.

212.1.4. Agreeing on the Depth of the Assessm ent and the Analytical Approach The analysis approach (discussed further in Section 2.2.3 and Chapter 3) m ay fall anywhere on a continuum from relatively unsophisticated m e thods that rely heavily on default (and often conservative) assum p tions, and consequently have greater uncertainty, to increasingly ref i ned assessm ents in which data are substituted f o r assum p tions and uncertainty is reduced. Som e of the factors that go into deciding on the approach and associated plans for data collection include the level of uncertainty in the risk estim ates that is acceptable to the participants, the intended use and audience for the assessm ent, the tim e and m oney resources available, and the am ount, quality, and accessibility of data.
Cum u lative risk assessm ents, because of their nature, m ay require m o re attention to tim e, space, and route of exposure than do m any traditional assessm ents, and m e thods should be chosen, if available, to accomm odate these needs. In m a king the decision on approach, there will need to be an understanding of both the level of effort necessary for conducting the assessm ent selected, with an insight to alternatives, and the features and lim itations of the selected approach in com p arison to other approaches.
2.1.5. Agreeing on the Schedule and Resources Available Schedule and resources are often interrelated. They m ay also determ ine whether the work is perform e d in-house by the organization or team desiring the assessm ent or by a contractor or other external source. The need to m eet external deadlines or to coordinate with the schedules of other organizations m ay becom e overriding f actors in def i ning what will be prepared. Assessm ents that require short-term , low-budget efforts or prelim inary screening assessm ents m ay not have the scope, tim e, or resources for extensive stakeholder involvem e nt. Wh en there is extensive stakeholder involvem e nt, it is especially im portant that a budget and tim e schedule be developed and known by all participants.
2.1.6. Review of Lessons Learned Much tim e and effort can be saved by taking the advice of those who have already been through this process or sim ilar processes. Risk assessm ent reports will often have a review chapter of lessons learned (or, “if I had to do this over again, I would

. . . . ”). W e have tried to include som e discussion of recent Agency experiences to illustrate parts of this fram ework report. In addition, the reader is encouraged to find sim ilar advice in other reports (e.g., USEPA, 2002b). For exam ple, EPA’s Office of W a ter has conducted several watershed studies over the past decade and has com p iled a W e b page with lessons learned (USEPA, 2001d) (see box on the next page for one of the lists). Even though not all studies were cum u lative risk assessm ents, m

u ch of the wisdom gained is relevant.

22Reed Holderman's Lessons Learned (California Coastal Conservancy, Santa Ynez W a tershed) 1. Be sure that [the project] is needed, and if it is, build comm unity support for it before proceeding. 2. Invite everyone into the process and ask political leaders to select the steer ing comm ittee. Otherwise, people will ask, “W ho appointed you? ”
3. Don' t be presum ptuous. On the Santa Ynez River, we assum e d everybody would appreciate a well thought out scope of work, budget, and schedule. W r ong. They said it only proved that the whole thing was a set-up. Next tim e, let [the whole planning team ] figure it out!
4. W h en the m a jority of stakeholders tell you that they want to deal with their issue first, believe them

. I rem a in convinced that our failure to sustain interest in the Santa Ynez River plan was prim arily because we were not willing to assist the County in carrying out its proposed channel-clearing activities in the Lom poc 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. Fam ily BBQs, softball gam e s, and parties have done wonders to im prove relationships am ong stakeholders and build trust. 6. Maintain constant comm unication am ong stakeholders throughout the process—and especially in the beginning—to pass inform ation along, answer questions, or deal with rum o rs. W h ether it' s through regular m eetings, newsletters, web sites, phone trees, or all four, good comm unication is a m u st. 7. And finally, line up your m oney and in-kind services in advance of starting your [assessm ent] 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 m o re tim e looking for cash than participating in the planning process. Either way, you lose. Source: USEPA, 2001d

232.2. Problem Formulation, Conceptual Model, and Analysis Plan
One outcom e of the problem form ulation phase is a conceptual m odel that is intended to identify relevant stressors, sources, pathways, exposure routes, receptors, and effects and the relationships am ong them

. The conceptual m odel serves as a basis for the analysis plan, which is used to focus the analysis phase of the assessm ent. 2.2.1. Problem Form ulation Problem form ulation is a system atic planning step that identifies the m a jor factors to be considered in a particular assessm ent. It is linked to the regulatory and policy context of the assessm ent. Problem form ulation is an iterative process within which the risk assessor develops prelim inary hypotheses about why adverse effects m i ght occur or have occurred. It provides the foundation for the technical approach of the assessm ent. The outcom e of the problem form ulation process is a conceptual m odel that identifies the stressors, the population exposed, and the assessm ent endpoints that will be addressed in the risk assessm ent and describes the relationships am ong them

. One of the m a jor differences between a cum u lative risk assessm ent and a m o re traditional, single-chem ical assessm ent is that in a cum u lative assessm ent special attention should be given to identification of stressors and endpoints and the relationship between them

. The box below shows desired outputs from the problem form ulation phase of an environm ental decision-m a king exercise. Although su ch an exercise is not precisely the sam e as a risk assessm ent, som e of the outcom e s are applicable, depending on the scope of the assessm ent. The Science Advisory Board’s Desired Outputs for Problem Formulation

! The initial goals for the decision-m a king exercise, including environm ental goals to be achieved ! W h ich environm ental problem s/stressors/system s 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, tem poral, and organizational dim e nsions to data analysis ! Scoping of the uncertainties involved and research n eeded to significantly reduce critical uncertainties ! Initial review of the range of options available to reduce risks, considering likely econom ic, political, or other constraints ! The endpoints upon which the condition of the ecological, hum an health, or societal system s ultim ately will be judged Source: USEPA, 2000a

242.2.2. Developing the Conceptual Model A conceptual m odel includes both a written description and a visual representation of actual or predicted relationships between hum ans (or populations or population segm ents) or ecological entities and the chem icals or other stressors to which they m ay be exposed. Conceptual m odels represent m any relationships and m ay describe prim ary, secondary, or tertiary exposure pathways. The m odel is developed by the risk assessor and m ay include input from other experts (including stakeholde rs). The m odel narrative should distinguish—to the extent possible—between what is known or determ ined and what is assum e d. Also, it should include a discussion of uncertainties in the form ulation of the assessm ent and state how the assessm ent is cum u lative, that is, for which sources, stressors/agents, pathways/exposure routes, receptors/populations, and endpoints. In som e cases, conceptual m odels will be subm itted for peer review. A general conceptual m odel (Figure 2-2) defines the com ponents of such a m odel and shows the theoretical pathways and routes of exposure between the stressors (and sources of stressors) and effects (endpoints) for hum an and ecological receptors. The conceptual m odel includes factors and endpoints that m ay not be analyzed in the risk assessm ent but m ay be evaluated in the overall decision-m a king process. The conceptual m odel and the associated narrative show the basic rationale for the decisions m a de in pursuing a particular course of action. It provides a record of decisions for future reference during risk analysis and characterization and comm unication of the risk m anagem e nt decision. It is also valuable as a risk comm unication tool both within the Agency and in interactions with the public. The conceptual m odel provides a scientific or technical work product that includes (1) the scientific rationale for selecting the stressors, sources, receptors, exposed populations, exposure or environm ental pathways, endpoints, or effects; (2) the scientific, technical, econom ic, or sociologic basis for the construction of the conceptual m odel; and (3) the scientific im plications of additional data gathering. Figure 2-3 is an exam ple of a conceptual m odel from the National Air Toxics Assessm ent (NATA). 8 It is not inconceivable, given the deliberative nature of the process of developing a conceptual m odel, that m o re than one m odel will be considered. If the team decides to ultim ately use m o re than one m odel and to evaluate each as part of hypothesis testing, a careful consideration of tim e and m onetary resources should be m a de, as well as a very careful consideration of how the results will be interpreted (see Section 2.3).

8 NATA is the technical support com ponent of EP A’s National Air Toxics Program (64FR38706-38740; USEPA, 2001e). 25

### A Generalized Co nceptual Model
w i th Exa m ples o f Possible Elements a n d L i nk ag e s

Sourc e s Str e s so rs P a thway s / E x p o sure Rou t es Re c e p t o r s E nd po i n t s
Ac ti vi ti e s that ge ner a te o r rele a s e s t re s s o rs Che m i c al , ph ysic al, or biologic a l age nts that ca u s e a n ef

f e c t Surf a c e w a t e r, air , in d o o r air , g r ou ndwa ter , or s o il ar e pathway s . Popula tions, ec olo g ical communities , an d ec osy s tems ma y b e re cep to rs fo r som e st re ssors. Ec ologic al Ec ologic al End p oints Habitat s t r u cture, spe c i es di st r i but i o n, div e rsit y E c osy s tem conditions •Population lev e ls •E nv ironm e nta l pr oc ess r a te s Status of cr itical spe c i es orspe c i e s of s p ecia l co n cer n
. -M an u f ac turing -F os s il f u el combus tion (e .g
. , f o r trans p ortation, heating , electricit y) -W a s t e r p r oc essing -Mining -A g r icultural activ ities -N atur al p r oc esse s Chemical -O r g an ic -I n o r g an ic Biolog ic al -P ath o g en s

- E xotic spp.
Ph y s ica l -Th e rm al -Er o s i o n / s e dimentation -H abitat alteration
A va r i ety o f oth e r fac t ors (e .g., he alth stat us, ac ce ss t o health) may impact indiv i dual or populatio n s u s c eptibility to abov e stre ssors Fo r indiv i dua l s, ing e s tion, inhalation, or ab s o r p tio nar e the ro u t es of exp o s u r e . F o r ec olog ic al entities , biotic and abiotic inter actions are ke y s to how st re ssor s a r e pr ese n te d to re cep to r s
. Hu man Health I n di v i duals a n d gr o up s o f pe ople a r e also re cep to rs -I nf an ts -S ens itiv e pop

- O c c upa tiona l -Minor ities -Env . Jus tice Co mmuni ties M o rt ali t y an d I l l n ess, suc ha s : Cancers •L eu k e mia, lung , etc •Othera dv e r s e h ealthef f e c t s •As t hma, res p irat ory impacts •Kidn e y dis eas e •CNS ef f ects •E tc. E n dp o i n t s a r e me a s ur e s o f ef

f e cts o f s t res s o r s Human He alth E n dpoints

Figure 2-2. An example of a generic conceptual model (adapted from USEPA, 2002b).

2627Figure 2-3.Specific conceptual model for a complex project,OAQPS’ National Scale Air Toxics Assessment.PBT=persistent, bioaccumulative, and toxicCNS=central nervous systemSource: USEPA, 2001e2.2.3. Constructing the Analysis Plan The analysis plan is the final stage of the planning and scoping process (see discussion in USEPA, 1998b). It describes how hypotheses about the relationships am ong the sources, stressors, exposure conditions, populations, and adverse effects/endpoints (see box) presented in the conceptual m odel and narrative will be considered during the risk analysis phase of the assessm ent. The plan includes the rationale for which relationships (referred to as “risk hypotheses” in USEPA, 1998b) are addressed, m e thods, m odels, and a discussion of data gaps and uncertainties. It also m ay include a com p ar ison between the level of confidence needed for the m anagem e nt decision and that expected from alternative analyses in order to determ ine data
Important Details for an Analysis Plan
Sources: Identification of sources to be included and m e thods and associated data for including them

. Stressors: Identification of stressors to be included and m e thods and associated data for including them

. Clarification of direct- and indirect-acting stressors. Exposure Conditions: Specification of exposure conditions to be assessed, along with m e thods. Populations: Identification of the populations on which analysis will focus. Endpoints or Adverse Effects: Identification of one or m o re unique, well-defined endpoint for analysis. Note that a concept such as “health of the comm unity” is not a well-defined endpoint. Identification of linkages between assessm ent endpoints and m easurable attributes. Specification of those endpoints or exposures that will be m easured directly and those that will be estim ated or for which surrogates will be used. Identification of comm on endpoints/effects for groups of stressors for which risks or im pacts are to be com b ined. Description of m e thods to be em ployed for com b ining risks in term s of endpoints. needs and evaluate which analytical approach is best. In som e cases, a phased or tiered risk assessm ent approach can f acilitate m anagem e nt decisions, particularly in cases involving m i nim a l data sets. The analysis plan provides a synopsis of m easures that will be used to evaluate risk hypotheses (as shown in Appendix D). The plan is strongest when it contains explicit statem ents of how m easures were selected, what adverse effect (or assessm ent endpoint) they are intended to evaluate, and which analyses they support. Uncertainties associated with selected m easures and analyses and plans for addressing them should be included in the plan when possible. The analysis plan can be a brief summ ary of the key com ponents of the risk assessm ent and how each com ponent will be m easured or calculated.
In a cum u lative risk assessm ent, a key aspect is considering whether and how m u ltiple stressors interact or act together in contributing to risks; thus, som e early thought should be given to the strategy for addressing this aspect of the assessm ent. The strategy should address m e thods to be em ployed for considering potential joint action of m u ltiple stressors on a single endpoint as well as whether

28the assessm ent will attem p t to describe cum u lative im pact on m u ltiple endpoints. The discussion of

this issue in the analysis plan can include both qualitative and quantitative approaches (see Chapter 3). As with the conceptual m odel, societal im portance, com p lexity, and available data and resources will determ ine the degree of sophistication and detail needed in the analysis plan. Key data gaps should be identified. The plan should also include thoughts about how to fill the inform ation needs in the near term using existing inform ation, in the m i dterm by conducting tests with currently available m e thods to provide data on the agent(s) of interest, and over the long term to develop better, m o re realistic understandings of exposure and effects and m o re realistic test m e thods to evaluate agents of concern. The plan should explain how m easures were selected, what they are intended to evaluate, and which analyses they support. Uncertainties associated with selected m easures and analyses and plans for addressing them should also be explicitly stated. The analysis plan should include (where feasible) m ilestones for com p leting the risk assessm ent. The plan m ay be revisited and revised periodically. If new inform ation is acquired, such revisions m ay refine hypotheses of expos ure and toxicity, m odify the risk hypotheses addressed, or com p are public concerns with the projected risk m anagem e nt options.
2.2.4. An Early Look at Uncertainty In preparing the conceptual m odel and analysis plan, there should be som e early thinking about uncertainty. In Section 4.2.1, there is a di scussion of different types of uncertainty that should be considered in the analysis: (1) param e ter uncertainty (uncertainty about technical, scientific, econom ic, and political quantities), (2) m odel uncertainty (uncertainty about the appropriate functional form of technical, scientific, econom ic, and political m odels), and (3) disagreem ents am ong experts (e.g., about the values of quantities or the functional form of m odels, as when different health scientists use different form s of dose-response m odels). These considerations are im portant for interpreting the results of the study and should be considered in the selection of m e thods as part of the pl anning, scoping, and problem form ulation process. The first of these uncertainties facing the planning team is the so-called epistem o logical uncertainty (not yet even knowing what questions to ask). It is likely that in planning any com p lex assessm ent, som e questions will only becom e evident af ter the data collection or analysis has begun. It is therefore im portant that the planning team m a ke provisions for revisiting the analysis plan—or even the conceptual m odel—at intervals during the process. Even m o re helpful would be an agreed-upon m echanism for changing the analysis plan or conceptual m odel bef o re the need f o r revision arises, as it alm o st assuredly will. The second general aspect of uncertainty that should be dealt with in the planning, scoping, and problem form ulation phase is “acceptable uncertainty.” How m u ch uncertainty is the planning team willing to accept in the results of the study? Typically, this is a very difficult question for risk assessors and decisionm akers to answer, but it is a key question that enorm ously affects the cost and usefulness of the study. 29At one end of this acceptable uncertainty spectrum are risk assessm ents that are based only on readily available inform ation. At the other end is an assessm ent that starts with carefully reasoned and detailed quality assurance param e ters, leading to specific data being accepted or rejected for the study based on predeterm i ned quality assurance guidelines. This process in turn leads to results with known and acceptable uncertainties, but it m ay either require expensive data collection or cause the study to fail when none of the data m eet the quality assurance requirem e nts. The planning team should decide where on this spectrum it wants to be for the study under consideration and whether the results will allow m eaningful decisions. Again, the decision on acceptable uncertainty is difficult, but consideration early in the process will im prove the potential for producing an analysis suited to the needs of the stakeholders.
2.3. Ecological versus Human Health versus “Integrated” Cumulative Risk Assessment
Cum u lative risk assessm ents m ay include both hum an health and ecological aspects. Several reports have dealt with cum u lative ecological risk assessm ent in som e detail (e.g., Foran and Ferenc 1999; Ferenc and Foran 2000; USEP A 1998b). USEPA (2002c) noted som e of the m a jor differences between hum an health and ecological assessm ents (see list below), and these differences need to be considered when planning a cum u lative risk assessm ent that includes both aspects:

C Ecological system s are not as well known biologically as are hum an health system s, either at the population and at the individual level;

C For this reason, and because biological comm unities and ecosystem s are inherently m o re com p lex, ecological risk assessm ent requires m o re prelim inary analysis and deliberation regarding endpoints and protective standards;

C Ecosystem s , habitats, and ecological comm unities have traits and properties that individuals do not or that are not app licable to individuals or populations;

C Ecological risk assessm ent has been generally applied to populations, not individuals, whereas the reverse is true for hum an health risk assessm ents; and

C Ecological risk assessm ent should assess risk at m u ltiple levels or organization, that is, the m o lecule, cell, organism , population, comm unity, and ecosystem

. The W o rld Health Organization (W HO, 2001) has published approaches to integrating hum an health and ecological risk assessm ents to im prove data quality and understanding of cum u lative risks for decision m a king. The organization’s approach includes an integrated fram ework (m odified from USEPA, 1998b) and case studies. Many tribal cultures view ecological and hum an health in an integrated way such that they cannot be easily separated. Sim ilarly, there is som e effort (especially in Canada) toward integrating hum an health and ecological assessm ent as well as decisionm aking in a field known as “strategic environm ental assessm ent” (Bonnell and Storey, 2000). This approach has not been applied widely in the United States, and it rem a ins to be seen how it will develop in the next f e w years. 302.4. The Final Step Before the Analysis Phase: Discussion of Possible Outcomes Before the analytical efforts of the cum u lative risk assessm ent are started, it is useful for the entire team to hold som e prelim inary discussions about the possible results and their im plications. Given that statutory m andates, regulations, property rights, or due process m ay constrain or define m o st or all acceptability criteria, what conclusions of the team will be associated with various results or risk levels? For exam ple, for a risk assessm ent team with m e m b ers from the comm unity, industry, and local and other governm e nt entities, what would happen if the assessm ent shows risk levels to be “low”? W ould m e m b ers accept this? Conversely, if “unacceptable” risks are determ ined, will all team m e m b ers accept the results and their potential responsibility to do som e thing about that risk? Do team m e m b ers understand the lim itations of the inform ation to be generated? Discussions like these will help determ ine whether the assessm ent can really address the questions of the team

. If not, the assessm ent m ay not be worth doing as planned. If m e m b ers of the team will not accept the possibility of a range of results, then it is im portant to reopen the entire planning and scoping discussion before anything is done in the analysis phase, because the planning and scoping phase has not been satisfactorily com p leted. Although it is not necessary to have unanim ity am ong stakeholders before proceeding with the plan, knowing where som e of the potential disagreem ents m ay occur after the analysis and risk characterization phases are started allows the stakeholders as a group to plan beforehand for how such disagreem ents will be addressed, should they occur. Although it is possible to ensure that all stakeholders have been heard and their opinions given due consideration and weight, that does not necessarily m ean that all of them will get what they want.
As an exam ple, USEPA (2000f) is a case study where the stakeholders thought they had agreem ent on roles, responsibilities, and approach, only to find that the group acrim oniously splintered af ter the analysis results cam e back. The Baltim ore report contains valuable lessons learned in the area of stakeholder disagreem ents and agendas and can provide som e insight for planning team s. 9 Discussions just prior to the analysis phase m ay lead to an assessm ent that is very different from the one originally envisioned. For exam ple, in the case of the cum u lative risk initiative for Cook County (IL) and Lake County (IN) (see box on next page) the original plan was for a quantitative cum u lative risk assessm ent, but because of the lack of som e critical inform ation, the scope was changed. This led to an assessm ent that, although not as broad as in the original plan—and that did not even directly calculate risk—had better stakeholder buy-in and a better chance of success in providing useful inform ation. Finally, it should be acknowledged by all practitioners of cum u lative risk assessm ent that in the current state of the science there will be lim itations in m e thods and data available. It will

9 This case study, along with several others, will be exam ined m o re fully in followup work to this fram e work report. 31Cumulative Risk Initiative (CRI) for Cook County (IL) and Lake County (IN ) ( formerly the Chicago Cumulative Risk Initiative, CCRI )

CRI B ACKGROUND AND OVERVIEW In 1995 the Chicago Legal Clinic and 11 Chicago-area comm unity advocacy groups filed a petition under the Toxic Substances Control Act requesting that the EP A Adm i nistrator prohibit or further regulate em issions from eight proposed or constructed incinerators in th e Chicago m e tropolitan area and Northwest Indiana. The petitioners believed that neither current statutes nor lo cal siting laws adequately addressed cum u lative im pacts of m u ltiple sources of toxic pollutants in a geographic area. They requested that the Adm i nistrator restrict em issions of dioxins, furans, m e rcury, lead, and cad m i um from these sources. In May 1996 the petition was withdrawn in response to an EPA offer to participate in an investigation of m u ltim edia pollutant im pacts in Cook County, Illinois, and Lake County, Indiana. Th is effort becam e the CRI. A CRI is an attem p t to investigate cum u lative loadings and hazards from pollutant sources, to develop comm unity-based activities to help address these concerns, and to use analytic results to help prioritize use of regulatory agency resources. EPA and the petitioners agreed to a four-phase projec t: (1) an environm ental loadings profile (EPA 747-R-1- 002); (2) a petitioner risk workshop (com pleted); (3) a h azard screening assessm ent (peer review draft available January 2002); and (4) a risk-hazard m a nagem e nt response.

