    Chemical Risk Assessment: Selected Federal Agencies' Procedures,
    Assumptions, and Policies (06-AUG-01, GAO-01-810).

    As used in public health and environmental regulations, risk
    assessment is the systematic, scientific description of potential
    harmful effects of exposures to hazardous substances or
    situations. It is a complex but valuable set of tools for federal
    regulatory agencies to identify issues of potential concern,
    select regulatory options, and estimate the range of a
    forthcoming regulation's benefits. However, given the significant
    yet controversial nature of risk assessments, it is important
    that policymakers understand how they are conducted, the extent
    to which risk estimates produced by different agencies and
    programs are comparable, and the reasons for differences in
    agencies' risk assessment approaches and results. GAO studied the
    human health and safety risk assessment procedures of the
    Environmental Protection Agency, the Food and Drug
    Administration, the Occupational Safety and Health
    Administration, and the Department of Transportation's Research
    and Special Programs Administration. This report identifies and
    describes (1) the agencies' chemical risk assessment activities,
    (2) the agencies primary procedures for conducting risk
    assessments, (3) major assumptions or methodological choices in
    their risk assessment procedures, and (4) the agencies'
    procedures or policies for characterizing the results of risk
    assessments.
    -------------------------Indexing Terms-------------------------
    REPORTNUM:   GAO-01-810
        ACCNO:   A01530
        TITLE:   Chemical Risk Assessment: Selected Federal Agencies'
                 Procedures, Assumptions, and Policies
         DATE:   08/06/2001
      SUBJECT:   Consumer protection
    	     Environmental monitoring
    	     Hazardous substances
    	     Occupational safety
    	     Regulatory agencies
    	     Safety regulation
    	     Safety standards
    	     EPA Integrated Risk Information System

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    GAO-01-810

    A

    Report to Congressional Requesters

    August 2001 CHEMICAL RISK ASSESSMENT

    Selected Federal Agencies? Procedures, Assumptions, and Policies

    GAO- 01- 810

    Letter 7 Results in Brief 9 Background 11 Context for Agencies? Chemical
    Risk Assessments Is Important 18 Agencies? Risk Assessment Procedures Share
    Common Features, But Substantive Differences Also Exist 23

    Agencies? Risk Assessment Procedures Often Include Precautionary Assumptions
    and Methods 30 Risk Characterization Policies and Practices Emphasize
    Transparency 43 Conclusions 46 Agency Comments and Our Evaluation 48

    Appendixes Appendix I: Objectives, Scope, and Methodology 50 Appendix II:
    Chemical Risk Assessment at the Environmental Protection Agency 55

    Context for EPA Chemical Risk Assessment 56 Risk Assessment Procedures 64

    Guidelines 65 Agencywide Risk Assessment Procedures 67

    Hazard Identification 68 Dose- response Assessment 71 Exposure Assessment 79
    Ecological Risk Assessment 81 Program- specific Risk Assessment Procedures
    84

    Office of Pesticide Programs 85 Office of Pollution Prevention and Toxics 90
    Office of Emergency and Remedial Response (Superfund

    Program) 94 Office of Solid Waste 99 Chemical Emergency Preparedness and
    Prevention Office 103 Office of Air and Radiation 107 Office of Water 112
    Risk Assessment Assumptions and Methodological Choices 118 Risk
    Characterization 151

    Appendix III: Chemical Risk Assessment at the Food and Drug Administration
    153 Context for FDA Chemical Risk Assessment 154 Risk Assessment Procedures
    158

    Differences in Risk Assessment Among FDA Product Centers 159 CFSAN Risk
    Assessment Procedures 162

    CVM Risk Assessment Procedures 166 CDRH Risk Assessment Procedures 167 Risk
    Assessment Assumptions and Methodological Choices 170 Risk Characterization
    182

    Appendix IV: Chemical Risk Assessment at the Occupational Safety and Health
    Administration 184 Context for OSHA Chemical Risk Assessment 184 Risk
    Assessment Procedures 186

    General Approach 186 Hazard Identification 187 Dose- response Assessment 188
    Exposure Assessment 193 Risk Assessment Assumptions and Methodological
    Choices 194 Risk Characterization 199

    Appendix V: Chemical Risk Assessment at the Department of Transportation?s
    Research and Special Programs Administration 201

    Context for RSPA Chemical Risk Assessment 201 Risk Assessment Procedures 204

    Guidance 204 Risk Assessment Approach 205

    Identifying Hazards 206 Analyzing the Consequences and Probabilities of
    Risks 212 Risk Assessment Assumptions and Methodological Choices 216 Risk
    Characterization 218

    Glossary 220 Tables Table 1: Comparison of Selected Major Assumptions or
    Methods Used in EPA, FDA, and OSHA Risk Assessments 41

    Table 2: Chemical Risk Statutes, Tasks, and Mandates for EPA Offices 57
    Table 3: EPA?s 1986 Classification System for Characterization of
    Carcinogenicity 68

    Table 4: Summary of EPA?s Ecological Risk Assessment Process 83 Table 5: EPA
    Risk Assessment Assumptions and Methodological

    Choices 120 Table 6: Differences in FDA Chemical Risk Assessment Factors 160
    Table 7: FDA Risk Assessment Assumptions and Methodological

    Choices 171

    Table 8: OSHA Risk Assessment Assumptions and Methodological Choices 194
    Table 9: UN Classification System for Transport of Dangerous

    Goods 207 Table 10: Hazard Classification System of RSPA?s Hazardous

    Materials Regulations 208 Table 11: Example of a Hazardous Materials Risk
    Assessment Matrix 215

    Figures Figure 1: Typical Sequence of Risk Assessment and Risk Management
    Processes 13 Figure 2: Full Toxicity Data Is Available for Only a Small
    Portion of High- Production- Volume Chemicals 15

    Figure 3: Extrapolation for Carcinogens 74 Figure 4: Derivation of a
    Reference Dose Using the Benchmark

    Dose Approach 78

    Abbreviations

    ADI acceptable daily intake AWQC ambient water quality criteria BAF
    bioaccumulation factor BAT best available technology CAA Clean Air Act CAAA
    Clean Air Act Amendments CEPPO Chemical Emergency Preparedness and
    Prevention Office CERCLA Comprehensive Environmental Response, Compensation,
    and

    Liability Act CSFII Continuing Survey of Food Intakes by Individuals CWA
    Clean Water Act DES diethylstilbestrol DOT Department of Transportation ED
    effective dose EPA Environmental Protection Agency EPCRA Emergency Planning
    and Community Right- to- Know Act FAA Federal Aviation Administration FDA
    Food and Drug Administration FDAMA Food and Drug Administration
    Modernization Act FFDCA Federal Food, Drug, and Cosmetic Act FHWA Federal
    Highway Administration FIFRA Federal Insecticide, Fungicide, and Rodenticide
    Act FQPA Food Quality Protection Act FRA Federal Railroad Administration FTA
    Federal Transit Administration GHS globally harmonized system HAZMAT
    hazardous materials HHS Department of Health and Human Services HMIS
    Hazardous Materials Information System HPV high production volume IRIS
    Integrated Risk Information System ISO International Organization for
    Standardization LED lowest effective dose LOAEL lowest observed adverse
    effect level LOEL lowest observed effect level MACT maximum achievable
    control technology MCL maximum contaminant level MCLG maximum contaminant
    level goal MEI maximally exposed individual MLE maximum likelihood estimate

    NAAQS national ambient air quality standards NAS National Academy of
    Sciences NCTR National Center for Toxicological Research NOAEL no observed
    adverse effect level NOEL no observed effect level NRC National Research
    Council OAQPS Office of Air Quality Planning and Standards OAR Office of Air
    and Radiation OERR Office of Emergency and Remedial Response OHMS Office of
    Hazardous Materials Safety OHMT Office of Hazardous Materials Technology OPP
    Office of Pesticide Programs OPPT Office of Pollution Prevention and Toxics
    OPPTS Office of Prevention, Pesticides and Toxic Substances ORD Office of
    Research and Development OSHA Occupational Safety and Health Administration
    OSW Office of Solid Waste OW Office of Water PBPK physiologically based
    pharmacokinetic PEL permissible exposure limit PMN premanufacture
    notification POD point of departure RCRA Resource Conservation and Recovery
    Act RfC reference concentration RfD reference dose RSC relative source
    contribution RSPA Research and Special Programs Administration SAR
    structure- activity relationship SARA Superfund Amendments and
    Reauthorization Act SDWA Safe Drinking Water Act SOPs standard operating
    procedures STEL short- term exposure limit TI tolerable intake TSCA Toxic
    Substances Control Act TWA time- weighted average UCL upper confidence limit
    UN United Nations USCG United States Coast Guard USDA United States
    Department of Agriculture

    Lett er

    August 6, 2001 The Honorable W. J. (Billy) Tauzin Chairman, Committee on
    Energy and Commerce House of Representatives

    The Honorable Paul E. Gillmor Chairman, Subcommittee on Environment

    and Hazardous Materials Committee on Energy and Commerce House of
    Representatives

    As used in public health and environmental regulation, risk assessment is
    the systematic, scientific description of potential adverse effects of
    exposures to hazardous substances or situations. It is a complex but
    valuable set of tools for federal regulatory agencies, helping them to
    identify issues of potential concern, select regulatory options, and
    estimate the range of a forthcoming regulation?s benefits. For example, the

    Environmental Protection Agency (EPA) used risk assessment information in a
    1998 final rule to conclude that disinfection byproducts (e. g., chloroform)
    in drinking water could cause as many as 9, 300 bladder cancer cases a year,
    and that a 24- percent reduction in those byproducts could result in
    monetized health benefits of about $4 billion. 1 However, risk assessments
    are also sometimes controversial, as evidenced by the fact that the
    disinfection byproduct rule was successfully challenged in court over
    whether the agency used the best scientific evidence available in

    support of certain assumptions. 2 Given the significant yet controversial
    nature of risk assessments, it is important that policymakers understand how
    risk assessments are conducted, the extent to which risk estimates produced
    by different agencies and programs are comparable, and the reasons for
    differences in agencies? risk assessment approaches and results.

    1 ?National Primary Drinking Water Regulations: Disinfectants and
    Disinfection Byproducts? (63 FR 69390, Dec. 16, 1998). The Food and Drug
    Administration published a related rule on disinfection byproducts in
    bottled water on March 28, 2001 (66 FR 16858). 2 Chlorine Chemistry Council
    v EPA, 206 F. 3d 1286 (D. C. Cir. 2000). In March 2001, EPA announced that
    it would propose a new assessment for chloroform, the disinfection byproduct
    that was the subject of the dispute, using an approach based upon different
    assumptions.

    You asked us to provide information on selected federal agencies? risk
    assessment procedures and the similarities and differences in how the
    agencies? personnel are directed to conduct risk assessments. As you
    requested, our review focused on the human health and safety (and, to a
    lesser extent, ecological) risk assessment procedures of the following four
    agencies with primary responsibility for regulating or managing risks from
    potential exposure to chemicals: (1) EPA; (2) the Food and Drug
    Administration (FDA) within the Department of Health and Human

    Services (HHS); (3) the Occupational Safety and Health Administration (OSHA)
    within the Department of Labor; and (4) the Department of Transportation?s
    (DOT) Research and Special Programs Administration (RSPA). These agencies
    regularly conduct chemical risk assessments in support of regulatory
    activities and/ or illustrate the diversity of risk

    assessment procedures. Our primary objectives were to identify and describe
    (1) the general context for the agencies? chemical risk assessment
    activities; (2) what the agencies view as their primary procedures for
    conducting risk assessments; (3) what the agencies view as their major

    assumptions or methodological choices in their risk assessment procedures;
    and (4) the agencies? procedures or policies for characterizing the results
    of risk assessments. In addressing each of these objectives, we also
    identified similarities and differences between and within the agencies. To
    the extent feasible, we were also asked to identify as part of the third
    objective, (a) at what stages of the risk assessment process the assumptions
    are used, (b) the reasons given for their selection, (c) their likely
    effects on risk assessment results, and (d) how they compare to the

    assumptions and choices used by other agencies or programs in similar
    circumstances.

    We addressed these objectives by reviewing agencies? general guidance
    documents or, if there were no such documents, specific examples of
    agencies? risk assessment procedures. We also reviewed previous reports on
    agencies? procedures, interviewed agency officials, and provided

    detailed descriptions of the relevant procedures to agency officials for
    their review and comment. Our review focused on chemical risk assessments in
    selected agencies, and therefore did not cover all types of risk assessments
    or even all agencies or programs that conduct chemical risk assessments.
    Also, our review did not evaluate how the selected agencies? procedures and
    policies are applied in individual risk assessments, or how risk assessment
    results are used in making regulatory decisions (risk management). We
    provided a draft of this report to five risk assessment experts to ensure
    technical accuracy. We also provided a draft to officials in each of the
    four agencies for their review and comment. The comments

    that we received from both the experts and the agencies are reflected in the
    ?Agency Comments and Our Evaluation? section of this letter. We conducted
    this review between February 2000 and March 2001 in accordance with
    generally accepted government auditing standards. Details of our scope and
    methodology are presented in appendix I. Results in Brief The context in
    which chemical risk assessments are conducted plays an

    important role in determining what type of assessments federal regulatory
    agencies perform and why certain approaches are used. The statutory and
    legal context determines the general focus and goals of an agency?s risk
    assessment activities and also may shape how risk assessments for those
    activities are supposed to be conducted. The specific tasks and purposes for
    which an agency will use the results of a particular risk assessment
    determine the questions that the assessment needs to address and its scope

    and level of detail. For example, risk assessments used by OSHA to set
    occupational health standards must demonstrate that a significant risk
    exists and that the proposed standard would reduce that risk. However, in
    different contexts, FDA and EPA might use risk assessment procedures to

    estimate the dose of a chemical that people could consume daily without
    harmful effect, and not necessarily need to estimate the actual risk
    associated with exposure to that chemical. In other words, the focus of
    federal agencies? ?risk? assessments can sometimes be characterized more
    accurately as safety assessment (i. e., estimating an exposure level below

    which no significant risk will occur) rather than as risk assessment (i. e.,
    simply describing the likelihood of a risk). All four of the agencies
    included in our review have standard procedures for conducting risk
    assessments involving chemical agents, although the agencies vary in the
    extent to which they have documented their procedures in written guidance.
    There are more similarities than differences in the overall chemical risk
    assessment procedures developed

    by three of the agencies- EPA, FDA, and OSHA. These agencies? procedures
    generally follow four- step process recommended by the National Academy of
    Sciences (NAS) of hazard identification, doseresponse assessment, exposure
    assessment, and risk characterization. However, there are variations both
    among and within the agencies in the details of those steps, particularly
    during the exposure assessment step because agencies? regulatory authorities
    regarding chemical agents tend to vary according to the kinds or sources of
    exposure. The risk assessment procedures in DOT?s RSPA are not based on the
    NAS four- step process because of the particular regulatory context in which
    RSPA operates.

    Instead, a classification system that is harmonized with international
    agreements defines what is to be considered a hazardous material for
    transportation purposes according to the general physical characteristics of
    the material (e. g., whether it is explosive, flammable, or toxic). RSPA?s
    analyses of risks then focus on identifying the potential circumstances
    under which unintentional releases of hazardous materials could occur during
    transit (e. g., due to transportation accidents) and assessing their
    consequences and probability of occurrence.

    Assumptions are an unavoidable part of risk assessment because science
    cannot always provide definitive answers to questions raised at various
    stages of an assessment. Agency guidelines and officials we contacted

    during our review identified a large number and wide variety of assumptions
    that may be used, in the absence of adequate information, during the first
    three steps of a risk assessment. The agencies frequently indicated that
    particular assumptions were chosen on the basis of their

    evaluation of available scientific information, precedents established in
    prior assessments, or policy decisions related to the agencies? regulatory
    missions or mandates. In about half of the assumptions and

    methodological choices identified, the agencies described their likely
    effects on risk assessment results, most commonly (particularly at EPA and
    FDA) indicating that they were precautionary in nature. 3 Agencies use
    precautionary assumptions to ensure that a risk assessment will not
    underestimate risks. Consequently, they have the effect of raising the
    agencies? estimates of risk, compared to less precautionary options, and
    potentially lowering the chemical doses or exposure levels at which agencies
    might take regulatory action. Precautionary assumptions are particularly
    common in the agencies? procedures for initial screening risk assessments,
    when the primary task is to determine whether a risk might exist and more
    detailed analysis is needed. Agency guidelines and related

    documents indicate that subsequent assessments should involve more rigorous
    analyses and fewer precautionary assumptions. There are both similarities
    and differences in the assumptions and methods identified by EPA, FDA, and
    OSHA. RSPA, given its focus on analyzing transportation accident scenarios
    rather than chemical toxicity, uses different 3 These are also referred to
    as ?conservative? or ?public- health conservative? assumptions. For
    consistency, we use the term precautionary throughout this letter. However,
    in the

    technical appendices on individual agencies we use the terms expressed in
    agency documents or by agency officials.

    assumptions and methods because it tends to deal with different analytical
    issues. Both EPA and DOT have written, agencywide risk characterization
    policies that emphasize clear, complete, and transparent disclosure of the
    data, methods, assumptions, and limitations of their risk assessments. The
    policies also encourage agency personnel to characterize their risk
    estimates in terms of ranges or distributions rather than simply providing a
    single point estimate of risks. Both agencies also encourage the use of peer
    review to obtain the views of other scientists and experts on the agencies?
    risk assessments. Although FDA and OSHA do not have written risk

    characterization policies, officials of those agencies said that in practice
    they tend to emphasize comprehensive characterizations of risk assessment
    results, discussions of limitations and uncertainties, and disclosure of the
    data and analytic methodologies on which the agencies relied.

    The complexity and diversity of risk assessment policies, procedures,
    assumptions, and other choices affecting risk estimates underscore the
    importance of transparency in both individual risk assessments and agencies?
    general guidance documents. That transparency is particularly important with
    regard to disclosing why certain data, methods, and default

    assumptions are selected, and under what conditions the agency would depart
    from its default assumptions or methods. Prudent use of risk assessment
    results in formulating public policy requires policymakers to be aware of
    the assumptions and methods used in the preparation of the assessments.

    Background Risk assessments are conducted to estimate whether and/ or how
    much damage or injury can be expected from exposures to a given risk agent
    and

    to assist in determining whether these effects are significant enough to
    require action, such as regulation. The effects of concern can be diseases
    such as cancer, reproductive and genetic abnormalities, workplace injuries,
    or various types of ecosystem damage. The risk agent analyzed in an
    assessment can be any number of things, including chemicals, radiation,
    transportation systems, or a manufacturing process. The product of a risk
    assessment is a quantitative and/ or qualitative statement regarding the

    probability that an exposed population will be harmed and to what degree.
    Risk assessment, particularly quantitative risk assessment, is a relatively
    new discipline, developed in the first half of the 20 th century to
    establish

    various health and safety codes and standards. The role of risk assessment
    in the regulatory process was accelerated by the enactment of various
    health, safety, and environmental statutes in the early 1970s. The
    development of chemical risk assessment procedures has traditionally
    followed two different tracks- one for assessments of cancer risks and

    another for assessments of noncancer risks. The procedures associated with
    cancer risks have historically assumed that there is no ?threshold? below
    which an agent would not cause adverse effects. In contrast,

    procedures for assessments of noncancer risks were largely developed under
    the assumption that there is such a threshold- that exposures up to a
    certain level would not be expected to cause harm.

    In 1983, NAS identified four steps in the risk assessment process: (1)
    hazard identification (determining whether a substance or situation could
    cause adverse effects), (2) dose- response assessment (determining the
    relationship between the magnitude of exposure to a hazard and the
    probability and severity of adverse effects), (3) exposure assessment
    (identifying the extent to which exposure actually occurs), and (4) risk

    characterization (combining the information from the preceding analyses into
    a conclusion about the nature and magnitude of risk). 4 This paradigm,
    originally intended to address assessments of long- term health risks, such
    as cancer, has become a standard model for conducting risk assessments, but
    is not the only model (e. g., different models are used for ecological risk

    assessments). According to NAS, the results of the risk assessment process
    should be conceptually distinguished from how those results are used in the
    risk management process (e. g., the decision on where to establish a
    particular standard). As illustrated by figure 1, the risk management
    decision considers other information in addition to the risk
    characterization.

    4 Risk Assessment in the Federal Government: Managing the Process (commonly
    referred to as the ?Red Book?), National Research Council of the National
    Academy of Sciences (National Academy Press, 1983).

    Figure 1: Typical Sequence of Risk Assessment and Risk Management Processes
    Risk assessment Risk management

    Control Legal

    Dose- response options considerations

    assessment Risk Hazard

    Risk management

    identification characterization

    decisions Exposure

    Other economic assessment

    and social factors Source: EPA Office of Research and Development.

    More recent reports have updated and expanded on these original concepts. In
    1996, NAS urged risk assessors to update the original concept of risk
    characterization as a summary added at the end of a risk assessment. 5
    Instead, the report suggested that risk characterization should be a
    ?decision- driven? activity directed toward informing choices and solving
    problems and one that involves decision makers and other stakeholders from
    the very inception of a risk assessment. In this updated

    view, the nature and goals of risk characterization are dictated by the
    goals of the risk management decisions to be made. Similarly, the
    Presidential/ Congressional Commission on Risk Assessment and Risk
    Management (hereinafter referred to as the Presidential/ Congressional
    Commission) recommended in 1997 that the performance of risk assessments be
    guided by an understanding of the issues that will be important to risk
    management decisions and to the public?s understanding of what is needed to
    protect public health and the environment. 6

    5 Understanding Risk: Informing Decisions in a Democratic Society, National
    Research Council of the National Academy of Sciences (National Academy
    Press, 1996). 6 Risk Assessment and Risk Management in Regulatory Decision-
    Making, The Presidential/ Congressional Commission on Risk Assessment and
    Risk Management, (Final Report, Volume 2, 1997).