HAZARD SCREENING ASSESSMENT The CRI hazard screening assessm ent was authored prim arily by Argonne National Laboratory, with input from local, State and Federal participants. Reflecting stak eholder deliberations, the report focuses on cum u lative hazard (not “ r isk” as typically defined by EPA) associat ed with noncriteria air pollutants (“ air toxics”) in the two-county study area. It relies on “off-the-shelf” air po llutant inform ation, including EPA’s Toxics Release Inventory, Cum u lative Exposure Project, Regional Air Pollutant Inventory Developm ent System , and outdoor air m onitoring data. Em ission estim ates are “toxicity weighted,” and m odeled/m onitored outdoor air pollutant concentrations are com p ared with reference values to develop hazard index-like ratios. The ratios or toxicityweighted em ission estim ates are used to derive i ndicators of cum u lative hazard and then m apped over study area locations. To identify geographic areas where poten tially elevated hazards and individuals with potentially greater susceptibility are collocated, another part of th e study assem b les pollutant hazard inform ation and data on existing hum an disease rates and indicators.
P RELIMINARY L ESSONS L EARNED 1. A m a jor planning/scoping/problem form ulation effo rt by a broad group of stakeholders narrowed the scope of the CRI hazard screening assessm ent and seem ed to increase stakeholder “ buy-in” with the process. This was valuable, given the com p lexity, expense, effort, tim e requirem e nt, and difficulty encountered in addressing even the narrowed scope.
2. Large data gaps m a ke risk and hazard assessm ent of environm entally relevant chem ical exposures highly uncertain, even for single agents. Expanded assessm ents that address cum u lative risk considerations (e.g. m i xtures, developm ental toxicity, nonchem i cal agents) are a better m a tch for real-world circum stances but require acknowledgm ent of even m o re uncertainty.
3. Obtaining and m a naging input from a large group of technical stakeholders is cum b ersom e and tim econsum ing, but that group’s perspective and expertise greatly im proved the CRI assessm ent. 4. Given that the National Research Council’s 1983 f our-step “fram e work” required several years for broad use and acceptance in the United States, the greater com p lexity of cum u lative risk (for CRI, cum u lative hazard ) assessm ent suggests that an equally long period m a y be needed for term inology standardization, refinem e nt of approaches, and developm ent of consensus m e thods.

32be im portant to identif y these lim itations and discuss them f

r ankly in the cum u lative risk assessm ent report. Data lim itations m ay be som e what m itigated by qualitative inf o rm ation; the collection of qualitative data m ay be valuable in cum u lative risk assessm ent. Still, lim itations in m e thods or data should not be seen as a convenient reason for com p letely ignoring or not posing questions for which stakeholders m a y be seeki ng answers. Lack of an appropriate m e thodology m ay indeed be a reason why certain questions cannot be addressed in the analysis phase, but capturing the questions and having som e discussion about why the questions could not be addressed in the assessm ent is of ten helpf u l.

333. THE ANALYSIS PHASE The analysis phase (Figure 3-1) is prim arily an analytic process in which risk experts apply risk assessm ent approaches to evaluating the problem at hand. 10 The risk assessm ent paradigm m o st widely used by risk assessors during the past two decades was first docum ented by the National Research Council (NRC) (NRC, 1983). It consists of four parts: hazard identification, dose-response assessm ent, exposure assessm ent, and risk characterization. This paradigm was developed when alm o st all risk assessm ents were being conducted on single chem icals. Nevertheless, it is a useful place to start when considering cum u lative risks. This f r am ework f o llows the NRC risk assessm ent paradigm in all respects except that the exposure and hazard/dose-response com ponents should be evaluated together rather than separately. As a prerequisite to using this fram ework, assessors considering cum u lative risk assessm ents should be fam iliar with the 1983 NRC risk paradigm as well as the various EPA risk assessm ent guidelines (see text box titled “EPA’s Risk Assessm ent Guidelines” in Section 1.1). In both single-stressor and m u ltiple-stressor risk assessm ents, 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 som e of the situations that arise in cum u lative risk assessm ent, m e thods currently available for addressing them , steps in the process, and som e lim itations to these m e thods. Finally, Section 3.3 identifies areas of ongoing work that are particularly relevant to cum u lative risk assessm ent. 3.1. General Process In developing the conceptual m odel and analysis plan (see Section 2.2), the scope of the assessm ent was specified (see exam ple in box on page 36). Som e of the aspects of scope include stressors, sources, pathways and m e dia, exposure routes, populations and subpopulations, endpoints, and m easures. The analysis plan should specify how data, m odeling, or assum p tions will be obtained, perform e d, or defined for all of the de tails concerning the characterization of exposure of the defined population and subpopulations to th e defined set of stressors. Additionally, the analysis plan specifies the strategy for obtaining and considering hazard and dose-response

10 Although the analysis phase is prim arily an analytic process, with heavy em phasis 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. Som e roles stakeholders m i ght have in the analysis phase include (1) suggesting sources of data or providing data for the assessm ent; (2) he lping clarify issues identified during problem form ulation; (3) working alongside the risk assessm ent experts to see what data and assum p tions are being used and why and to better understand how the risk assessm ent process works; and (4) suggesting alternate scenarios that m a y reflect m o re realistic exposure conditions in the comm unity. A variet y of roles for stakeholders in the analysis phase can be proposed and adapted for the particular circum stances of the individual case, assum i ng that the roles can be agreed upon by the team

. 34Figure 3-1. The Analysis phase. inform ation for these stressors and the m e thod for com b ining the exposure inform ation with the hazard and dose-response inform ation to generate risk estim ates or m easures. As the risk analysis is refined, it m ay be appropriate to revisit and refine the exposure, hazard, and doseresponse inform ation in an iterative fashion. In the integration of exposure, hazard, and dose-response inform ation for a cum u lative risk assessm ent, several aspects of the assessm ent m ay be particularly im portant. These include m

u ltiple-stressor hazard, dose-response and exposure issues, exposure tim e or duration-related issues, vulnerability (including susceptibility) of the study population along with the influencing factors (including life stage), and subpopulations with special exposures. These item s are discussed in the following section along with the currently recognized m e thods for evaluating the toxicity or risk associated with m i xtures.

35The area of identifying and assessing risk to susceptible subpopulations has an increased profile in cum u lative risk assessm ents. A variety of f actors m ay be inf l uential in af f ecting population susceptibility. The extent to which these can be considered will be heavily dependent on existing knowledge and available inform ation.

3.2. Available Methods and Approaches Many aspects of traditional risk assessm ent m e thodology apply to cum u lative risk assessm ent. Predicting cum u lative risk of m u ltiple stressors, however, has required the developm ent of additional specific m e thods or approaches. Additionally, there are som e aspects of risk assessm ent that, although comm on to both single-stressor and m u ltiple-stressor assessm ents, m ay increase in com p lexity or significance in a cum u lative risk assessm ent. Scope of EPA’s National-Scale Assessment for Haz a rdous Air Pollutants (also see Figure 2-3):
S t res s o rs 33 priority urban hazardous air pollutants (HAPs) S o u rces Major industrial, small “area,” mobile (on- and off-road), and extrinsic “background” in air Pathw a ys/media Outdoor air, indoor air Microenvironments Routes Inhalation Subpopulations General population only Endpoints Cancers , developm ental, central nervous sy stem, kidney , liver, res p iratory effects Metrics F o r cancer: distribution of high-end cancer ris k es tim ates , predicted percent of population within predicted cancer risk ranges, predicted number of cancer cas es , HAP -s pecific and cumu lative For other effects: distribution of es tim ated hazard index values and estimated percent of population within specified ranges of index values

Although the aspects comm on to single-stressor and m u ltiple-stressor assessm ents m a y be m any (e.g., the added dim e nsion of m u ltiple stressors influences consideration of stressor sources, routes of exposure, environm ental m e di a/pathways, and other factors), several exam ples are cited here. As one exam ple, the assessm ent of the dose-response relationship and the corresponding characterization of exposures in term s of duration, tim ing relevant to life stage, and exposure history gain an additional dim e nsion with the need to consider them cum u latively in som e way. The consideration of population susceptibility (as a part of vulnerability), as recomm e nded by EPA (USEPA 1995a, b, 2000c), also increases in com p lexity. A third exam ple of a com p licating aspect in cum u lative risk assessm ent is the consideration of subpopulations that have particularly distinctive exposures. These exam ples are further discussed in Section 3.2.1. Although it is beyond the scope of this fram ework report to describe all risk m e thods in detail, Appendix B lists a variety of resources relevant to various exposure assessm ent m e thods. Relatively speaking, there is a great deal of inform ation on assessing hum an and environm ental exposures to chem ical stressors and there is som e inform ation on biological and radiological stressors, but there is com p aratively little inf o rm ation on m any other types of stressors.

36The m o st prom inent aspect of cum u lative risk assessm ent is often the prediction of the com b ined ef f ects of m u ltiple stressors. Past and current activities in the developm ent of approaches for predicting risk of m u ltiple stressors are described in USEPA (1986b, 2000e). Concepts, approaches, or m e thods described in these docum ents or elsewhere are discussed in section 3.2.2, with clarification of their applicability, lim itations and notable points regarding interpretation of the results they produce.
3.2.1. Exam ples of Increased Com p lexity of Cum u lative Risk Assessm ent Cum u lative risk assessm ents can be quite com p lex (see text box on the following page for an exam ple). Three factors that can increase com p lexity in a cum u lative risk assessm ent are (1) tim e-related aspects, (2) vulnerability (including susceptibility), and (3) subpopulations with special or particularly distinctive exposures. All three are relevant in single-stressor assessm ents, but they have the potential to be m o re com p licated in m u ltiple-stressor assessm ents Time-related aspects. The issue of repeated exposures to a single stressor or exposures to m u ltiple stressors that m ay vary in tim e dim e nsions m ay have im plications f o r susceptibility, which, consequently, has im plications for the dose-response relationship. Traditionally in doseresponse assessm ent, there is an inherent presum ption that, for m any stressors and effects, it is the aggregate exposure (the com b ination of intensity and duration) to which the organism responds (e.g., Haber, 1924). Thus dose-response assessm ents based on one pattern of exposure (e.g., 6 hours per day, 5 days per week over a lifetim e) are routinely applied to the assessm ent of risk associated with a variety of patterns of exposure. In the case of linear carcinogens, this aggregate exposure assum p tion has been carried as an explicit assum p tion in the risk assessm ent step. Regardless of the details of the exposure circum stances in the study on which the cancer potency was based, it is assum e d that there is a linear relationship between am ounts of exposure and associated cancer risk. For nonlinear carcinogens 11 , and conceivably for linear carcinogens, if data indicate deviation from the assum p tion that cancer risk is proportional to lifetim e dose, the details and sequence of exposure m ay be im portant, both in developing the dose-response relationship and in predicting risk associated with exposures and life stages of interest.
Because som e chem icals m ay have the ability to affect an organism ’s response to other chem icals, consideration of the tim e sequence of exposure m ay take on an additional layer of com p lexity in m u ltiple-chem i cal cum u lative risk assessm ents. For exam ple, persons with relevant past exposures m i ght have increased susceptibility to the effects of a particular chem ical due to a previous exposure to the sam e —or a second—chem i cal.

11 The draft cancer guidelines (USEPA, 1999l) explicitly recognize the potential for nonlinear doseresponse. It is only in the case where nonlinear res ponse is m odeled that tim e sequence of exposure can be considered in the risk assessm ent. 37The National-Scale Air Toxics Assessment The National Air Toxics Assessm ent (NATA), which is based on 1996 em issions data is an ongoing series of studies—som e of which are com p leted—that will ultim ately provide results that are useful in understanding the quality of air and its possible effect on hum an health nationwide. The assessm ent includes 32 air toxics (a subset of EPA' s list of 188 air toxics) and also diesel par ticulate m a tter (which is used as a surrogate m easure for diesel exhaust). Specifically, the assessm ent consists of four steps that will produce nationwide estim ates of (1) the release of these pollutants into the air from various sources, (2) the concentration of these com pounds in the air, (3) the exposure of populations to this air, and (4) the risk of both cancer and noncancer health effects resulting from this exposure. Purpose: The results of the national-scale assessm ent will pr ovide im portant inform ation to help EPA continue to develop and im plem ent various aspects of the national air toxics program

. They will not be used directly to regulate sources of air toxics em issions. Although regulat ory priority setting will be inform ed by this and future national assessm ents, risk-based regulations will be based on m o re refined and source-specific data and assessm ent tools. More specifically, the assessm ent resu lts will help identify air toxics of greatest potential concern, characterize the relative contributions to air t oxics concentrations and population exposures of different types of air toxics em issions sources (e.g., m a jor, m obile ), and set priorities for the collection of additional air toxics data and research to im prove estim ates of ai r toxics concentrations and their potential public health im pacts. Im portant additional data collection activitie s will include upgrading em ission inventory inform ation, am bient air toxics m onitoring, and inform ation on advers e effects to health and the environm ent; establishing a baseline for tracking trends over tim e in m odeled am bient concentrations of air toxics; and establishing a baseline for m easuring progress toward m eeting goals for inhalation risk reduction from am bient air toxics. The Four Steps : The national-scale assessm ent includes the fo llowing four m a jor steps for assessing air toxics across the contiguous United States (also Puerto Rico and the Virgin Islands). (1) Compiling a 1996 national emissions inventory of air toxics emissions from outdoor sources. The types of em issions sources in the inventory include m a jor stationary sources (e.g., large waste incinerators and factories), area and other sources (e.g., dry cleaners, sm all m a nuf acturers, wildfires), and both onroad and nonroad m obile sources (e.g., cars, trucks, boats). EPA m a de som e m odifications to the 1996 National Toxics Inventory to prepare the em issions for com puter m odeling. (2) Estimating 1996 ambient concentrations based on the 1996 emissions as input to an air dispersion model ( t he ASPEN model)

. As part of this m odeling exercise, EPA com p ared estim ated am bient concentrations to available am bient air toxics m onitoring data to evaluate m odel perform ance. (3) Estimating 1996 population exposures based on a scr eening-level inhalation exposure model ( H

APEM4) and the estimated ambient concentrations ( f

rom the ASPEN model) as input to the exposure model. Estim ating exposure is a key step in determ ining potential health risk. People m ove around from one location to another, outside to inside, etc., so exposure is not the sam e as concentration at a static site. People also breathe at different rates depending on their activity levels, so the am ount of air they take in varies. For these reasons, the average concentration of a pollutant that people breat he (i.e., exposure concentration) m a y be significantly higher or lower than the concentration at a fixed location (i.e., am bient concentration). (4) Characterizing 1996 potential public health risks due to inhalation of air toxics. This includes both cancer and noncancer effects using available inform ation on air t oxics health effects, current EPA risk assessm ent and risk characterization guidelines, and estim ated populati on exposures. Using the toxicological independence form ula and the default assum p tion of additivity of risks (USEPA, 1986b, 2000e), this assessm ent com b ines cancer risk estim ates by summ i ng them for certain wei ght-of-evidence groupings and also across all groupings. For noncancer effects, the assessm ent assum e s dose add itivity and aggregates or sum s hazard quotients for individual air toxics that affect the sam e organ or organ system (USEPA, 2000e), in this case com b ining air toxics that act as respiratory irritants.

38These considerations suggest that for cum u lative risk assessm ent, chem ical exposures need to be characterized in term s of which other chem icals are present, and when. As noted in ILSI (1999), “Data collected specifically to support a cum u lative exposure assessm ent should conserve the covariance and dependency structures associated with the chem icals of concern.” It is im portant to note, however, that the level of detail to which exposures are characterized should be closely tied to the level of detail of inform ation available in the dose-response assessm ent, because a lack of corresponding detail in the dose-response assessm ent can pose a lim itation on the interpretation and usefulness of detailed exposure estim ates. Cum u lative risk assessm ent can present challenges in m a tching exposure estim ates with dose-response relationships. Ideally, the dose-response assessm ent will indicate whether the tim e sequence f o r the chem ical(s) or stressors of interest in the assessm ent is im portant f o r risk estim ation. In cum u lative assessm ents involving chem icals for which the tim e sequence of exposure is im portant, it m ay be necessary to characterize the details and sequence of exposure to the exposed population (see text box on the following page), so that there will be a m a tch in not only the form , but also in the assum p tions between the dose-response relationship and the exposure/dose estim ate. Vulnerability. One of the concepts that can be used in risk assessm ents (both for hum an health and ecological assessm ents) is that of vulnerabilityof the population or ecosystem

. Vulnerability has been a comm on topic in socioeconom ic and environm ental studies. The European Comm i ssion’s TEMRAP (The European Multi-Hazard Risk Assessm ent Project), studying vulnerability to natural disasters such as floods, windstorm s, fires, earthquakes, and others, defines vulnerability as “the intrinsic predisposition of an exposed elem ent [organism , population, or ecologically valuable entity] to be at risk of suffering losses (life, health, cultural or econom ic) upon the occurrence of an event of [a specific] intensity” (European Comm i ssion, 2000). Kasperson et al. (1995) defines vulnerabilityas “The propensity of social or ecological system s to suffer harm from external stresses and perturbations. Involves the sensitivity to exposures and adaptive m easures to anticipate and reduce future harm .” Kasperson (2000) identif ied f our types of vulnerability, discussed f urther below. The Agency’s risk characterization policy and guidance (USEPA, 2000c) touches on this concept by recomm e nding that risk assessm ents “address or provide descriptions of [risk to]...im portant subgroups of the population, su ch as highly exposed or highly susceptible groups.” Further, the Agency’s guidance on planning and scoping for cum u lative risk assessm ents (USEPA, 1995b) recognizes the im portance of “defining the characteristics of the population at risk, which include individuals or sensitive subgroups....” That guidance also recognizes the potential im portance of other social, econom ic, behavioral, or psychological stressors that m ay contribute to adverse health effects (e.g., existing health condition, anxiety, nutritional status, crim e, and congestion). As discussed below, the ways in which the Agency and others describe these concepts in the context of hum an health risk assessm ent overlap the various ways described by Kasperson (2000) in which hum an and biological ecosystem s, comm unities, and populations m ay be vulnerable: susceptibility/sensitivity, differential exposure, differential preparedness, and differential ability to recover.

39Examples of Exposure Models that Consider Time Aspects

Calendex (Novigen Sciences, Inc) integrates different pathways (e.g., dietary [food and water] and residential) and routes of exposure (oral, derm al, inhalation) usi ng a calendar-based probabilistic approach. One of the im portant factors of this approach is that it provides estim ates of risk that reflect aggregate and cum u lative exposure to discrete individuals, with exposure pathways and routes appropriately linked for the scenarios being assessed. Calendex also allows one to estim ate exposur e before and after the use of a chem ical, as well as during degradation periods
. Calendar-based assessm ents m a intain the integrity of the individual by capturing the location of the exposed individual, the tim e of year in which he or she was exposed, and the patterns of exposure. Calendex also allows for a variety of tim e-breakout options for the analysis of exposure.
APEX - The Air Pollution Exposure (APEX) m odel is ba sed on the probabilistic National Am bient Air Quality Standards exposure m odel (pNEM) for carbon m onoxide (J ohnson et al., 2000). This m odel m i m i cs the basic abilities of the pNEM/CO m odel; it calculates the distri butions of hum an exposure to selected airborne pollutants within a selected study area as a functi on of tim e. As a dose m odel (for carbon m onoxide), it calculates the pollutant dose within the body, specifically sum m a rized by the blood carboxyhem oglobin (COHb) concentration. APEX is a cohort-microenvironment exposure m odel in that it com b ines daily activity diaries to form a com posite year-long activity pattern that represents specific population cohorts as they m ove from one microenvironment to another. A cohort consists of a subset of the population that is expected to have som e what sim ilar activity (and hence exposure) patterns; it is form ed by com b ining dem ographic groups and geographic locations (districts). Once each cohort ha s been m odeled and its relative size determ ined, an exposure distribution for the entire population can be assem b led. A microenvironment is a description of the imm e diate surroundings of an individual that serves as an indicator of exposure (e.g., inside a residence, school, or car; outdoors; etc.). APEX has been developed as one of the inhalation exposure m odels accessible in the Exposure Event Module of the Total Risk Integrated Methodology (TRIM.Expo) for assessm ent of exposures to either criteria or hazardous air pollutants (USEPA, 1999j) Other m odels include LifeLine , developed under a cooperative agreem ent between EPA/OPP and Ham p shire Research Institute (HRI, 1999, 2000); Stochastic Human Exposure and Dose Simulation (SHEDS), under developm ent by EPA’s Office of Research and Developm ent (Zartarian et al., 2000), and Cumulative and Aggregate Risk Evaluation System (CARES), under developm ent by m e m b er com p anies of the Am erican Crop Protection Association (ACPA, 1999) along with Residential Exposure Year (RExY), which is being developed by Infoscientific.com

.