    Data on Chemical Health Substantial numbers and amounts of chemical
    substances and mixtures are

    Effects and Exposures Are produced, imported, and used in the United States.
    For example, there are

    Limited over 70, 000 commercial chemicals in EPA?s Toxic Substances Control
    Act (TSCA) Chemical Substances Inventory, and the agency receives about
    1,500 petitions each year requesting the approval of new chemicals or new

    uses of existing chemicals. 7 However, there is relatively little empirical
    data available on the toxicity of most chemicals and the extent to which
    people or the environment might be exposed to the chemicals. For example, we
    previously reported that EPA?s Integrated Risk Information System (IRIS),
    which is a database of the agency?s consensus on the potential health
    effects of chronic exposure to various substances found in the environment,
    lacks basic data on the toxicity of about two- thirds of

    known hazardous air pollutants. 8 Furthermore, to the extent that data on
    health effects are available, the data are more often from toxicological
    studies involving animal exposures than from epidemiological studies
    involving human exposures. As a consequence, chemical risk assessments must
    rely often on extrapolation from animal studies and are quite different from
    risk assessments that use epidemiological studies or actuarial data (such as
    accident statistics). 7 Excluding polymers (which are considered unlikely to
    present significant risk concerns), EPA?s TSCA inventory identified about
    15, 000 chemicals produced or imported at levels above 10, 000 pounds per
    year. There are also other categories of chemical substances (such

    as drugs, cosmetics, food additives, and pesticides) that are exempt from
    TSCA but subject to control under other federal statutes. The number of
    chemicals actually in commerce varies as new chemicals are added and other
    chemicals are withdrawn. 8 Major Management Challenges and Program Risks:
    Environmental Protection Agency (GAO/ OCG- 99- 17, Jan. 1999).

    The limited nature of information on chemical toxicity was illustrated in a
    1998 EPA report on the data that were publicly available on approximately
    3,000 high- production- volume (HPV) chemicals. 9 For each of these
    chemicals, EPA examined the available data corresponding to six basic tests
    that have been internationally agreed to as necessary for a minimum
    understanding of a chemical?s toxicity. 10 As shown in figure 2, the agency
    concluded that the full set of basic toxicity data was available for only

    about 200 (7 percent) of the chemicals, and that 43 percent of the chemicals
    did not have publicly available data for any of the six tests.

    Figure 2: Full Toxicity Data Is Available for Only a Small Portion of High-
    Production- Volume Chemicals

    7% Have all six of basic tests for

    minimum understanding of toxicity per the international Screening
    Information Data Set

    50% 43% Are missing all of these tests

    Have one to five of these tests N= 2863 HPV chemicals Source: EPA, Chemical
    Hazard Data Availability Study: What Do We Really Know About the Safety of
    High Production Volume Chemicals? (April 1998).

    9 High- production- volume chemicals are those imported or produced at
    volumes of more than 1 million pounds per year. Note that, for regulatory
    approval purposes, some offices within EPA have access to confidential
    business information on commercial chemicals and pesticides that would not
    be reflected in this study of ?publicly available? toxicity data. 10 The six
    tests are acute toxicity, chronic toxicity, developmental/ reproductive
    toxicity, mutagenicity, ecotoxicity, and environmental fate. Collectively,
    these tests are known as the Screening Information Data Set program.

    There are also significant gaps in the available data on the extent to which
    people are exposed to chemicals. For example, last year we reviewed federal
    and state efforts to collect human exposure data on more than 1, 400

    naturally occurring and manmade chemicals considered by HHS, EPA, and other
    entities to pose a threat to human health. 11 We reported that, taken
    together, HHS and EPA surveys measured the degree of exposure in the

    general population for only 6 percent of those chemicals. Even for those
    chemicals that were measured, information was often insufficient to identify
    smaller population groups at high risk (e. g., women, children, and the
    elderly). Uncertainty Contributes to

    There is an ongoing debate about the appropriate application of risk
    Controversy about

    assessment in federal regulation. In 1990, Congress mandated that a Chemical
    Risk Assessment commission be formed to ?make a full investigation of the
    policy implications and appropriate uses of risk assessment and risk
    management in regulatory programs under various Federal laws to prevent
    cancer and

    other chronic human health effects which may result from exposure to
    hazardous substances.? The Presidential/ Congressional Commission published
    its final report in 1997, and noted that often ?the controversy arises from
    what we don?t know and from what risk assessments can?t tell us.? 12 NAS has
    also emphasized that science cannot always provide

    definitive answers to questions raised during the course of conducting a
    risk assessment, so risk assessors must use assumptions throughout the
    process that reflect professional judgments and policy choices. 13

    11 Toxic Chemicals: Long- Term Coordinated Strategy Needed to Measure
    Exposures in Humans (GAO/ HEHS- 00- 80, May 2, 2000). See also Environmental
    Information: EPA Needs Better Information to Manage Risks and Measure
    Results (GAO- 01- 97T, Oct. 3, 2000). 12 Framework for Environmental Health
    Risk Management, The Presidential/ Congressional Commission on Risk
    Assessment and Risk Management, (Final Report, Volume 1, 1997), p. 23.

    13 See Risk Assessment in the Federal Government: Managing the Process
    (1983) and Science and Judgment in Risk Assessment (1994).

    One focus of the risk assessment debate has been agencies? use of
    precautionary assumptions and analytical methods. The term

    ?precautionary? refers to the use of methods and assumptions that are
    intended to produce estimates that should not underestimate actual risks.
    Some critics of federal risk assessment practices believe agencies use

    assumptions that are unjustifiably precautionary in the face of new
    scientific data and methods, thereby producing estimates that overstate
    actual risks. The critics contend that this effect is compounded when
    multiple precautionary assumptions are used. Others, however, criticize

    agency practices for not being precautionary enough in the face of
    scientific uncertainties, failing, for example, to adequately account for
    the synergism of exposures to multiple chemicals or the risks to persons
    most exposed or most sensitive to a particular toxic agent. 14 Other
    observers, including NAS, have expressed concerns about whether the
    agencies? procedures and assumptions are sufficiently transparent, thereby
    providing decision makers and the public with adequate information about the
    scientific and policy bases for agencies? risk estimates as well as the
    limitations and uncertainties associated with those estimates.

    14 Proposals have been introduced in Congress regarding this issue. For
    example, H. R. 199, proposed in the 106 th Congress, would have required the
    EPA Administrator to evaluate, among other things, environmental health
    risks to vulnerable subpopulations (e. g., children, pregnant women, and the
    elderly) and to ensure that all EPA standards protect such subpopulations
    with an adequate margin of safety.

    We have discussed these issues in several previous reports. For example, in
    1993, we noted that EPA used precautionary assumptions throughout the
    process that it used to assess risk at Superfund hazardous waste sites, and
    that the agency had been criticized for overstating risk by combining
    precautionary estimates. 15 In September 2000, we reported on EPA?s use of
    precautionary ?safety factors? pursuant to the Food Quality Protection Act
    of 1996. 16 In October 2000, we said that three factors influenced EPA?s use

    of precautionary assumptions in assessing health risks: (1) the agency?s
    mission to protect human health and safeguard the natural environment, (2)
    the nature and extent of relevant data (e. g., animal versus human studies),
    and (3) the nature of the health risk being evaluated (e. g., cancer versus
    noncancer risks). 17 Context for Agencies? The context in which chemical
    risk assessments are conducted plays an

    Chemical Risk important role in determining what type of assessments federal
    regulatory agencies perform and why certain approaches are used. Two
    dimensions Assessments Is

    seem particularly important to understanding the context for an agency?s
    Important

    chemical risk assessment activities: (1) the general statutory and legal
    framework underlying the agency?s regulation of chemicals and (2) how the
    agency plans to use the risk assessment information. 18 The statutory and
    legal framework determines the general focus and goals of an agency?s
    chemical risk assessment activities and also can shape how risk assessments
    for those activities are supposed to be conducted. The specific tasks and
    purposes for which an agency will use the results of a particular risk
    assessment determine the questions that the assessment needs to address and
    the scope and level of detail of the assessment.

    15 Superfund: Risk Assessment Process and Issues (GAO/ T- RCED- 93- 74,
    Sept. 30, 1993). 16 Children and Pesticides: New Approach to Considering
    Risk Is Partly in Place (GAO/ HEHS- 00- 175, Sept. 11, 2000).

    17 Environmental Protection Agency: Use of Precautionary Assumptions in
    Health Risk Assessments and Benefits Estimates (GAO- 01- 55, Oct. 16, 2000).
    18 Other contextual factors, such as the data limitations and scientific
    uncertainty, are also important. On a practical level, the availability of
    resources (e. g., staff, schedule, funding, data) also affects the scope and
    level of detail that an agency can provide in any given risk assessment.
    However, such factors are either so broadly applicable or so case specific
    that they do not distinctively characterize the risk assessment procedures
    of an agency or program.

    Statutory and Legal A diverse set of statutes addresses potential health,
    safety, and Framework

    environmental risks associated with chemical agents. These statutory
    mandates generally focus on different types and sources of exposure to
    chemicals, such as consumption of pesticide residues in foods, occupational
    exposures to chemicals, or inhalation of toxic air pollutants. Therefore,
    different agencies (and different offices within those agencies)

    have distinctive concerns regarding chemical risks. For example, each major
    program office within EPA (e. g., the Office of Air and Radiation or the
    Office of Water) is responsible for addressing the risk- related mandates of
    one or more statutes (e. g., the Clean Air Act, the Clean Water Act, or the
    Safe Drinking Water Act). Also, international agreements provide

    important legal context for transportation risk assessment activities. For
    example, criteria for classifying dangerous chemicals in transportation have
    been internationally harmonized through the United Nations? Recommendations
    on the Transport of Dangerous Goods.

    The legal framework underlying chemical regulation influences both the
    extent to which risk assessment is needed for regulatory decision making and
    how risk assessments are supposed to be conducted. Some statutes require
    regulatory decisions to be based solely on risk (considering only

    health and environmental effects), some require technology- based standards
    (such as requiring use of the best available control technology), and still
    others require risk balancing (requiring consideration of risks, costs, and
    benefits). For example, section 112 of the Clean Air Act (CAA), as amended,
    has a technology- based mandate requiring the use of the

    maximum achievable control technology to control emissions of hazardous air
    pollutants. A risk assessment is not needed to determine such technology,
    but would be used to evaluate residual risks that remain after that
    technology is in use. Some statutes also place the primary responsibility
    for conducting risk assessments and compiling risk- related data for a
    particular chemical or source of exposure to chemical agents with industry,
    states, or local entities, rather than with the federal regulatory agencies.
    For example, industry petitioners have the primary

    responsibility to provide the data needed to support registration and
    tolerances from EPA for their pesticides, including information on the
    toxicological effects of the pesticides. 19

    19 Registration involves the licensing of pesticides for sale and use in
    agriculture and extermination. No chemical may be sold in the United States
    as a pesticide without such registration, which establishes the conditions
    of legal use. Pesticide tolerances are the

    concentrations permitted to remain in or on food, as it is available to the
    consumer.

    Statutes can also affect risk assessment by specifically defining what will
    be considered a hazard, directing the agency to take certain methodological
    steps, or specifying the exposure scenario of regulatory concern. For
    example, in response to the ?Delaney Clause? amendments to the Federal Food,
    Drug, and Cosmetic Act, FDA identifies any food additive

    for which an adequately conducted animal cancer study indicates that the
    additive produces cancer in animals as a carcinogen under the conditions of
    the study. No further corroboration or weight- of- evidence analysis is
    required. The Food Quality Protection Act of 1996 requires EPA to add an
    additional 10- fold safety factor to protect infants and children when
    deriving standards for allowable pesticide residues in foods, unless
    reliable data show that a different factor will be safe. Provisions in the

    Occupational Safety and Health Act focus OSHA?s risk assessments on
    estimating the risks to workers exposed to an agent for a working lifetime.
    However, in most cases the statutes simply provide a general framework
    within which the agencies make specific risk assessment assumptions and
    methodological choices. For example, section 109 of the CAA requires EPA to
    set national ambient air quality standards that in the judgment of the EPA
    Administrator- and allowing for an ?ample margin of safety?- are

    requisite to protect the public health. 20 EPA risk assessors translate that
    general requirement into specific risk assessment assumptions and methods
    (e. g., whether to assume a threshold or no- threshold relationship between
    dose and response at low doses).

    Use of Risk Assessment The specific purpose or task of an assessment
    determines the kinds of risk Results information needed for the agency to
    make its risk management decisions, and can significantly influence the
    scope and level of detail required of a risk assessment. For example,

     If the agency?s task is to set a specific health- based standard (e. g., a
    national air quality standard), a rigorous and detailed estimate of risks at
    particular exposure levels might be required.

     If the agency?s task is to decide whether to approve the production and
    use of commercial chemicals or pesticides, risk assessors may initially
    focus on potential upper- bound exposures (e. g., assuming that a chemical
    agent will be used at the maximum level permitted by law or

    20 An ambient air quality standard is a national target for an acceptable
    concentration of a specific pollutant in air.

    focusing on individuals who consume the greatest amounts of a food
    containing residues of the agent at issue). If such upper- bound estimates
    exhibit no cause for concern, the agency may have no need to complete a more
    comprehensive and refined risk assessment.

     A decision on whether to add or remove a chemical from the list of
    potential hazards might focus the risk assessors on determining whether the
    potential risk is above or below a specific threshold level, such as the
    risk of 1 extra cancer case over the lifetime of 1 million people.

    The influence of the specific regulatory task at hand is illustrated by a
    method commonly used by agencies for risk assessments of noncancer health
    effects. Agencies such as EPA and FDA have historically attempted to
    identify a dose level of a chemical associated with no observed adverse
    effect level (NOAEL) in animal experiments- or the lowest observed

    adverse effect level (LOAEL) in the study, if every tested dose exhibited
    some effect. 21 They then divided that NOAEL or LOAEL dose by multiple
    ?safety? or ?uncertainty? factors to account for the possibility that humans

    may be more sensitive to the chemical than animals and other uncertainties.
    This procedure is designed to identify a dose not likely to result in harm
    to humans, not to provide an explicit quantitative estimate of the risks
    associated with a given chemical. In other words, sometimes the focus of
    federal agencies? ?risk? assessments could more accurately be described as a
    safety assessment (i. e., estimating a ?safe? level of exposure to chemical
    agents or a dose below which no significant risk is expected to occur)
    rather than a risk assessment (i. e., estimating the actual risks associated
    with exposures to chemical agents).

    Implications of Contextual Because of contextual differences, the risk
    assessment procedures used, Differences

    the resulting risk estimates (and regulatory actions based upon those
    estimates), and even whether a substance would be subject to risk
    assessment, can vary among different agencies and programs within the same
    agency. The following examples illustrate how contextual differences affect
    the conduct of risk assessments.

     Because regulation of certain wastes may be impractical or otherwise
    undesirable, regardless of the hazards that the waste might pose, 21 FDA
    often determines a no observed effects level (NOEL) rather than a NOAEL
    because

    many significantly altered, standard toxicological endpoints are assumed to
    be adverse to animals and/ or humans even in the absence of data affirming
    that assumption.

    Congress and EPA exempted certain materials (e. g., agricultural or mining
    and mineral processing wastes) from the definitions of hazardous wastes. If
    a material meets one of the categories of exemptions, it cannot be
    identified as a hazardous waste even if it otherwise meets the criteria for
    listing as a hazardous waste. For example, according to EPA?s RCRA
    Orientation Manual, wastes generated in raw material, product storage, or
    process (e. g., manufacturing) units are exempt from EPA?s hazardous waste
    regulation while the waste remains in such units. However, OSHA might assess
    and regulate risks associated with such materials as part of its mission

    to protect the health of employees in the workplace.

     FDA and EPA both assess potential human health risks associated with
    ingestion of chemical substances. If a substance is being assessed by FDA as
    a food additive and results from any adequate study indicate that the
    substance produces cancer in animals, FDA labels that additive as a
    carcinogen without considering other scientific evidence (per the Delaney
    clause of the Federal Food, Drug, and Cosmetic Act, as

    amended). However, when assessing the risks associated with consumption of
    residues from animal drugs (FDA) and pesticides (EPA) the agencies may need
    to consider many scientific studies in determining whether and under what
    conditions an agent might cause cancer or other adverse health effects in
    humans.

     EPA?s risk assessments of commercial chemicals under TSCA vary depending
    on whether the chemical at issue is ?existing? or ?new.? For EPA to control
    the use of an existing chemical, the agency must make a

    legal finding that the chemical will present an unreasonable risk to human
    health or the environment. EPA said this standard requires the agency to
    have conclusive data on risks associated with that particular chemical. By
    comparison, newly introduced chemicals can be regulated

    based on whether they may pose an unreasonable risk, and this finding of
    risk can be based on data for structurally similar chemicals, not just data
    on that particular chemical. Because industrial chemicals in commerce were
    ?grandfathered? under TSCA into the inventory of existing chemicals more
    than 20 years ago, without considering whether they were hazardous, there
    are situations in which existing chemicals might not be controlled while, at
    the same time, EPA would act to control a new chemical of similar or less
    toxicity.

     Within EPA?s Office of Water, risk assessments vary depending on whether
    the assessment is done to establish drinking water standards or standards
    for ambient water (e. g., bodies of water such as lakes and rivers). Risk
    assessments for drinking water standards focus solely on human health
    effects, but assessments used to establish ambient water

    quality criteria consider both human health and ecological effects. Even
    when considering just the human health risks, an important difference
    between the ambient and drinking water risk assessments is an additional
    focus for ambient water on exposures to contaminated water through
    consumption of contaminated fish or shellfish. This additional factor is a
    primary reason for potential differences in drinking water and ambient water
    risk estimates and standards for the same chemical.

    Appendices II through V describe the relevant contextual factors for each of
    the four selected agencies in greater detail.

    Agencies? Risk All four of the agencies included in our review have standard
    procedures

    Assessment for conducting risk assessments, although the agencies vary in
    the extent to which their procedures are documented in written guidance. In
    general, Procedures Share there are more similarities than differences
    across EPA, FDA, and OSHA

    Common Features, But procedures, because each of these agencies generally
    follows the four- step Substantive

    NAS risk assessment process. The procedures address the same basic questions
    regarding hazard identification, dose- response assessment, and

    Differences Also Exist exposure assessment. The specific analytical methods
    and approaches in those procedures are also very similar (e. g.,
    extrapolating from animal study data to model dose- response relationships
    in humans, and generally

    using different procedures for assessing cancer and noncancer risks). The
    most substantive differences across and within these agencies are related to
    exposure assessment, reflecting the diversity in the agencies? regulatory
    authorities regarding chemical agents across different kinds or sources of

    exposure. For example, both OSHA and EPA consider methylene chloride (also
    known as dichloromethane) to be a probable human carcinogen. However, this
    same chemical can be identified as a significant hazard by one agency in one
    exposure setting (OSHA for purposes of assessing health risks associated
    with occupational exposures) but as a low hazard by another agency in a
    different setting (EPA for purposes of Superfund

    hazard ranking screening). 22 RSPA, although sharing a concern over
    identifying risks and analyzing their consequences and probabilities of 22
    EPA has taken other actions regarding exposures to methylene chloride. For
    example, EPA requires that releases of methylene chloride of 1,000 pounds or
    more be reported to the federal government. EPA also has guidelines on how
    much of this chemical people can be exposed to without harming their health
    (e. g., EPA recommends that children not drink water that contains more than
    13. 3 parts of methylene chloride per million parts of water for longer than
    1 day or with more than 1.5 parts per million for longer than 10 days).

    occurrence, has a different structure to its risk assessments than the other
    three agencies because of its focus on risks associated with unintentional
    releases of hazardous materials during transportation. In general, all four
    agencies are incorporating more complex analytical models and methods into
    their risk assessment procedures. However, some of the advanced models
    require much more detailed information than may be currently available for
    many chemicals.

    Risk Assessment EPA has extensive written internal risk assessment
    procedures. For Procedures at EPA

    example, EPA has agencywide guidelines, policy memoranda, and handbooks
    covering the following aspects of risk assessment:

     carcinogen risk assessment,

     neurotoxicity risk assessment,

     reproductive toxicity risk assessment,

     developmental toxicity risk assessment,

     mutagenicity risk assessment,

     health risk assessment of chemical mixtures,

     exposure assessment,

     ecological risk assessment,

     evaluating risk to children,

     use of probabilistic analysis in risk assessment,

     use of the benchmark dose approach in health risk assessment, and

     use of reference dose and reference concentration in health risk
    assessment. EPA also has numerous program- specific guidelines and policy
    documents, such as the Risk Assessment Guidance for Superfund series and a
    set of more than 20 science policy papers and guidelines from the Office of
    Pesticide Programs in response to the Food Quality Protection Act of 1996.
    Many of the agency?s guidance documents are draft revisions to earlier

    documents or procedures or draft guidance on new issues that have not
    previously been addressed by EPA. Although such drafts are not yet final,
    official statements of agency policies or procedures, they may better
    represent the current practice of risk assessment in EPA than earlier
    ?final? documents.

    EPA generally follows the NAS four- step risk assessment process. (The major
    exception is the agency?s Chemical Emergency Preparedness and Prevention
    Office, which follows a different set of procedures because of its focus on
    risks associated with accidental chemical releases from fixed facilities.
    See app. II for a discussion of this office?s risk assessment procedures.)
    EPA?s risk assessment activities generally involve both the program offices
    (e. g., the Office of Air and Radiation or the Office of Solid Waste) and
    the Office of Research and Development (ORD), which is the principal
    scientific and research arm of the agency. ORD often does risk assessment
    work for EPA program offices that focuses on the first two steps in the
    four- step NAS process- hazard identification and doseresponse

    assessment- in particular, the development of ?risk per unit exposed?
    numbers. 23 Preparation of the final two steps in the process- exposure
    assessment and risk characterization- tends to be the responsibility of the
    relevant program offices. Several programs, for example, frequently use a
    single hazard assessment, but for different exposure scenarios. There are,
    however, exceptions to this generalization.

    For example, ORD carries out all steps for highly complex, precedentsetting
    risk assessments, such as those for dioxin and mercury. There are also
    instances when EPA program offices carry out all four steps of the process.
    In some situations, EPA agencywide procedures also depart slightly from the
    NAS paradigm. For example, when assessing noncancer health effects, EPA?s
    normal practice is to do hazard identification in conjunction with the
    analysis of dose- response relationships, rather than as distinct steps.
    According to EPA?s guidelines, this is because the

    determination of a hazard is often dependent on whether a dose- response
    relationship is present. In the case of ecological risk assessments, EPA?s
    guidelines suggest a three- step process consisting of (1) problem
    formulation, (2) analysis, and (3) risk characterization, rather than the
    fourstep process used for health risk assessments.

    23 ORD also manages EPA?s IRIS database that contains agency- consensus
    information on human health effects that may result from exposure to various
    chemicals in the environment.

    EPA has identified several new directions in its approach to exposure
    assessment. First is an increased emphasis on total (aggregate) exposure to
    a particular agent via all pathways. EPA policy directs all regulatory
    programs to consider in their risk assessments exposures to an agent from

    all sources, direct and indirect, and not just from the source that is
    subject to regulation by the office doing the analysis. 24 Another area of
    growing attention is the consideration of cumulative risks, when individuals
    are exposed to many chemicals at the same time. The agency is also
    increasing its use of probabilistic modeling methods to analyze variability
    and

    uncertainty in risk assessments and provide better estimates of the range of
    exposure, dose, and risk to individuals in a population than are provided by
    single point estimates. EPA?s guidance on probabilistic methods outlines
    standards that exposure data prepared by industry or other external analysts
    must meet to be accepted by EPA.

    Risk Assessment FDA and OSHA also generally follow the NAS risk assessment
    paradigm,

    Procedures at FDA and but neither FDA nor OSHA had written internal guidance
    specifically on OSHA

    conducting risk assessments at the time of our review. However, both
    agencies? standard procedures are well documented in the records of actual
    risk assessments and in summary descriptions that have appeared in
    scientific and professional literature. In addition, FDA has published
    volumes of guidance on risk assessments for use by external parties affected
    by the agency?s regulations (e. g., animal drug manufacturers seeking FDA
    approval for their products). According to FDA officials, the

    documents are meant to represent the agency?s current thinking on the
    scientific data and studies considered appropriate for assessing the safety
    of a product, and sometimes include detailed descriptions of the risk
    assessment methods deemed appropriate to satisfy FDA?s requirements under
    various statutory provisions. However, these guidelines do not preclude the
    use of alternative procedures by either FDA or external parties.

    The responsibility for conducting risk assessments in FDA is divided among
    the agency?s program offices. For example, FDA?s Center for Food

    24 The Presidential/ Congressional Commission noted that, traditionally,
    risk assessments have largely focused on assessing the risks of just one
    chemical in one medium at a time. Although some EPA offices, such as the
    Office of Pesticide Programs and Office of Water, conduct more comprehensive
    risk assessments, the Commission pointed out that few other regulatory
    agencies consider exposures or risks comprehensively, and EPA often does not
    do so because of resource or statutory limitations.

    Safety and Applied Nutrition (CFSAN) is responsible for assessing risks
    posed by food additives and contaminants, while the Center for Veterinary
    Medicine (CVM) is responsible for assessing risks posed by animal drug
    residues in food. In addition, FDA?s National Center for Toxicological
    Research conducts scientific research to support the agency?s regulatory
    needs, including research aimed at understanding the mechanisms of toxicity
    and carcinogenicity and at developing and improving risk assessment methods.
    FDA officials said that there are variations in the risk

    assessment approaches used among the agency?s different product centers and,
    in some cases, within those centers. In general, those variations are
    traceable to differences in factors such as the substances being regulated,
    the nature of the health risks involved (particularly carcinogens versus
    noncarcinogens), and whether the risk assessment is part of the process to
    review and approve a product before it can be marketed and used

    (premarket) or part of the process of monitoring risks that arise after a
    product is being used (postmarket). For example, risk assessments by CFSAN?s
    Office of Food Additive Safety and Office of Nutritional Products, Labeling
    and Dietary Supplements are mandatory for new dietary ingredients (and are
    used for premarket review of such ingredients) but discretionary for other
    food (and are associated with postmarket review). A unique characteristic of
    the hazard identification phase of risk assessment in FDA is that, by
    statute, if there is an adequate study that indicates a food additive can
    cause cancer in animals, that additive is labeled as a carcinogen under the
    conditions of the study. No additional

    corroboration or weight- of- evidence analysis is required in such cases,
    and there is no need to complete the other three risk assessment steps
    before proceeding to a regulatory decision. FDA?s CVM is permitted to allow
    the use of carcinogenic drugs in food- producing animals under the DES
    proviso of the Federal Food, Drug, and Cosmetic Act, as amended, provided
    that ?no residue of such drug will be found.?

    OSHA?s Directorate of Health Standards Programs is primarily responsible for
    conducting the agency?s chemical risk assessments. Such assessments focus
    specifically on the potential risks to workers associated with exposures to
    chemicals in an occupational setting. In contrast to agencies regulating
    environmental exposures to toxic substances, OSHA frequently has relevant
    human data available on occupational exposures. Even when the agency
    assesses risks based on animal data, OSHA said that the workplace exposures
    of concern are often not far removed from levels tested in the animal
    studies. Therefore, OSHA?s risk assessments do not extrapolate as far beyond
    the range of observed toxicity as might be

    necessary to characterize environmental exposure risks. OSHA?s risk
    assessment procedures have also evolved to consider data from advanced
    physiologically based pharmacokinetic (PBPK) models on the relationship
    between administered doses and effective doses (i. e., the amounts that
    actually reach a target organ or tissue). 25 However, PBPK models are

    complicated and require substantial data, which may not be available for
    most chemicals. OSHA therefore developed a set of 11 criteria to judge
    whether available data are adequate to permit the agency to rely on PBPK
    analysis in place of administered exposure levels when estimating human
    equivalent doses.

    25 Pharmacokinetics is the study of the absorption, distribution,
    metabolism, and elimination of chemicals in humans and animals. It is the
    basis for developing what are believed to be more realistic and accurate
    models of the movement and interactions of a chemical with blood, tissues,
    and organs once it enters the body, including consideration of the body?s

    ability to repair damage caused by a chemical.

    Risk Assessment The applicable risk assessment guidance for RSPA is
    generally documented

    Procedures at RSPA within broader DOT- wide guidance on conducting
    regulatory analyses and also in materials describing the agency?s Hazardous
    Materials Safety Program. Because of the particular regulatory context in
    which it operates,

    RSPA does not apply the NAS four- step paradigm for risk assessment used by
    EPA, FDA, and OSHA. RSPA is primarily concerned with potential risks
    associated with the transportation of hazardous materials. In particular, it
    is concerned with short- term or acute health risks due to relatively high
    exposures from unintentional release of hazardous materials. For its
    purposes, RSPA identifies chemicals as hazardous materials according to a
    regulatory classification system that is harmonized with internationally
    recognized criteria and EPA- defined hazardous substances. This
    classification system defines the type of hazard associated with a given

    material according to chemical, physical, or nuclear properties (e. g.,
    whether it is an explosive, a flammable liquid, or a poisonous substance)
    that can make it dangerous in or near transporting conveyances.

    Therefore, a chemical?s toxicity is only one of its characteristics of
    concern to RSPA, rather than being the primary focus of analysis as in
    assessments of the other three agencies. The risk analyses by RSPA focus on
    identifying the potential circumstances under which unintentional releases
    of hazardous materials could occur during transit (e. g., due to
    transportation accidents) and assessing their consequences and probability
    of occurrence. Analysis of different modes (e. g., via truck, rail, or
    aircraft) and routes of transportation is an important component of RSPA?s
    consequence and

    probability analyses. 26 Through DOT databases, directly relevant data on
    the incidence and severity of hazardous materials transportation accidents
    are available to assist RSPA in identifying and analyzing hazard scenarios.
    Appendices II through V provide more detailed descriptions of the standard
    procedures for chemical risk assessments in each of the four selected
    agencies.

    26 Assessment and regulation of risks associated with substances transported
    by bulk marine carriers are the responsibility of the United States Coast
    Guard.

    Agencies? Risk Assumptions and methodological choices are an integral and
    inescapable

    Assessment part of risk assessment. They are often intended to address
    uncertainty in the absence of adequate scientific data. However, those
    assumptions and

    Procedures Often methods may also reflect policy choices, such as how to
    address variability Include Precautionary in exposures and effects among
    different individuals and populations, or

    Assumptions and particular contextual requirements. To the extent that the
    four agencies identified the specific reasons for selecting their major
    assumptions or Methods

    methods, they most often attributed their choices to an evaluation of
    available scientific data, the precedents established in prior risk
    assessments, or policy decisions related to their regulatory missions.
    Agencies? statements regarding the likely effects of their preferred
    assumptions and methods most often addressed the extent to which the default
    options would be considered precautionary. Some of the major assumptions and
    methodological choices of EPA, FDA, and OSHA address similar issues and
    circumstances during the risk assessment process, especially regarding
    assessment of a chemical?s toxicity.

    Agencies? Assumptions and Agency procedural guidelines and officials we
    contacted during our review

    Methodological Choices identified a large number and wide variety of major
    assumptions and

    Vary methodological choices that they might use when conducting chemical
    risk assessments, in the absence of information that would indicate the
    particular assumption or method is not valid in a given case. Some of these

    assumptions and methodological choices were very broad (e. g., the common
    assumption that, in the absence of evidence to the contrary, substances that
    produce adverse health effects in experimental animals

    pose a potential threat to humans). Other assumptions and choices were more
    specific, covering particular details in the analytical process (e. g.,
    identifying the preferred options for extrapolating high dose- response
    relationships to low doses). EPA and OSHA identified some of their choices

    as the default assumptions and methods of their agencies. FDA officials said
    that their agency does not require the use of specific default assumptions
    or risk assessment methods, but there are assumptions and methods that
    typically have been used as standard choices in FDA risk assessments.
    Although assumptions are also needed in RSPA?s risk assessments, RSPA
    officials said that they do not have any default assumptions. Instead, they
    said that their assumptions are specific to, and must be developed as part
    of, each risk assessment. Appendices II through V present detailed
    information on some of what the agencies identified as their major
    assumptions and methodological choices

    in chemical risk assessments. The tables illustrate both the number and
    variety of assumptions that agencies may use when conducting those
    assessments.

    The following sections summarize information that was available from the
    four agencies? procedures and related documents on (a) when the agencies
    employ major assumptions and methods, (b) their reasons for selecting these
    options, (c) the likely effects on risk assessment results of these options,
    and (d) how they compare to the assumptions and choices used by

    other agencies or programs in similar circumstances. In some cases the
    agencies? documents did not contain this information, but there is no
    requirement that the agencies do so. Also, the reason for using a particular
    assumption and its effect on risk assessment results can vary on a case-
    bycase basis, and therefore might not be addressed in general risk
    assessment guidance. Nevertheless, both NAS and the Presidential/
    Congressional Commission recommended greater transparency regarding the
    procedures,

    assumptions, and results of agencies? risk assessments. Also, as will be
    discussed more fully later in this report, the agencies? own risk
    characterization policies and practices emphasize the value of such
    transparency in communicating information about risk assessment procedures
    and results. Recent regulatory reform proposals considered by Congress have
    had provisions requiring transparency in the use of assumptions. 27

    When Assumptions and As previously mentioned, NAS and the Presidential/
    Congressional Methods Are Used

    Commission have both emphasized that science cannot always provide
    definitive answers to questions raised during a risk assessment. For
    example, in 1983, NAS identified at least 50 points during the course of a
    cancer risk assessment when choices had to be made on the basis of
    professional judgment, not science. EPA?s guidelines similarly point out
    that, because there is no instance in which a set of data on an agent or
    exposure is complete, all risk assessments must use general knowledge and
    policy guidance to bridge data gaps. Except in the case of RSPA, default or
    standard assumptions and methods may be used by agencies to

    27 For example, S. 746, proposed in the 106 th Congress, provided that when
    a risk assessment involves a choice of assumptions the agency must (1)
    identify significant assumptions and their scientific and policy bases, (2)
    explain the basis for any choices among assumptions, and (3) describe
    reasonable alternative assumptions not selected that would have had a
    significant effect on the results of the assessment.

    address these gaps in knowledge, and to encourage consistency in the efforts
    of agencies? risk assessors to address such basic issues as:

     uncertainty in the underlying data, model parameters, or state of
    scientific understanding of how exposure to a particular chemical could lead
    to adverse effects;

     variability in the potential extent of exposure and probability of adverse
    effects for various subgroups or individuals within the general population;
    28 and

     statutory requirements (and the related general agency missions) to be
    protective of public health and the environment (e. g., to set standards
    with ?an adequate margin of safety?).

    However, agency risk assessors have considerable flexibility regarding
    whether to use particular assumptions and methods, even when the agency has
    default or standard options. For example, EPA stated that its revised
    guidelines for carcinogen risk assessment were intended to be both explicit
    and more flexible than in the past concerning the basis for making
    departures from defaults, recognizing that expert judgment and peer review
    are essential elements of the process. The Executive Director of ORD?s Risk
    Assessment Forum pointed out that, although EPA?s guidelines always
    permitted such flexibility, without detailed guidance on departing from
    default assumptions there had been a tendency for analysts to not do so. He
    also stated that when determining whether to use a default, the decision
    maker must consider available information on an underlying scientific
    process and agent- specific data, and that scientific peer review, peer
    consultation workshops, and similar processes are the principal ways of
    determining the strength of thinking and the general acceptance of these
    views within the scientific community. FDA officials emphasized that their
    agency does not presume that there is a ?best way? of doing a risk
    assessment and does not require the use of a specific risk assessment
    protocol or of specific default assumptions, but they are continually
    updating procedures and techniques with the goal of using the ?best

    available science.? 28 There is a conceptual difference between uncertainty
    and variability. Uncertainty is a property of a lack of knowledge and may be
    reduced through study and additional information. Variability is a property
    of a system or population (e. g., every person has different physical
    characteristics) and can only be understood, not reduced, through further
    study. See Adam Finkel, ?A Second Opinion on an Environmental Misdiagnosis,?
    New York University Environmental Law Journal, Volume 3 (1995), p. 299.

    Agencies identified assumptions and methodological choices throughout the
    risk assessment process, and each of the first three steps in the process
    can have its own set of issues and choices that risk assessors need to
    address. During hazard identification, agencies must make choices about

    which types of data to use and what types of adverse effects and evidence
    will be considered in their analyses. For example, risk assessors need to
    decide whether data on benign tumors should be used along with data on
    malignant tumors as the basis for quantitative estimates of cancer risks, or
    whether only data on malignant tumors should be used. During doseresponse

    assessment, agencies may need to make assumptions when extrapolating effects
    from animals to humans (e. g., how to determine equivalent doses across
    different species). In particular, choices among assumptions and methods are
    needed when estimating dose- response relationships at doses that are much
    lower than those used in the scientific studies that provided the data for
    quantitative analysis. During exposure assessments, assumptions might be
    needed to address issues such as when exposures occur (e. g., in infancy or
    childhood versus as an adult), how long exposures last (e. g., short versus
    long term and continuous versus episodic), differences in exposures and
    effects for the population as a whole versus those affecting subpopulations
    and individuals, and questions about the concentration and absorption of
    chemical agents. Assumptions about human behavior also affect the relative
    likelihood of different

    exposure scenarios. For example, in assessing children?s residential
    exposures to a pesticide, risk assessors might need to make assumptions
    about how long children play in a treated area, the extent to which they are
    wearing clothing, and potential hand- to- mouth exposure to treated soil,
    among other factors.

    Why Particular Assumptions Agencies generally indicated that they use their
    major assumptions and

    and Methods Are Selected methodological choices in risk assessments when
    professional judgments

    or policy choices must substitute for scientific information that is not
    available or is inconclusive. We examined risk assessment guidance documents
    and procedures in the four agencies to determine whether the agencies stated
    a specific scientific or policy basis for their choices, as recommended by
    NAS and the Presidential/ Congressional Commission. In

    approximately three- quarters of the choices that we reviewed, the agencies
    provided at least some rationale for the use of particular assumptions or
    methods. The reasons most commonly cited were (1) an evaluation of available
    scientific data, (2) the precedents established in prior risk assessments,
    and (3) policy decisions related to their regulatory mandates. In some
    instances, the agencies cited more than one reason in support of their
    choices. For example, officials from FDA?s Center for Veterinary Medicine
    said they assume that an adult weighs 60 kilograms when

    converting an acceptable daily intake (ADI) to an intake level of residues
    in food because of historical precedent and because this assumption should
    protect women, growing adolescents, and the elderly. 29

    29 According to FDA officials, if there is a need to convert an ADI
    (expressed as milligrams per kilogram body weight per day) to an intake
    level (expressed as the number of milligrams of an additive that would be
    acceptable on a daily basis), they multiply the ADI by the assumed weight of
    a person. Officials from FDA?s Center for Food Safety and Applied Nutrition
    said they assume values of 60 kilograms for adults and 15 kilograms for
    children, based on historical precedents which were based on population-
    based surveys.

    Of the three reasons, the agencies most often cited their evaluation of
    available scientific evidence as a reason for selecting particular
    assumptions or analytical methods. For example, one of the default
    assumptions in EPA?s carcinogen risk assessment guidance is that positive
    effects in animal cancer studies indicate that the agent under study can
    have carcinogenic potential in humans. EPA cited scientific research
    supporting this assumption, such as the evidence that nearly all agents

    known to cause cancer in humans are carcinogenic in animals in tests with
    adequate protocols. Other EPA guidelines stated that, in general, a
    threshold is assumed for the dose- response curve for agents that produce
    developmental toxicity. EPA?s guidelines noted that this assumption is based
    on the known capacity of the developing organism to compensate for

    or repair a certain amount of damage at the cellular, tissue, or organ
    level. OSHA cited scientific evidence and the views of the Office of Science
    and Technology Policy on chemical carcinogenesis (the origin or production
    of a tumor) to support its choice to combine data on benign tumors with the
    potential to progress to malignancies with data on malignant tumors
    occurring in the same tissue and the same organ site. 30

    30 The National Science and Technology Policy, Organization, and Priorities
    Act of 1976 created the Office of Science and Technology Policy within the
    Executive Office of the President to provide advice to the President on
    issues relating to science and to coordinate federal efforts in science and
    technology.

    Even when basing a choice upon available scientific studies and data,
    professional judgment may still be required regarding which particular
    method or assumption to choose among competing alternatives. The

    scientific evidence might show a range of assumptions or methods that
    provide plausible results and may, in specific cases, vary in terms of which
    one best fits the available evidence. For example, different mathematical
    models can be used for estimating the low- dose effects of exposure to
    suspected carcinogens. A basic problem for risk assessors is that, while

    the results produced by different models may be similar at higher doses, the
    estimates can vary dramatically at the low doses that are of concern to
    agency regulators. One study of 5 dose- response models showed that all of
    the models produced essentially the same dose- response curves at higher

    doses, but the models? estimates differed by 3 or 4 orders of magnitude
    (values 1, 000 to 10, 000 times different) at lower doses. 31 Because the
    mechanism of carcinogenesis is not sufficiently understood, none of the
    mathematical procedures for extrapolation has a fully adequate biological
    basis. 32 Furthermore, because of the limitations in the ability of
    toxicologic or epidemiologic studies to detect small responses at very low
    doses, doseresponse relationships in the low- dose range are practically
    unknowable.

    Agencies can encounter similar problems in attempting to determine how much
    of a chemical will produce the same effect in humans that was observed in
    animals. An interagency group of federal scientists that studied this issue
    noted that, although many alternatives had been

    developed for such cross- species scaling, and despite considerable study
    and debate, ?no alternative has emerged as clearly preferable, either on
    empirical or theoretical grounds.? 33 The group noted further that the
    various federal agencies conducting chemical risk assessments therefore
    developed their own preferences and precedents, and this variation ?stands

    among the chief causes of variation among estimates of a chemical?s
    potential human risk, even when assessments are based on the same data.? For
    purposes of consistency in federal risk assessments, the group

    recommended a method intermediate between the two methods most 31 See
    ?Criteria for Evidence of Chemical Carcinogenicity,? Interdisciplinary Panel
    on Carcinogenicity, Science 225 (1984), pp. 682- 687. 32 See, for example,
    General Principles for Evaluating the Safety of Compounds Used in Food-
    Producing Animals, DHHS/ FDA/ CVM (revised July 1994). 33 ?Draft Report: A
    Cross- Species Scaling Factor for Carcinogen Risk Assessment Based on
    Equivalence of mg/ kg 3/ 4 /Day,? 57 FR 24152 (June 5, 1992). No final
    report has been issued.

    commonly used by federal agencies, but reiterated that methodologies in use
    ?have not been shown to be in error.?

    Other reasons cited by the agencies for selecting assumptions or methods
    included the precedents established in prior risk assessments and policy
    decisions related to their regulatory missions and mandates. For example,
    FDA officials said that their practice of using the most sensitive species
    and

    sex when calculating the ADI of animal drug residues in food was based on
    historical precedents dating back to at least 1954. In other instances, FDA
    said that its use of precautionary assumptions was based on the agency?s

    statutory responsibility to ensure to a ?reasonable certainty? that the
    public will not be harmed. Similarly, EPA guidelines pointed out that the
    default assumptions used in the agency?s risk assessments were chosen to be
    health protective because EPA?s overall goal is public health protection.
    For example, EPA?s neurotoxicity guidelines said that a choice to use the
    most sensitive animal species to estimate human risk ?provides a
    conservative estimate of sensitivity for added protection to the public.?