The first of Kasperson’s categories is susceptibilityor sensitivity

. Although these two words m ay have slightly different m eanings, they are often used interchangeably. They refer to an increased likelihood of sustaining an adverse effect, and they are often discussed in term s of relationship to a factor describing a hum an subpopulation. For exam ple, susceptible persons or populations m ay be those who are significantly m o re liable than the general population to be affected by a stressor due to life stage (e.g., children, the elderly, or pregnant wom e n), genetic polym orphism s (e.g., the sm all but significant percentage of the population who have genetic susceptibilities), prior imm une reactions (e.g., individuals who have been “sensitized” to a particular chem ical), disease state (e.g., asthm a tics), or prior dam a ge to cells or system s (e.g., individuals with dam a ged ear structures due to prior exposure to toluene, m a king them m o re sensitive to dam a ge by high noise levels) (Morata et al., 1997). Confronted with equal concentrations of a chem ical for equal durations, for exam ple, a biologically susceptible or

40sensitive individual m ay show effects, whereas the typical individual within the population would have no or less severe effects. This category would also include generation-skipping effects. Although we generally do not have a lot of data available on this topic, susceptibilities or sensitivities m ay also exist am ong races or genders. Kasperson’s second category of vulnerability is differential exposure

. Although it is obvious from exam ining a dose-response curve that two individuals at different exposure levels m ay have a different likelihood of effects, this category extends to differences in historical exposure, body burden, and background exposure, which are som e tim es overlooked in an assessm ent. Wh en looking at the dose-response curves for a typical individual and an individual vulnerable due to differential exposure, the curves m ay be the sam e , but the vulnerable individual m ay be currently at a higher dose due to greater current or prior exposure and body burden, so an increm ent of additional exposure m ay (due to slope of the curve at that point) produce a m o re pronounced effect than in a typical individual. Kasperson’s third category of vulnerability is differential preparedness to withstand the insult of the stressor. This is linked to what kind of coping system s and resources an individual, population, or comm unity has: the m o re prepared, the less vulnerable. As an exam ple, consider two individuals, one of whom has had a childhood disease imm unization shot and the other has not. The two m ay be exposed to the sam e insult, but due to a difference in preparedness, the effects on the person with the imm unization shot m ay be m u ch m ilder or nonexistent. As another exam ple, hurricanes typically cause less dam a ge to boarded up hom es than they do to hom es without this reinforcem ent, even though the weather insult to both hom es m ay be the sam e
. Kasperson’s fourth category is the differential ability to recover from the effects of the stressor. This again is linked to what kind of coping system s and resources an individual, population, or comm unity has. One aspect of differential ability to recover is illustrated by differing survival rates for the sam e disease (e.g., Lantz et al., 1998). Put in term s of progression of disease, for exam ple, two persons in an ear ly stage of cancer have different prospects for recovery if one is treated imm e diately while the other does not have access to, or does not trust, health care. On the ecological side, opportunistic infections in m arine m a mm a ls 12 appear to be related to accum u lation of polychlorinated biphenyls and organotin com pounds, which cause an imm unosuppression response in laboratory anim als (Tanabe, 1998). Preparedness and ability to recover are of ten crucial f actors in ecological assessm ents. In hum an health assessm ents, lack of access to health care, incom e differences, unem p loym ent, or lack of insurance, f o r exam ple, m ay af f ect a comm unity’s ability to prepare f o r or recover f r om a stressor. Cum u lative risk assessm ents m ay be uniquely suited to addressing the issues related to vulnerability. In order to do so, however, there should be som e relationship between the factors

12 That is, infections easily warded off by healthy m a rine m a mm a ls. 41discussed above and changes in risk. Many of these factors have not yet been extensively developed beyond correlations between m o rtality rates and several socioeconom ic factors, such as incom e (e.g., Lynch et al., 1998). Susceptibility has been m o re developed than the other factors, and current approaches im plem ented by EPA and others to address risk of noncancer endpoints routinely em ploy a 10-fold factor to address heterogeneity in sensitivity. Variability with regard to susceptibility is discussed in detail by NRC (1994), and the current state of knowledge concerning epidem iologically based (e .g., oncogene-specific) risk factors provides em pirical data upon which at least crude estim ates of the m a gnitude of heterogeneity in susceptibility to toxic response can be based. However, m u ch research in this area rem a ins to be done. Subpopulations w i th Special Exposures

. Certain subpopulations can be highly exposed to stressors because of geographic proxim ity to the sources of these stressors, coincident direct or indirect occupational exposures, activity patterns, or a com b ination of these factors. The Agency’s risk characterization policy and guidance (USEPA, 2000c) includes recognition of the need for risk inform ation to include, as available, inform ation on highly exposed subgroups. Accordingly, risk assessm ents, including cum u lative assessm ents, m ay need to put special em phasis on identifying and evaluating these subpopulations. Subpopulations at risk of high exposure due to geographic proxim ity could include workers at a f acility that is a source of a stressor or residents near such sources. Specif i c exam ples m i ght be people living downwind from a coal-burning power plant, those near and using a polluted water body (e.g., for fishing or recreation), or those living or working near roadways with high levels of vehicular traffic. Occupational exposures m ay be either direct (occurring in the workplace) or indirect (occurri ng at hom e). Indirect occupational exposures include those experienced by fam ily m e m b ers who m ay be exposed to occupational chem icals brought into the house by the worker (e.g., on clothing). Thus, workers or fam ily m e m b ers m a y be subject to greater exposures than others in the population who do not have this additional burden.
Exam ples of subpopulations at high exposure due to activity patterns m ay include people who exercise heavily in polluted air, recreational or subsistence fishers or hunters who consum e large quantities of fish or gam e , farm ers or others who get a large proportion of their food from a location near a source of pollution and live in areas with high pesticide use, individuals who have long comm u tes in autom obiles, or children (because they consum e a larger am ount of food, drink, and air relative to their body weight and because of additional exposure routes such as incidental soil ingestion). Additionally, som e subpopulations m ay be affected by the com b ined im pact of high geographic exposure and high-exposure activity patterns (e.g., runners who run along heavily traveled roadways and people who fish for food in heavily polluted urban rivers). It is im portant to recognize that som e heavily exposed populations m ay also be particularly vulnerable or susceptible to the e ffects associated with the stressors of concern. Exam ples of those who could be particularly vulnerable to certain stressors include children during certain stages of developm ent, people withchronic respiratory problem s, the elderly, and those who are econom ically disadvantaged and do not have access to m e dical care. A 42cum u lative risk assessm ent m ay need to take into account potential com b inations of high exposure and high vulnerability, but few, if any, m e thods are currently available and accepted to address the com b ined effects of exposure and vulnerability. This is an im portant area for further research and m e thods developm ent. 3.2.2. Approaches for Predicting Risk of Multiple Stressors
Com b ination toxicology (Carpy et al., 2000) is the study of the toxicity of m i xtures. In such studies, one m ay either m easure the m i xture toxicity directly (whole m i xture toxicity), or one m ay develop an estim ate of the com b ined toxicity f r om inf o rm ation on the m u ltiple com ponent stressors acting in concert with each other. (Toxicity of chem ical m i xtures has also been m odeled on a physiologically based pharm acokinetic basis [e.g., Haddad et al., 2000, 2001].) If evaluated using its com ponent chem icals, the m i xture toxicity data set should be treated only as a snapshot of a m u ltidim ensional dose-response relationship, because the joint toxicity and interactions can change with changes in exposure route, duration, relative proportions of the com ponents, or the effect being tracked. The application of such a data set to a specific situation then requires careful m a tching of the test m i xture com position and exposure conditions to those of the target situation. In whole m i xture toxicity, once the m i xture toxicity is known, a risk evaluation can be done on the m i xture using the 1983 NRC risk assessm ent paradigm

. On the other hand, com ponent-based m i xture assessm ents are rarely evaluated using the strict NRC paradigm , because the exposure and toxicity inform ation should be com p atible, requiring som e iteration to obtain toxicity inform ation that is relevant to the actual exposure estim ates (USEPA, 2000e). To address concerns over health risks from m u ltichem i cal exposures, EPA issued guidelines for health risk from exposure to chem ical m i xtures in 1986 (USEPA, 1986b). The guidelines described broad concepts related to m i xtures 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 m i xtures risk assessm ent (USEPA, 1989a). Also in 1989, EPA published the revised docum ent on the use of TEFs for characterizing health risks of the class of toxicologically sim ilar chem icals that included the dibenzodioxins and dibenzofurans (USEPA, 1989b). In 1990, EPA published a technical support docum ent to provide m o re detailed inform ation on toxicity of whole m i xtures and on toxicologic interactions (e.g., synergism ) between chem icals in a two-chem ical m i xture (USEPA, 1990a). Wholem i xture assessm ents, toxicologic independence and sim ilarity, and risk m e thods using toxicologic interactions are discussed at length in USEPA (2000e). Risk assessm ent for m i xtures usually involves substantial uncertainty. If the m i xture is treated as a single com p lex substance, these uncertainties range from inexact descriptions of exposure to inadequate toxicity inform ation. Wh en viewed as a collection of a few com ponent chem icals, the uncertainties also include the generally poor understanding of the m a gnitude and

43nature of toxicologic interactions, especially those involving three or m o re chem icals. Because of these uncertainties, the assessm ent of health risk from chem ical m i xtures should include a thorough discussion of all assum p tions and the identification, when possible, of the m a jor sources of uncertainty.
3.2.2.1. Single stressor inform ation
Assessm ents that evaluate the risk from a single stressor do not fall into the category of cum u lative risk assessm ents under the definition given in Section 1.3, whether these single

stressor assessm ents address a single (dom inant) endpoint or m u ltiple endpoints or whether the exposures are sim p le or com p lex (e.g., m u ltisource, m u ltipathway, m u ltiroute exposure). Som e m ay be term ed “aggregate risk assessm ents” by extension of the FQPA term inology. They can, however, provide useful inform ation for cum u lative assessm ents. A cum u lative risk assessm ent considers the joint im pact of m u ltiple stressors. Studies on individual stressors can, however, provide inf o rm ative qualitative inf o rm ation f o r m u ltistressor assessm ents, particularly regarding hazard identification. The collection of single-stressor effects can indicate the variety of types of a dverse ef f ects likely to result f r om the stressor com b ination, although perhaps not the m a gnitude or extent of the effects. Factors affecting population susceptibility to the individual chem icals are also likely to be im portant with the com b ined exposure. To go further in term s of quantitative risk assessm ent requires consideration of the potential for joint toxicity. For m o st exposure situations, hazard and doseresponse studies of all of the joint effects from th e m u ltiple stressors will not be available, so that conclusions will have to be based at least partly on the single stressor inf o rm ation. Exposure assessm ents for single stressors also need further consideration before they can be used to characterize long-term exposure to all the stressors by all pathways. Transport and environm ental transform a tion of a chem ical can be influenced by the presence of other chem icals. Consequently, both the exposure levels and the relative proportions of chem icals at future tim es m ay not correspond well to present m easurem ents of a com b ination of chem icals unless these influences are taken into account. In addition, exposure to one stressor m ay influence the uptake of a second stressor. For exam ple, a nonchem i cal stressor that increases ventilation rate will increase the inhalation uptake of airborne chem icals. Toxicologic independence. Two situations allow plausible approxim a tions of the joint exposure-response relationship using only the single stressor inform ation: toxicologic independence and toxicologic sim ilarity (USEPA, 2000e). In the case of toxicologic independence, if the toxicity m odes of action ar e biologically independent, then as long as there are no pre-toxicity interactions (e.g., m e tabo lic inhibition, influence on uptake), the single stressor inform ation is sufficient to approxim a te the joint exposure-response relationship. Wh en the effects from two or m o re stressors are diffe rent, the cum u lative response, if toxicologically independent, is m e rely all the single-stressor responses, as if the other stressors were not present. For exam ple, joint but low exposure to heat (causing m i nor elevated heart rate and toluene (causing m i nor hearing loss) would be expected to cause both the m i nor heart rate elevation and m i nor hearing loss, but to the sam e extent as expected for each stressor alone. If each stressor is 44below its toxicity threshold, then f o r stressors exhibiting toxicologic independence, there will be no estim ated cum u lative response, because the set of individual responses is then a collection of zeros. Wh en the single stressor and cum u lative toxicities are each represented by a frequency or probability f o r af f ected individuals—also term ed a probabilistic risk—then independence m eans that “response addition,” as defined in USEPA (2000e), can be applied for each adverse effect that the stressors have in comm on. Wh en all the single-stressor risks are low, the joint risk of a comm on effect under response addition can be approxim a ted by the sim p le sum of the single

stressor risks. For exam ple, if reproductive toxicity is the general effect comm on to the m u ltiple chem icals, the cum u lative risk of reproductive effects (at low single-chem ical risk levels) is approxim a tely the sum of the single-chem ical reproductive risks. Risk addition under independence places no constraints on the individual chem ical dose-response curves. Toxicologic Similarity. In the second situation, the stressors are grouped according to the comm on m ode of action for each effect of concern determ ined in the planning and scoping phase (USEPA, 2002a). For all effects caused by that m ode of action, “dose addition” (USEPA, 2000e) can be applied to the stressor group. Thus far, this approach has been used only with com b inations of toxicologically sim ilar chem i cals, not with com b inations of chem icals with other kinds of stressors such as radiation, physi cal factors, or health status. W ith sim ilar chem icals, each chem ical exposure is converted into the equivalent exposure level of one of the chem icals, called the index chem ical. The joint toxicity or risk from the com b ined exposure is then estim ated by determ ining the effects or risk for that equivalent exposure level using the dose-response inform ation for the index chem ical. For exam ple, with the dioxins and furans (see text box on next page), each congener exposure level is converted into its equivalent exposure as the index chem ical, 2,3,7,8-TCDD (USEPA, 1989b). Although the assum p tion itself is not com p licated, the decision to assum e toxicologic sim ilarity can be com p licated, depending on the level of assessm ent decided on in the planning and scoping phase and described in the analysis plan. The im plem entation used in Superfund assessm ents (USEPA, 1989a, Part D) is a rough approxim a tion to dose addition where a hazardindex is determ ined whenever chem icals have a comm on target organ. The im plem entation by the Office of Pesticide Pr ogram s in support of FQPA (USEPA, 2002a) is m

u ch m o re extensive and requires knowledge of m odes of action in order to calculate the Relative Potency Factors (RPFs) for the effect of concern (see exam ple in Appendix E). The TEF m e thod used for the dioxins is a special case of the RPF m e thod (see Appendix E); it requires the m o st toxicologic sim ilarity because the sim ilarity applies to every toxic effect by any type of exposure (USEPA, 2000e). Single stressor inform ation can also be used with dissim ilar chem icals to gauge the potential for toxicologic interaction. For exam pl e, chem icals with long whole-body half-lives or long tissue residence tim es have the potential to be present in those tissues at the sam e tim e. Such overlapping exposures can result in a higher effective tissue dose, altered tissue doses caused by toxicokinetic interactions, or altered toxicity from interacting toxic m echanism s
.

45Toxicologic Similarity: The Dioxin Reassessment
Scientists from EPA, other Federal agencies, and the ge neral scientific comm unity have been involved in a com p rehensive reassessm ent of dioxin exposure and hum an health effects since 1991 (USEPA, 2002d). The final dioxin reassessm ent will consist of three parts. Part 1: Estimating Exposure to Dioxin-Like Compounds will include four volum es that focus on sources, levels of dioxin-like com pounds in environm ental m e dia, and hum an exposures. Part 2: Human Health Assessment Document for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin ( T

CDD) and Related Compounds will consist of two volum es that include inform ation on critical hum an health endpoints, m ode of action, pharm acokinetics, dose-res ponse, and toxicity equivalence factors (TEFs) Part 3: Integrated Summary and Risk Characterization for 2,3, 7,8-Tetrachlorodibenzo-p-Dioxin ( T

CDD) and Related Compounds will be a stand-alone docum ent. In this summ a ry and characterization, key findings pertinent to understanding the potential hazards and risks of dioxins are described and integrated, including a discussion of all im portant assum p tions and uncertainties. 2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) is highly toxic to m a ny anim al species, producing a variety of cancer and noncancer effects. Other 2,3, 7,8-substituted polychlorinated dibenzo- p -dioxins (PCDDs) and dibenzofurans (PCDFs) and coplanar polychlorinated biphe nyls (PCBs) exhibit sim ilar effects, albeit at different doses and with different degrees of confidence in the data base. The sim ilarities in toxicity between species and across different dioxin congeners stem from a comm on m ode of action via initial binding to the aryl hydrocarbon (Ah) receptor. This comm on m ode of action is suppor ted by consistency in effects evident from data from m

u ltiple congeners. This has led to an international scie ntific consensus that it is prudent science policy to use the concept of TEFs to sum the contributions of i ndividual PCDD, PCDF, 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 m a jor contributors to the risk to hum an populations. In addressing receptor-m ediated responses resulting from com p lex m i xtures of dioxin-like congeners, this assessm ent has provided a basis for the use of integrated m easures of dose, such as average body burden, as m o re appropriate default m e trics than daily intake. The Agency recognizes, however, that the final choice of an appropriate dose m e tric m a y depend on the endpoint under evaluation. In this study, 2,3,7,8-TCDD was chosen as the index chem ical, and the other dibenzo- p -dioxins and dibenzofurans and coplanar PCB doses were adjusted to 2,3,7,8-TCDD-equivalent toxicities so the doses could be added.

Wh en a caref ul evaluation indicates no internal dose overlap, including m e tabolites, the single exposures m i ght be considered independently.
3.2.2.2. Inform ation on stressor interactions and m u ltiple exposures One im portant sim p lification that is comm on in single-stressor hum an health assessm ents is the separate evaluation of m any of the key steps. That is, sim p lifying assum p tions have often been m a de regarding m any characteristics of exposure (e.g., continuous vs. interm ittent variations in m a gnitude). For a given exposure route, for exam ple, only one dose-response curve m a y be used for the bounding case of setting a cleanup or action level of exposure and also the predictive case of estim ating existing risk. These sim p lifying assum p tions allow the doseresponse step to be perform e d in isolation from the exposure assessm ent step, with the two steps executed in either order. For health-protective action levels, one m ay use bounds, such as the upper bounds on toxic potency and exposure and lower bounds on the resulting acceptable 46exposure level. Such bounds m ay be m u ch easier to calculate, but they m ay be m o re difficult to interpret in term s of the uncertainties, likelihood, and closeness to the best or central estim ate. The incorporation of m u ltiple chem icals, other stressors, and m u ltiple exposure conditions obviously com p licates the assessm ent and the use of sim p lifying assum p tions. 13 In cum u lative assessm ents, perform i ng the exposure and dose-response steps of the risk assessm ent paradigm separately is an approxim a tion that obviously invokes a sim p lifying assum p tion. If the dose-response data do not represent the sam e conditions as the exposure being assessed, an extrapolation has to be m a de, which introduces additional uncertainty that should be clearly stated. Joint or cum u lative toxicity depends on the total dose or exposure, relative exposure levels, and the m any characteristics of exposure (e.g., duration, continuous vs. interm ittent presence, route, co-occurrence with other chem icals). In m any cases, the com p lexities introduced by m u ltiple stressors will not allow use of som e of the comm on sim p lif ying assum p tions of single-stressor assessm ents. For exam ple, toxicologic interactions have been shown to change when the sam e doses are used but the sequence of exposure is reversed (i.e., chem ical B then A instead of A then B), so that the exposure and dose-response analysis should be com p atible and perform e d together. Nonchem i cal stressors (e.g., biological entities or even physical stressors such as noise) can also interact with chem icals to change the risks either that would cause separately. For exam ple, chem icals such as toluene can dam a ge the auditory system and have been shown to potentiate the effects of a physical stressor, noi se, on hearing loss (Morata et al., 1997; Morata, 2000). For aquatic organism s, the toxicity of polyarom a tic hydrocarbons increased with exposure to ultraviolet radiation (Oris and Geisy, 1985).Toxicity and interaction data that cover the full range of exposures for the exposureresponse relationship for the m i xture of interest is usually im possible to obtain because of lim its on budget and other resources. More feasible approaches to cum u lative risk characterization, beyond that with various sim p lifying assum p tions, then require close m a tching of the exposure and dose-response steps to m i nim i ze the data requirem e nts. In m any cases, screening-level ranking m ay be the only practical assessm ent. In som e cases there will be suf f i cient inf o rm ation f o r som e quantitative evaluation of cum u lative health risks that ref l ect both the com p lex exposures and toxicologic interactions. “Joint chem ical toxicity” m eans the outcom e of exposure to m u ltiple chem icals that includes the single-chem ical effects along withany toxicologic interactions. Chem ical interactions can be divided into two m a jor categories: those resulting from a toxicokinetic m ode of action and those resulting from a toxicodynam i c m ode of action (USEPA, 2000e). Toxicokinetic m odes of interaction involve altera tions in m e tabolism or disposition of the toxic chem icals, for exam ple, by the induction or inhibition of enzym e s involved in xenobiotic activation and detoxification. Toxicodynam i c m odes of interaction include those processes that

13 For ecological risk assessm ents, Gentile et al. (1999) review the theory and several m e thods for evaluating stressor/response linkages and stre ssor interactions for m u ltiple stressors. 47affect a tissue’s response or susceptibility to toxic injury. A sim p lifying observation is that m o st interactions seem to involve pharm acokinetics. Unfortunately, m o st studies of toxicologic interaction to date have involved only two chem icals, and few have quantified the m a gnitude of the interaction or its dependence on exposure conditions. Toxicologic interactions are comm only described in term s of synergism or antagonism

. These term s are only m arginally useful, in part because the underlying toxicologic concepts are only defined for two-chem ical m i xtures, and m o st environm ental and occupational exposures are to m i xtures of m any m o re chem icals. Further, the m a them atical characterizations of synergism and antagonism are inextricably linked to the prev ailing definition of "no interaction," instead of to som e intrinsic toxicologic property (Hertzberg and MacDonell, 2002). EPA (USEPA, 2000e) has selected “dose addition” as the prim ary “no interaction” definition for m i xture risk assessm ent, so that synergism would represent observed toxic effects that exceed those predicted from dose addition . The EPA m i xture risk guida nce also describes a m odified hazard index that incorporates evidence of pairwise toxicologic in teractions but notes that the pairwise evidence m ay be specific to the exposure conditions of the study. The guidance further encourages developm ent of full biom athem a tical m odels for the joint toxicity—such as those based on pharm acokinetics—so that qualitative interaction labels such as synergism are replaced by quantitative estim ates of m i xture response that directly reflect the actual environm ental exposure levels.
3.2.2.3. Decision indices
Am ong the com p lexities of cum u lative risk assessm ents is the frequent need to com b ine widely differing types of data. Exposure data for som e stressors m a y be available only as tim eweighted averages, whereas other data reflect daily hum an activity patterns. Toxicity data for som e chem icals m ay allow estim ation of probabilistic risk for one endpoint while providing only qualitative descriptions of other endpoints. It is possible to develop the risk characterization using the original inf o rm ation in a m a trix, but such a summ ary will be dif f i cult to evaluate and comm unicate. One approach to diverse m u ltivariate data that has been used successfully for weather forecasting is the decision index, with exam ples such as the sm og index, the pollen count, and the m o ld index comm only used to assist in public and personal decisions about environm ental exposure. A sim ilar approach can be taken for cum u lative risk assessm ent (Hertzberg, 2000). The advantage of a decision index is the sim p licity in converting highly m u ltivariate technical inform ation into a single num ber. The m o st comm on exam ple used for cum u lative health risk is the hazard index for m i xture risk (see box on next page). Although specific for a single affected target organ, each hazard index reflects m u ltiple studies of m u ltiple chem icals, often involving m u ltiple test anim al species and test exposures and highly varied m easures of toxicity.