    Effects of Agencies? The agencies provided information in their guidelines
    on the likely effects Assumptions and Methods of using particular
    assumptions or methods in about half of the examples on Risk Estimates

    that we reviewed. When that information was provided, it was usually in the
    context of whether and to what extent the agencies? choices could be
    considered precautionary. In a number of cases, EPA and FDA characterized
    their assumptions and methods as precautionary in that they were intended to
    avoid underestimating risks in the interest of protecting

    public health. Such assumptions tend to raise an agency?s estimate of risk
    and lower the levels of exposure that are of regulatory concern.
    Precautionary assumptions and methodological choices were a common component
    of programs that have ?tiered? approaches for conducting risk assessments
    (e. g., EPA?s Superfund and pesticides programs). In these tiered risk
    assessment approaches, agencies move from initial rough

    screening efforts to increasingly more refined and detailed levels of
    analyses. The initial screening assessments will typically involve very
    precautionary ?upper- bound? or even ?worst- case? assumptions to determine
    whether there is cause for concern. Successive tiers of assessment, if
    deemed necessary, are characterized in agency documents as more detailed and
    focused assessments that require more extensive data and rigorous analysis.
    For example, EPA indicated that its screening assessments might well use
    precautionary upper- bound point estimates of exposures (e. g., that a
    chemical is used on 100 percent of the eligible crop and at the maximum
    permissible limit). However, subsequent tiers of

    assessments might refine those estimates through the use of probability
    distributions of exposure parameters or the use of monitoring data on actual
    exposures, when feasible. OSHA and RSPA also use precautionary assumptions
    in certain parts of their risk assessment procedures. However, these
    agencies identified few of their risk assessment assumptions and methods as
    precautionary. In fact, OSHA sometimes selected assumptions or methods that
    it explicitly characterized as less precautionary than those used by other
    agencies in similar circumstances. For example, OSHA stated that its
    standard

    approach to low- dose extrapolation can be much less precautionary than
    EPA?s or FDA?s approaches because it tends to use central estimates of
    potency rather than upper- bound confidence limits. OSHA officials also
    noted that the algorithm they use is less precautionary because it may lead
    to models that are sublinear at low doses.

    The effect on risk estimates of using any one assumption is likely to be
    less significant than that of applying a series of assumptions while
    conducting a risk assessment, particularly if the assessment is compounding
    a string of largely precautionary assumptions. As we previously pointed out,

    assumptions and choices may be needed at many points during each step of an
    agency?s analysis. The agency?s policy may well be to use precautionary
    choices at most, if not all, of those points, if adequate information is not

    available to indicate that the precautionary choice is invalid in a specific
    case. The potential for such a string of precautionary assumptions is
    illustrated by the set of standard choices identified by FDA for risk

    assessments of carcinogenic animal drug residues in foods consumed by
    humans.

    1. Regulation is based on the target tissue site exhibiting the highest
    potential for cancer risk for each carcinogenic compound.

    2. If tumors are produced at more than one tissue site, the minimum
    concentration of the compound that produced a tumor is used.

    3. Cancer risk estimates are generally based on animal bioassays, using
    upper 95- percent confidence limits of carcinogenic potency. 34

    4. Low- dose extrapolation is done using a nonthreshold, conservative,
    linear- at- low- dose procedure (i. e., assuming that there is no dose that
    would not cause cancer and that effects vary in proportion to the

    amount of the dose). 5. It is assumed that the carcinogenic potency in
    humans is the same as

    that in animals. 6. The concentration of the residue in the edible product
    is at the permitted concentration.

    7. Consumption is equal to that of the 90 th percentile consumer. 8. All
    marketed animals are treated with the carcinogen. 9. In the absence of
    information about the composition of the total

    residue in edible tissue, assume that the entire residue is of carcinogenic
    concern.

    FDA?s description of its risk assessment procedures acknowledged that these
    assumptions ?result in multiple conservatisms? and stated that some of these
    choices are likely to overestimate risk by an unknown amount (although the
    fourth assumption could also underestimate risk by an order of magnitude).
    However, the agency also said that these assumptions are prudent because of
    the uncertainties involved and cited its statutory

    responsibility to ensure to a reasonable certainty that the public will not
    be harmed. It is important to keep in mind that the primary purposes for
    preparing such assessments are to identify safe concentration levels in
    edible tissues and residue tolerances (the amount permitted to remain on

    food) for postmarket monitoring rather than to produce a general estimate of
    the risk posed by use of the animal drug. 34 Bioassay refers to the use of
    living organisms to measure the effect of a risk agent or condition- for
    example, a test for carcinogenicity in laboratory animals that includes
    nearlifelong exposure to the agent being tested.

    Comparison of Agencies? Agency documents very rarely made direct comparisons
    of their Assumptions

    assumptions and methodological choices to those used by other agencies, and
    there is no requirement that they do so. Our review indicated that EPA, FDA,
    and OSHA risk assessment procedures have many basic assumptions in common-
    for example, that one can use results of animal experiments to estimate
    risks to humans, and that most potential carcinogens do not have threshold
    doses below which adverse effects would not occur. There are other default
    or standard assumptions and models in the three

    agencies? risk assessment procedures that are similar, but not identical.
    For example, all three agencies employ a linear mathematical model for low-
    dose extrapolation (in the absence of information indicating that a

    linear model is inappropriate in a particular case). However, the agencies
    prefer different options in the details of fitting such models, such as the
    point of departure to low doses. EPA and FDA also consider similar, but not
    identical, sets of uncertainty or safety factors when using the NOAEL

    approach for noncancer risk assessments. Finally, as the discussion above
    regarding low- dose extrapolation illustrates, there are also instances in
    which the agencies use different assumptions in similar circumstances.

    Table 1 compares and contrasts some of the risk assessment assumptions or
    analytical methods identified in the guidelines or other descriptive
    documents of EPA, FDA, and OSHA for use under similar circumstances. 35
    (Note that, for comparability, the examples in table 1 all focus on

    carcinogen risk assessments based on animal studies, but the agencies? major
    assumptions and methods are not limited to only carcinogen risk assessments.
    Note also that the ?circumstances? listed in the table also include that the
    assumption or method would be used in the absence of data to the contrary.)

    35 RSPA is not included in this table because it uses a different process
    for risk assessments, and its assessments do not focus on the carcinogen
    risk assessment issues highlighted in the table. However, RSPA?s risk
    assessment methods are similar to EPA?s Chemical Emergency Preparedness and
    Prevention Office, which also focuses primarily on short- term risks
    associated with accidental releases of chemicals.

    Table 1: Comparison of Selected Major Assumptions or Methods Used in EPA,
    FDA, and OSHA Risk Assessments Circumstance EPA FDA OSHA

    Which species/ sex to use in Use most sensitive species/ sex. Use most
    sensitive species/ sex. Use most sensitive species/ sex

    animal studies. for tumor sites appropriate for routes of exposure
    experienced by workers.

    Whether to include data on Include data on benign tumors if Include data on
    benign tumors if Combine data on benign tumors benign tumors in a cancer
    they have the capacity to

    they have the capacity to with the potential to progress to assessment.

    progress to the malignancies progress to the malignancies malignancies with
    data on with which they are associated. with which they are associated.

    malignant tumors occurring in Benign tumors that are not Benign tumors that
    are not the same tissue and the same observed to progress to observed to
    progress to organ site. malignancy are assessed on a

    malignancy are assessed on a case- by- case basis. case- by- case basis.

    Preferred cancer low- dose Default depends on the agent?s Use a no-
    threshold, linear

    Use a particular no- threshold, extrapolation method if a

    mode of action. For example, if extrapolation method. linear approach known
    as the

    mathematical model is used. mode is not understood or ?maximum likelihood
    estimate in

    believed to be linear, a linear the Crump- Howe approach is recommended.

    reparameterization of the When data supports a nonlinear multistage model.?
    (This mode of action, the default particular approach may lead to changes to
    a margin of exposure models that are sublinear at low analysis. doses.)

    Point of departure in preferred Use the lower 95- percent limit of

    Use data at the upper 95- According to agency officials, approach to low-
    dose

    the doses that are estimated to percent confidence limit. OSHA does not use
    a point of extrapolation (i. e., the data point

    cause a 10- percent response departure. OSHA tends to use from which the
    agency (i. e., an effect in 10 percent of central estimates of potency,
    extrapolates to lower, exposed subjects). (This dose is such as the maximum
    likelihood

    unobserved dose- response referred to as the LED 10 .)

    estimate of the parameterized relationships). dose- response function.

    Preferred method for cross For oral exposure, recommends Recommends use of
    scaling

    Assumes that equivalent doses species scaling of equivalent use of a scaling
    factor of body factor of body weight to the � scaled by body weight would
    doses (i. e., how the agency weight to the � power.

    power. (However, risk assessors lead to equivalent risks. converts data from
    doses given may also use the default of body

    (However, it may in the future to one species, such as rats in a

    weight scaling.) move to � -power scaling.)

    toxicological study, to doses presumed to have an equivalent effect on
    another species, such as humans). Source: GAO analysis

    There appears to be some convergence in the agencies? risk assessment
    assumptions in at least one area where there had been significant
    differences- their methods for cross- species dose scaling. In the absence
    of adequate information on differences between species, EPA?s standard
    practice in carcinogenic risk assessments had been to scale daily
    administered doses by body surface area, whereas FDA?s and OSHA?s standard
    practice had been to scale doses by body weight. Recently, the agencies have
    either adopted, or consider as one of their options, the expression of doses
    in terms of daily amount administered per unit of body weight to the �
    power. 36

    All four of the agencies included in our review have also been incorporating
    more complex analytical methods and models into their risk assessment
    procedures. Some of these methods (such as the use of probabilistic analyses
    to provide distributions of exposure parameters) help to address

    issues of uncertainty and variability in risk assessments and lessen the
    need for some precautionary assumptions. Other advances, such as the use of
    PBPK models, can provide better insights into how and to what extent a
    chemical might produce adverse effects in humans. One outcome of the

    integration of these methods into agencies? procedures is a diminishing of
    the traditional distinction between cancer and noncancer risk assessment
    methods. EPA, in particular, has noted that it is less likely to consider
    cancer and noncancer endpoints in isolation as it develops and incorporates
    more advanced scientific methods to measure and model the biological events
    leading to adverse effects. According to EPA, the science of risk assessment
    is moving toward a harmonization of the methodology

    for cancer and noncancer assessments. The use of newer, more complex models
    and methods also opens up a new range of choices and assumptions in the
    analysis- along with the potential for risk estimates to diverge because of
    the different assumptions that might be used. For example, in its methylene
    chloride final rule OSHA

    reported on the results of its analyses as well as risk assessments
    submitted to OSHA by other risk assessors. 37 Although most of the risk
    assessments used a linearized multistage model to predict risk, there were
    differences in the estimates produced by these assessments. OSHA 36 Across
    the range of plausible values, the body weight approach is generally
    considered the least precautionary, surface area scaling the most
    precautionary, and (body weight) 3/ 4 the midpoint value.

    37 ?Occupational Exposure to Methylene Chloride,? 62 FR 1494 (Jan. 10,
    1997).

    pointed out that the differences in risk estimates were not generally due to
    the dose- response model used, but to whether the risk assessor used PBPK
    modeling to estimate target tissue doses and what assumptions were used in
    the PBPK modeling.

    Appendices II through V present more detailed information on some of the
    major assumptions and methodological choices in each of the four selected
    agencies.

    Risk Characterization In the risk characterization step of a risk
    assessment, agencies bring

    Policies and Practices together the results of the preceding analyses in the
    form of estimates and

    conclusions about the nature and magnitude of a potential risk. Agencies?
    Emphasize risk characterizations play a crucial role in explaining to
    decision makers Transparency and other interested parties what the agency?s
    risk assessors have concluded and on what basis they reached those
    conclusions. Both EPA

    and DOT have agencywide written policies on risk characterization that
    emphasize the importance of providing comprehensive and transparent
    characterizations of risk assessment results. Although FDA and OSHA do

    not have written risk characterization policies, officials of those agencies
    pointed out that, in practice, they also tend to emphasize comprehensive
    characterizations of risk assessment results, discussions of limitations and
    uncertainties, and disclosure of the data and analytic methodologies on
    which the agencies relied.

    EPA?s program offices are generally responsible for completing risk
    characterizations, and EPA?s agencywide guidance on this issue includes a
    risk characterization policy, a guidance memorandum, and a handbook. EPA?s
    policy stipulates that risks should be characterized in a manner that is
    clear, transparent, reasonable, and consistent with other risk

    characterizations of similar scope. EPA said that all assessments ?should

    identify and discuss all the major issues associated with determining the
    nature and extent of the risk and provide commentary on any constraints
    limiting fuller exposition.? EPA?s policy documents also recommend that risk
    characterization should (1) bridge the gap between risk assessment and risk
    management decisions; (2) discuss confidence and uncertainties involving
    scientific concepts, data, and methods; and (3) present several types of
    risk information (e. g., a range of exposures and multiple risk descriptors
    such as high- end estimates and central tendencies). It is also

    EPA?s policy that major scientifically and technically based work products
    related to the agency?s decisions normally should be peer- reviewed. 38 In
    its guidelines for carcinogen risk assessment, EPA also suggests preparing
    separate ?technical? characterizations to summarize the findings of the
    hazard identification, dose- response assessment, and exposure assessment
    steps. The agency?s risk assessors are then to use these technical
    characterizations to develop an integrative analysis of the whole

    risk case, followed by a less extensive and nontechnical summary intended to
    inform the risk manager and other interested readers. EPA identified several
    reasons for preparing separate characterizations of each analysis phase
    before preparing the final integrative summary. One is that different

    people often do the analytical assessments and the integrative analysis. The
    second is that there is very often a lapse of time between the conduct of
    hazard and dose- response analyses and the conduct of the exposure
    assessment and integrative analysis. Thus, according to EPA, it is necessary
    to capture characterizations of assessments as the assessments

    are done to avoid the need to go back and reconstruct them. Finally, several
    programs frequently use a single hazard assessment for different exposure
    scenarios. 38 Peer review generally takes one of two forms: (1) internal
    peer review by a team of relevant experts from within EPA who have no other
    involvement with respect to the work product that is to be evaluated or (2)
    external peer review by a review team that consists primarily of independent
    experts from outside EPA.

    DOT?s policy principles regarding how the results of its risk or safety
    assessments should be presented are straightforward and encourage agency
    personnel to:

     make public the data and analytic methods on which the agency relied (for
    replication and comment);  state explicitly the scientific basis for
    significant assumptions, models,

    and inferences underlying the risk assessment, and explain the rationale for
    these judgments and their influence on the risk assessment;

     provide the range and distribution of risks for both the full population
    at risk and for highly exposed or sensitive subpopulations and encompass all
    appropriate risk to health, safety, and the environment;

     place the nature and magnitude of risks being analyzed in context
    (including appropriate comparisons to other risks); and

     use peer review for issues with significant scientific dispute. FDA does
    not have a written risk characterization policy, but FDA officials said
    that, in practice, the agency uses a standard approach that is similar to
    EPA?s official policy. They said that FDA?s general policy is to reveal the
    risk assessment assumptions that have the greatest impact on the results of
    the analysis, and to state whether the assumptions used in the assessment
    were conservative. FDA officials also said that their risk assessors attempt
    to show the implications of different distributions and choices (e. g., the
    results expected at different levels of regulatory intervention). FDA may

    employ probabilistic methods, such as Monte Carlo analysis, to provide
    additional information on the effects of variability and uncertainty on
    estimates of risk, and there are some differences in FDA risk
    characterization procedures depending on the products being regulated and
    the nature of the risks involved. 39

    Although OSHA does not have written risk characterization policies, in
    recent rules the agency emphasized (1) comprehensive characterizations of
    risk assessment results; (2) discussions of assumptions, limitations, and

    uncertainties; and (3) disclosure of the data and analytic methodologies on
    which the agency relied. The agency devoted considerable effort to
    addressing uncertainty and variability in its risk estimates. Such efforts
    39 Monte Carlo analysis involves a repeated random sampling from the
    distribution of values for each of the parameters in a calculation (such as
    average daily exposure) to derive a distribution of estimates of exposures
    for a population. According to FDA, because Monte Carlo modeling is a
    probabilistic technique that can use all the available data, it will result
    in more accurate estimates at upper percentiles of exposure.

    included performing sensitivity analyses and providing estimates produced by
    alternative analyses and assumptions (including analyses by risk assessors
    outside of OSHA). In its risk characterizations, OSHA provided

    both estimates of central tendency and upper limits (such as the 95 th
    percentile of a distribution). Appendices II through V provide more detailed
    descriptions of the risk characterization policies or approaches of each of
    the four selected agencies.

    Conclusions Risk assessment is an important, but extraordinarily complex,
    element in federal agencies? regulation of potential risks associated with
    chemicals. The assessments can help agencies decide whether to regulate a
    particular chemical, select regulatory options, and estimate the benefits
    associated with regulatory decisions. Scientific studies in such areas as
    toxicology

    and epidemiology are often used to produce the information needed for risk
    assessment decisions. However, assessors frequently must produce estimates
    of risk without complete scientific information about the extent of
    exposures to potentially hazardous substances and the effects of those
    exposures on human health and safety or the environment. Therefore,
    professional judgment with regard to assumptions and methodological choices
    is an inherent part of conducting risk assessments. The

    appendices to this report identify many of the major assumptions and methods
    that can be used in risk assessments prepared for EPA, FDA, OSHA, and RSPA.
    The number and variety of those assumptions and methods illustrate the range
    of issues that risk assessors confront during the course of their analyses.

    Although there were more similarities than differences in the general risk
    assessment procedures of three of the four agencies, there were also some
    notable differences in the agencies? specific approaches, methods, and
    assumptions. These differences can significantly affect the results and
    conclusions drawn from the assessments. Therefore, risk estimates prepared
    by different agencies, or by different program offices within those
    agencies, may not be directly comparable, even if the same chemical agent is
    the subject of the risk assessment. In some cases, the reasons for those

    differences are readily apparent, such as when agencies focus on different
    types of adverse effects (e. g., cancer versus noncancer) or different types
    and sources of exposure. For example, the same chemical (e. g., methylene
    chloride) might be identified as a significant hazard by one agency in one
    exposure setting (OSHA for occupational exposures) but as a low hazard

    by another agency in a different setting (EPA for Superfund hazard ranking
    screening). In other cases, the reasons for different estimates may be more
    subtle and harder to discern within the many layers of analyses and
    professional judgments used to prepare the risk assessment. Because of the
    range of assumptions and methods that are scientifically plausible in a
    given situation, the risk characterization phase of the risk

    assessment process takes on added importance. In their risk characterization
    policies or procedures, the four agencies acknowledge the importance of
    clearly communicating not only their conclusions about the nature and
    likelihood of a given risk but also disclosing (1) the assumptions, methods,
    data, and other choices that had the greatest impact on risk estimates; (2)
    why those choices were made; and (3) the effect that alternative choices
    would have had on the results of a risk assessment.

    Transparency is important with regard to both individual risk assessments
    and in agencies? general procedures regarding how the assessments should be
    conducted. Those procedures encourage consistency in how agencies conduct
    risk assessments and provide insights into agencies? decision making when
    analyzing risks. For example, frameworks delineated by EPA

    and OSHA for departing from certain default assumptions inform both agency
    personnel and external parties as to whether particular data or analyses are
    acceptable to the agency. Our review focused on describing the framework for
    agencies? chemical risk assessments. We did not evaluate how that framework
    is applied in practice, or how risk assessment results affect risk
    management decisions by agencies and other policymakers. Nevertheless, our
    report highlights the value of policymakers and other interested parties
    becoming aware of the underlying risk assessment context, procedures,
    assumptions, and

    policies when using risk assessment data for risk management and other
    public policy decisions. For example, prudent use of risk data requires the
    user to be aware of the extent to which the data:

     represent estimates from screening assessments (which may rely heavily on
    precautionary assumptions) or estimates from subsequent, more rigorous
    assessments (which are likely to rely on more detailed and case- specific
    data and analyses);

     show the distribution of exposures and potential adverse effects across
    the population, including the extent to which the data address risks of the
    most exposed or sensitive subgroups of the population, or focus on only part
    of that distribution;

     were produced using directly relevant scientific data that were available
    or had to rely on general assumptions and models; and

     reflect the flexibility permitted in agencies? standard procedures or
    guidelines to depart from past precedent and default choices to use
    alternative assumptions and models, when appropriate.

    In our review we also found that, although the underlying statutes specified
    the use of particular methods or assumptions in only three instances, the
    legal and situational context within which an agency is conducting a
    chemical risk assessment has a major effect on the specific focus, scope,
    and level of detail of the resulting assessment. Comparison of risk
    assessment estimates from different agencies and programs therefore

    requires careful consideration of these contextual differences. Because the
    central purpose of our review was to describe the framework for selected
    agencies? chemical risk assessments, rather than to evaluate and critique
    how that framework is applied in practice, we are not making any
    recommendations in this report.

    Agency Comments and At the end of our review, we sent a draft of this report
    to five experts in the

    Our Evaluation field of risk assessment to ensure the technical accuracy of
    the report. The

    three experts who provided comments were (1) the Executive Director of the
    Presidential/ Congressional Commission, (2) the individual who prepared the
    Survey of Methods for Chemical Health Risk Assessment Among Federal
    Regulatory Agencies for the Commission, and (3) an expert in risk assessment
    at Resources for the Future. The experts generally indicated that the report
    had no material weaknesses, but provided a number of technical suggestions
    that we incorporated as appropriate. For example, two of the reviewers
    suggested that the report?s

    discussion of the NAS four- step risk assessment paradigm, although
    reflecting the definitions generally relied upon by federal agencies, should
    also identify an updated view regarding the concept of risk
    characterization. The updated view is that risk characterization should be a
    decision- driven activity performed as part of the risk management

    decision making process rather than a stand- alone activity at the end of a
    risk assessment. We included this perspective in the report?s background
    section. During our review, we obtained technical comments from officials in
    each of the four agencies on a draft of the appendices to this report, which
    we incorporated as appropriate. On June 18, 2001, we sent a draft of the
    full

    report to the Secretaries of Health and Human Services, Labor, and
    Transportation, and the Administrator of EPA for their review and comment.
    None of the agencies provided formal comments on the report, but we received
    additional technical comments and suggestions from all

    four of the agencies, which we incorporated as appropriate. As arranged with
    your office, unless you publicly announce the contents of this report
    earlier, we plan no further distribution until 30 days after the date of
    this report. At that time, we will send copies of this report to the Ranking
    Minority Member, House Committee on Energy and Commerce; the Ranking
    Minority Member, Subcommittee on Environment and Hazardous Materials, House
    Committee on Energy and Commerce; the Secretaries of Health and Human
    Services, Labor, and Transportation; and the Administrator of EPA. We will
    also make copies available to others on request.

    If you have any questions concerning this report, please call me or Curtis
    Copeland at (202) 512- 6806. Key contributors to this assignment were
    Timothy Bober and Aaron Shiffrin. Victor S. Rezendes Managing Director,
    Strategic Issues

    Appendi Appendi xes x I

    Objectives, Scope, and Methodology Scope and Objectives As requested, our
    review focused on the chemical risk assessment procedures, assumptions, and
    policies of four federal agencies with responsibilities for regulating or
    managing risks from potential exposure to chemicals- the Environmental
    Protection Agency (EPA), the Food and Drug Administration (FDA) within the
    Department of Health and Human Services (HHS), the Occupational Safety and
    Health Administration (OSHA) within the Department of Labor, and the
    Department of Transportation?s (DOT) Research and Special Programs
    Administration (RSPA- in particular the Office of Hazardous Materials
    Safety). Our specific objectives were to identify and describe (1) the
    general context for the agencies? chemical risk assessment activities; (2)
    what the agencies view as their primary procedures for conducting risk
    assessments; (3) what the agencies view as the major assumptions or
    methodological choices in their risk assessment procedures; and (4) the
    agencies? procedures or policies for characterizing the results of risk
    assessments. To the extent feasible, we were also asked to identify for the
    assumptions and choices identified in the third objective (a) at what stages
    of the risk assessment process they are used, (b) the reasons given for
    their selection, (c) their

    likely effects on risk assessment results, and (d) how they compare to the
    assumptions and choices used by other agencies or programs in similar
    circumstances.

    Methodology To address our objectives, we relied primarily on a detailed
    review and analysis of agencies? general guidance documents on chemical risk

    assessment or, if there were no guidance documents, reviews of specific
    examples of agency risk assessments. We supplemented that information with
    material from secondary source reports on risk assessment and interviews
    with agency officials. Among the secondary sources that we used were
    relevant reports by the Congressional Research Service, National Academy of
    Sciences (NAS), and the Presidential/ Congressional Commission on Risk
    Assessment and Risk Management (hereinafter referred to as the Presidential/
    Congressional Commission). In particular,

    as a starting point for our review we used a report on federal agencies?
    chemical risk assessment methods that was prepared by Lorenz Rhomberg for
    the Presidential/ Congressional Commission. 1 That report provided the
    baseline descriptions of some of the chemical risk assessment procedures at
    EPA, FDA, and OSHA. 2 We asked officials of those agencies to review
    Rhomberg?s report to identify information that was still relevant to
    addressing the objectives of this report as well as information that they
    felt should be revised or added to reflect the agencies? current procedures.

    There are several important limitations to our review. First, chemical risk
    assessment is just one of several types of risk assessment being conducted
    in federal agencies. Therefore, our review cannot be used to characterize
    other types of risk assessments (e. g., risks associated with radiation
    exposure). In fact, FDA officials considered risk assessments related to the
    human drug approval process to be outside the scope of our review because a
    completely different protocol is used in those assessments. However,
    limiting the scope of our review to chemical risk assessments

    makes comparisons among the agencies included more relevant and meaningful.
    Second, our review did not include all agencies or programs that conduct
    risk assessments involving chemicals. For example, we did not include the
    Consumer Product Safety Commission, which periodically assesses products
    with potential risks from chemicals. Nor did we include

    the Agency for Toxic Substances and Disease Registry, which prepares

    ?health assessments? that closely resemble risk assessments but has no
    regulatory authority. We focused on the risk assessment procedures in four
    federal agencies that regularly conduct chemical risk assessments in

    1 A Survey of Methods for Chemical Health Risk Assessment Among Federal
    Regulatory Agencies, Lorenz Rhomberg (1996). 2 RSPA was not included in the
    scope of Rhomberg?s report.

    support of regulatory activities and/ or could illustrate the diversity of
    risk assessment procedures. However, the results of our review cannot be
    considered representative of chemical risk assessments in all federal
    agencies. Third, our review does not describe every chemical risk assessment
    procedure or assumption used by the agencies we reviewed.

    The material describing the agencies? procedures is both voluminous and
    extremely complex. The detailed information that we provide on agency
    assumptions is illustrative of the assumptions included in agencies?
    procedures, but not a compendium of all such assumptions. In addition,

    we concentrated primarily on the human health and safety risk assessment
    procedures of the four agencies and, to a lesser extent, on ecological risk
    assessment procedures. Fourth, this report describes agencies? general
    procedures and policies, but it is not a compliance review of how well those
    procedures and policies are applied with regard to individual

    assessments. The agencies? guidelines represent suggested procedures and are
    not binding, so the agencies? practices may justifiably vary from the
    general frameworks we describe. In practice, risk assessments do not

    follow a simple recipe or formula. Each assessment has unique issues or
    characteristics that require case- specific resolutions. Finally, this
    report does not address risk management issues- e. g., using the results of
    a risk assessment to determine what level of exposure to a risk agent
    represents an acceptable or an unacceptable risk and deciding what control
    options should be used.

    We conducted this review between February 2000 and March 2001 in the
    Washington, D. C., headquarters offices of the selected agencies in
    accordance with generally accepted government auditing standards. We
    obtained technical comments on our descriptions of the agencies? procedures,
    assumptions, and policies in the appendices from

    knowledgeable agency personnel. We then provided the draft report to
    external experts in risk assessment, including the Center for Risk Analysis
    at the Harvard School of Public Health in Boston, MA; Resources for the
    Future in Washington, D. C.; the Executive Director of the Presidential/
    Congressional Commission; and Lorenz Rhomberg, the analyst who surveyed
    federal agencies? chemical risk assessment procedures for the Commission.
    After incorporating their comments, we provided a draft of this report to
    the Secretaries of Health and Human Services, Labor, and Transportation; and
    the Administrator of the Environmental Protection Agency for their review
    and comment.

    Organization of In the following appendices, we provide more detailed
    information Appendices on

    regarding the framework and methods applicable to chemical risk assessment
    activities of EPA, FDA, OSHA, and RSPA. There is a separate Chemical Risk

    technical appendix covering each of these four agencies, along with their
    Assessment at Selected relevant offices, programs, or centers that are
    involved in conducting Federal Agencies

    chemical risk assessments. For consistency and ease of presentation, we have
    generally organized the appendices on each agency according to a standard
    format with four major sections.

    1. We describe the general context for the chemical risk assessment
    activities of each agency. This includes a summary of the primary risk
    statutes, mandates, and tasks related to potential risks from exposure to
    chemical agents.

    2. We identify and summarize the standard risk assessment procedures of each
    agency and, if applicable, each agency?s various offices, programs, or
    centers. This section is generally organized by the major analytical steps
    of the risk assessment process: hazard identification, doseresponse
    assessment, and exposure assessment. These correspond to the first three
    steps of the four- step paradigm for risk assessment as defined by NAS and
    used by three of the four agencies covered by our review. (We address the
    fourth step of the process, risk characterization, as a separate objective
    in the final section of each

    agency appendix.) Within the descriptions of those steps, we often
    distinguish between the procedures used for assessing cancer and noncancer
    effects. Given developments in risk assessment methods, these distinctions
    are sometimes more artificial than real. 3

    3. We present additional information about major assumptions and
    methodological choices in the agencies? standard risk assessment procedures.
    For EPA, FDA, and OSHA, the primary focus of this

    section is a detailed table identifying some of the major agencywide or
    program- specific assumptions that may be used in chemical risk assessments.
    To the extent that such information was available, each 3 For example,
    agencies may omit or combine some of the steps in certain situations. Also,
    with increasing research attention on the modes of action of chemical
    agents, the line between procedures for identifying carcinogenic and
    noncancer effects is blurring.

    of these tables also includes information on the agency?s reason( s) for
    selecting a particular assumption, when in the risk assessment process the
    agency would apply the assumption, and the likely effect of using the
    assumption on risk assessment results. (Because agencies very rarely made
    direct comparisons of their choices to those of other agencies in their risk
    assessment guidelines or related documents, we have not included a separate
    column on that topic in the appendix

    tables. That objective is, however, addressed in the letter portion of this
    report.) The appendix on RSPA does not include all of these elements because
    of differences in its context and approach to chemical risk assessment.

    4. The final section of each appendix addresses each agency?s approach or
    policies for characterizing the results of risk assessments for agency
    decision makers and other interested parties. In particular, we describe

    the agency?s policies or practices with regard to the transparency of risk
    assessment results, such as reporting the range and distribution of risks
    and identifying the uncertainties in the risk analysis and underlying data.

    To avoid repetition in the appendices on agencies? risk assessment
    procedures, our most detailed descriptions of basic methods and issues
    appear in the EPA appendix under the discussion of agencywide procedures.
    Descriptions of procedures used by other agencies or programs, including the
    individual program offices within EPA, then reference the EPA- wide
    descriptions of those particular methods, if they are similar. Although we
    provide much more detailed technical information in these

    appendices than in the main body of the report, it is still important to
    recognize that agencies? risk assessment methods are more involved and
    complex than we have described in this report. In particular, the tables of
    assumptions do not represent a comprehensive listing of all assumptions and
    choices of the agencies. Agencies might use many different types and numbers
    of assumptions in any given assessment, and the assumptions are being
    altered over time to reflect scientific improvements and changes in risk
    approaches and the regulatory context. However, the information

    presented is intended to illustrate the types and diversity of procedures
    and assumptions employed by the agencies we examined.

    Chemical Risk Assessment at the

    Appendi x II

    Environmental Protection Agency Chemical risk assessment at the
    Environmental Protection Agency (EPA) is a complex and diverse undertaking.
    The variety and range of the relevant regulatory authorities and activities
    has a major effect on the organization and conduct of risk assessment at the
    agency. An expanding set of agency guidelines reflects the evolving nature
    of EPA?s risk assessment procedures. EPA generally follows the four- step
    risk assessment process identified by the National Academy of Sciences
    (NAS). Changes are occurring in EPA?s approaches to cancer, noncancer, and
    exposure assessments, with a general trend toward the development and
    application of more complex and comprehensive methodologies. To a greater
    extent than the other agencies we reviewed, EPA has established a set of
    default assumptions (often precautionary in nature) and standard data
    factors for use by its risk assessors. In the ?tiered? risk assessment
    approaches commonly employed by EPA?s program offices, precautionary default
    assumptions are most often used during initial screening assessments, when
    the primary task generally is to determine whether a risk might exist

    and more rigorous analysis is needed. However, the information necessary for
    more detailed analysis is not always available, so for regulatory purposes
    the agency may be limited to using results from its initial tiers of

    risk assessments. In presenting the results of its risk assessments, it is
    EPA?s policy that risk characterizations should be prepared in a manner that
    is clear, transparent, reasonable, and consistent with other risk
    characterizations of similar scope prepared across the programs in the
    agency. The following sections describe for EPA and its component offices,
    the context for chemical risk assessment, the general procedures for
    conducting risk assessments, major assumptions and methodological choices in
    those procedures, and the agency?s policy for risk characterization. Because
    chemical risk assessment at EPA is such a complex and diverse activity, this
    appendix can only summarize and

    illustrate the range of contexts, procedures, assumptions and methods, and
    policies that affect the conduct of EPA risk assessments. For example, as in
    our report as a whole, this appendix focuses primarily on human health and
    safety risk assessment and less on ecological risk assessment.

    However, we have included a brief section on EPA?s ecological risk
    assessment guidelines under our discussion of agencywide risk assessment
    procedures and illustrated the role played by ecological risk assessment in
    the risk assessment activities of some, but not all, of EPA?s program
    offices under our discussion of program- specific procedures. As a practical
    matter, this appendix reflects risk assessment topics that were addressed in
    agencywide or program- specific guidelines or descriptions of chemical

    risk assessment at EPA. To the extent that such activities were not
    explicitly addressed in the agency?s risk assessment guidelines and related
    documents, there may be little information on them in this appendix.

    Context for EPA EPA is responsible for a wide range of regulatory- and
    related risk

    Chemical Risk assessment- activities pertaining to potential health, safety,
    and

    environmental risks associated with chemical agents. This range of
    Assessment activities reflects an equally broad and diverse range of
    underlying environmental statutes. According to EPA, close to 30 provisions
    within the major environmental statutes require decisions based on risk,
    hazard, or exposure assessment, with varying requirements regarding the
    scope and depth of the agency?s analyses. In general, EPA?s regulatory
    authority

    regarding chemical agents is compartmentalized according to the various
    kinds and sources of exposure- such as pesticides, drinking water systems,
    or air- borne pollutants- and reflected in the agency?s organization

    into various program offices- such as the Office of Air and Radiation,
    Office of Solid Waste, and Office of Water. Table 2 summarizes the principal
    statutes, regulatory tasks, and risk mandates associated with chemical risk
    assessment activities of EPA?s offices.

    Table 2: Chemical Risk Statutes, Tasks, and Mandates for EPA Offices Office
    or program Major risk- related statute( s) Primary risk- related tasks
    Primary risk- related mandate( s)

    Chemical Emergency Emergency Planning and Under EPCRA, evaluates Under
    EPCRA, the EPA list of

    Preparedness and Community Right- to- Know Act substances for toxicity,
    reactivity,

    extremely hazardous substances Prevention Office (CEPPO) (EPCRA) in the
    Superfund

    volatility, dispersability, and their thresholds, along with Amendments and
    combustibility, or flammability to reporting requirements, are used by
    Reauthorization Act of 1986 develop and maintain a list of state and local
    entities to manage

    (SARA), Title III extremely hazardous substances the risks associated with
    chemical and threshold quantities. Also

    emergencies at the local level. Clean Air Act Amendments of develops
    regulatory requirements 1990 (CAAA)

    for reporting accidental releases Under Section 112( r) of the and for
    emergency planning. amended CAA, EPA must develop a list of at least 100
    substances that Under Section 112( r) of the

    pose the greatest risk of causing amended Clean Air Act (CAA),

    death, injury, or serious adverse evaluates substances for acute effects to
    human health or the adverse health effects, likelihood environment from
    accidental of accidental release, and releases. EPA must also develop
    magnitude of exposure to regulations for preparation and

    develop a list of substances for submission of risk management

    prevention of accidental release. programs and plans by industrial Evaluates
    accidental chemical facilities handling these listed release risk management
    and

    substances. prevention practices for development of accidentprevention Also
    under the amended CAA, for

    and risk- reduction clean air research, EPA shall develop

    regulations at industrial facilities. methods and techniques necessary to
    identify and assess the risks to Also under the CAAA,

    human health from accidental investigates chemical incidents, exposures.
    evaluates the risks associated with accidental releases, and conducts
    research on risk analysis and assessment.

    (Continued From Previous Page)

    Office or program Major risk- related statute( s) Primary risk- related
    tasks Primary risk- related mandate( s)

    Office of Air and Radiation Clean Air Act; Clean Air Act

    Regulation of emissions of airborne For criteria air pollutants, set (OAR
    air quality side) Amendments of 1990 pollutants, including

    standards to protect public health

     setting national ambient air with an adequate margin of safety.

    quality standards (NAAQS) for six ?criteria? pollutants, and

    For hazardous air pollutants, set  setting standards for regulating
    standards using maximum emissions of hazardous air achievable control
    technology pollutants (toxic chemicals other (MACT) for a specified list of
    than the criteria pollutants).

    chemicals identified in the CAAA. However, if applying the MACT is Under the
    CAA, EPA is also found to lower risks insufficiently, required to review the
    scientific

    EPA may pursue further regulation to data upon which air quality control the
    residual risk, applying the standards are based and revise pre- CAAA
    standard of providing an the standards, if necessary, every ample margin of
    safety. 5 years. Office of Emergency and

    Comprehensive Environmental Remediation of hazardous waste Remedial actions
    are authorized at a

    Remedial Response Response, Compensation, and sites, including

    site whenever any hazardous (OERR Superfund)

    Liability Act of 1980 (CERCLA);

     defining hazardous substances substance is released or there is a
    Superfund Amendments and and the amounts of release that substantial threat
    of such a release Reauthorization Act of 1986

    must be reported to EPA, into the environment, or when there

     screening and ranking risks is a release or substantial threat of posed by
    hazardous waste sites release into the environment of any and identifying
    action priorities pollutant or contaminant which may among them,

    present an imminent and substantial

     evaluating need for action at danger to the public health or hazardous
    waste sites, and

    welfare.

     evaluating effectiveness of options for remediation.

    Remedial action priorities are to be based on relative risk or danger to
    public health or welfare or the environment, taking into account the
    population at risk, the hazard potential of the hazardous substances, and
    the potential for contamination of air and drinking water, among other
    factors. Need for

    action is determined by evaluation of risks to human health and the
    environment; effectiveness is determined by meeting requirements of other
    laws or risk- based goals.

    (Continued From Previous Page)

    Office or program Major risk- related statute( s) Primary risk- related
    tasks Primary risk- related mandate( s)

    Office of Pesticide Federal Insecticide, Fungicide,

    Regulation of pesticides, For pesticide residues in all foods, Programs
    (OPP) and Rodenticide Act (FIFRA); including

    determine whether there is Federal Food, Drug, and

     approving the registration of reasonable certainty of no harm, with

    Cosmetic Act (FFDCA); pesticides to set allowable uses consideration of

    Food Quality Protection Act in agriculture and extermination,  an
    additional safety factor to protect

    (FQPA) and

    infants and children,

     setting tolerances for pesticide  aggregate exposure to a pesticide
    residues permitted to remain in (including all exposures for which or on
    foods available to the there is reliable information), and consumer.

     cumulative exposures to pesticides with a common mechanism of toxicity.
    For other exposures, determine whether use of the pesticide would present
    any unreasonable risk to

    man or the environment. Office of Pollution Toxic Substances Control Act

    Evaluation and regulation of For chemicals listed on the inventory

    Prevention and Toxics (TSCA) existing and new chemicals used of ?existing
    chemicals,? determine (OPPT)

    in manufacturing and commerce whether use of that chemical will to identify
    any potentially present an unreasonable risk to dangerous products or uses.

    human health or the environment. For newly introduced chemicals, or
    significant new uses of existing chemicals, determine whether use

    may present an unreasonable risk to human health or the environment.

    (Continued From Previous Page)

    Office or program Major risk- related statute( s) Primary risk- related
    tasks Primary risk- related mandate( s)

    Office of Solid Waste Resource Conservation and

    ?Cradle- to- grave? regulation of Hazardous waste is defined as a

    (OSW) Recovery Act of 1976 (RCRA) hazardous waste management, solid waste,
    or combination of solid

    including the use of risk wastes, which because of its assessment
    information in

    quantity, concentration, or physical,  defining (and delisting) chemical,
    or infectious substances as hazardous

    characteristics may wastes,

     cause, or significantly contribute to,  evaluating the hazards posed an
    increase in mortality or an by waste streams, increase in serious
    irreversible, or  assessing the need for incapacitating reversible,
    illness; or corrective action at disposal

     pose a substantial present or sites, and

    potential hazard to human health or  granting waste disposal permits. the
    environment when improperly treated, stored, transported, or

    disposed of, or otherwise managed. Treatment, storage, or disposal of waste
    is to be conducted so as to minimize the present and future

    threat to human health and the environment.

    (Continued From Previous Page)

    Office or program Major risk- related statute( s) Primary risk- related
    tasks Primary risk- related mandate( s)

    Office of Water (OW) Clean Water Act (CWA); Safe Evaluation and regulation
    of Under CWA, EPA is to establish Drinking Water Act (SDWA);

    ambient water and drinking water criteria for ambient water quality on SDWA
    Amendments of 1996

    quality, including the basis of health and ecological  recommending water
    quality

    effects and accurately reflecting the criteria and establishing latest
    scientific knowledge on the national minimum effluent

    kind and extent of all identifiable standards, effects on health and
    welfare.

     prohibiting discharge of toxic pollutants in toxic amounts, Also under
    CWA, effluent standards  establishing national drinking for toxic
    pollutants are to be at that water standards for public water level which
    the EPA Administrator systems, and

    determines will provide an ample  identifying subpopulations at margin of
    safety, so standards more elevated risk of health effects stringent than
    those based on the from exposure to contaminants best available technology
    in drinking water and economically achievable (the normal conducting studies

    basis) may be named at EPA characterizing health risk to discretion.
    sensitive populations from contaminants in drinking water.