48The m a in disadvantage of a sim p le index is that the uncertainties in its calculation are largely hidden. Another key disadvantage is in quantifying what are often scientific judgm ents. For exam ple, the hazard index im plem ented under Superfund (USEPA, 1989a) is a num ber whose decision threshold is usually given as 1.0, so that when the hazard index is greater than 1, additional action is indicated. The actual value of a hazard index is not that inform ative: a value of 6 is not necessarily twice as bad as a value of 3. This is partly due to the uncertainty factors necessary to develop the reference dose (RfD) or the reference concentration (RfC). The total value of these factors can be as low as 3 or as high as 3 000, depending on The Ha z a rd Index The hazard index (HI) for oral exposure is i m ple m ented by Superfund assessors by the form ula:
HI = su m [ HQ j ] = su m [ E j /Rf D

j ] where E j and Rf D

j are the daily exposure and reference dose of che m ical 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 dose-response data on all effects are considered in determ ining each RfD. Uncertainties in the RfD will differ across the che m icals, m a king the uncertainty in HI difficult to characterize.
the data upon which the RfD or RfC for a specific che m ical is based (Barnes et al., 1988; Beck et al., 1993; USEPA, 1994; Dourson et al., 1996 ; USEPA, 2002e ). One alternative for addressing m u ltiple effects is to recast these qualitative judgm ents in term s of severity categories or levels of concern (e.g., high/m e dium /low) and then use statistical m e thods 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 m i nim um toxic severity level or level of m i nim a l concern (Hertzberg, 1989; Guth et al., 1993). In the best situations, such as the EPA interaction-based hazard index (USEPA, 2000e), the decision index form ula is m odular, so com ponent pieces can be evaluated separately for accuracy and im provem e nts in one area can be easily incorporated to give an im proved index. Another exam ple of a decision index with m o re overt display of its diverse parts is the Hazard Ranking System (HRS) (47 Fed. Reg. 31219, dated July 16, 1982, and am ended 55 Fed. Reg. 51532, dated Decem ber 14, 1990), a form ula developed for characterizing the relative hazards of a particular waste site. These hazards were highly diverse and include corrosivity, explosivity, toxicity, and soil conditions. As with the hazard index, different uncertainties in the com ponents m a ke the uncertainty of the HRS index difficult to describe. Instead of m e rely presenting the index as a num ber, a graphical presentation such as the star plots of m u ltivariate data could be used (Cham b ers et al., 1983; Hertzberg, 2000), where each arm of the star represents one of the sub-indices. Although this approach shows the relative contribution of each factor, it again hides the uncertainties of th e factors as well as of the HRS index itself. Hybrid m e thods that com b ine judgm ent with num erical descriptions of risk or doseresponse have also been used for com p lex risk assessm ents. The EPA interaction-based hazard index (USEPA, 2000e) and the m i xture risk approaches of the Agency for Toxic Substances and Disease Registry (ATSDR) (Hansen, et al., 1998) both include a judgm ental weight-of-evidence 49(W OE) score to reflect the strength of evidence for toxicologic interactions and relevance to hum an health risk. The ATSDR W O E is used in comm unicating risks and intervention options, whereas the EPA W O E is used to calculate a m odified hazard index. A slightly different approach is the Integral Search System database program for com b inations of carcinogens (W oo et al., 1994) by which available studies on pairwise interactions of carcinogenicity are used to m odify the risk range of the com b ination from that predicted by response addition (USEPA, 2000e). In all these cases, scientific judgm ent is used to alter the risk description or quantitative estim ate, but only in term s of an approxim a te 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 m e thods used for integrated quantitative treatm e nt of uncertainty and variability are m a de consistent with those used f o r probabilistic assessm ent of cancer risk. This report addresses m any issues concerning the im plem entation of probabilistic m e thods for noncancer endpoints and cites a num ber of related references (e.g., Lewis, 1993; Dourson et al., 1997; Slob and Pieters, 1998). Any approach to cum u lative risk assessm ent should carefully define the set of relevant endpoints. Precisely how this is done has im portant logical and practical im plications for how the cum u lative risk m ay be calculated and interpreted. For exam ple, the risk of inducing a given endpoint m ay differ am ong different people in a population at risk for som e endpoints, (e.g., cancer conditional on all carcinogen exposures) but m ay be unaffected by interindividual variability (e.g., in exposure or susceptibility) for other endpoints (such as ecological or aesthetic ef

f ects). Def i ning the latter risks in term s of individual risk per se will thus com p licate calculating cum u lative risk if a probabilistic approach to cum u lative risk assessm ent is used and perhaps if other approaches are used as well. In contrast, the probabilistic approach to cum u lative risk assessm ent m ay be f a cilitated by defining the risk of a given endpoint in term s of population risk , that is, in term s of the predicted num ber of cases of that endpoint. Alte rnatively (or additionally), sim ilar sim p lification can be achieved for all heterogeneous endpoints by defining the risk only with respect to those persons in the population at risk who are reasonably m a xim a lly exposed (e.g., individuals adjacent to a proposed source) or to those persons who will incur the greatest increased risk (e.g., persons at a vulnerable lif e stage, such as children, or other m e m b ers of a sensitive subpopulation who m i ght be located adjacent to a proposed source).
3.3. Areas of Complexity and Current Research One reason f o r the som e what lim ited availability of cum u lative risk assessm ents m a y be the accom p anying com p lexity that arises in various aspects of the assessm ent. Som e of this com p lexity is discussed in the previous section, along with currently available m e thods specific to hum an health risk assessm ent. In this section, som e areas where research is ongoing are discussed, and som e existing m e thods for quantitatively assessing m u ltiple types of risk or hazard using a single m e tric are described. 503.3.1. Interactions Between Stressors and Other Factors In identifying and characterizing susceptible subpopulations, it m ay be im portant to consider a variety of factors, such as current phys ical and m e ntal health status and past exposure histories, that m ay exacerbate the effects of the stressors of interest. Social factors such as comm unity property values, source of incom e , level of incom e , and standard of living m a y also affect vulnerability of subpopulations to certain other stressors. Risks associated with chem ical or biological stressors m ay be signif i cantly af f ected by “vulnerability f actors” such as lack of health care or genetic predisposition to som e diseases and effects. Comm unity traditions and beliefs m ay affect activity patterns and behaviors and therefore affect exposure to stressors as well as the acceptability of the risk m anagem e nt options. Depending on the scope of the assessm ent and the stressors included, lifestyle factors such as sm oking and nutritional habits, am ong others, m ay be im portant to susceptibility. In what could be characterized as an explor ation of how som e what abstract factors m ay affect susceptibility, ATSDR held an expert panel workshop on the subject of psychological responses to hazardous substances (ATSDR, 1995). In its report, the panel noted that there is “a significant lack of inform ation” about how often comm unities near hazardous waste sites or spills suffer chronic stress reactions, but that psychological stress causes both psychological changes that can be m easured by self-reports and objective tests as well as physical changes such as increased blood pressure and heart rate and biochem i cal param e ters such as changes in stress horm ones. Assessing the levels of stress and their potential contribution to risk is difficult for a variety of reasons. The report notes that unlike the dam a ge and injuries caused by a natural disaster, m any toxic substances are invisible to the senses.... In the face of no external cues and uncertain circum stances, 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 comm unity.... 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 chem icals in the comm unity can show m easurable physical effects, it stopped short of saying that long-term health effects from this stress can be converted to risk estim ates at this tim e. 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 m e thodology does not exist that would allow for discrim i nation between stress or neurotoxicant-m e diated effects in comm unity-based studies.... Experim e ntal anim al data exist to suggest that stress levels can m odulate a toxic response; however, the question of specificity rem a ins. Given that stress can induce or unm ask a latent ef f ect of a toxicant, there is the possibility that chronic stress 51could alter basal levels of neurofunctioning and shift the threshold for neurotoxicity. Indeed, one m ay find a shift in the dose response to a neurotoxicant; however, a specific effect of the neurotoxicant should be exam ined in greater detail than the generalized non-specific endpoints. Detecting such a shift would require the knowledge of toxicant-specific biological m echanism s of actions, which m o st often are not known. The ATSDR report contains m any suggestions for research to fill data gaps in this area, and scientists m ay m a ke significant progress in the com i ng years. “Quality-of

- lif e” issues m ay also inf l uence risk to health or the environm ent, and evaluating those issues m ay require an appro ach that differs from the traditional NRC risk paradigm

. Although a cum u lative hum an health or ecological health risk assessm ent is not a cum u lative im pact analysis such as is conducted under NEPA, changes in quality-of-life factors m ay affect the vulnerability of a population to health or ecological risks and consequently m ay be part of the considerations in a cum u lative risk assessm ent. Because few, if any, established and accepted relationships are currently available to quantitatively link quality-of-life factors and health or ecological risk, this further research in this area m ay prove valuable. To evaluate the effects on hum an or ecological health from these types of stressors, a m o re deliberative approach (in the analytical-deliberative process) is needed than is used in, say, cancer risk analysis. EPA (USEPA, 1993b) suggests a six-step process that m ay help characterize quality-of-life factors, som e of which m ay be relevant to the assessm ent (e.g., in considering population susceptibility). An exam ple of a set of quality-of-life criteria developed by the State of Verm ont’s Agency of Natural Re sources is provided in Appendix F; however, it should be noted that quality-of-life issues can encom p ass m u ch m o re than the criteria m e ntioned in this exam ple. Som e hum an health or ecological cum u lative risk assessm ents m ay consider quality-of

- lif e f actors as having a role in susceptibility to the stressors being assessed.
3.3.2. The Prom ise of Biom arkers and Biom onitoring There are a variety of m easures that are inherently cum u lative. These include biom arkers (they give the full effect or full exposure, regardless of source) and m easures of the incidence and prevalence of disease in a comm unity. The latter give an indication of the total effect of m

u ltiple sources of exposure. In light of our understanding of the m u ltifactorial basis of disease, a public health approach that says “regardless of the cause, a comm unity has x level of disease” can be inform ative. Such statistics can be com p ared across geographical areas that have different sources or groups that have different levels of vulnerability. The approach is based strongly in the field of epidem iology. Indeed, the m o st often-heard critique of epidem iology—that it is the prevalence or incidence of disease docum ented as a function of the com b ined effect of m any exposures (over tim e and/or space)—is exactly what m a kes it so well suited f o r cum u lative risk assessm ent. It is likely that epidem iological concepts will f i gure prom inently in cum u lative risk assessm ent, both in identifying the underlying vulnerability of a population and in generating hypotheses regarding the determ ination of relative contributions of m

u ltiple stressors (IPCS, 1983). 52Sources of data include cross-sectional analyses that determ ine prevalence levels as well as basic surveillance techniques. W ith respect to the latter, The Pew Environm ental Health Comm i ssion (http://pewenvirohealth.jhsph.edu/htm l/hom e/hom e.htm l ) has recently com p leted a series of reports that docum ent the extent of national- and state-level resources for chronic disease surveillance. Reports f o cus on the type of surveillance system s needed as well as the status of registries for birth defects and asthm a
. Health Track (http://health-track.org/ and http://healthyam e ricans.org/) is the outgrowth of that research; it is devoted to tracking and m onitoring chronic disease to help comm unities to identif y patterns of health problem s. Like epidem iologic data, som e biom arkers reflect the cum u lative history of individuals and populations. The use of biom arkers is based on the concept that the biological unit (organ, body, etc.) can be an effective and accurate elem ent for integrating the aggregate exposures or doses or cum u lative risks. Using biological m easurem ents—biom arkers—to determ ine prior exposures (biom arkers of exposure) or the current health status of individuals (biom arkers of effect) holds som e prom ise for cum u lative risk assessm ents of the future (IPCS, 1993, 2001). Use of biom arkers for a group of chem icals or stressors that act upon individuals in the sam e way can give the assessor a picture of where an individual currently falls on the continuum from exposure to effects, m a king it m u ch easier to predict risks if additional exposure occurs. A few biom arkers (or even a single one) can possibly represent exposure to a suite of chem icals. Although this approach reduces the analytical burden and sim p lifies the process of estim ating cum u lative risk, it loses som e of the advantages of single-chem ical assessm ent (especially being able to quickly discern the im portance of different pathways and routes of exposure contributing to the risk). Biom arkers have a num ber of advantages; one disadvantage, however, is that they generally cannot link an effect to any particular exposure. For exam ple, inform ation on the cum u lative risks in a local population of a group of chem icals that are toxic to the liver m i ght be provided by selective liver function tests, but causal inferences would have to take account of m a ny other factors that m a y affect liver func tion. Likewise, body burden data for chlorinated dioxins and related com pounds m a y show that exposure has occurred, but assum p tions would need to be m a de as to the pathways, route, and tim ing of exposures and scenarios developed for future exposures if risks are to be estim ated. For a regulatory agency such as EPA, a decision to act to reduce risk often depends on separating contributions from exposure pathways so that ef

f ective policies can be determ ined. One of the benefits of the biom arker appro ach—the developm ent of data that show the actual current exposure and risk status of a population—is also its m a jor im pedim e nt: it can require extensive (or for hum ans, possibly invasive) m onitoring. Monitoring data can be not only costly, but also difficult to obtain. This approach uses prim arily m easurem ent m e thods; it can also be used to develop statem ents of probability of adverse ef f ects of additional increm ental exposures. This approach holds great prom ise for sim p lifying cum u lative risk assessm ents, but few m e thods exist at this tim e for such applications. Although this fram ework report provides

53only a cursory discussion of the biom arker approach, it is hoped that the planned guidelines for cum u lative risk assessm ent will discuss this approach in greater detail.
3.3.3. A Single Metric for Multiple Types of Hazard The m o st com p lex cum u lative risk assessm ents will evaluate both m u ltiple exposures (potentially, m u ltiple sources, stressors, pathways, and durations) and m u ltiple ef f ects. Ideally this evaluation would provide projections regarding the potential for a particular com p lex exposure to cause particular effects to diffe rent physiological system s and also provide an integration of these projections into a qualitative characterization of overall potential im pact to hum an health. Som e applications have attem p ted to integrate the potential im pacts across the different physiological system s. Approaches vary from treating the assessm ent as a num ber of m

u ltistressor, single-ef f ect assessm ents, where the risks are com b ined only at the f i nal step, to assessm ents that are m o re integrated throughout all the steps in the assessm ent process.
For exam ple, cum u lative ecological risk assessm ents conducted in the Colum b ia River Basin and the Chesapeake Bay (Barnthouse et al., 2000) focused on a num ber of observed adverse conditions, and then determ ined from am ong all the possible stressors, which particular com b ination was m o st influential in creating those conditions. Stressors such as over harvesting of natural resources; m odification of natural hydrology; land use change; point-source and nonpoint-source pollution, including toxic chem icals; and the presence of exotic species were analyzed, with the goal of designing effective restoration strategies to elim inate or am eliorate the conditions. If it is considered desirable for the assessm ent, an im portant activity m ay be to determ ine how (if at all possible) to com b ine risks from different effects—or the even-m ore-problem atic disparate m easures of risk—and present them in an integrated m anner. Depending on the purpose and risk m anagem e nt objectives (see Section 2.1.1), som e cum u lative risk assessm ents m ay em ploy som e sort of single, comm on m e tric to describe overall risk. One—but certainly not the only—approach to sim p lifying this problem is to collapse this “n-dim ensional m a trix” of hazards and risks into a few or even a single m easure (Murray, 1994). However, this requires converting the various m easures of risk into a comm on m e tric or otherwise translating them into a comm on scale or index. Som e m e thods for com b ining disparate m easures of risk are briefly described below.

543.3.3.1. Creating a comm on m e tric As discussed earlier in this chapter, there are several different theoretical approaches to cum u lative risk assessm ent. Som e of them require synthesizing a risk estim ate (or risk indication) by “adding up” risks from different part s of the risk picture. Actual m a them atical addition, of course, requires a “comm on denom inator,” or a comm on m e tric. Frequently used comm on m e trics are risk, m oney, tim e, and effort. Finding a comm on m e tric for dissim ilar risks (e.g., cancer vs. noncancer, hum an vs. ecological) is not strictly an analytic process, because som e judgm ents should be m a de as to how to link two or m o re separate scales of risks. These judgm ents often involve subjective values, and because of this, it is a deliberative process. EPA’s Office of Pollution Prevention and Toxics has released a CD-ROM (USEPA, 1999i) 14 that shows an exam ple of com b ining different effects into a comm on m e tric and the consequent judgm ent needed to achieve a comm on m e tric. In this m odel, em issions for both carcinogens and noncarcinogens are weighted by a toxi city factor so that they can be com b ined 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 noncarcinogens is based on the RfD. According to the authors, it is possible to link these two different scales by m a king a deliberative judgm ent or assum p tion as to their relationship. They note that in their case, “when com b ining cancer and noncancer endpoints, it is assum e d 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 15 value of 1.0 (i.e., exposure is at the RfD) with a cancer risk of 2.5 x 10 -4 is a judgm ent that is outside the strictly analytic part of an assessm ent; the equating of th e two points in the respective scales represents a value judgm ent and as such can be debated. Therefore, this particular part of the assessm ent is deliberative in nature. In m a king these types of judgm ents in a risk assessm ent, som e care should be taken not to lose inform ation in the aggregation, especially if all stakeholders do not agree on the relative tradeoffs necessary to arrive at the comm on scale of risk. If there is disagreem ent on constructing the scale, or even if m o re clarity is desired in the final report, the disaggregated risks can also be presented. Equity issues m ay also arise here, m a king it necessary to break out risks into relative burdens for different subpopulation.
In m o st cases, construction of a single scal e for different types of endpoints will involve comparative risk, a field where different types of ri sks or endpoints are ranked, com p ared, weighted, or converted to a scale on the basis of the judgm ents and values of the persons doing the assessm ents (USEPA, 1990b, 1993b, 1998f, 1999j). Groups of stakeholders such as are

14 As of this writing, version 2.0 is in beta test. Details are available at <www.epa.gov/oppt/env_ind/beta_test.htm >

.