    Under SDWA, the EPA Administrator is to promulgate national primary drinking
    water regulations for each contaminant which may have any adverse effect on
    the health of persons and which is known or anticipated to occur in public
    water

    systems. Such regulations specify two levels of contamination

     a maximum contaminant level goal (MCLG) set solely on health grounds at a
    level at which no known or anticipated effects on the

    health of persons occur and which allows an adequate margin of safety, and

     a maximum contaminant level (MCL) set as close as feasible to the MCLG.

    The 1996 amendments to SDWA require EPA, when developing drinking water
    regulations, to (1) use the best available, peer- reviewed science and
    supporting studies and data; and (2) make publicly available a risk
    assessment document that discusses estimated risks, uncertainties, and
    studies used in the assessment.

    (Continued From Previous Page)

    Office or program Major risk- related statute( s) Primary risk- related
    tasks Primary risk- related mandate( s)

    Office of Research and (Not applicable; supports the No direct regulatory
    authority, but (Not applicable; supports the efforts Development (ORD)
    efforts of other EPA program supports risk- related activities of of other
    EPA program offices.)

    offices.) other EPA offices by:

     conducting the hazard identification and doseresponse assessment steps of
    risk assessments for specific chemicals at the request of program offices,

     preparing or assisting in the development of EPA risk assessment
    guidelines and policies, and

     conducting complex, precedentsetting risk assessments.

    Source: EPA documents and comments provided by EPA officials.

    A number of other contextual factors affect the extent of involvement by EPA
    offices in assessing and using risk assessment information in support of the
    various statutes, mandates, and tasks identified in table 2.

     Risk assessment information may not be the only, or even the primary,
    basis for the ultimate risk management decision. EPA statutes vary
    fundamentally by whether the basis for regulation is (1) risk (health and
    environmental) only, (2) technology- based, or (3) risk balancing
    (consideration of risks, costs, and benefits).

     For some chemical risk assessment activities, EPA has a secondary role.
    Instead, the main responsibility for determining the relative risk of a
    chemical, compiling and analyzing risk- related data, or completing other
    tasks associated with a particular statute might lie with industry, states,
    or local entities.

     In practical terms, the resources available for conducting a risk
    assessment for a given chemical might limit the depth and scope of EPA?s (or
    other parties?) analysis. Such resource limitations might include not only
    schedule and staffing constraints, but often the amount and quality of
    directly relevant scientific data available for analysis.

    Risk assessment activities involve both EPA?s program offices and its Office
    of Research and Development (ORD), which is the principal scientific and
    research arm of the agency. ORD often does risk assessment work for EPA
    program offices that focuses on the first two steps in the four- step NAS
    process- hazard identification and dose- response assessment- in particular,
    the development of ?risk per unit exposed? numbers. The

    exposure assessment and risk characterization steps tend to be the
    responsibility of the various regulatory programs at EPA. However, according
    to agency officials, both program offices and ORD may conduct all of the
    risk assessment steps in particular cases. For example, OW?s

    Office of Science and Technology does all of the assessments for purposes of
    the SDWA, and, because of their particular statutory mandates, OPP and OPPT
    have developed the capability to conduct all steps of a risk assessment on
    their own. 1 ORD carries out all steps of highly complex, precedent- setting
    risk assessments of specific chemicals, such as dioxin

    and mercury. 1 Also, some of the material submitted by industry petitioners
    seeking regulatory approvals of chemicals is confidential business
    information, which precludes OPP and OPPT from sharing all of their risk
    assessment data with other parts of EPA.

    ORD also helps to coordinate the development of EPA?s risk assessment
    methods, tools, models, and policies. In particular, much of EPA?s
    agencywide guidance on conducting risk assessments is developed and
    disseminated through ORD, with input from EPA?s program offices, Science
    Policy Council, and Science Advisory Board, as well as other external
    parties. Coordination of risk assessment activities also occurs through

    EPA?s Risk Assessment Forum and the agency workgroups that approve
    information for entry into EPA?s Integrated Risk Information System (IRIS).
    The Risk Assessment Forum is a standing committee of senior EPA scientists
    that was established to promote agencywide consensus on difficult and
    controversial risk assessment issues and to ensure that this consensus is
    incorporated into appropriate EPA risk assessment guidance.

    Managed by ORD, IRIS is a computerized database that contains information on
    human health effects that may result from exposure to various chemicals in
    the environment. IRIS was initially developed for EPA staff in response to a
    growing demand for consistent information on chemical substances for use in
    risk assessments, decision making, and regulatory activities. The entries in
    IRIS on individual chemicals represent a consensus opinion of EPA health
    scientists representing the program offices and ORD and have been subject to
    EPA?s peer review policy since its issuance in 1994. 2 Risk Assessment

    There are agencywide risk assessment procedures that EPA?s various
    Procedures

    program offices generally follow, but each office also has different
    statutory mandates and risk assessment tasks associated with its regulatory
    authority. These contextual differences contribute to some

    program- specific variations in the conduct of chemical risk assessments. In
    addition, EPA?s procedures are in transition from more simplistic
    traditional methods for identifying and assessing risks to increasingly
    complex models and methods. It is particularly important to recognize

    that, while most EPA guidelines (and this appendix) distinguish between
    cancer and noncancer procedures, this distinction is becoming increasingly
    blurred as new scientific methods are being developed and applied. In
    general, EPA follows the NAS four- step process for human health risk
    assessments: (1) hazard identification, (2) dose- response assessment, (3)
    exposure assessment, and (4) risk characterization. However, for

    ecological risk assessment, EPA?s guidelines recommend a three- step 2 IRIS
    does not, however, incorporate OPP or OPPT risk assessment data from
    confidential business data.

    process: (1) problem formulation, (2) analysis, and (3) risk
    characterization.

    Guidelines To a much greater extent than the other agencies we reviewed, EPA
    has documented its risk assessment procedures and policies in a voluminous
    and expanding set of guidelines, policy papers, and memoranda. These
    documents are primarily intended as internal guidance for use by risk

    assessors in EPA and those consultants, contractors, or other persons who
    perform work under EPA contract or sponsorship. 3 However, the documents
    also make information on the principles, concepts, and

    methods used in EPA?s risk assessments available to other interested
    parties. EPA?s guidelines undergo internal and external peer review.

    Beginning in 1986, EPA published a series of risk assessment guidelines to
    set forth principles and procedures to guide EPA scientists in the conduct
    of agency risk assessments, and to inform agency decision makers and the

    public about these procedures. In general, EPA adopted the guiding
    principles of fundamental risk assessment works, such as the 1983 Red Book
    by the NAS? National Research Council (NRC). 4 EPA?s guidelines supplement
    these principles. Five sets of guidelines were finalized in 1986, including
    guidelines for carcinogen risk assessment, mutagenicity risk

    assessment, health risk assessment of chemical mixtures, health assessment
    of suspect developmental toxicants, and estimating exposures. 5 In part to
    respond to advances and changes in risk assessment methods- but also in
    response to criticisms of its guidelines by NRC, among others- EPA has
    revised most of these guidelines, in either proposed or final form, and
    produced additional guidance documents.

    3 Guidelines are not rules, are not binding on either EPA or any outside
    parties, and do not alter applicable EPA statutes and regulations. 4 NRC is
    the principal operating agency and research arm of NAS in advising and
    providing services to the federal government, the public, and the scientific
    community. 5 Mutagenicity risk assessment focuses on analysis of agents that
    may cause genetic mutations. Developmental toxicity risk assessment focuses
    on risk to human development, growth, survival, and function because of
    exposure to environmental agents prior to conception, prenatally, or to
    infants and children.

    Statutory changes have also prompted revisions and expansions of EPA?s risk
    assessment guidelines and policy papers. In the Clean Air Act Amendments of
    1990, for example, Congress directed EPA to revise its

    carcinogen risk assessment guidelines, taking into consideration the NAS
    recommendations, before making any determinations of the ?residual risks?
    associated with emissions of hazardous air pollutants. 6 The results

    of the NAS study appeared in the 1994 NRC report, Science and Judgment in
    Risk Assessment. Among other things, NRC recommended that EPA better
    identify the inference (default) assumptions in its guidelines, explain the
    scientific or policy bases for selecting them, and provide guidance on when
    it would be appropriate to depart from the assumptions. The current set of
    agencywide risk assessment guidelines and policies includes the following
    major topics: 7

     carcinogen risk assessment,

     neurotoxicity risk assessment,

     reproductive toxicity risk assessment,

     developmental toxicity risk assessment,

     mutagenicity risk assessment,

     health risk assessment of chemical mixtures,

     guidelines for exposure assessment,

     guidelines for ecological risk assessment,

     other risk assessment tools and policies,

     probabilistic analysis in risk assessment,

     use of the benchmark dose approach in health risk assessment,

     reference dose (RfD) and reference concentration (RfC),

     evaluating risk to children, and

     EPA risk characterization program. In addition to these agencywide
    documents, there are also numerous program- specific guidelines and policy
    documents. For example, the Risk Assessment Guidance for Superfund series
    covers various stages of human health evaluation as well as ecological risk
    assessment and

    probabilistic risk assessment. There are also guidelines and policy
    memoranda at the headquarters and regional office level that supplement

    6 Residual risks are those remaining after the maximum achievable control
    technology is in effect. 7 There are other documents, but they are mostly on
    narrow topics- the assessment of thyroid follicular cell tumors, for
    example.

    these general Superfund guidelines. Similarly, OPP, with input from ORD, has
    developed a series of science policy papers specifically on issues related
    to pesticide risk assessments, in response to provisions of the Food

    Quality Protection Act of 1996. Describing EPA?s risk assessment procedures
    with any certainty is a difficult task, given the sheer volume of EPA
    guidance documents, the continuing evolution of risk assessment practices,
    and the extent to which many of EPA?s revisions are currently draft in
    nature. For example, the official guidelines for cancer risk assessment are
    still the 1986 version, but

    the agency published a proposed revision of those guidelines in 1996, and
    continued to revise them in 1999, but the revised guidelines have not yet
    been made final by EPA. 8 Although the various revisions since 1986 do not
    represent official agency policy at this stage, the approaches that they
    describe are likely to provide a more accurate reflection of current
    practices and directions in EPA risk assessments. To some extent EPA is
    already applying these newer approaches, for example in the Office of
    Water?s revised methodology for deriving ambient water quality criteria for

    the protection of human health and the Office of Pesticide Programs? Cancer
    Peer Review Committee. Agencywide Risk

    The following sections summarize the basic elements of EPA?s agencywide
    Assessment Procedures

    procedures for conducting risk assessments. Because most of EPA?s guidelines
    focus on human health risks, this section also focuses primarily on health
    assessments in describing EPA?s general approach. EPA

    generally uses the NAS four- step process for those assessments. However, a
    separate short section on EPA?s approach to ecological risk assessment
    appears at the end of this agencywide summary. Also, while this appendix
    (and most of the source material from which it was derived) discusses
    procedures for assessing cancer and noncancer effects separately, this
    distinction is increasingly artificial. As EPA noted in its Strategy for
    Research on Environmental Risks to Children, the agency is less likely to

    consider cancer and noncancer endpoints in isolation as it develops and
    incorporates more advanced scientific methods to measure and model the
    biological events leading to adverse effects. 9 According to EPA, the
    science

    8 A particular focus of changes in the 1999 version is additional attention
    to issues of human variability, especially risks to children versus adults.
    9 EPA/ 600/ R- 00- 068 (August 2000).

    of risk assessment is moving toward a harmonization of the methodology for
    cancer and noncancer assessments.

    Hazard Identification Carcinogens

    EPA?s approach to hazard identification changed significantly between the
    agency?s 1986 guidelines and its proposed revision. In its 1986 guidelines,
    EPA defined a hierarchical classification scheme for hazard identification
    of chemical agents (see table 3). In this scheme, analysis of whether an
    agent is a potential human carcinogen proceeds through distinct steps based
    on the type of human, animal, or ?other? evidence available and its

    quality (whether such evidence is sufficient, limited, or inadequate),
    resulting in classification of the agent in one of six alphanumeric
    categories.

    Table 3: EPA?s 1986 Classification System for Characterization of
    Carcinogenicity Group Description Weight of evidence for carcinogenicity

    A Human carcinogen Sufficient evidence from epidemiologic (human) studies B1
    Probable human carcinogen Limited evidence from epidemiologic studies B2
    Probable human carcinogen Sufficient evidence from animal studies and
    inadequate evidence or no data from epidemiologic studies C Possible human
    carcinogen Limited evidence in animals and absence of adequate human data

    D Not classifiable Inadequate or no data E Evidence of noncarcinogenicity
    for No evidence in adequate studies in at least two species or in both
    epidemiologic humans and animal studies

    Source: Adapted from EPA?s 1986 Guidelines for Carcinogen Risk Assessment
    and other agency documents that describe the agency?s classification system.

    In response to further developments in the understanding of carcinogenesis,
    and to address limitations of its 1986 scheme, EPA proposed a revised
    approach that melds the separate human- animal- other processes into a
    single comprehensive evaluation. In this approach, weighing the evidence and
    reaching conclusions about the carcinogenic potential of an agent would be
    accomplished in a single step after assessing all individual lines of
    evidence. Compared to the 1986 guidelines, the proposed revision also
    encourages fuller use of all biological information- instead of relying
    primarily on tumor findings- and emphasizes analysis of the agent?s mode of
    action in leading to tumor development. 10 EPA?s proposed revision replaces
    the 1986 alphanumeric classifications with a ?weight of evidence? narrative
    to provide more complete information not only on the likelihood of human
    carcinogenic effects but also the conditions under which such effects may be
    expressed. To provide

    some measure of consistency in the narratives, standard descriptors are to
    be utilized to express the conclusion regarding the weight of evidence for
    carcinogenic hazard potential. These descriptors have also been undergoing
    some changes, but, according to EPA?s July 1999 discussion draft, would
    include:

    1. carcinogenic to humans, 2. likely to be carcinogenic to humans, 3.
    suggestive evidence of carcinogenicity but not sufficient to assess

    human carcinogenic potential, 4. data are inadequate for an assessment of
    human carcinogenic potential,

    and 5. not likely to be carcinogenic to humans.

    The narrative might also reflect more than one conclusion for a given agent.
    For example, a narrative could say that an agent is likely to be
    carcinogenic by inhalation exposure but not likely to be carcinogenic by

    oral exposure.

    Noncancer effects

    10 ?Mode of action? is defined as a series of key events and processes,
    starting with interaction of an agent with a cell and proceeding through
    operational and anatomical changes resulting in cancer formation.

    EPA starts with a review and assessment of the toxicological database to
    identify the type and magnitude of possible adverse health effects
    associated with a chemical. Exposure to a given chemical might result in a
    variety of toxic effects, so EPA has produced separate guidelines for the
    assessment of mutagenicity, developmental toxicity, neurotoxicity, and
    reproductive toxicity. 11 However, assessments for these noncancer health
    effects may also overlap. For example, developmental effects might be traced
    to exposures and factors also covered by reproductive toxicity assessments,
    and developmental exposures may result in genetic damage that would require
    evaluation of mutagenicity risks. The EPA guidelines for noncancer effects
    are not step- by- step manuals, and they do not

    prescribe a hazard identification classification scheme. Instead, they focus
    on providing general advice to risk assessors on different types of toxicity
    tests or data and on the appropriate toxicological interpretation of test
    results (e. g., which outcomes should be considered adverse effects). In
    addition to considering the types and severity of potential adverse effects,
    hazard identification would also consider and describe the nature of
    exposures associated with these effects. A review of the full range of
    possibilities would consider:

     acute effects- generally referring to effects associated with exposure to
    one dose or multiple doses within a short time frame (less than 24 hours,
    for example);

     short- term effects- associated with multiple or continuous exposure
    occurring within a slightly longer time frame, usually over a 14- day to
    28day time period;

     subchronic effects- associated with repeated exposure over a limited
    period of time, usually over 3 months; and

     chronic effects- associated with continuous or repeated exposure to a
    chemical over an extended period of time or a significant portion of the
    subject?s lifetime.

    Procedurally, there is an important variation from the distinct four steps
    of the risk assessment paradigm. In its guidelines, EPA notes that its
    normal practice for assessments of noncancer health effects is to do hazard

    11 Neurotoxicity focuses on adverse changes in the structure or function of
    the central or peripheral nervous system following exposure to a chemical,
    physical, or biological agent. Reproductive toxicity focuses on toxic
    effects on the male and female reproductive systems, including outcomes of
    pregnancy and lactation. Mutagenicity and developmental toxicity were
    described in a previous footnote.

    identification in conjunction with the analysis of dose- response
    relationships. This is because the determination of a hazard is often
    dependent on whether a dose- response relationship is present. According

    to EPA, this approach has the advantages of (1) reflecting hazards in the
    context of dose, route, duration, and timing of exposure; and (2) avoiding
    the potential to label chemicals as toxicants on a purely qualitative basis.

    Dose- Response Assessment Carcinogens

    Risk assessors conducting dose- response assessments must make basic choices
    regarding which data to base analyses upon and which models and assumptions
    to use for extrapolation of study results to the potential

    human exposures of regulatory interest. Data choices focus on the
    availability and quality of human or animal studies. Three of the more
    important extrapolation tasks are estimation of low- dose relationships (i.
    e.,

    those that fall below the range of observation in the studies supporting the
    agency?s analysis), calculation of toxicologically equivalent doses when
    dose- response data from animal studies are applied to human exposures, and
    extrapolating results from data on one route of exposure to another route.
    12  Data choices

    The two main types of studies that provide data useful in a quantitative
    dose- response assessment are (1) epidemiological studies of human
    populations and (2) toxicological laboratory studies using animals or,
    sometimes, human cells. Epidemiological studies examine the occurrence of
    adverse health effects in human populations and attempt to identify the
    causes. At a minimum, such studies can establish a potential link between
    exposures to chemical agents and the occurrence of particular adverse
    effects by comparing differences in exposed and nonexposed populations. If
    there is adequate information on the exposure levels associated with adverse
    effects, these studies can also provide the basis for a doseresponse

    assessment. Because such data obviate the need to extrapolate from animals
    to humans, EPA (like other agencies) prefers to use data from
    epidemiological studies, if available.

    12 Risk assessors might also need to make other types of extrapolations (e.
    g., when estimating effects for less than a full lifetime).

    Often, however, the available data for dose- response assessment will come
    from animal studies. A common assumption underlying risk assessments by EPA
    (and other agencies) is that an agent that produces adverse effects in
    animals will pose a potential hazard to humans. EPA?s guidelines emphasize
    that case- specific judgments are necessary in considering the

    relevance of particular studies and their data. However, in the absence of
    definitive information to the contrary, EPA?s guidelines establish some
    standard default choices to assist risk assessors in selecting which studies
    and data to use. (See the section on assumptions in this appendix for more
    information on such default choices and assumptions.)  Extrapolation to low
    doses

    Quantifying risks engenders another set of issues and choices. In
    particular, some type of low- dose extrapolation is usually necessary, given
    that the doses observed in studies tend to be higher than the levels of
    exposure of regulatory concern. There are limits to the ability of both
    epidemiological and toxicological studies to detect changes in the

    likelihood of health effects with acceptable statistical precision,
    especially at the low- dose exposures typical of most environmental
    exposures and given practical limits to the sizes of research studies. A
    number of different models might be used for extrapolation, all giving
    plausible results. In its proposed revision of the carcinogen risk
    assessment guidelines, EPA identifies use of a biological extrapolation

    model as the preferred approach for quantifying risk. Such models integrate
    events in the carcinogenic process throughout the dose- response range from
    high to low doses and include physiologically based pharmacokinetic (PBPK)
    and biologically based dose- response models. PBPK models address the
    exposure- dose relationship in an organism taken

    as a whole, estimating the dose to a target tissue or organ by taking into
    account rates of absorption into the body, metabolism, distribution among
    target organs and tissues, storage, and elimination of an agent.
    Biologically based dose- response models describe specific biological
    processes at the cellular and molecular levels that link target- organ dose
    to the adverse event. These models are useful in extrapolation between
    animals and humans and between children and adults because they allow
    consideration of species- and age- specific data on physiological factors
    affecting dose levels and responses. However, biological models require
    substantial quantitative data and adequate understanding of the carcinogenic
    process for a specific agent. EPA cautions that the necessary data for using
    such

    models will not be available for most chemicals. Therefore, the agency?s
    guidelines describe alternative methods.

    Dose- response assessment is a two- step process when a biologically based
    model is not used. The first step is the assessment of observed data to
    derive a point of departure, and the second step is extrapolation from that
    point of departure to lower (unobserved) exposures. According to EPA

    guidelines, the agency?s standard point of departure for animal studies is
    the effective dose (ED) corresponding to the lower 95- percent confidence
    limit on a dose associated with 10- percent extra risk (LED 10 ) compared to
    the control group. 13 EPA may use a lower point of departure for data from
    human studies of a large population or from animal studies when such data
    are available. For the extrapolation step, EPA?s proposed guidelines provide
    three default approaches which assume, respectively, that the

    dose- response relationship is linear, nonlinear, or both. The choice of
    which default approach to apply is to be based on the available information
    on the mode( s) of action of the chemical agent.

    In the absence of sufficient mode of action information, or if the available
    mode of action information indicates that the dose- response curve at low
    doses is expected to be linear, the default is to use a linear approach for
    the extrapolation step. The assumption of linearity is generally considered
    a conservative, public- health protective default, intended to avoid
    underestimating risks at low doses. It is rooted in EPA?s traditional

    assumption for suspected carcinogens that no threshold exists regarding
    adverse effects (i. e., any exposure to carcinogenic substances, no matter
    how small, poses some risk of developing cancer). A linear, no- threshold
    model generally assumes that adverse health effects are proportional to
    exposure for any dose above zero. The linear approach is to draw a

    straight line between the point of departure from observed data- typically
    the LED 10 -and the origin (zero incremental dose, zero incremental
    response). (See fig. 3 below.) According to EPA?s guidance, this linear
    default approach is thought to generally provide an upper- bound calculation
    of potential risk at low doses. The agency also pointed out that it gives
    numerical results about the same as a linearized multistage approach, which
    is the default approach under the 1986 cancer guidelines.

    13 According to EPA, the LED is chosen to account protectively for
    experimental variability 10 and is an appropriate representative of the
    lower end of the observed range, because the limit of detection in studies
    of tumor effects is about 10 percent.

    Figure 3: Extrapolation for Carcinogens Extrapolation range Observed range
    Response

    on dose)

    x

    limit (Confidence

    x estimate)

    Human

    (Central

    exposure of interest

    x LED 10

    ED 10 10%

    Projected linear

    0% MOE Dose

    LED 10 = Lower 95 percent confidence limit on a dose associated with a 10
    percent extra risk ED 10 = Dose associated with a 10 percent extra risk MOE
    = Margin of exposure

    = Central estimate of dose- response curve = Confidence limit = Linear low-
    dose extrapolation

    Source: EPA Proposed Guidelines for Carcinogen Risk Assessment.

    The default changes to a ?margin of exposure? analysis when (1) adequate
    data on mode of action show that linearity is not plausible, and (2) the
    data provide sufficient evidence to support a nonlinear mode of action for
    the general population and any sub- populations of concern. Rather than
    estimating the probability of effects at low doses, a margin of exposure
    analysis compares the point of departure from study data with the dose

    associated with the environmental exposure( s) of interest by computing the
    ratio between the two. (See fig. 3 for a graphical representation of these
    two points.) If the available evidence indicates that the doseresponse may
    be adequately described by both a linear and a nonlinear approach, EPA?s
    default is to present both the linear and the margin of exposure analysis.

     Extrapolation from animal to human- equivalent doses When dose- response
    relationships are being extrapolated from the observed results of animal
    studies, it is also necessary to estimate what doses are of equivalent risk
    in the experimental animals (usually mice or rats) and humans. The objective
    of this interspecies ?scaling? is to define dose units that are presumed to
    lead to equivalent risk across species. Not

    only are rodents much smaller in size than humans, but they have shorter
    life spans and quicker metabolisms, all of which affect the equivalent dose.
    For carcinogens, EPA?s historical default had been to assume that end-
    oflife

    cancer risks will be equivalent across species when lifetime dosing is
    proportional to each species? body surface area. In practice, this ?surface

    area scaling? was calculated by using daily milligrams scaled by the 2/ 3-
    power of the species? body weight. EPA?s draft revision of the carcinogen
    guidelines presents a default for oral dose of scaling daily applied doses
    in proportion to body weight raised to the 3/ 4- power. This would be

    consistent with the 1992 recommendation from an interagency group. 14
    Scaling by this method generally results in human risk estimates that are
    slightly lower than those obtained from surface area scaling. For cross-
    species scaling of inhalation exposures, EPA uses a different approach- its
    reference concentration (RfC) methodology- to determine what is
    toxicologically equivalent. In the RfC approach, the agency estimates the
    respiratory deposition of particles and gases and the internal doses of
    gases with different absorption characteristics. EPA uses this

    approach because it is the concentration needed to produce an equivalent
    rate of loading the target tissue with deposited or absorbed chemical agent
    that is important in inhalation exposures, not simply the dose in the air.

    14 FDA and OSHA traditionally used an alternative assumption that risks are
    equivalent when dosing is proportional to each species? body weight but are
    now also using or considering (body weight) 3/ 4 .

     Extrapolation to different routes of exposure Exposure to a chemical agent
    may occur through inhalation, oral ingestion, or dermal contact. However,
    the data being used for a risk assessment may only reflect one of these
    routes of exposure, and that route may be different than the route of
    concern to agency regulators in a particular case. For example, available
    animal study data might indicate that ingestion of a chemical substance is
    associated with cancer, but risk

    assessors may need to consider the relevance of this ingestion data to the
    prediction of risks associated with inhalation exposures. In general, it is
    EPA?s position that adverse effects manifested through one route of exposure
    are relevant to consideration of any other route of exposure.

    However, EPA?s guidelines also caution that such route- to- route
    extrapolation should be consistent with existing biological information. 15

    Noncancer effects

    In contrast to its assessments of cancer risks, EPA?s traditional view of
    noncancer toxic effects has been that a threshold exists. In other words,
    the agency typically assumes that noncancer adverse effects occur only after
    a threshold level of exposure to an agent has been exceeded. 16 For
    noncancer effects, the primary objective of the agency?s assessment is to

    derive an RfD or, in the case of inhalation exposures, an RfC representing a
    concentration of the agent in the air rather than a dose. This RfD or RfC is
    an estimate of a daily exposure to an agent by the human population

    (including sensitive sub- groups) that is expected to be without an
    appreciable risk of deleterious effects during a lifetime. For most of its
    history, EPA has relied on a no observed adverse effect level (NOAEL)
    approach to estimate the RfD. However, the agency may also use other
    approaches, such as the benchmark dose approach, depending on the quality
    and type of data available. The NOAEL and benchmark dose approaches are
    described in more detail below.

    15 For example, a chemical that acts as a carcinogen because of the way the
    body metabolizes it via one route- such as ingestion into the stomach
    transforming the chemical into a toxin- may not be metabolized in the same
    way by another route. Carcinogenic effects, therefore, would not be expected
    via another route of exposure that does not produce this same metabolite.

    16 There are, however, exceptions to this general rule, such as reproductive
    toxicants that may act through genetic mutation mechanisms. In such cases,
    EPA will use the nothreshold approach described for suspected carcinogens.

    Similar to other agencies, EPA?s traditional procedure for addressing
    noncancer effects has been to define a NOAEL from experimental data and then
    apply uncertainty factors to estimate an RfD or RfC. In this approach,
    toxicologists first seek to identify the top of the range of dose levels
    without any observed adverse effect in animals. 17 Then, to estimate a dose
    to humans that will be similarly without effect, this dose level is divided
    by

    a set of uncertainty factors, typically factors of 10. 18 These uncertainty
    factors are used to account for the possibility of greater sensitivity among
    humans than in experimental animals, of greater sensitivity in some humans
    compared to average humans, and for other concerns. One such concern is if
    there was no dose in a study at which harmful effects were not detected. In
    such cases, extrapolation is instead based on the lowest observed adverse
    effect level (LOAEL), but an additional uncertainty factor

    would then be incorporated in the agency?s estimated dose. The choice and
    size of factors (e. g., 10 or 3) can vary from case to case, and EPA?s
    guidelines note that professional scientific judgment must be used in
    assigning uncertainty and modifying factors. EPA typically uses two or three
    factors (a division of the NOAEL dose by 100- to 1000- fold), and,

    under current policy, generally will use a maximum uncertainty factor of no
    greater than 3, 000. 19 However, EPA may also reduce the standard
    uncertainty factors if it has more informative pharmacokinetic data about

    variability among humans or across species. An additional ?modifying? factor
    may also be used when the areas of scientific uncertainty addressed with
    uncertainty factors do not represent all of the uncertainties in the
    estimation of a reference dose or concentration.

    EPA may also use the benchmark dose approach to identify a dose without
    appreciable effect from an experimental study. Unlike the NOAEL approach,
    the benchmark dose approach uses the entire set of available data on doses
    and responses; it is not limited to only considering the specific dose
    levels tested in the study. In this benchmark dose approach,

    17 Sometimes, a no observed effect level (NOEL) is used instead of a NOAEL.
    18 These are often referred to as ?safety factors? by other agencies and in
    general risk assessment literature. EPA, however, uses the term uncertainty
    factor instead of safety factor because of concerns that the latter implies
    an absolutely safe level, an assurance that the agency does not believe it
    can provide.

    19 It is EPA?s opinion that toxicity databases that are weaker and would
    result in uncertainty factors in excess of 3, 000 are too uncertain as a
    basis for quantification. In such cases, EPA no longer estimates an RfD.
    Before this policy was in place, factors of 10, 000 were applied for a few
    chemicals.

    researchers fit a dose- response curve using all of the data in the observed
    experimental range. EPA would typically use the modeled LED 10 dose as a
    point of departure to derive an RfD, and the agency would still apply
    uncertainty factors to this dose, as in the NOAEL approach. (See fig. 4.)

    Figure 4: Derivation of a Reference Dose Using the Benchmark Dose Approach
    100

    Increasing response 90 80 70 60

    UFs

    50 40 30 20 10

    LED ED10 10

    0 0 RfD

    50 100 150 200 250 300 350 Dose

    LED 10 = Lower 95 percent confidence limit on a dose associated with a 10
    percent extra risk

    ED 10 = Dose associated with a 10 percent extra risk RfD = Reference dose
    UFs = Uncertainty factors

    = Central estimate of dose- response curve = Confidence limit

    Source: EPA Methodology for Deriving Ambient Water Quality Criteria for the
    Protection of Human Health (2000); Technical Support Document Volume 1: Risk
    Assessment.

    Exposure Assessment EPA?s program offices usually perform the exposure
    assessment step, given the different exposure scenarios of interest for the
    separate regulatory programs. 20 However, EPA has published agencywide
    guidelines for

    exposure assessment that describe general principles and practices for
    conducting such assessments. The focus of EPA?s guidelines is on human
    exposures to chemical substances, but the agency noted that much of the
    guidance also applies to wildlife exposure to chemicals or human exposure to
    biological, physical (e. g., noise), or radiological agents. 21 EPA points
    out, though, that assessments in these other areas must consider additional
    factors that are beyond the scope of the exposure assessment guidelines.

    EPA?s guidelines establish a broad framework for agency exposure assessments
    by describing the general concepts of exposure assessment, standardizing the
    terminology (such as defining concepts of exposure, intake, uptake, and
    dose), and providing guidance on the planning and implementation of an
    exposure assessment. The guidelines are not, however, intended to serve as a
    detailed instructional guide. EPA?s guidance prescribes no standard format
    for presenting exposure assessment results, but recommends that all exposure
    assessments, at a minimum, contain a narrative exposure characterization
    section that

     provides a statement of purpose, scope, level of detail, and approach used
    in the assessment, including key assumptions;

     presents the estimates of exposure and dose by pathway and route for
    individuals, population segments, and populations in a manner appropriate
    for the intended risk characterization;

     provides an evaluation of the overall quality of the assessment and the
    degree of confidence the authors have in the estimates of exposure and dose
    and the conclusions drawn; 22

     interprets the data and results; and 20 As mentioned earlier in this
    appendix, sometimes ORD may do the entire risk assessment, including the
    exposure assessment step. 21 The guidelines also discuss the implications
    for exposure assessment if the assessment is to be used for purposes other
    than risk assessment (e. g., to determine whether exposure occurs, to
    monitor status and trends, or to establish exposure- incidence in
    epidemiologic studies).

    22 The guidelines note that it is common for the single largest source of
    uncertainty in an exposure assessment to be the estimate of the duration of
    an individual?s contact with a chemical at a given concentration. The
    concentration of the chemical in the media (e. g., air, soil, or water)
    often is known with more certainty than the activities of the exposed
    individual( s).

     communicates the results of the exposure assessment to the risk assessor,
    who can then use this information with the results from other risk
    assessment elements to develop the overall risk characterization. The
    guidelines encourage agency staff to use multiple ?descriptors? of both
    individual and population risks, rather than a single descriptor or risk
    value. The exposure guidelines also emphasize the use of more realistic

    estimates of high- end exposures than had been the case in some previous
    practices. In the past, EPA sometimes relied on exposure estimates derived
    from a hypothetical ?maximally exposed individual? who might spend, for
    example, a 70- year lifetime drinking only groundwater with the highest
    concentrations of contaminants detected. According to the 1997 report of the
    Presidential/ Congressional Commission, this approach was

    often based on such unrealistic assumptions that it impaired the scientific
    credibility of risk assessments. Now, however, EPA has adopted the use of
    distributions of individual exposures as the preferred practice. EPA?s
    guidance indicates that risk assessments should include both central
    estimates of exposure (based on either the mean or median exposure) and

    estimates of the exposures that are expected to occur in small, but
    definable, high- end segments of the population. EPA states that a high- end
    exposure estimate is to be a plausible estimate of the individual exposure
    for those persons at the upper end of an exposure distribution. The agency?s
    intent is to convey an estimate of exposure in the upper range of the
    distribution, but to avoid estimates that are beyond the true distribution.
    23

    EPA has identified several new directions in its approach to exposure
    assessment. First is an increased emphasis on total (aggregate) exposure via
    all pathways. EPA policy directs all regulatory programs to consider in
    their risk assessments exposures to an agent from all sources, direct and

    indirect, and not just from the source that is subject to regulation by the
    office doing the analysis. Another area of growing attention is the
    consideration of cumulative risks, when individuals are exposed to many
    chemicals at the same time. The agency is also increasing its use of
    probabilistic modeling methods, such as Monte Carlo analysis, to analyze
    variability and uncertainty in risk assessments and provide better estimates

    of the range of exposure, dose, and risk in individuals in the population.
    23 The guidelines state that, conceptually, the high end of the distribution
    means above the 90 th percentile of the population distribution, but not
    higher than the individual in the population who has the highest exposure.

    EPA policy directs regulatory programs to pay special attention to the risks
    of children and infants. EPA has produced some reference documents for
    exposure assessments, such as the Exposure Factors Handbook. 24 This
    handbook is intended to provide parameter values for use across the agency
    and to encourage use of reasonable exposure estimates by providing
    appropriate data sources and suggested methods. The handbook provides a
    summary of available

    statistical data on various factors used to assess human exposure to toxic
    chemicals. These factors include: drinking water consumption; soil
    ingestion; inhalation rates; dermal factors including skin area and soil
    adherence factors; consumption/ intake of fruits and vegetables, fish,

    meats, dairy products, homegrown foods, and breast milk; human activity
    patterns, such as time spent performing household tasks; consumer product
    use; and residential characteristics. EPA provides recommended values for
    the general population and also for various segments of the population who
    may have characteristics different from the general population (e. g., by
    age, gender, race, or geographic location). EPA

    guidance cautions, though, that these general default values should not be
    used in the place of known, valid data that are more relevant to the
    assessment being done. The default values used in EPA risk assessments,
    however, sometimes vary slightly from the recommended values appearing in
    the handbook. For example, while the handbook?s mean recommended

    value for adult body weight is 71. 8 kilograms (kg), the handbook also noted
    that a value of 70 kg has been commonly assumed in EPA?s risk assessments.
    Similarly, the recommended value to reflect average life expectancy of the
    general population is 75 years, but 70 years also has been

    commonly assumed in EPA risk assessments. Officials from EPA program offices
    pointed out that they may use different exposure factors in their risk
    assessments because they sometimes develop exposure assessment methods
    specific to their programs using different data sources or

    population characteristics than those used by ORD for the Exposure Factors
    Handbook.

    Ecological Risk Assessment Ecological risk assessment is different from
    human health risk assessment in that it may examine entire populations of
    species and measure effects on partial or whole ecosystems. Often, the focus
    is on not just a single ecological entity, but on the potential adverse
    effects on multiple species 24 The agency also has a Wildlife Exposure
    Factors Handbook for ecological risk assessments, and a Children?s Exposure
    Factors Handbook is also in development.

    and their interactions (for example, on the food chain). While human health
    risk assessment is primarily concerned with an agent?s toxicity to humans,
    ecological risk assessment might consider a range of adverse

    effects on natural resources (such as crops, livestock, commercial
    fisheries, and forests), wildlife (including plants), aesthetic values,
    materials or properties, and recreational opportunities. For example, a
    chemical agent could be considered a risk to wildlife if exposure to it
    caused death, disease, behavioral abnormalities, mutations, or deformities
    in the members of a species or their offspring. It could be considered a
    risk to aesthetic values if it affected the color, taste, or odor of a water
    source. By EPA?s definition, ecological risk assessment is a process that
    evaluates the likelihood that adverse ecological effects may occur or are
    occurring as a result of exposure to one or more ?stressors.? In other
    words, ecological risk assessments may be prospective or retrospective, and,
    in many cases,

    both approaches are included in a single risk assessment. Chemicals are only
    one of the possible ecological stressors that EPA might consider, along with
    physical and biological ones. 25 EPA?s guidance focuses on stressors and
    adverse ecological effects generated or influenced by human activity, which
    could be addressed by the agency?s risk management decisions.

    In comparison to human health risk assessment procedures, the approaches for
    ecological risk assessment are more recent and less well developed. However,
    as these methods have changed to incorporate and

    better characterize dynamic, interconnected ecological relationships, EPA
    has updated its guidance documents on the subject, with input from multiple
    interested internal and external parties. According to EPA, the solicitation
    of input from an array of sources is based, in part, on the need

    to establish a framework for characterizing risks based on numerous
    stressors, interconnected pathways of exposure, and multiple endpoints
    (adverse effects).

    25 For example, the alteration of a wildlife habitat would be a physical
    stressor and the introduction of a nonnative invasive species would be a
    biological stressor.

    The most recent version of EPA?s framework appears in Guidelines for
    Ecological Risk Assessment, published in 1998. 26 EPA?s guidelines describe
    an iterative three- phase process consisting of problem formulation,
    analysis, and risk characterization. These guidelines incorporate many of
    the concepts and approaches called for in human health risk assessments.
    However, particularly in the addition of a problem formulation phase, the
    ecological risk assessment framework deviates from the standard four- step

    process used for human health risk assessments. EPA pointed out that, unlike
    human health assessments where the species of concern and the endpoints (e.
    g., cancer) have been predetermined, ecological risk assessments need a
    phase that focuses on the selection of ecological

    entities and endpoints that will be the subject of the assessment. Table 4
    summarizes the activities and expected outcomes for each of the three phases
    of an ecological risk assessment. Prior to these phases, according to EPA, a
    planning stage occurs during which risk assessors, risk managers, and other
    interested parties are to have a dialogue and scope the problem.

    Table 4: Summary of EPA?s Ecological Risk Assessment Process Phase Actions
    Products

    Problem formulation  Articulate purpose for assessment

     Assessment endpoints

     Define problem

     Conceptual models

     Determine plan for analyzing and characterizing risk

     Analysis plan

     Integrate available information on sources, stressors, effects, and
    ecosystem and receptor characteristics Analysis  Characterize exposure

     Exposure profile

     Characterize ecological effects  Stressor- response profile Risk
    characterization  Estimate risk

     Risk description

     Summarize assumptions, scientific uncertainties, and strengths and
    limitations of the analyses

    Source: EPA Guidelines for Ecological Risk Assessment.

    Among the things considered during problem formulation is the selection of
    assessment endpoints, which are ?explicit expressions of the actual
    environmental value that is to be protected.? This is unlike human health

    26 EPA has published other, more detailed guidance documents addressing
    specific ecological risk assessment topics relevant to its program offices.
    For example, Ecological Risk Assessment Guidance for Superfund: Process for
    Designing and Conducting Ecological Risk Assessments from 1997 is specific
    to EPA?s Superfund Program requirement for an ecological risk assessment.

    assessments, where the species of concern and the endpoints have been
    predetermined. The selection of endpoints at EPA has traditionally been done
    internally by program offices, but more recently, affected parties or
    communities are assisting in the selection of endpoints with their selection

    based on ecological relevance, susceptibility, and relevance to management
    goals. Furthermore, conceptual models are developed during the problem
    formulation phase. Such models contain risk hypotheses in the form of
    written descriptions and visual representations, outlining predicted
    relationships between ecological entities and the stressors to which they
    may be exposed. According to EPA the hypotheses are in effect assumptions,
    being based on theory and logic, empirical data, mathematical models,
    probability models, and professional judgment.

    Subsequently, during the analysis phase data are selected that will be used
    on the basis of their utility for evaluating risk hypotheses. The major
    items considered during this phase are the sources and distribution of
    stressors in the environment, the extent of contact and stressor- response

    relationships, the evidence for causality, and the relationship between what
    was measured and the assessment endpoint( s). Field studies involving
    statistical techniques (i. e., correlation, clustering, or factor analysis),
    surveys, the formation of indices, and the use of models are approaches to

    evaluating the determined risk hypotheses. (EPA?s guidance on the risk
    characterization phase of an ecological risk assessment is discussed in the
    final section of this appendix.)

    Program- Specific Risk EPA?s various program offices generally follow the
    agencywide risk

    Assessment Procedures assessment procedures and guidelines described above.
    The major exception to this is the Chemical Emergency Preparedness and
    Prevention

    Office, which does not follow the NAS four- step process for its risk
    assessment procedures because of its focus on risks associated with
    accidental chemical releases. Overall, there is great diversity in the
    context for risk assessment activities across EPA?s program offices. Each
    program has different statutory mandates and risk assessment tasks
    associated with its specific regulatory authority, and these contribute to
    variations in the way the offices conduct risk assessments. In particular,
    there are differences in the exposure assessment step across, and sometimes
    within,

    EPA?s program offices. This is not surprising, given that EPA?s regulatory
    authorities regarding chemical agents primarily vary according to types and
    sources of exposure. Although there are overlaps in these various exposures
    to chemicals, EPA?s program offices generally assess and regulate different
    aspects of the risks associated with exposures to humans

    and/ or the environment. There are also some variations in the conduct of
    hazard identification and dose- response analysis. The following sections
    summarize the risk assessment activities and procedures of those EPA

    program offices that are most likely to conduct assessments involving
    chemical risks. The descriptions highlight some of the major variations and
    similarities across the program offices.