15 A hazard quotient, or HQ, in this context is the es tim ated exposure or dose level for a given individual chem ical divided by the RfD (or RfC) for that chem ical. Values of less than 1.0 for HQ indicate levels that are generally expected to be without effect during a lifetim e. 55gathered for cum u lative risk assessm ent can provide ranking of various effects in term s of im portance even if the effects cannot be put on a single scale or m e tric. This inform ation m ay subsequently be used by decisionm akers for dealing with “worst risks first.” There have been som e attem p ts to allow f o r transparent and quantitative incorporation of values into a comm on m e tric. One exam ple flows from the suggestion that “tim e is the unit of m easure f o r the burden of disease,” whether the disease results in disability or prem ature m o rtality (Murray, 1994). On this prem ise, econom ic analyses of the costs and benefits of disease intervention strategies have used quality-adjusted life years (QALYs) and disabilityadjusted life years (DALYs) as the m e trics for the adverse effects of disease. These m e trics are intended to reflect the years of life spent in disease states (considering the variation in severity of ef

f ects) and the years of lif e lost due to prem ature m o rtality resulting f r om disease as a surrogate m easure for risk from a variety of different types of effect. Even if this conversion of effects into QALYs or DALYs is successful, for diseases that result in periods of m o rbidity and disability (but not death), weighting f actors (based on judgm ents) are used to equate tim e spent in various disease states with years lost to m o rtality. In this way, dissim ilar adverse effects can be com b ined to provide a single m e asure of disease burden. However, it should be noted that aggregation of effects in this m anner obscures the m eaning of the final m easure. QALYs and DALYs do not represent an actual shortening of the life span but are indicators of the overall degrad ation of well-being that results from various disease states. Experience with applying such m easures as QALYs and DALYs to environm ental risk problem s is extrem ely lim ited. Som e very early m e thods developm ent work has been initiated that explores the use of QALYs for com b in ing m i crobial and disinfection by-product risks (USEPA, 1998f). However, som e concerns have been raised about the adequacy of such m easures, especially when integrated with econom ic inform ation for decision m a king (USEPA, 2000g). Further m e thods developm ent work is needed to im prove the usefulness of QALYs and DALYs for environm ental risk assessm ents, especially with respect to the incorporation of uncertainty (USEPA, 1999j). Categorical regression m ay provide another t ool for com b ining disparate effects using a comm on m e tric. In this approach, adverse effects are assigned to severity categories (again, a judgm ent m a king the process deliberative) and the ordered categories are regressed against increasing dose (Teuschler et al., 1999). This use of categorical regression puts definite lim its on the interpretation of the results. Because the toxicities are only represented by categories and judgm ent is used to place the observed response into a severity category, the results are rather coarse. But because the analysis is alm o st totally em pirical—that is, no low-dose extrapolation is required—the results can still be quite usef ul. EPA has also used decision indices (see Section 3.2.2.3) that are based on dissim ilar m easures, and although they do not produce risk estim ates, they can still prove useful. The approach involves developing a com posite scor e—or index—from m easures of various risk dim e nsions. Various environm ental risk indices have been developed and applied to ranking and 56com p arative analyses. Often, these indices use surrogate m easures for risk rather than actual calculations of the probability of adverse ef f ects. One such index is the HRS, which is used to place uncontrolled waste sites on the National Priorities List for Superfund. This index is based on the likelihood of off-site m ovem e nt of waste, the toxicity of the waste, and the people and sensitive environm ents that m ay be affected. It also uses corrosivity, toxicity, fire hazard, and other factors, which are scored and com b ined into one num erical indicator of overall hazard potential. Such an approach for a com posite index has been suggested for the comm unication of cum u lative risk (Hertzberg, 2000). Fischhoff et al. (1984) provides an exam ple 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 dim e nsion). The scores are then weighted to reflect value judgm ents about the im portance of the various risk dim e nsions, and the com posite score is calculated by summ i ng the individual weighted scores. Again, the aggregation of dissim ilar adverse effects obscures the m eaning of the final score, m a king this approach m o re appropriate for ranking and com p arative analyses. Recently, EPA has been working on several index-based approaches to dealing with cum u lative risk issues. EPA Region 3 and the Office of Research and Developm ent have been jointly working to develop a potential risk indexing system (USEPA, 1993c, 1995d, 1997c). This index also uses a vulnerability index, and it gauges the overall well-being of a locale and various subpopulations. Again, the volum e and toxicity of released stressors serve as surrogate m easures of risk in developing this index.
Com b ining the diverse effects and risk using either comm on m e trics or indices has both pros and cons. A weakness of the index approachis that, by aggregating dissim ilar inform ation, inform ation is “lost,” and the m eaning of the final score can be obscured. However, both approaches have one strength in comm on: the ability to incorporate social values into the risk assessm ent in an explicit and quantitative m anner. For exam ple, in the derivation of DALYs, weights can be used to reflect the different so cial roles people play as they age (Murray, 1994). In the com posite scores developed by Fischhoff etal. (1984), public concern was incorporated as an adverse effect. The ability to incorporate issues suach as public concern into the com posite scores is an im portant feature for m e thods that will be applied to cum u lative risk assessm ents, especially for comm unities. Given that cum u lative assessm ents have a comm unity/population f o cus, the ability to incorporate social values into an overall assessm ent of well-being will be critical.
3.3.3.2. General issues regarding a single m e tric As described above, each approach to portraying the results of a cum u lative risk assessm ent has desirable and undesirable features. Although comm on m e trics and indices can incorporate social values in an explicit and quantitative m anner, the m eaning of the f i nal m easure can be obscured by the aggregation of dissim ilar effects. The abstract nature of the final m easure could lead to dif f i culties when comm unicating the results of the assessm ent to the public. The use of graphical and m apping techniques do not necessarily overcom e 57comm unication problem s. Although these techniques do not have som e of the problem s associated with the m a them atical aggregation of dissim ilar ef f ects, it still m ay be dif f i cult, f o r exam ple, to accurately describe the inform ation that a graphic is intended to convey. Because we have relatively little experience in com b ining 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 m e thods and to find additional m e thods that are flexible, that can incorporate social values, that are easy to comm unicate, and that provide an integrated portrayal of the overall well-being of a comm unity and its various subpopulations.

3.3.4. Qualitative Approaches There will be cases where cum u lative risk cannot be quantified in any m eaningful or reliable way. Qualitative approaches can be valuable for cum u lative risk assessm ent and, in the near term , they m ay be the only practical way to address m any of the com p lexities involved. Qualitative approaches m ay be used as a way to overcom e the com p lexity and data def i ciencies that hinder quantitative approaches. In m any assessm ents, risk m ay not be a quantif iable variable. For these cases, there m ay be qualitative approaches that provide som e insight. Broad indicators related to exposure in com p lex ways (e.g., production volum es, em issions inventories, environm ental concentrations, etc.) and indicators of toxicity can be comm unicated using geographic inf o rm ation system s. Displaying com p lex, m u ltidim ensional m a trices on a m ap can help in visualizing locations of areas with m u ltiple stressors. Furtherm ore, geographically based m easures of hazard are potentially useful cum u lative m e asures; although they do not provide inform ation on the risks, the locations of hazards can be used as an indicator of aggregate exposures and, thus, cum u lative risks from all of the potential chem icals associated with that site. The environm ental justice literature has used this approach. Quantitative results m i ght eventually be reduced to a m o re qualitative scale (high, m e dium , or low), or the qualitative results could provide “comm e nts” tacked onto the quantitative results. The assessm ent m i ght sim p ly raise red f l ags associated with specif i c issues (e.g. density of em itters in a comm unity, presence of m i nority populations, special exposure pathways, etc); a high num ber of such flags would indicate unacceptable cum u lative risk, even if the risk is not quantified. This approach has been used in the European Union (CEU, 1996), and its experience in using qualitative m e thods for perm itting suggests that “qualitative” is not “irrational.” Other relevant tools include e xpert judgm ent techniques, focus groups, opinion surveys, citizen juries, and alternative dispute resolution.

584. THE RISK CHARACTERIZ ATION PHASE The last phase of cum u lative risk assessm ent, risk characterization, integrates and interprets the results of the analysis phase and addresses the problem (s) form ulated in the planning and scoping phase (Figure 4-1). It s hould describe the qualitative and/or quantitative risk assessm ent results; list the im portant assum p tions, lim itations, and uncertainties associated with those results; and discuss the ultim ate use of the analytic-deliberative outcom e s. Given the com p lexity of cum u lative risk issues and the need for clarity and transparency in risk characterization, such “full disclosure” presents a m a jor comm unication challenge. There is a substantial analytical com ponent of the risk characterization phase, but there is also a considerable need for deliberation. At a m i nim um , stakeholders in this phase should (1) understand the outcom e of the cum u lative risk assessm ent, (2) ask questions about how best to fram e the interpretation, and (3) confirm that the cum u lative risk assessm ent m e t the goals set in the problem form ulation, or if not, why not. As in the previous phase, the stakeholders’ role is only lim ited by what is proposed and agreed upon in the particular case being assessed. Risk estim ation in a cum u lative risk assessm ent will involve som e com b ination of risks, whether the risks from different stressors cause sim ilar effects or different types of effects. The stressors them selves m ay be sim ilar or widely different. Com b inations of m any types of stressors that have different endpoints will quickly cause the risk estim ation step to becom e very com p lex and difficult. Because of its potential com p lexity, and because in som e cases the cum u lative risk assessm ent will be dealing m e thodologically with “uncharted territory,” it is very im portant that the planning, conduct, analysis, and characterization of an assessm ent be transparent. As stated by the Office of Managem e nt and Budget (OMB, 2002) , the “benefit of transparency is that the public will be able to assess how m u ch an agency’s analytic result hinges on the specif i c analytic choices m a de by the agency.” The process, m e thodology, data, assum p tions, and selection am ong alternate interpretations should be very carefully docum ented and very clearly stated. This is noted again in the next section.

59

### Planning , Scopin g , and Problem F o rmulation

Ana l y s i s

I n terpr e tationand Ris k Characteriz ation Planning , Scopin g , and Problem F o rmulation

Ana l y s i s

I n terpr e tationand Ris k Characteriz ation

Ri sk De sc r i pti o n

- C entra l T e ndenc y and Hi g h -End I ndi v i dual Ris k

- P opulation Ris k

- R is k to I m portant Subpop ulations Unc e r tai n ty Analysi s -Being Explicit a bout Unc e rtaint y

- U nce rta int y and Va riabili t y

- U ncertaint y and Ris kA d dition

- S ensitiv it yA n al y s is

Inf o rmation Provi ded by Cu mul a ti ve Ri s k Asse s s m e nt

Usi n g the Re sul t s of Cu m u l a tive Ri s k Asse ss m e nt

Figure 4-1. The Risk Characteriz a tion phase.

604.1. Risk Description The ultim ate product in the risk assessm ent process is the risk characterization, in which the inform ation from all the steps is integrated and an overall conclusion about risk that is com p lete, inform ative, and useful for decisionm akers is synthesized. The nature of the risk characterization will depend on the inf o rm ation available, the regulatory application of the risk inform ation, and the resources available (including tim e). It is im portant to identify and discuss

Risk Characteriz a tion Guiding Principles Regarding inform ation content and uncertainty aspects:

< The risk characterization integrates the inform ation from the exposure and dose-response assessm ents using a com b ination of qualitative inform ation, quantitative inform ation, and inform ation regarding uncertainties.

< The risk characterization includes a discussion of uncertainty and variability.

< W e ll-balanced risk characterizations present risk conclusions and inform ation regarding the strengths and lim itations of the assessm ent for other risk assessors, EPA decisionm akers, and the public. Regarding risk descriptors:

< Inform ation about the distribution of individual exposures is im portant to comm unica ting the results of a risk assessm ent.

< Inform ation about population exposure leads to another im portant way to describe risk.

< Inform ation about the distribution of exposure and risk for different subgroups of the population are im portant com ponents of a risk assessm ent.

< Situation-specific inform ation adds perspective on possible future events or regulatory options.

< An evaluation of the uncertainty in the risk descriptors is an im portant com ponent of the uncertainty discussion in the assessm ent. Source: USEPA, 1995b all m a jor issues associated with determ ining the nature and extent of the risk. Further, USEPA (1995a) specifies that a risk characterization “be prepared in a m anner that is clear, transparent, reasonable, and consistent with other risk characterizations of sim ilar scope prepared across program s in the Agency.” In short, estim ates of health risk are to be presented in the context of uncertainties and lim itations in the data and m e thodology. USEPA (1995b) lists several guiding principles for defining risk characterization in the context of risk assessm ent (see text box), both with respect to inform ation content and uncertainty aspects and with respect to descriptions of risk. EPA has also published a handbook on risk characterization (USEPA, 2000c). Risk assessm ents are intended to address or provide descriptions of risk to one or m o re of the following: (1) people exposed at average levels and people in the high-end portions of the risk distribution, (2) the exposed population as a whole, and (3) im portant subgroups or life stage strata of the population (e.g., children) or other highly susceptible groups or individuals, 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

61Some Thoughts on Risk Characteriz a tion Understanding Risk (NRC, 1996) focuses on risk both the m a gnitude and character of uncertainty.... characterization and reaches the following Getting the right science. The analysis has addressed conclusions: the significant risk-related concerns of public officials 1. Risk characterization should be a decision-driven and the spectrum of interested and affected parties, activity , directed towards inform ing choices and such as risks to health, econom ic well-being, and solving problem s. The viewof risk characterization ecological and social values, with analytic priorities as a translation or summ a ry is seriously deficient.... having been set so as to em phasize the issues m o st Risk characterization should not be an activity added relevant to the decision. at the end of risk analysis; rather, its needs should Getting the right participation

. The analytic- largely determ ine the scope and nature of risk deliberative process has had sufficiently broad analysis. participation to ensure that the important, decision2. Coping with a risk situation requires a broad relevant inform ation enters the process, that all understanding of the relevant losses, harm s, or im portant perspectives are considered, and that the consequences to the interested and affected parties. parties’ legitim ate concerns about inclusiveness and A risk characterization m u st address what the openness are m e t. interested and affected parties believe to be at risk in Getting the participation right. The analytic- the particular situation, and it m u st incorporate their deliberative process satisfies the decision m a kers and perspectives and specialized knowledge. interested and affected parties that it is responsive to 3. Risk characterization is the outcom e of an analytic- their needs: that their inform ation, viewpoints, and deliberative process.... Analysis and deliberation can concerns have been adequately represented and taken be thought of as two com p lem e ntary approaches to into account; that they have been adequately consulted; gaining knowledge about the world, form ing and that their participation has been able to affect the understandings on the basis of knowledge, and way risk problem s are defined and understood. reaching agreem ent am ong people. Developing an accurate, balanced, and informative 4. The analytic-deliberative process leading to a risk synthesis

. The risk characterization presents the state characterization should include early and explicit of knowledge, uncertainty, and disagreem ent about the attention to problem formulation. risk situation to reflect the range of relevant knowledge and perspectives and satisfies the parties to a decision 5. The analytic-deliberative process should be that they have been adequately inform ed within the mutual and recursive.

... A recurring criticism of risk lim its of available knowledge. characterization is that the underlying analysis failed to pay adequate attention to questions of central 6. Those responsible for a risk characterization should concern to som e of the interested and affected parties. begin by developing a diagnosis of the decision situation This is not so m u ch a failure of analysis as a failure to so that they can better m a tch the analytic-deliberative integrate it with broadly based deliberation: the process leading to the char acterization to the needs of analysis was not fram e d by adequate understanding the decision, particularly in term s of level and intensity about what should be analyzed.... Structuring an of effort and presentation of parties.... Diagnosis of risk effective analytic-deliberative process for inform ing a decision situations should follow eight steps: (1) risk decision is not a m a tter for a recipe. Every step diagnose the kinds of risk and the state of knowledge, involves judgm ent, and the right choices are situation (2) describe the legal m a ndate, (3) describe the purpose dependent. Still, it is possible to identify objectives of the risk decision, (4) describe the affected parties that also serve as criteria for judging success: and anticipate public reactions, (5) estim ate resource needs and tim etable, (6) plan for organizational needs, Getting the science right

. The underlying analysis (7) develop a prelim inary process design, and (8) m eets high scientific standards in term s of m easurem ent, analytic m e thods, databases used, summ a rize and discuss the diagnosis with the plausibility of assum p tions, and respectfulness of responsible organization.

62conditions), socioeconom ic (e.g., nutrition), or de m ographic variables or because of significantly greater levels of exposure (USEPA, 1992a). S ubpopulations can be defined using age, race, gender, and other factors. If enough inform ation is available, a quantitative risk estim ate for a subpopulation can be developed; if not, then any qualitative inform ation about subpopulations gathered during hazard identification should be summ arized as part of the risk characterization (USEPA, 2000c). The box on the previous page summ arizes som e of the points m a de in Understanding Risk (NRC, 1996), which devotes a great deal of discussion to risk characterization. Risk characterization is m o stefficiently conducted with early and continued attention to the risk characterization step in the risk assessm ent process (NRC, 1996; USEPA, 2000c).
4.2. Uncertainty Analysis Morgan and Henrion (1990) note that, historically, the m o st comm on approach to uncertainty in policy analysis (including in risk assessm ent) has been to ignore it. In a section titled “Why Consider Uncertainty?” they advance three prim ary reasons, all of which are especially relevant to an analytic-deliberative process such as cum u lative risk assessm ent. They suggest that it is im portant to worry about uncertainty

• “ when one is perf orm i ng an analysis in which people’s attitude toward risk is likely to be im portant, for exam ple, when people display significant risk aversion;

• “ when one is perform i ng an analysis in which uncertain inform ation from different sources m u st be com b ined. The precision of each source should help determ ine its weighting in the com b ination; and

• “ when a decision m u st be m a de about whether to expend resources to acquire additional inform ation. In general, the greater the uncertainty, the greater the expected value of additional inform ation.” Morgan and Henrion provide ten requirem e nts for good policy analysis, and although all are comm e ndable and several have been discussed elsewhere in this fram ework report, we should look m o re closely at num bers 6–8 in the box at right for som e insight into uncertainty analysis. There are m any resources available that talk in detail about how to perform uncertainty analysis (e.g., USEPA, 1997b; Morgan and Henrion, 1990). Although detailed instruction is beyond the scope of this fram ework report, we believe that a discussion of som e general principles is in order. Morgan and Henrion’s Ten Requirements for Good Policy Analysis

1. Do your hom ework with literature, experts, and users. 2. Let the problem drive the analysis. 3. Make the analysis as sim p le as possible, but no sim p ler. 4. Identify all significant assum p tions. 5. Be explicit about decision criteria and policy strategies. 6. Be explicit about uncertainties. 7. Perform system atic sensitivity and uncertainty analysis. 8. Iteratively refine the problem statem ent and the analysis. 9. Docum e nt clearly and com p letely. 10. Expose the work to peer review. Source: Morgan and Henrion, 1990

634.2.1. Assum p tions in the Assessm ent Cum u lative risk assessm ent will typically be used in a decision-m a king process to help inform the decisionm aker(s). For this reason, it is im portant that the decisionm akers be m a de explicitly aware of any assum p tions that m ay signif i cantly af f ect the conclusions of the analysis (requirem e nt num ber 4 in the box on previous page). Morgan and Henrion (1990) suggest that these assum p tions include:

• the m a in policy concerns, issues, or decisions that prom pted the assessm ent, • the evaluation criteria to be used to define issues of concern or options,

• the scope and boundaries of the assessm ent and ways in which alternate selections m i ght influence the conclusions reached,

• s oft or intangible issues that are ignored or inadequately dealt with in the quantitative analysis (e.g., intrinsic value of wilderne ss, equity of distribution of risks and benefits), • approxim a tions introduced by the level of aggregation or by level of detail in m odels, • v alue judgm ents and tradeoffs, and

• the objective function used, including m e thods of com b ining ratings on m u ltiple criteria (or com b ining risk scales). Identifying significant assum p tions can often highlight “soft” uncertainties that are not easily quantif ied and are theref ore of ten lef tout of a quantitative uncertainty analysis. Nevertheless, these “soft” uncertainties can often contribute m o re to the overall uncertainty of the assessm ent than the f actors m o re easily quantif ied. Morgan and Henrion’s sixth requirem e nt for good policy analysis (see box on previous page) includes three types of uncertainty that analysts should explicitly address:

• U ncertainty about technical, scientific, econom ic, and political quantities (e.g., quantities such as rate constants of ten lend them selves to quantitative uncertainty estim ates relatively easily);

• U ncertainty about the appropriate functional form of technical, scientific, econom ic, and political m odels (e.g., are the m odels used, such as dose-response m odels, biologically sound? ); and

• D isagreem ents am ong experts about the values of quantities or the functional form of m odels (e.g., different health scientists using different form s of dose-response m odels). In requirem e nt num ber 7, Morgan and Henrion suggest that an assessor should find out which assum p tions and uncertainties m ay significantly alter the conclusions, and that this process can be conducted using sensitivity and uncertainty analysis. Techniques include:

• D eterm i nistic, one-at-a-tim e analysis of each factor, holding all others constant at nom inal values;

64• D eterm i nistic joint analysis, changing the values of m o re than one factor at a tim e;

• P aram etric analysis, m oving one or a few inputs across reasonably selected ranges to observe the shape of the response; and

• P robabilistic analysis, using correlation, rank correlation, regression, or other m e ans to exam ine how m u ch 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 statem ent of the im plications and lim itations of their work. Attem p ts to f u lly characterize and deal with im portant associated uncertainties help them to execute this responsibility better.”
4.2.2. Uncertainty and Variability NRC (1994) notes a clear difference between uncertainty and variability and recomm e nds that the distinction between these two be m a intained:A distinction between uncertainty (i.e., degree of potential error) and interindividual variability (i.e., population heterogeneity) is generally required if the resulting quantitative risk characterization is to be optim ally usef ul f o r regulatory

The Cumulative Exposure Project

EPA’s Cum u lative Exposure Project (CEP), com p leted in 1998, m odeled 1990 outdoor concentrations of hazardous air pollutants (HAPs) across the United States, which were com b ined with unit risk estim ates to estim ate the potential increase in excess cancer risk from m u ltiple HAPs. The cancer risks of different HAPs were assum e d to be additive and were sum m e d across pollutants in each census tract to estim ate a total cancer risk in each census tract. Consideration of som e specific uncertainties, including underestim ation of am bient concentrations, com b ining upper 95% confidence bound potency estim ates, and changes to potency estim ates, found that cancer risk m a y be underestim ated by 15% or overestim ated by 40-50%. Other unanalyzed uncertainties could m a ke these under- or overestim ates larger.
Source: W oodruff et al., 2000 purposes, particularly insofar as risk characterizations are treated quantitatively. The distinction between uncertainty and individual variability ought to be m a intainedrigorously at the level of separate riskassessm ent com ponents (e.g., am bient concentration, uptake, and potency) as well as at the level of an integrated risk characterization. Variability and uncertainty have beentreated separately and distinctly in singlechem ical assessm ents such as the assessm ent of TCE in ground water at Beale Air Force Base in California (Bogen, 2001). The treatm e nt of variability and uncertainty will also be an im portant issue in cum u lative risk assessm ents, although at the tim e of this writing there are no good exam ples of an elegant treatm e nt of this issue f o r cum u lative risk.

654.2.3. Uncertainty and Risk Addition Calculating individual stressor risks and then com b ining them largely presents the sam e challenges as com b ination toxicology but also adds som e statistical stum bling blocks. Toxicity addition, independence, synergism , or antagonism still need to be evaluated, but because risk estim ates for various stressors are often presented as values on the sam e num eric scale (e.g., as cancer probabilities), cancer risks are of ten sim p ly added together. Because cancer slope factors are not “m ost probable estim ates,” but rather 95% upper confidence levels, adding traditional risk levels can cause the resulting sum to overestim ate a 95% upper confidence level risk for a m i xture. There have been several recent papers discussing this problem and how it m ay affect the resulting estim ates. Kodell and Chen (1994) looked at several binary m i xtures and calculated that the summ a tion of individual upper 95% confidence intervals for chlorobenzene and hexachlorobenzene would overestim ate the upper-bound risk of a binary m i xture of these com pounds by 2 to 6%, whereas for chlorobenzene and TCE the overestim ate would be in the range of 12 to 15%. Seed et al. (1995) noted that, “in m o st cases, the m a gnitude of the difference in cancer risk estim ates calculated by [Kodell and Chen’s] various m e thods will be greatest for m i xtures of equipotent com pounds. However, even for m i xtures of equipotent com pounds, the differences in joint risk estim ated by summ i ng the upper 95% confidence levels...are not great.” After analyzing four cases, Cogliano (1997) concluded that “as the num ber of risk estim ates increases, their sum becom e s increasingly im probable, but not m i sleading.” For exam ple, in adding 20 different cancer risk estim ates based on a 95% upper bound, the resulting sum of the upper bounds was no m o re than 2.2 tim es the true upper bound. Cogliano went on to suggest that, for certain cases not involving synergistic or antagonistic interactions, “depending on the num ber 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.” The assum p tion of toxicologic independence (see Section 3.2.2) m ay not be a bad one if other evidence supports it, but it should be addressed in the assessm ent if used (i.e., if risks are added). Although som e scientists believe that toxicologic interactions are of m i nor consequence at concentrations observed in the environm ent (see discussion in USEPA, 2000e), the scientific evidence for such an assum p tion has not been firm ly established. Notwithstanding the statistical lim itations of adding traditional risk estim ates and the im plicit assum p tion that the toxicities will be additive 16 (i.e., no interactions such as synergism or antagonism occur), the num erical ease for com b ining risks in this way m ay m a ke it the m o st

16 At risk levels often seen with pollutant concentra tions observed in the environm ent, the com b ined risks calculated assum i ng “response additivity” (that is, each co m ponent acts as if the other were not present) are approxim a tely the sam e as with dose additivity (USEPA, 2000e). 66popular m e thod for approxim a ting cum u lative risks in the short term , at least at a screening level of assessm ent. 4.2.4. Other Cum u lative Risk Assessm ent Uncertainties This fram ework does not, and cannot, provide an exhaustive list of uncertainties unique to cum u lative risk assessm ent. W ithout question, however, there will be uncertainties inherent in a cum u lative risk analysis that have not been as im portant in traditional assessm ents. As an exam ple, because cum u lative risk assessm ents can be geographically based and GIS technology seem s to be a potentially usef ul tool f o r displaying results, there will be issues concerning how to present uncertainty inform ation, for exam ple, by overlaying im pacts or risks for several chem icals, on a GIS m ap. Specific uncertainties can arise when adding doses for chem icals that operate by the sam e m ode of action, such as the organophosphorous (OP) pesticides. In this case, USEPA (2002c) notes that uncertainties arise in estim ating the RPFs of the OP pesticides. These RPF uncertainties can be partitioned into three groups: those that are basic (e.g., uncertainty in the dose-response relationship for the reference chem ical), those that deal with chem icals in relation to one another (relative potencies of other chem icals relative to the reference chem ical), and those concerning joint m ode of action (e.g., m e m b ers of the comm on m echanism group m ay have other m odes of action that are not fully captured via the comm on-m echanism potency calculation). As risk assessors develop m o re experience with cum u lative risk assessm ents, m any m o re of these uncertainties m ay arise, but it is not possible to foresee all of them

. 4.3. Information Provided by Cumulative Risk Assessment It is im portant to clarify how cum u lative risk assessm ent and this fram ework report relate to comm unity assessm ents and comm unity decision m a king. Certainly, the Agency’s risk characterization handbook (USEPA, 2000c) em phasizes that whatever inform ation is im parted should be transparent, clear, consistent, and reasonable. For exam ple, if it is known that the results of a particular cum u lative risk assessm en t will be severely lim ited because of a lack of data or available m e thods, it m ay be advisable to start with a screening analysis to set priorities for a subsequent study that is m o re detailed and focused. In sim p le term s, what can a cum u lative risk assessm ent tell us, and what can’t it tell us?
4.3.1. Making Sense of Multiple-Stressor Effects The inform ation provided by cum u lative risk assessm ent is only a portion of that needed by comm unities and governm e nts to m a ke inform ed decisions about risks. There are alm o st always a m u ltitude of factors that affect health in a comm unity (e.g., crim e, drugs, health care access, vehicle safety, clim ate, infectious disease, diet) that m ay not have been considered within the scope of a given cum u lative risk assessm ent. Comm unity decision m a king will typically take into account risks to the environm ent as well as consideration of historical and cultural values and questions of fairness and distribution of risk s. The m e thodology is not currently available to understand how these factors (or stressors) m ay affect cum u lative health risk. 67Additionally, benefits such as jobs and useful products or services that m ay be associated with chem ical or other stressor exposures m ay be im portant contexts for decisions on the risks considered in cum u lative risk assessm ents. This fram ework report is not an attem p t to lay out protocols to address all the risks or considerations that are needed to adequately inform comm unity decisions. Rather, its focus is on describing various aspects of cum u lative risk, whether or not the methods or data currently exist to adequately analyze or evaluate those aspects of the assessment

. It devotes considerable tim e to a discussion on im proving the m e thods for a singl e part on the broader picture: characterizing health risks associated with exposures to m u ltiple chem icals via m u ltiple routes. Because of the lim itations of the current state of the science, cum u lative risk assessm ents in the near f u ture will not be able to adequately answer all the questions posed by stakeholders or interested parties. This does not m ean, however, that they would not be useful in providing insights to some of the questions asked; in fact, cum u lative risk assessm ent m ay be the best tool available to address certain questions dealing with m u ltiple-stressor im pacts. 4.3.2. Cum u lative Risk Assessm ents in a Public Health Context The public often asks—in a variety of ways—for clarification of the relationship between environm ental pollution (and risk assessm ents concerning it) and public health. Although cum u lative risk assessm ent holds the prom ise of better public health-related inf o rm ation f o r comm unities, it is not a panacea. To draw relationships between environm ental pollutant exposures and disease incidence, a body of epidem iological study is necessary. Trying to “work backwards” from health statistics to risk f actors requires full knowledge of the risk factors associated with the relevant disease(s). This is challenging under the best of circum stances, with good data; m any tim es it is not possible with the data at hand. Health statistics, including death rates and incidence of various diseases, illustrate the im pact of a variety of risk factors (e.g., sm oking as well as environm ental pollutants) and risk reduction factors (e.g., exercise and good nutrition as well as pollution control m easures). Indeed, population health statistics are reflective of all risk and risk reduction factors in a population’s history to date. Even the best cum u la tive risk assessm ent, given today’s state of the science, could not include an evaluation of the m a gnitude and interactions of all stressors and their ef f ects. At best, the risk estim ates of a cum u lative risk assessm ent will ref l ect some of the risks that m ay be ref l ected in comm unity health statistics. W ith rare exceptions 17 , cum u lative risk assessm ent estim ates would not be expected to m a tch exactly with comm unity health statistics, even for specific health endpoints such as specific cancers.

17 It is conceivable that high risks to rare specific effects could be com p arable for a risk assessm ent and comm unity health statistics, given current state of the art. To be sure this is not coincidental, a substantial effort to m a tch risk assessm ent scenarios with actual hist ories or exposures would have to be m a de. 684.3.3. How the Scope and Purpose of the Assessm ent Affect Results Historically, the Agency’s risk assessm ents have focused on assessing the risks from environm ental pollutants to public health or the environm ent, usually for the purposes of prioritizing risk m anagem e nt activities or triggering regulatory action. Given the need for public health-protective decisions, traditional risk assessm ent tools usually focus on predicting high ends of the risk distribution. Also, the trad itional tools are not designed to predict risk of diseases other than cancer. Additionally, the m any environm ental pollutants m a ke up only som e of the categories of risks to public health. Although quite adequate for their original purpose, when the results of these types of assessm ents are viewed from another perspective, such as that of a comm unity concerned about the cum u lative health im pacts of five industrial and comm e rcial f acilities within a two-block area, they m ay not be usef ul. The Agency is doing m o re place-based hum an health and ecological assessm ents (i.e., com p ared to source- or m e dia-specif i c assessm ents) than in the past, but it will be som e tim e before they becom e comm onplace. Consistent with good practices for planning and scoping, they often m ay be driven by specific risk-m anagem ent needs. The desired objectives and purpose of parties who were outside the process m ay differ from those for which the assessm ent was designed. For this reason, users of cum u lative risk assessm ents are advised to carefully study the scope and purpose of the assessm ent at hand as well as the analysis plan and resulting characterization to determ ine whether it is suitable (or partly suitable) to answer questions outside its stated objectives and purpose.
4.3.4. Docum e nting Stakeholder Input
Som e where in the discussion of how the assessm ent m eets or does not m eet the objectives laid out in the planning and scoping phase, it is useful to docum ent how stakeholder input has influenced the process, noting also those suggestions that were not included and why. This docum entation supports stakeholder participation and provides assurance that individuals have been heard.
4.4. Using the Results of the Assessment Once the results of an assessm ent are in hand, the assessm ent participants will usually focus prim arily on the comm unication and use of those results. The intended use of the assessm ent was considered at the beginning, in the problem form ulation phase, both to plan the assessm ent work and to set the stage for possible actions that m i ght be taken at this point. A detailed discussion of the comm unication and use of the results of a cum u lative risk assessm ent is beyond the scope of this docum ent, but it should be noted that in deciding on a course of action, considerations other than the results of the assessm ent will also need to be taken into account. If

the goals of a cum u lative risk analysis are to estim ate the risk f r om m u ltichem i cal and m

u ltipathway exposure to people living within a geographical area of concern, then an

69im portant objective in presenting the results is to identify the m a jor risk contributors in order to understand the sources, pathways, and stressors that contribute m o st to that overall risk. The results of a cum u lative risk assessm ent provide an additional tool for the risk m anager, one that perm its a m o re com p lete accounting and m o re explicit analysis to target follow-up risk m itigation strategies toward those stressors that m o st contribute to the population’s risk.
If

action to m itigate or prevent risk is the goal of the stakeholders, then the options f o r action discussed in the planning of the assessm ent can be re-evaluated in light of the results of the assessm ent. Som e questions that m i ght arise from this re-evaluation 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 assessm ent or are the options for m itigation and prevention beyond the scope of their control? ” In the latter case, for exam ple, siting issues are usually decided locally and m ay be within the authority of the participants of a local assessm ent. In contrast, risk from m obile sources or acid rain are likely to require action that is beyond the scope of a single local comm unity. In that case, taking action will require working with other comm unities and is likely to take m o re tim e. Discussion of the options available f o r addressing the results of a risk assessm ent will help to keep expectations in line with possibilities.
W ith regard to taking—or not taking—action after a cum u lative risk assessm ent has been interpreted, the team m ay benefit from lessons learned by others, just as in the planning, scoping, and problem form ulation phase. In early 2002 the European Environm ent Agency (EEA, 2001) released an extensive study of 12 classic case studies in hum an and environm ental health protection and the lessons learned from them (see text box on the next page). The report is available on the Internet and should be food fo r thought for any group contem plating protective actions, particularly for comm unity assessm ents. Finally, it is im portant to keep in m i nd that the results of the risk assessm ent are only one of the factors to be considered in m a king a decision on action to address the risk. Risk inform ation can m a ke an im portant and valued contribution to the decision-m a king process, but it cannot by itself determ ine the decision. Factors such as the availability of resources for change; perceived f a irness; politics; business and em ploym ent; quality-of

- lif e issues; the religious, cultural, aesthetics, or social values of a comm unity; or concern for future generations m ay also influence decisions. In the siting exam ple m e ntioned above, the assessm ent m ay determ ine that the new f acility does not signif i cantly increase risk to the comm unity but a decision not to site the f a cility m i ght still be m a de on the basis of a quality-of

- lif e issue that is unrelated to risk. Or, a comm unity m ay decide that the econom ic and em ploym ent benefits outweigh the risks associated with the siting. Other risk factors not considered in the assessm ent m ay also enter into the decision-m a king process, including both the environm ental risks not covered in the cum u lative risk assessm ent and the nonenvironm ental risks that m ay affect a comm unity. W ith lim ited resources, a comm unity m ay use all available risk inf o rm ation to m o st ef f e ctively target its resources.

70The European Environment Agency’s 12 Lessons Learned Late

• A cknowledge and respond to ignorance, as well as

uncertainty and risk, in technology appraisal and public policy-m a king.

• P rovide adequate long-term environm ental and health m onitoring and research into early warnings.

• I dentify and work to reduce blind spots and gaps in

scientific knowledge.

• I dentify and reduce interdisciplinary obstacles to

learning.

• E nsure that real world conditions are adequately

accounted for in regulatory appraisal.

• S ystem a tically scrutinize the claim e d justifications

and benefits alongside the potential risks.

• E valuate a range of alternative options for m eeting

needs alongside the option under appraisal, and prom ote m o re robust, diverse and adaptable technologies so as to m i nim i ze the costs of surprises and m a xim i ze the benefits of innovation.

• E nsure use of “lay” and local knowledge as well as

relevant specialist expertise in the appraisal.

• T ake full account of the assum p tions and values of different social groups.

• M aintain regulatory independence from interested parties while retaining an inclusive approach to inform ation and opinion gathering.

• I dentify and reduce institutional obstacles to

learning and action.

• A void “paralysis by analysis” by acting to reduce

potential harm when there are reasonable grounds for concern. Source: EEA, 2001

715. GLOSSARY
Adverse effect - A biochem i cal change, functional im pairm e nt, or pathological lesion that either singly or in com b ination adversely affects the perform ance of the whole organism or reduces an organism ’s ability to respond to an additional environm ental challenge. Agent - a chem ical, physical, or biological entity that m ay cause deleterious effects in an organism after the organism is exposed to it. Aggregate exposure - The com b ined 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 predeterm i ned, altered response for an effect. A BMD 10 , for exam ple, would be calculated on the basis of a benchm ark response of 10%. Benchmark response (BMR) - A predeterm i ned level of altered response or risk at which the benchm ark dose is calculated. Typically, the BMRs used are 1%, 5%, or 10%. Conceptual model - A written description and/or a visual representation of actual or predicted relationships between hum ans or ecological entities and the chem icals or other stressors to which they m ay be exposed.
Cumulative risk - The com b ined risks from aggregate exposures to m u ltiple agents or stressors.
Cumulative risk assessment - An analysis, characterization, and possible quantification of the com b ined risks to health or the environm ent f r om m u ltiple agents or stressors. Dose additivity- In a m i xture, when each chem ical behaves as a concentration or dilution of every other chem ical. The response of the com b ination of chem icals is the response expected from the equivalent dose of an index chem ical (the chem ical selected as a basis for standardization of toxicity of com ponents in a m i xture). The equivalent dose is the sum of com ponent doses scaled by their toxic potency relative to the index chem ical. For exam ple, for chlorinated dibenzodioxins (CDDs), 2,3,7,8-TCDD is selected as the index chem ical; other CDD concentrations are adjusted for their potency relative to 2,3,7,8-TCDD and then treated as if they were 2,3,7,8-TCDD “equivalents.” Dose-response relationship - A relationship between (1) the dose, either “adm i nistered dose” or absorbed dose and (2) the extent of toxic injury produced by that chem ical or agent. Response can be expressed either as the severity of injury or the proportion of exposed subjects affected. Endpoint - An observable or m easurable biological or chem ical event that is used as an index of the effect of a stressor on a cell, tissue, organ, organism , etc.
72Exposure pathw a y- The physical course that a chem ical or pollutant takes from the source to the organism exposed. Exposure route - The way a chem ical or pollutant enters an organism after contact, for exam ple, by ingestion, inhalation, or derm al absorption.
Low e st-observed-adverse-effect level (LOAEL) - The lowest dose or exposure level at which there is a statistically or biologically significant increase in the frequency or severity of an adverse effect in the exposed population as com p ared with an appropriate, unexposed control group. Model - A m a them atical representation of a natural system that is intended to m i m i c the behavior of the real system , allowing descri ption of em pirical data and predictions about untested states of the system

. Use of m odels is usually f acilitated by com puter programm i ng of the m a them atics and construction of a convenient input and output form at. No-observed-adverse-effect level (NOAEL) - An exposure level at which there are no statistically or biologically signif i cant increases inthe frequency or severity of adverse effects between the exposed population and its appropriate control; som e effects m ay be produced at this level, but they are not considered to be adverse or precursors to adverse effects. In an experim e nt with several NOAELs, the comm on usage of the term NOAEL is the highest exposure without adverse effects. Reference concentration (RfC) - An estim ate (with uncertainty spanning perhaps an order of m a gnitude) of a continuous inhalation exposure to the hum an population (including sensitive subgroups) that is likely to be without an appreci able risk of deleterious noncancer effects during a lif etim e. Reference dose (RfD) - An estim ate (with uncertainty spanning perhaps an order of m a gnitude) of a daily exposure to the hum an population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious noncancer effects during a lifetim e. Response additivity - In a m i xture, when the toxic response (rate, incidence, risk, or probability of effects) from the com b ination is equal to the conditional sum of com ponent responses as def i ned by the f o rm ula f o r the sum of independent event probabilities. For two chem ical m i xtures, for exam ple, the body’s response to the first chem ical is the sam e whether or not the second chem ical is present.
Risk - Absolute risk: The probability of injury, disease, or death under specific circum stances. In quantitative term s, risk is expressed in values ranging f r om 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 circum stances, relative to the background probability. In quantitative term s, risk is expressed in values ranging

73f r om 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 contem plated project (usually involving a group or team planning the project, analyzing one or m o re problem s, and m a king decisions for possible actions on the basis of the interpretation of that analysis).
Stressor - Any physical, chem ical, or biological entity that can induce an adverse response. A stressor m ay also be the lack of an essential entity, such as a habitat.

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86USEPA, 1998i. “Handbook for Air Toxics Em i ssion Inventory Developm ent, Volum e I: Stationary Sources.” Of f i ce of Air Quality Planni ng and Standards, Of f i ce of Air and Radiation. Research Triangle Park, NC. EPA-454/B-98-002. USEPA, 1998j. “Hum an Health Risk Assessm ent Protocol for Hazardous W a ste Com bustion Facilities.” Peer Review Draft. Office of So lid W a ste and Em ergency Response. W a shington, DC. EPA530-D-98-001 Internet: www.epa.gov/epaoswer/hazwaste/com bust/riskvol.htm

. USEPA, 1998k. “A Comm on Mechanism of Action: The Organophosphate Pesticides.” Scientific Advisory Panel. W a shington, DC. Internet: www.epa.gov/scipoly/sap/1998/m arch/com ec.htm

. USEPA, 1999a. “Guidelines for Carcinogen Risk Assessm ent.” Review draft dated July, 1999. Risk Assessm ent Forum , Office of Research and Developm ent. W a shington, DC. NCEA-F-0644. USEPA, 1999b. “Review of Revised Sections of the Proposed Guidelines for Carcinogen Risk Assessm ent.” Science Advisory Board. W a shington, DC. EPA-SAB-EC-99-015. USEPA, 1999c. “Risk Assessm ent Guidance for Superfund: Volum e 1 - Hum an Health Evaluation Manual. Supplem ent to Part A: Comm unity Involvem e nt in Superfund Risk Assessm ents.” Office of Solid W a ste and Em ergency Response. W a shington, DC. EPA 540-R98-042/PB99-963303. USEPA, 1999d. “Risk Managem e nt Program Guidance for Offsite Consequence Analysis.” Chem ical Em ergency Preparedness and Prevention Office, Office of Solid W a ste and Em ergency Response. W a shington, 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. Res earch Triangle Park, NC. 40CFR Ch. I (7-1-99 Edition), Appendix W to Part 51, pages 390–481. USEPA, 1999f. “EPA’s Fram ework for Comm unity-Based Environm ental Protection.” Office of Policy/Office of Reinvention. W a shington, DC. EPA 237-K-00-001. USEPA, 1999g. “Guidance for Perform i ng Aggregate Exposure and Risk Assessm ents.” Office of Pollution Prevention and Toxic Substances, Office of Pesticide Program s. W a shington, DC. Item 6043, dated October 29, 1999. Available on the internet at: http://www.epa.gov/fedrgstr/EPA-PEST/1999/Novem b er/Day-10/6043.pdf. USEPA, 1999h. “Guidance for Identifying Pesticide Chem icals and Other Substances that Have a Comm on Mechanism of Toxicity.” Office of Pesticide Program s, Office of Prevention, Pesticides, and Toxic Substances. W a shington, D.C. Internet: http://www.epa.gov/fedrgstr/EPA_PEST/1999/February/Day_05/.

87USEPA, 1999i. “Risk-Screening Environm enta l Indicators: 1988-1997 TRI Data ‘Air-Only’ Model.” Office of Pollution Prevention and Toxic Substances, Office of Prevention, Pesticides, and Toxic Substances. W a shington, 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 Environm ental Assessm ent’s Com p arative Risk Fram ework Methodology.” Sc ience Advisory Board. W a shington, DC. EPASAB-DW C-99-016. USEPA, 1999k. “Handbook for Criteria Pollutant I nventory Developm ent: A Beginner’s Guide f o r Point and Area Sources.” Of f i ce of Air Quality Planning and Standards, Of f i ce of Air and Radiation. Research Triangl e Park, NC. EPA-454/R-99-037. USEPA, 1999l. “Federal Guidance Report No. 13: Cancer Risk Coefficients for Environm ental Exposure to Radionuclides.” Office of Air and Radiation. W a shington, DC. EPA-402-R-99-001. USEPA, 2000a. “Toward Integrated Envir onm ental Decision-Making.” Science Advisory Board. W a shington, DC. EPA-SAB-EC-00-011. USEPA, 2000b. “Benchm ark Dose Technical Guidance Docum e nt” Draft report. Risk Assessm ent Forum , Office of Research and Developm ent. W a shington, DC. EPA/630/R-00/001. USEPA, 2000c. “Science Policy Council Handbook: Risk Characterization.” Science Policy Council. W a shington, DC. EPA 100-B-00-002. USEPA, 2000d. “Science Policy Council Handbook: Peer Review.” 2 nd Edition. Science Policy Council. W a shington, DC. EPA 100-B-00-001. USEPA, 2000e. “Supplem entary Guidance for Conduc ting Health Risk Assessm ent of Chem ical Mixtures.” Risk Assessm ent Forum , Office of Research and Developm ent. W a shington, DC. EPA/630/R-00/002. USEPA, 2000f. “Baltim ore Comm unity Environm ental Partnership Air Comm ittee Technical Report. Comm unity Risk-Based Air Screening: A Case Study in Baltim ore, MD.” Office of Pollution Prevention and Toxics, Office of Prevention, Pesticides, and Toxic Substances. W a shington, DC. EPA 744-R-00-005. USEPA, 2000g. “Handbook for Non-Cancer Health Effects Valuation.” Non-Cancer Health Effects Valuation Subcomm ittee of the EPA Social Science Discussion Group, Science Policy Council. W a shington, DC. Dated Novem b er, 2000. USEPA, 2000h. “AP-42: Com p ilation of Air Pollutant Em ission Factors, Volum e II: Mobile Sources.” Office of Transportation and Air Qu ality, Office of Air and Radiation. W a shington, DC. EPA AP-42, Volum e II Internet: www.epa.gov/otaq/ap42.htm

. 88USEPA, 2000i. “Catalog of Hazardous and Solid W a ste Publications.” 13 thEdition. Office of Solid W a ste and Em ergency Response. W a shington, DC. EPA530-B-00-001 Internet: www.epa.gov/epaoswer/osw/catalog.htm

. USEPA, 2000j. “Guide to Field Storage of Bi osolids, Appendix A: Odor Characterization, Assessm ent and Sam p ling.” Office of W a stewater Managem e nt, Office of W a ter. W a shington, DC. EPA/832-B-00-007. Internet: www.epa.gov/owm / bio/fsguide/. USEPA, 2001a. Personal comm unication. Debby Sisco,. Biological and Econom ic Analysis Division, Office of Pesticide Program s, Office of Prevention, Pesticides, and Toxic Substances. W a shington, DC. August 1, 2001. USEPA, 2001b. Personal comm unication. Anna Koutlakis, Office of Prevention, Pesticides, and Toxic Substances. W a shington, DC. August 1, 2001. USEPA, 2001c. “Stakeholder Involvem e nt & Pub lic Participation at the U.S. EPA: Lessons Learned, Barriers, & Innovative Approaches.” Office of Policy, Econom ics and Innovation. W a shington, DC. EPA-100-R-00-040. USEPA, 2001d. “Top 10 W a tershed Lessons Learned.” Office of W e tlands, Oceans and W a tersheds, Office of W a ter. W a shington, DC. Internet: http://www.epa.gov/owow/watershed/lessons/top10.pdf. USEPA, 2001e. “National-Scale Air Toxics Asse ssm ent for 1996.” SAB Review Draft. Office of Air Quality, Planning and Standards, Office of Air and Radiation. W a shington, DC. EPA-453-R01-003. USEPA, 2002a. “Guidance on Cum u lative Risk Assessm ent of Pesticide Chem icals that Have a Comm on Mechanism of Toxicity.” Office of Pesticide Program s, Office of Prevention, Pesticides, and Toxic Substances. W a shington, DC. January 14, 2002. Internet: http://www.epa.gov/pesticides/trac/science/cum u lative_guidance.pdf. USEPA, 2002b. “Lesson Learned on Planning and Scoping for Environm ental Risk Assessm ents.” Science Policy Council. W a shington, DC. January, 2002. Internet: http://www.epa.gov/ORD/spc/2cumrisk.htm

. USEPA, 2002c. “Summ ary Report of the Technical Peer Review W o rkshop on the EPA Risk Assessm ent Forum Draft Framework for Cumulative Risk Assessment. ” Risk Assessm ent Forum , W a shington, DC; EPA/630/R-03/002. Internet: http://www.epa.gov/ncea/raf. USEPA, 2002d. “Exposure and Hum an Health Reassessm ent of 2,3,7,8-Tetrachlorodibenzo -p-Dioxin (TCDD) and Related Com pounds.” Na tional Center for Environm ental Assessm ent, Office of Research and Developm ent. W a shington, DC, (to be published).

899 0 USEPA, 2 002 e “A Review of the Reference Dose and Reference Concentration Processes.” Risk Assess m ent Foru m , W ashington, DC; EPA/630/P-02/002F. Internet: http://www.epa.gov/ncea/raf

. 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, Ti m othy 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 (World Health Organization), 2001. “Approaches to Integrated Risk Assessment.” International Programme on Chemical Safety. Gene va. WHO/IPCS/IRA/01/12 Internet: http://www.who.int/pcs/e m erg_ m ain.htm l

. Woo, Yin-Tak, Fred J. DiCarlo, Joseph C. Arcos, Mary Argus, Greg Polansky, and Jeff DuBose, 1994. Assessment of carcinogenic hazard of chemical mixtures through analysis of binary chemical interaction data. Environmental Health Perspectives 102 (Supplement 9): 113–118. 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. 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.APPENDIX A: RESEARCH AND DEVELOPMENT NEEDS Framework for Cumulative Risk Assessment is intended to provide a basic structure for the issues and define key term s and concepts. In som e cases, the concepts introduced in the fram ework report require the application of knowledge and m e thods that are not currently available. The following is a discussion of the needed areas of research and m e thods developm ent highlighted within the report that m ay be m o st im portant to an evaluation of cum u lative risks. This is not intended to be a com p rehensive listing of cum u lative risk assessm ent research needs. EPA and other scientists are currently investigating the use of sim ilar approaches for cancer and noncancer assessm ents. Although we do not discuss this research need here, it would be useful to cum u lative risk assessm ent to have sim ilar 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 cum u lative risk is that it represents an accum u lation of risk over time

. However, unlike the traditional approach to risk assessm ent, where exposure events are summ e d and averaged over a period of tim e, cum u lative risk assessm ent involves developing an understanding of how the sequence and tim ing of exposures influence the ultim ate risk for effects. For exam ple, for m u ltiple stressors, it is im portant to understand how prior exposures to one or several stressors influence the risks from subsequent exposures to the sam e or different stressors. In addition, it is im portant to understand the im plications of these exposures occurring during critical periods of an individual’s life (e.g., im portant periods of developm ent or periods of disease). Several exposure m odels are under developm ent that recognize the need to understand the tim ing of various exposure events (e.g., Calendex, APEX, Lifeline, SHEDS, and CARES/RExY). In addition to gaining a better understanding of the sequence and tim ing of exposures and their relationship to effects, it is im portant to understand how acute, nonlethal exposures from accidents contribute to chronic or long-term effects. Understanding the Composition and Toxicity of Mixtures Chem ical m i xtures can change or degrade over tim e and space, m a king the assessm ent of exposure a particular challenge. For cum u lative risk assessm ent, the com position of the m i xture at the point of contact with the receptor should be well characterized. Measurem ent techniques (at the receptor) and predictive m odels are both applicable in this characterization. EPA’s guidance for the health risk assessm ent of chem ical m i xtures (USEPA, 2000e) presents approaches f o r com b ining the toxicities of m u ltiple chem ical stressors. These approaches necessarily involve a num ber of sim p lifying assum p tions when the m i xtures are com p lex. Although the current m e thods provide a valuable resource for assessing cum u lative

91risks, future cum u lative risk assessm ent will need a m o re com p lete understanding of the interactions am ong chem icals in com p lex m i xtures. Som e current research efforts are seeking to identify toxicologic principles of joint action that are applicable to m i xtures involving m a ny chem icals. Applying the Risk Factor Approach to Environmental Health Risks The risk factor approach has been used in the m e dical profession to predict the chances of individuals developing various diseases. It has proved to be a useful approach not only in assessing certain cum u lative risks, but also in comm unicating with patients. In this approach, characteristics of a population (e.g., age, ethnicity, personal habits, genetic polym orphism s, prior diseases, etc.) are correlated with the incidence of disease. For som e diseases (e.g., breast cancer, coronary artery disease, stroke) these correlations are well established. However, there are substantial data gaps in term s of the role played by exposures to environm ental stressors in the developm ent of hum an disease, and correlations of environm ental exposures with disease outcom e s are generally not available. Using Biomarkers and Biomonitoring The use of biom arkers of exposure or effect holds a great deal of prom ise for cum u lative risk assessm ent. This approach can provide a m e thod for assessing stressors in groups. Currently, however, this approach is not practicable when considering a large num ber of diverse stressors, because appropriate biom arkers for m any types of stressors have not yet been developed. Considering Hazards Presented by Nonchemical Stressors
Cum u lative risk assessm ent could encom p ass the interactions of chem ical stressors with biological, radiological, and other physical stressors; socioeconom ic stressors; and lifestyle conditions. In trying to assess all these different types of stressors, it is helpful to determ ine what types of effects the stressors produce and then to try to group stressors by like effects. Ideally, one would like to know the m echanism or m ode of action by which various stressors cause effects to allow a m o re refined grouping. Currently, however, there are few m e thods for understanding 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 m easured. However, assessing levels of stress and their potential contribution to risk is difficult for a variety of reasons. The Agency for Toxic Substances and Disease Registry began the process of identifying research needs in this area through an expert panel workshop held in 1995. Considering All Aspects of Vulnerability

92The issue of the vulnerability of a population can be thought of as having four com ponents: susceptibility of individuals, differential exposures, differential preparedness to withstand the insult, and dif f e rential ability to recover f r om ef f ects. Traditional risk assessm ent m ay consider one or m o re of these categories, but rarely are all considered. The overall consideration of all four categories m ay be m o re im portant in cum u lative risk assessm ent than in traditional one-chem i cal assessm ents. A cum u lative risk assessm ent, for exam ple, m ay need to consider potential com b inations of high exposure and high vulnerability across stressors. Methods developm ent work is needed in this area. Methods for Combining Different Types of Risk Another key concept in the definition of cum u lative risk assessm ent is that such an assessm ent represents the com b ined risk f r om m u ltiple stressors. This im plies that, in som e cases, it m ay be necessary to com b ine disparate m easures of risk (i.e., different types of effects) to sim p lify the expression of cum u lative risks. There have been som e attem p ts to collapse com p lex arrays of risk into a few or even a single m easure. These approaches have involved the use of comm on m e trics (e.g., quality-adjusted life year s, disability-adjusted life years, loss of life expectancy, etc.) and indices (e.g., hazard ranking sy stem , etc.) and the categorization of effects (e.g., as for categorical regression). Alterna tively, geographic inform ation system s and m apping techniques can be used to graphically portray integrated inform ation on risks without m a them atically com b ining disparate m easures. Much m e thods developm ent work rem a ins to be com p leted in each of these areas. Development of Default Values for Cumulative Risk Assessments Conventional risk assessm ents use a series of default values for screening or other applications, and it m ay be necessary to investigate whether certain defaults need to be established specif i cally f o r cum u lative risk assessm ents. Development of Case Studies and Issue Papers on Specific Cumulative Risk Topics The m o re detailed technical issues and m e thodologies should be developed as a series of issues papers that would augm ent the fram ework report. The level of detail would, of course, vary, depending on the topic. The issues papers (or white papers) should also include details on additional approaches to cum u lative risk assessm ent that are currently being explored (including screening-level analyses, place-based assessm ents, com p arative risk assessm ents, National Environm ental Policy Act cum u lative effects analyses, and hazard assessm ents). In addition, the issues papers could include summ aries of case studies of cum u lative risk projects that would extend the fram ework from theoretical to practical approaches and applications.

93APPENDIX B: SELECT RESOURCES FO R 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. Air-related sources and activities: EPA’s Clearinghouse for Inventories and Em ission Factors (CHIEF) website (www.epa.gov/ttn/chief/) is an excellent starting place. It has m any of the relevant docum ents on m e thods and data for constructing em issions inventories available for download, including 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 the two volum es and supplem ent of Compilation of Air Pollutant Emission Factors (for both stationary and m obile sources) (USEPA, 1995e, 1996d, 1997d, 2000h), as well as m any other docum ents and software. EPA’s Support Center for Regulatory Air Models (SCRAM) website (www.epa.gov/ttn/scram /) provides extensive inform ation on the m odels discussed in Guideline on Air Quality Models (USEPA, 1999e), including downloadable software and users guides for m any of the m odels. The Am bient Monitoring Technology Inform ation Center (AMTIC) website (www.epa.gov/ttn/amtic/) contains inform ation on m onitoring program s and m e thods and other m onitoring-related inform ation. The um brella website for all three of the above is the Technology Transfer Network (www.epa.gov/ttn/), which also has other useful inform ation and links in addition to those noted above. Sources for land and waste-related activities: EPA’s Office of Solid W a ste and Em ergency Response has com p iled an extensive catalog summ arizing their publications (USEPA, 2000i). It has also published a “peer review draf t” docum ent titled 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.

94Chemical accidents and transportation-related spills: Assessing an accidental chem ical release exposure involves several steps. The typical analytical steps in the overall assessm ent are process analysis, likelihood or frequency of accidents, source term m odeling, dispersion or consequence m odeling, and the exposure assessm ent.

< The process analysis is a form al, system atic analysis of the process where a chem ical is handled to determ ine the probabilities and consequences of acute, catastrophic failures of engineered system s leading to an accidental release of the chem ical. This analysis is often called a process hazards analysis (PHA). Several form al PHA evaluation techniques are available, including “What-If,” “Failure Mode and Effect Analysis,” “Event-Tree,” and “Fault-Tree” analyses (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 estim ates the am ount or rate of release in case of accident, is perform e d once the failure scenarios are determ ined. A wide variety of published calculation m e thods or m odels are available (USEPA, 1998e, 1999d) to determ ine the source term s for an accidental chem ical release.

< Dispersion or consequence modeling is perform e d once the source term s (rate and duration of the release) are known. A wide variety of dispersion and consequence m odeling tools, ranging from sim p le screening m odels to sophisticated and com p lex com puter applications, are available for this step (USEPA, 1993a, 1999d; AIChE, 1996). In addition to the source term s generated above, several other data elem ents are needed, such as physical/chem i cal properties (e.g., whether the vapor cloud is heavier than air or water reactive), m e teorological conditions (e.g., wind speed and direction, tem p erature, hum idity), and terrain surrounding the facility (e.g., buildings or valleys that m ay channel or disperse a vapor cloud). Physical/chem i cal properties can be found in chem ical 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) 18 , or Risk Management Guidance for Offsite Consequence Analysis (USEPA, 1999d). Meteorological conditions are often collected on-site or at local airports. Inform ation about terrain can be collected from topological m aps or by visual inspection. Guidance on all these param e ters is available in USEPA (1999d).

18 There are m a ny searchable MSDS databases on-line th at can be located with m o st search engines. 95< The f i nal step is the exposure assessment , which is related to, and builds from , the dispersion or consequence m odeling step. The dispersion or consequence m odeling 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 comm on toxic substances (NIOSH, 1997; ACGIH, 1998; AIHA, 2000).
B.2. Resources Relevant to Exposures to Nonchemical Stressors Biological stressors: The International Life Sciences Institute’s Risk Science Institute has published a workshop report entitled “Revised Fram ework for Microbial Risk Assessm ent” (ILSI, 2000), which looks at m e thods for assessing risks to m i croorganism s such as Cryptosporidium , which has caused disease outbreaks when it contam inates drinking water. The m e thodology is superficially sim ilar to that of a risk assessm ent conducted for a chem ical pollutant, but only at the m o st general level. For exam ple, the characterization of exposure in the ILSI fram ew ork differs from that in an environm ental chem ical exposure assessm ent; it 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 m a intains a web page at <http://www.epa.gov/radiation/assessm ent/>. This page provides (or cites) m u ch of the needed docum entation for perform i ng risk assessm ents for radionuclides, including 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. Departm e nt of Housing and Urban Developm ent (HUD) has issued The Noise Guidebook (HUD, 1991), which im plem ents the existing noise regulations (24 CFR 51- B) and includes the HUD noise assessm ent guidelines. (The guidebook is available in hard copy only.) The Federal Railroad Adm i nistration has developed a m anual titled High-Speed Ground Transportation Noise and Vibration Impact Assessment (DOT, 1998), which provides the theory, equations, and applications of noi se and vibration analysis for high-speed railroads. Much of the theory and inform ation is also applicable to other noise and vibration problem s. Appendix A of the DOT guide is a general discussion of noise concepts, with references. The guide is available on-line (http://project1.parsons.com /ptgnechsr/noise_m anual.htm )

. 96The National Institute of Occupational Health and Safety has done m u ch research on the interaction of noise with chem ical exposures (Morata, 2000). Odor: EPA’s Of f i ce of W a stewater Managem e nt has issued a report titled Guide to Field Storage of Biosolids (USEPA, 2000j), which contains an appendix on “Odor Characterization, Assessm ent, and Sam p ling.” Odor assessm ent is an analyticdeliberative process involving both science-based analytical m e thods and m o re subjective analysis. The appendix of the guide discusses sensory characterization of odors (character, intensity, pervasiveness, quantity), som e practical options for assessing odors in a comm unity, and the chem istry of odors (including range of odor thresholds). It also discusses odor sam p le collection and analysis and has several dozen references for further inform ation. This report is available on-line (www.epa.gov/owm / bio/fsguide/).

97APPENDIX C: SOME THOUGHTS ON BACKGROUND EXPOSURES 19
Wh en looking at aggregate exposures or cum u lative risks of citizens, “background exposures” to specific chem icals are no less “real” than the exposures to pollution usually studied for regulatory purposes. Wh ereas in hi storical single-chem ical assessm ents conducted for lim iting pollution, background sources of the chem ical were often irrelevant to the questions being asked of the assessm ent (or ignored as having negligible effect on risk), background sources in cum u lative risk assessm ents are rarely irrelevant. 20 Background concentrations can be categorized as either naturally occurring , that is, chem icals that are naturally present in the environm ent before it was influenced by hum ans, or anthropogenic , that is, present in the environm ent due to historical hum an-m ade sources. Naturally occurring background chem icals m ay be either localized or ubiquitous. Anthropogenic background sources can be either localized from a point source or generalized from unidentified sources or nonpoint sources.
Assessm ents of m o rbidity incidence and death rates, m arket basket surveys, and pesticide residue surveys also provide inform ation that can be reflective of background chem ical concentrations as well as overt pollution. Background issues extend across all m e dia, beyond regulated sources, and beyond direct exposure. Many chem icals are naturally present in the environm ent (e.g., soils, water, vegetation, and other biota) and are consequently part of dietary, derm al, and inhalation exposures. In som e cases, naturally occurring substances m ay be present at levels that exceed health-based or risk-based regulatory standards (e.g., drinking water standards) or other levels established to protect hum an health and the environm ent. Because cum u lative risk assessm ents are population based, exposures due to naturally occurring background concentrations should typically be considered im portant.

19 Several term s are used to discuss background, and ther e are several ways to describe different aspects of this issue. It has been suggested (d eFur, 2002) that a m o re appropriate term for present conditions is “am b ient,” and that “background” should be reserved for som e untouched, even pristine state or condition. Although the Technical Panel discussed this use of the word “background” as a pr istine reference area, the discussion in this appendix is m eant to m o re closely reflect the way the word is used in practice within EPA. It is acknowledged that not all program s or scientists even within EPA use this term to m ean the sam e thing.

20 The word “background” is often used to describe expos ures to chem icals or other stressors that derive from sources other than the sources being assessed. Fo r exam ple, in the Agency’s assessm ent of residual risk associated with hazardous air pollutant em issions from pa rticular categories of sources that rem a in after the im plem entation of technology-based controls, “ b ackground” is defined as all hazardous air pollutant exposures (via inhalation or other routes) not associated with the s ource(s) being assessed. At a Superfund site, “background contam ination” refers to contam ination that is not re lated to the site release of chem icals, as defined by Comprehensive, Environmental Response, Compensation and Liability Act (CERCLA) (P.L. 96-510, Decem ber 11, 1980, as am ended by P.L. 98-802, August 23, 1983, and P.L. 99-499, October 17, 1986). Such focusing or segregation in a risk assessm ent can be useful to decisions involving pollution sources covered by particular statutory authorities, but it is typical of a chem ically fo cused assessm ent rather than a population-focused assessm ent such as a cum u lative risk assessm ent. 98There are several im portant issues related to natural or anthropogenic background concentrations in cum u lative risk assessm ent. First, if the risks posed by background concentrations of certain chem icals are significant (and som e m ay approach or exceed health reference levels), their exclusion from the cum u lative risk estim ates and characterization m ay seriously distort the portion of the total estim ated risk thought to be posed to the population by a specific evaluated source. A second issue is the problem of whether background chem ical exposures can be clearly distinguished from specific source-related chem icals and how to quantify these exposures. It m ay be im portant in a cum u lative risk assessm ent to estim ate background exposures separately from specific source-related exposures, so that the risk assessor can provide the comm unity with a m o re com p lete picture of both total and known source-related risks. This also provides a clearer, m o re com p lete picture for m a king risk m anagem e nt decisions. Finally, there m ay be problem s in identifying representative geographic areas for determ ining background levels for com p arison. Finally, background exposures for a comm unity or population m ay also include both voluntary and involuntary exposures and subsequentrisks. 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 sm oking, consum ing char-grilled m eats with polycyclic arom atic hydrocarbons, or other choice-based exposures and m ay also som e tim es be defined in the assessm ent as background exposures if they are not assessed directly in the cum u lative risk assessm ent.

99APPENDIX D: EXAMPLES OF OUTLINES OF ANALYSIS PLANS 21
D.1. Outline for Human Health Analysis Plan for Pesticides Under the 1996 Food Quality Protection Act (FQPA) Risk m anagem e nt/regulatory goal: Protection of the general hum an population and susceptible subpopulations to adverse effects from exposure to pesticide “X” under FQPA.
Assessm ent Endpoints: - hum an or anim al 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, developm ental effects, neurotoxicity, developm ental neurotoxi city, imm unotoxicity, hepatotoxicity, pulm onary effects, cardiovascular effects, etc. - general classes of toxic effects such as carcinogenicity, m u tagenicity Measures of Exposure: - m onitoring of food, water, residential, occupational exposures, etc. (direct or surrogate) - m onitoring of biological fluids or biom arkers (blood, urine, DNA or other m acrom olecules)
Wh at Can and Cannot Be Done Based on Planning and Scoping - pathways and relationships to be evaluated - resource restraints - m ilestones for com p letion of risk assessm ent Methods for Conducting Risk Analysis - RfD - m argin of exposure - probabilistic risk assessm ent based on dose-response or exposure param e ters - quotients (e.g., ratio of exposure level to toxicity threshold) - narrative discussions - other considerations (e.g., m echanism s of action, toxicokinetic m odels, tim ing of dose, sensitive population characteristics) Data Needs and Uncertainties

21 Conceptual m odels are not included here. 100D.2. Outline for Ecological Analysis Plan Risk m anagem e nt/regulatory goal: Viable, self-sustaining coho salm on population that supports a subsistence and sport fishery.
Assessm ent endpoints: Coho salm on 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 sedim e ntation - population data over tim e in relation to fish passage Measures of Ecosystem and Receptor Characteristics: - water tem p erature, 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 m o rtality rates Measures of Exposure: - num ber of hydroelectric dam s and associated ease of fish passage - toxic chem ical concentrations in water, sedim e nt, and fish tissue - nutrient and dissolved oxygen levels in am bient waters - riparian cover, sedim e nt loading, and water tem p erature
Wh at Can and Cannot Be Done Based on Planning and Scoping - pathways and relationships to be evaluated - resource restraints - m ilestones for com p letion of risk assessm ent Methods for Conducting Risk Analysis - quotients - narrative discussions - stressor-response curves with probabilities Data Needs and Uncertainties

101APPENDIX E: TOXICOLOGIC SIMILARITY—ORGANOPHOSPHORUS PESTICIDES The Food Quality Protection Act of 1996 (FQPA) requires that EPA reassess pesticide tolerances (legal lim its for residues in food) that were in effect as of August 1996. As part of the reassessm ent, EPA should consider available inform ation concerning the cum u lative effects on hum an health resulting from exposure to m u ltiple chem icals that have a comm on m echanism of toxicity. In this context, pesticides are determ ined to have a comm on m echanism of toxicity if they produce the sam e toxic effect in the sam e organ or tissue by essentially the sam e sequence of m a jor biochem i cal events (USEPA, 1999h). Shortly after enactm e nt of FQPA, EPA be gan developing new m e thods and tools that would allow the consideration of com b ined risks from exposure to several pesticides via several pathways and routes of exposure. Actual da ta sets for organophosphorus (OP) pesticides were used in pilot analyses to test these m e thods. The m e thods and pilot analyses were subjected to peer review through the FIFRA Scientific AdvisoryPanel to ensure the use of sound science. As part of this ongoing effort, on Decem ber 28, 2001 EPA’s Office of Pesticide Program s (OPP) announced the availability of the prelim inary organophosphorus cum u lative risk assessm ent [66FR67249-67250]. The risk assessm ent is available electronically at <http://www.epa.gov/pesticides/cum ulative>. In preparing the cum u lative risk assessm ent for the OP pesticides, OPP f o llowed f i ve m a jor steps.
1. Selection of the specific pesticides, pesticide uses, and pathways and routes of exposure to include in the quantitative analysis. The selection of the specific OP pesticides began with identifying a “comm o n m echanism group.” This was accom p lished following 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 comm on m echanism for causing adverse effects (USEPA, 1998k). The comm on m echanism group was further refined to reflect current use patterns and inform ation on the detection of residues from USDA’s Pesticide Data Program

. This resulted in the f o llowing recomm e ndations f o r 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 on the basis of use patterns and their individual assessm ents.

1022. Dose-response analysis for toxic potencies, relative contribution from each OP pesticide, and selection of an index chemical to use as the point of reference in the dose-response analysis. To determ ine the com b ined risk f r om m u ltiple OP pesticides, EPA used the relative potency factor approach (for additional exam ples of com p arative potency approaches, see Albert et al., 1983; Lewtas, 1985, 1988). The i ndex chem ical was selected on the basis of the quality of the dose-response data. Then the relative potency of each OP pesticide was estim ated by taking the ratio of its toxic potency to that of the index chem ical. 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 m o re. This practice was adopted to reflect cholinesterase inhibition at a point in the treatm e nt schedule at which a steady state had been achieved. OPP elected to use data that reflected a steady state in the interest of producing relative potency factors that are reproducible and reflect less uncertainty due to rapidly changing tim e-sensitive m easures of cholinesterase. Also, EPA considered that people generally have som e level of prior exposure to OP pesticides. Further, the effects of exposure can persist for several days to weeks. Therefore, people m ay be m o re vulnerable to subsequent exposures to OP pesticides than m i ght be predicted if these prior exposures are not considered.
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 m ay overlap, co-occur, or vary between chem icals. In addition, the use of profiles allowed for the identification of popul ations of potential concern. On the basis of 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 tim e of year or geographic location). For the residential and drinking water pathways of exposure, EPA divided the nation into 12 regions for assessm ent. This allowed for theconsideration of such factors as the location of vulnerable surface watersheds and regionspecific pest pressures. To estim ate risks, EPA used Calendex, a calendar-based com puter m odel. This m odel integrates the various pathways of exposure while sim u ltaneously incorporating the tim e dim e nsions of the data. The m odel 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 prelim inary organophosphorous cum u lative risk assessm ent is ongoing, there are som e early indications concerning contribution to risk. The drinking water pathway for exposure does not appear to be a m a jor contributor to the

103total cum u lative risk. Residential exposure appears to be a contributor to risk, particularly inhalation exposures from certain no-pest strips and crack and crevice treatm e nts. Childhood exposure from m outhing hands also appears to be a contributor, but there is a great deal of uncertainty associated with the estim ates.
5. Characterization of the confidence in the results and the uncertainties encountered. In addition to som e uncertainties noted above, EPA identified m any areas for additional analysis, including sensitivity analyses on input param e ters, verification of residential use patterns, closer exam ination of the tails of the food consum ption distribution, and evaluation of the effect of assum p tions a bout residue concentrations in baby foods.

104APPENDIX F: OTHER TYPES OF CUMULATIVE ASSESSMENTS Several other types of cum u lative assessm ents are related to the types of hum an health and ecological cum u lative assessm ents done by the Agency. It is beyond the scope of this fram ework to discuss these in detail, but a short explanation of several other types of cum u lative assessm ents are given in this appendix.
F.1. Quality-of-Life Assessments One type of assessm ent that resem b les a cum u lative risk assessm ent—but whose evaluation m ay require a different approach fr om the traditional National Research Council risk paradigm —is the quality-of

- lif e assessm ent. These assessm ents def i ne “harm ” to an individual or comm unity broadly, then evaluate the im portance of the various threats of harm to a set of “quality-of

- lif e” criteria. These assessm ents do not usually attem p t to predict probability that the harm will occur (as would a cum u lative risk assessm ent), but rather aim to apply the comm unity’s values to deal with the m o st im portant perceived threats. Although a quality-of-life assessm ent is not a risk assessm ent in m o st cases, changes in quality-of-life factors m ay affect the vulnerability of a population to health or ecological risks and consequently m ay be part of the considerations in a cum u lative risk assessm ent. Because few, if any, established and accepted relationships are currently available quantitatively linking quality-of

- lif e f actors and health or ecological risk, this is an area in which f urther research m ay prove valuable. To evaluate the effects on hum an or ecological health from these types of im pacts, a m o re deliberative approach (in the analytical-deliberative process) is needed than is used in, say, cancer risk analysis. To better help characterize these im pacts, EPA’s A Guidebook to Comparing Risks and Setting Environmental Priorities (USEPA, 1993b) suggests a six-step process in quality-of

- lif e analysis:
1. Identify im pacts and determ ine the values of the comm unity. 2. Identify and define evaluative criteria. 3. Collect and analyze data on im pacts. 4. Characterize im pacts for all problem areas. 5. Present f i ndings and rank problem areas f o r quality-of

- lif e im pacts. 6. Analyze future environm ental conditions and risk m anagem e nt considerations.

105Vermont’s Quality-of-Life Criteria Impacts on Aesthetics: Reduced visibility, noise, odors, dust and other unpleasant sensations, and visual im pact from degradation of natural or agricultural landscapes. Economic Well-Being: Higher out-of-pocket expenses to fix, replace, or buy item s or services (e.g., higher waste disposal fees, cost of replacing a well, higher housing costs), lower incom e or higher taxes paid because of environm ental problem s, and health-care costs and lost productivity caused by environm ental problem s. Fairness: Unequal distribution of costs and benefits (e.g., costs and benefits m a y be econom ic, healthrelated, aesthetic).
Future Generations: Shifting the costs (e.g., econom ic, health risks, environm ental dam a ge) 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 stream s). Sense of Community: Rapid growth in population or num ber of structures or developm ent that changes the appearance and feel of a to wn; loss of m u tual respect, cooperation, ability, or willingness to solve problem s together; individual liberty exercised at the expense of the comm unity; the loss of Verm ont’s landscape and the connection between the people and the land. Source: State of Verm ont, 1991 Quality-of

- lif e im pacts are determ ined by analyzing a set of criteria developed for each comm unity, depending on what it values. Stressors are those things that threaten to degrade the quality-of

- lif e criteria for that comm unity. An exam ple of a set of quality-of

- lif e criteria and their descriptions is shown in the box on this page. These criteria were developed by the State of Verm ont’s Agency of Natural Resources (State of Verm ont, 1991). Verm ont’s experience in evaluating these criteria was described as a qualitative description of harm or, in their term s, “risk”:
Because m o st of these seven criteria are intangible, they are extrem ely difficult to m easure or quantify. The Quality-of

- Lif e W o rk Group described how each problem area affects each criterion and how widespread or intense the effects are. Although these non-quantitative descriptions of risk often lack precision and scientific objectivity, they focus attention on specific critical issues and thus are useful tools for com p aring the problem s system atically and consistently. (State of Verm ont, 1991) Quality-of

- lif e issues can encom p ass m

u ch m o re than the criteria shown in the exam ple and thus m ay introduce m u ch additional com p lexity into the analysis. For instance, there m ay be feedback loops that cannot be easily evaluated, for exam ple, loss of property value or aesthetics tends to negatively affect the socioeconom ic system , which tends to increase rates of crim e, traf f i c accidents, and comm unicable pathogen transm ission, all of which in turn ultim ately reflect on overall comm unity health or ecological risk. Som e cum u lative risk assessm ents m a y consequently include quality-of

- lif e im pacts as indirect m easures of health ef f ects if suf f i cient links can be established between the two.

106F.2. Cumulative Impact Assessments The National Environm ental Policy Act (NEPA) defines “cum u lative im pact” (see box), and has certain requirem e nts for a cum u lative im pacts analysis. Although the Council on Environm ental Quality’s guidelines for cum u lative im pact analysis (CEQ, 1997) take a prim arily qualitative approach to the analysis, this is a m u ltiple-stressor, m u ltiple-effect analysis that looks at a variety of im pacts on the environm ent. The projects or actions that NEPA addresse s can be viewed as sources of stressors. Under NEPA, a description of the affected envi ronm ent in an environm ental im pact assessm ent contains four types of inform ation: (1) data on the status of im portant natural, cultural, social, or econom ic resources and system s; (2) data that characterize im portant environm ental or social stress factors; (3) a description of pertinent regulations, adm i nistrative standards, and developm ent plans; and (4) data on environm ental and socioeconom ic trends. Health effects on populations and susceptible individuals are part of the affected environm ent as considered by the NEPA cum u lative effects analysis, but the NEPA analysis m ay also consider effects on historic and archaeological resources, socioeconom ic factors such as em ploym ent, hum an comm unity structure, and quality of lif e changes. Although there is not always a clear relationship between these NEPA cum u lative im pacts and effects relevant to hum an health, the NEPA m e thods and tools for cum u lative im pact analysis m ay be useful for cum u lative risk assessm ents. For exam ple, cum u lative im pact analysis begins with an extensive scoping process and relies on conceptual m odels to plan the analysis. NEPA effects data m ay help risk assessors identify susceptible subpopulations, environm ental pathways, or exposure patterns. EPA Region 6 has developed a system called the Cum u lative Risk Index Analysis (CRIA), prim arily for NEPA-type assessm ents (Osowski et al., 2001). The CRIA contains som e 90 criteria with which to evaluate the health of an area and its ecosystem /hum an populations. These criteria help evaluate such diverse factors as hum an health, ecosystem health, and environm ental justice considerations. Each criterion, which leads to an indexing of 1 through 5, has been through the deliberative process and peer review and is well docum ented.
W e also acknowledge that other Federal agencies have been preparing “cum u lative risk analyses” for various NEPA’s “Cumulative Impact” Definition
Council on Environm ental Quality Regulation 1508 for Im plem enting the National Environmental Policy Act of 1969 [P.L. 91-190, 42 U.S.C. 4321-4347, January 1, 1970, as am ended 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 “cum ulative im pact” as “the im pact on the environm ent which results from the increm ental im pact 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. Cum u lative im pacts can result from individually m i nor but collectively significant actions taking place over a period of tim e.” Source: CEQ, 1997

107purposes related to their own m i ssion as part of environm ental im pact statem ents (e.g., NOAA, 1999).
F.3. Empirically Derived Medical Models The m e dical profession has long used em pirically derived m odels 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 exam ple, the risk factors for stroke are increasing age, heredity (fam ily history) and race, prior stroke, high blood pressure, cigarette sm oking, diabetes m e llitus, carotid and other artery disease, heart disease, transient ischem ic attacks, high red blood cell count, sickle cell anem ia, socioeconom ic factors, excessive alcohol c onsum ption, and certain types of drug abuse (Am e rican Heart Association, 2000). Each of thes e risk factors can be correlated with stroke incidence, and then the risk of stroke from vari ous com b inations of these factors can be explored. In this way, the analysis is “cum u lative,” but “risk factors” are not always synonym ous with “stressors.” Physicians use m odels containing effect-speci fic risk factors to advise patients of the probabilities of future effects (e.g., stroke, breast cancer) on the basis of their m e dical history. Although the m e dical data upon which these factors are based have been well developed for m any effects in hum ans, there are substantial data gaps in term s of the role played by exposures to m any chem icals in the environm ent in the developm ent of hum an disease. This em pirically derived m e dical m odel approach to cum u lative risk m ay be built on links between risk f actors and effects for better-studied stressors but m ay be lim ited or nonexistent for less robust health effects databases. Although this approach m ay som e day be applicable to hum an health and environm ental risk assessm ent such as EPA conducts, at present the data and m e thods are not available. In a larger sense, although em pirically derived m odels m ay be cum u lative risk m odels, the approach to determ ining risk is substantially different from the risk assessm ent approach used by EPA, where a com b ined effect is estim ated as the predicted aggregation of the effects of several different stressors. In an em pirical m odel such as physicians use, the focus is on an effect of concern, and the m odel derives the influence of various “stressors” or “risk factors” from actual observations, usually through the use of m u ltiple regression analyses. Although ideally the equations derived to represent the influences of various factors on the m easured outcom e (the effect of concern) would be causal-predictive m odels, in practice they are usually the m o st parsim onious “best f it” equations that satisf ystatistical criteria. The versatility of this approach, however, is the ability to tease apart contributions of dif f e rent sources of environm ental exposures of interest. This is illustrated by Laden et al. (2000) in the association of

particulates f r om dif f e rent sources with short-term m o rtality changes. This approach also has considerable potential to be used in conjunction with biom arkers as dependent variables (Hattis, 2002). The topic of cum u lative risk m odels will likely be covered in m o re detail in the f u ture guidelines f o r cum u lative risk assessm ent.
108F.4. Risk Surrogates Geographic inform ation system s and related m apping techniques (see, e.g., Environm ental Defense, 2001) appear to hold som e prom ise as tools for presenting integrated inform ation concerning cum u lative risks without m a them atically com b ining disparate m easures. Considerable m e thods developm ent work rem a ins to be com p leted. Not all statem ents of probability of harm are expressed as probabilities of specif ic health effects. Cohen (1991) uses m o rtality ratios to derive “loss of life expectancy” (LLE) estim ates f o r a wide variety of risk-related activities. For exam ple, workers in all occupations have a 60- day LLE as a result of working, but workers in agriculture have a 320-day LLE and construction workers a 227-day LLE as a result of their particular occupation. These types of statem ents are em pirically derived, probability-based statem ents of harm that do not use “probability of adverse health effect” as the basis for the risk statem ent. For estim ates such as LLEs, one could theoretically add up the various activities and the corresponding LLEs in days to estim ate a cum u lative risk in term s of loss of lif e expect ancy. These “other” types of risk-surrogate probability statem ents could conceivably be used in cum u lative risk assessm ent, although currently they are not widely used, perhaps due to lack of m e thods.

109