    Office of Pesticide Programs OPP is part of EPA?s Office of Prevention,
    Pesticides and Toxic Substances (OPPTS). The primary risk assessment-
    related activities of OPP are the registration of pesticides and the setting
    of tolerances for pesticide residues. 27 Registration involves the licensing
    of pesticides for sale and use in agriculture and extermination. No chemical
    may be sold in the United States as a pesticide without such registration,
    which establishes the conditions of legal use. All uses within the scope of
    the registration conditions and limits are permissible, although actual
    practice may vary. Pesticide tolerances are the concentrations (maximum
    pesticide residue

    levels) permitted to remain in or on food, as it is available to the
    consumer. Registrations and tolerances are obtained through petitions to
    OPP. The petitioner has the primary responsibility to provide the data
    needed to support registration and tolerances, including information on the
    toxicological effects of the pesticide. There are three major risk statutes
    affecting EPA?s actions regarding pesticides. Registration is carried out
    under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).
    Tolerances are established under

    the Federal Food, Drug, and Cosmetic Act (FFDCA). 28 In 1996, Congress
    amended both FIFRA and FFDCA through the FQPA, which mandated some key
    changes in risk assessment of pesticides. Major features and characteristics
    of chemical risk assessment by OPP are summarized below.

     OPP conducts all steps of risk assessments. Because OPP generally follows
    the NAS four- step process for human health risk assessment and 27 The term
    ?pesticide? includes many kinds of ingredients used in products, such as
    insecticides, fungicides, rodenticides, insect repellants, weed killers,
    antimicrobials, and swimming pool chemicals, which are designed to prevent,
    destroy, repel, or reduce pests of any sort. 28 While EPA administers the
    setting of pesticide tolerances, FDA has authority over enforcement of the
    tolerances.

    the EPA- wide risk assessment guidelines, most of its procedures mirror
    those used elsewhere in the agency.

     OPP officials noted that, over the last three decades, their office has
    developed a rigorous process to support the development of chemical risk
    assessments. This process includes regulations to establish

    baseline data requirements and published guidelines for conducting required
    studies. OPP officials emphasized the transparency of the process used to
    develop EPA?s risk assessment procedures and the transparency of the
    procedures EPA uses to make decisions on the risk of individual pesticides.
    As an example, they noted that their program has consulted with outside
    experts and asked for public comment on its

    guidelines for reviewing studies, science policies for assessing the
    significance of study data, and standard operating procedures for
    implementing these policies in the development of a hazard identification or
    exposure assessment for a chemical. They also pointed out that OPP adopted a
    public participation process for reregistration and tolerance reassessment
    decisions on registered pesticides and that they publish for public comment
    proposed tolerances for proposed new uses of pesticides. In some
    circumstances, OPP consults with outside experts concerning a risk
    assessment of an individual pesticide.

     Pesticide registration decisions are based primarily on OPP?s evaluation
    of the test data provided by petitioners (applicants). EPA has established a
    number of requirements, such as the Good Laboratory Practice Standards, to
    ensure the quality and integrity of pesticide data. OPPTS has also developed
    harmonized test guidelines for use in the testing of pesticides and toxic
    substances and the development of test

    data that must be submitted to EPA for review under federal regulations. 29
    Depending on the type of pesticide, OPP can require more than 100 different
    tests to determine whether a pesticide has the potential to cause adverse
    effects to humans, wildlife, fish, and plants.

    29 OPPTS developed these guidelines through a process of harmonization that
    blended the testing guidance and requirements that existed in OPP, OPPT, and
    guidelines published by the Organization for Economic Cooperation and
    Development. The purpose of harmonizing

    these guidelines into a single set of OPPTS guidelines was to minimize
    variations among the testing procedures that must be performed to meet EPA
    data requirements under FIFRA (for OPP) and TSCA (for OPPT). The pesticide
    data requirements are set out in 40 CFR 158.

     The FQPA established a single, health- based standard-? reasonable
    certainty of no harm?- for pesticide residues in all foods. 30 All existing
    tolerances that were in effect when the FQPA was passed are to be
    reevaluated by 2006 to ensure that they meet the new safety standard.

    The law requires EPA to place the highest priority for tolerance
    reassessment on pesticides that appear to pose the greatest risk. To make
    the finding of ?reasonable certainty of no harm? OPP considers: 1. the
    toxicity of the pesticide and its break- down products; 2. how much of the
    pesticide is applied and how often; and 3. how much of the pesticide remains
    in or on food by the time it is marketed and prepared (the residue).

     Among other key changes affecting OPP?s risk assessments when setting
    tolerances, the FQPA requires the agency to:

    1. Explicitly address risks to infants and children and to publish a
    specific safety finding before a tolerance can be established. It also
    requires an additional tenfold uncertainty factor (unless reliable data show
    that a different factor will be safe) to account for the possibly greater
    sensitivity and exposure of children to pesticides.

    2. Consider aggregate exposure from a pesticide, including all anticipated
    dietary and all other exposures for which there is reliable information.
    These include exposures through food, drinking water, and nondietary

    exposures encountered through sources in the home, recreational areas, and
    schools. 31 3. Consider cumulative exposures to pesticides with a common
    mechanism of toxicity, which previously had been considered separately. 32

    30 This eliminated problems caused by prior differences in the standards
    that applied to raw versus processed foods. 31 Occupational exposures are
    regulated separately.

    32 See Children and Pesticides: New Approach to Considering Risk Is Partly
    in Place (GAO/ HEHS- 00- 175, Sept. 11, 2000) for more detailed information
    on EPA?s progress in implementing the FQPA provisions.

     Title III of the FQPA also requires certain data collection activities of
    the Secretary of Agriculture, in consultation or cooperation with the
    Administrator of EPA and the Secretary of Health and Human Services,
    regarding food consumption patterns, pesticide residue levels, and pesticide
    use that, according to EPA, affect its risk assessments when setting
    tolerances.

     Also as a result of the FQPA, OPP uses a population adjusted dose (PAD),
    which involves dividing the acute or chronic reference dose by the FQPA
    uncertainty factor. According to OPP officials, this allowed OPP to be
    consistent with the rest of the agency regarding setting RfDs, but still use
    the FQPA factor for regulating pesticides.

     OPP is concerned with both cancer and noncancer toxicity. However, for
    noncancer effects, OPP has paid special attention to neurotoxicity (because
    many pesticides work through this mechanism) and, more recently, to
    endocrine disrupting effects (those affecting the body?s hormone system). 33

     OPP officials noted that, while their agency has made important use of
    ?real life? monitoring or incident data, it primarily relies on studies
    conducted in laboratory animals and on laboratory or limited field studies.
    They stated that, in their experience, ?real life? data have profound
    limitations and that such data are inconsistent, expensive, inconclusive,
    and are not available for premarket decision making.

    They said that, most importantly, by the time there are observable health or
    environmental effects, it is too late to prevent the harm that could have
    been predicted from judicious use of animal or environmental fate studies
    conducted in the laboratory.  During the exposure assessment step, OPP is
    concerned with a variety of routes, sources, and types of exposure. The
    three routes by which

    people can be exposed to pesticides are inhalation, dermal (absorbing 33
    Because of the potentially serious consequences of human exposure to
    endocrine disrupting chemicals, Congress included specific provisions on
    this topic in both the FQPA and the 1996 amendments to the Safe Drinking
    Water Act. In response to the FQPA language, EPA developed its Endocrine
    Disruptor Screening Program, which focuses on providing methods and
    procedures to detect and characterize endocrine activity of pesticides,
    commercial chemicals, and environmental contaminants. EPA uses a tiered
    approach for these risk assessments, sorting chemicals into four categories
    on the basis of the existing scientific data.

    pesticides through the skin), and oral (getting pesticides in the mouth or
    digestive tract). Depending on the situation, a pesticide could enter the
    body by any one or all of these routes. Typical sources of pesticide

    exposure include food, home and personal use of pesticides, drinking water,
    and work- related exposure to pesticides (in particular, to pesticide
    applicators or vegetable and fruit pickers). In its approach to exposure
    assessment, OPP distinguishes between residential and occupational types of
    exposures. OPP officials noted that their program is further developing
    procedures to conduct drinking water exposure assessments and residential
    exposure assessments and that they have new procedures for ecological risk
    assessments.

     OPP calculates estimates of acute (i. e., short- term) pesticide exposure
    slightly differently from those for chronic (i. e., longer- term) exposures.
    This is because an acute assessment estimates how much of a pesticide

    residue might be consumed in a single day, while a chronic assessment
    estimates how much might be consumed on a daily basis over the course of a
    lifetime. In an important difference, acute assessments are based on high-
    end individual exposure assumptions, while chronic

    assessments use average exposure assumptions.

     In assessing both acute and chronic risks, OPP uses a tiered approach,
    starting with an initial screening tier and proceeding through progressively
    more elaborate risk assessments, if needed. The analytical tiers proceed
    from more conservative to less conservative assumptions. For the first- tier
    risk assessment, OPP uses ?worst- case? assumptions (e. g., that pesticide
    residues are at tolerance levels and that

    100 percent of the food crop is treated with the pesticide) that give only
    an upper- bound estimate of exposure. For more refined analyses, OPP
    officials noted that they have new procedures for conducting probabilistic
    dietary exposure assessments. Generally, the level of resources and the data
    needed to refine exposure estimates increase with each tier. Typically, if
    risks from pesticide residues are not of concern using lower- tier exposure
    estimates, OPP does not make

    further refinements through additional tiers. However, with the aggregate
    and cumulative exposure assessments now required by the FQPA, EPA notes that
    it is likely that higher- tier exposure estimates will be needed.

     The agency has developed procedures for modeling the environmental fate of
    pesticides. OPP officials said that these models use real data on the
    physical and chemical properties of the pesticide, information on the

    proposed or actual uses of the pesticide, and real data on the movement of
    pesticides or other materials through soil, air, water, skin, textiles, or
    other media to predict potential exposures to a pesticide. These models are
    guided by scientific judgments that are based upon data and

    scientists? experience in drawing inferences from these data. Office of
    Pollution Prevention OPPT (formerly the Office of Toxic Substances) is also
    part of OPPTS. and Toxics

    OPPT was established to implement the Toxic Substances Control Act (TSCA),
    which authorizes EPA to screen existing and new chemicals used in
    manufacturing and commerce to identify potentially dangerous products or
    uses. 34 TSCA focuses on the properties of a chemical and paths of exposure
    to that chemical. Risk assessment activities are primarily related

    to four sections of TSCA:

     Section 4 directs EPA to require manufacturers and processors to conduct
    tests for existing chemicals when: (1) their manufacture, distribution,
    processing, use, or disposal may present an unreasonable risk of injury to
    health or the environment; or (2) they are to be produced in substantial
    quantities and the potential for environmental release or human exposure is
    substantial or significant. Under either condition, EPA must issue a rule
    requiring testing if existing data are insufficient to predict the effects
    of human exposure and environmental releases and testing is necessary to
    develop such data. Rhomberg pointed out that these conditions require OPPT
    to do some preliminary

    risk assessment and that, unlike testing mandates under other statutes (e.
    g., regarding pesticides), the agency has the burden of showing that such
    testing is necessary. 35

     Section 5 addresses future risks through EPA?s premanufacture screening-
    the premanufacture notification (PMN) process. This also applies to a
    ?significant new use? of an existing chemical.

     Section 6 directs EPA to control unreasonable risks presented or that will
    be presented by existing chemicals. 34 15 U. S. C. 2601 et seq. In addition
    to its original role to implement TSCA, OPPT has been given responsibility
    for pollution prevention programs; regulation of specific toxic substances,
    including asbestos, radon, and lead; and administration of the Toxics
    Release Inventory. 35 Lorenz Rhomberg, A Survey of Methods for Chemical
    Health Risk Assessment Among Federal Regulatory Agencies, a report prepared
    for the Presidential/ Congressional

    Commission on Risk Assessment and Risk Management (1996).

     Section 8 requires EPA to gather and disseminate information about
    chemical production, use, and possible adverse effects to human health and
    the environment. This section requires EPA to develop and maintain an
    inventory of all chemicals, or categories of chemicals, manufactured or
    processed in the United States. All chemicals not on the inventory are, by
    definition, ?new? and subject to the notification provisions of section 5.
    Once a chemical enters commerce through the section 5 process, it is listed
    as an existing chemical.

    Although TSCA gives EPA general authority to seek out and regulate any
    ?unreasonable risk? associated with new or existing chemicals, there are two
    major limitations on the agency?s regulatory actions. First, as implemented
    by EPA, regulation under TSCA involves consideration of both risks and
    applying the least burdensome requirement needed to

    regulate the risk. The term ?unreasonable risk? is not defined in TSCA.
    However, according to EPA, the legislative history indicates that
    unreasonable risk involves the balancing of the probability that harm will
    occur, and the magnitude and severity of that harm, against the effect of a
    proposed regulatory action on the availability to society of the expected
    benefits of the chemical substance. The second major limitation on EPA?s
    authority under TSCA is a requirement to defer to other federal laws.
    Generally, if a risk of injury to health or the environment could be
    eliminated or reduced to a sufficient extent by actions taken under another
    federal law, that other law must be deferred to unless it can be shown to be
    in the public interest to regulate under TSCA.

    The major distinction in the procedures that apply to OPPT risk assessments
    is between the evaluation of potential risks associated with exposures to
    new versus existing chemicals. For EPA to control the use of a chemical
    listed on the inventory of existing chemicals, according to

    OPPT, a legal finding has to be made that the chemical will present an
    unreasonable risk to human health or the environment. According to OPPT,
    this standard requires the agency to have conclusive data on that particular
    chemical. The agency noted, in comparison, that newly introduced chemicals
    (or uses) can be regulated under TSCA based on whether they may present an
    unreasonable risk, and this finding of risk can

    be based on data for structurally similar chemicals. Because industrial
    chemicals in commerce in 1975- 1977 were ?grandfathered? into the inventory
    without considering whether they were hazardous, there are situations in
    which existing chemicals might not be controlled, while EPA would act to
    control a new chemical of similar or less toxicity under the PMN program.
    Additional information on the major features and

    characteristics of assessments for new versus existing chemicals is
    presented below.

    Premanufacture notification for new chemicals or significant new uses

     TSCA requires manufacturers, importers, and processors to notify EPA at
    least 90 days prior to introducing a new chemical into the U. S. or
    undertaking a significant new use of a chemical already listed on the TSCA
    inventory. If available, test data and information on the chemical?s
    potential adverse effects on human health or the

    environment are to be submitted to EPA. Much of this submission must be kept
    confidential by OPPT. However, there is no defined toxicity data set
    required before PMN, and, unless EPA promulgates a rule requiring the
    submission of test data, TSCA does not require prior testing of new
    chemicals. Consequently, according to EPA, less than half of the PMNs
    submitted include toxicological data. OPPT reviews approximately 1,500 PMNs
    annually.

     EPA has 90 days after notification to evaluate the potential risk posed by
    the chemical. EPA must then decide whether to (1) permit manufacture and
    distribution (the default if EPA takes no action), (2) suspend manufacture
    and distribution or to restrict use pending the development of further data,
    or (3) initiate rulemaking to regulate manufacture or distribution.

     OPPT typically has very limited chemical- specific data on toxic effects
    and exposure associated with new chemicals. When no data exist on the
    effects of exposure to a chemical, EPA may make its determination on what is
    known about the chemical?s molecular structure (called the structure-
    activity relationship, or SAR) and the effects of other chemicals that have
    similar structures and are used in similar ways.

    OPPT?s New Chemicals Program has issued a document entitled

    Chemical Categories that describes information for numerous classes of
    chemicals. In assessing exposures for new chemicals where exposure
    monitoring data are unavailable, OPPT uses several screeninglevel
    approaches, including (1) estimates based on data on analogous chemicals;
    (2) generic scenarios (i. e., standardized approaches for

    assessing exposure and release for a given use scenario); (3) mathematical
    models based on empirical and theoretical data and information; and (4)
    assumptions of compliance with regulatory limits, such as OSHA Permissible
    Exposure Limits (PELs).

     Rhomberg noted that OPPT cannot require full testing for all chemicals,
    because of statutory limitations under TSCA. He therefore characterized
    OPPT?s assessments as ?rough screens? designed to flag situations in which
    further testing should be required.

    Assessments of existing chemicals

     Chemicals that OPPT assesses for regulation under sections 4 or 6 of TSCA
    are subject to a more rigorous risk assessment process. Compared to PMN
    reviews, such assessments are much more similar to those conducted elsewhere
    in EPA, so the EPA- wide guidelines generally apply.

     For hazard identification and dose- response assessment of carcinogens and
    noncancer effects, OPPT follows EPA- wide procedures. Because TSCA focuses
    on the properties of a chemical, rather than on a specific pathway or mode
    of exposure, OPPT considers the potential hazards posed through multiple
    routes of exposure. In lieu of information to the contrary, OPPT typically
    presumes that the results for one route are applicable to other routes.

     Similarly, in exposure assessment OPPT considers a variety of types and
    routes of exposure. Unlike other programs that focus on exposure through one
    medium, assessments under TSCA must assess all potential exposures to a
    chemical that may lead to unreasonable risk, considering, for example, both
    residential and occupational exposures. These risks may be assessed
    separately for each mode of exposure, even

    if occurring in the same setting. Overall, OPPT aims to provide both central
    estimates and upper- bound estimates of exposure, and it considers
    population risks as well as individual risks.

     OPPT shares overlapping concerns about a number of different kinds of
    exposure with other federal regulatory agencies. However, some aspects of
    OPPT?s exposure assessments may differ from those of other

    programs or agencies concerned with similar exposures. For example, with
    regard to occupational exposures OPPT assumes that a working lifetime is 40
    years, rather than the 45 years assumed by OSHA. Another example is the
    assumption of body weight; OPPT uses 70kg, whereas ORD recommends a value of
    71.8 kg in its Exposure Factors Handbook.

    In addition to the assessment of chemicals for regulation under sections 4
    and 6 of TSCA, OPPT has recently launched a new program to voluntarily add
    screening- level hazard information on approximately 2, 800 highproduction-
    volume industrial chemicals and has proposed a second new voluntary program
    to address the risks of certain industrial chemicals to which children may
    be exposed. These two new programs operate under the same risk assessment
    processes used in the other OPPT programs noted above.

    Office of Emergency and OERR is part of EPA?s Office of Solid Waste and
    Emergency Response Remedial Response (Superfund (OSWER). Risk assessments
    are a required component of a larger Program)

    remediation process established by the Comprehensive Environmental Response,
    Compensation, and Liability Act of 1980 (CERCLA or Superfund), as amended by
    the Superfund Amendments and Reauthorization Act of 1986 (SARA). 36 Congress
    enacted CERCLA to facilitate the cleanup of hazardous waste sites. The act
    gave EPA broad

    authority to respond to releases of hazardous substances. SARA requires EPA
    to emphasize cleanup remedies that treat- rather than simply contain-
    contaminated waste to the maximum extent practicable and to

    use innovative waste treatment technologies. Hazardous substances are
    defined by CERCLA to include substances identified under the Solid Waste
    Disposal Act, the Clean Water Act, the Clean Air Act, and the Toxic
    Substances Control Act, or designated by EPA. After investigating
    potentially hazardous sites, EPA ranks them according to the severity of
    their waste problems and places the worst on its National Priorities List
    for Superfund cleanup. Under CERCLA section 105, EPA uses a Hazard Ranking
    System to decide which sites to include on the list. Section 105 states that
    priorities are to be based upon relative risk or

    danger to public health or welfare or the environment, taking into account
    the population at risk, the hazard potential of the hazardous substances,
    and the potential for contamination of air and drinking water, among other
    factors.

    OERR has developed a human health and environmental evaluation process as
    part of its remedial response program. Major features and characteristics of
    the Superfund risk assessment procedures are summarized below.

    36 42 U. S. C. 9601- 9675.

     Overall, the risk scenarios for Superfund can be very complex. Superfund
    sites are often associated with multiple potential pathways and routes of
    exposure, and mixtures of chemicals at Superfund sites are common. In
    addition, the Superfund program is required to consider ecological as well
    as human health risks.

     A risk assessment is performed after a particular site has been identified
    according to the National Contingency Plan, EPA?s regulation outlining
    requirements relevant to response action( s) for hazardous substances. The
    remedial response process under the National Contingency Plan- and the role
    of risk information in the process- is summarized in the following seven
    steps:

    1. Site discovery or notification:

     report determinations about which substances are hazardous. 2. Preliminary
    assessment and site inspection:

     collect and review all available information to evaluate the source and
    nature of hazardous substances. 3. Hazard ranking system:

     compile data from steps one and two in a numerical scoring model to
    determine a relative risk measure. 4. Possible inclusion of site on the
    National Priorities List based on one of the following criteria:

     the release scores sufficiently high pursuant to the Hazard Ranking
    System,

     a state designates a release as its highest priority, or

     the release satisfies all of the following criteria:

     the Agency for Toxic Substances and Disease Registry has issued a health
    advisory that recommends dissociation of individuals from the release, 37

     EPA determines that the release poses a significant threat to public
    health, and 37 The Agency for Toxic Substances and Disease Registry within
    the Department of Health and Human Services has an oversight role but no
    regulatory authority. It prepares ?health assessments? rather than risk
    assessments that tend to be qualitative in nature, site specific, and
    focused on medical and public health perspectives. Exposures to site
    contaminants are presented in terms of sensitive populations, mechanisms of
    toxic chemical action, and possible disease outcomes. In contrast, EPA?s
    human health evaluation, which is more quantitative, is a characterization
    of the potential for adverse effects from human exposures

    to environmental hazards.

     EPA anticipates that it will be more cost effective to use its remedial
    authority than to use removal authority to respond to the release.

    5. Remedial investigation and feasibility study:

     characterize the contamination at site where data is obtained to identify,
    evaluate, and select cleanup alternatives. 6. Selection of a remedy:

     choose remedy that is protective of human health and the environment by
    eliminating, reducing, or controlling risks posed through each pathway, and

     utilize risk information obtained during step five. 7. 5- year review.

    One intended result of the remedial steps is the facilitation of a
    sitespecific baseline risk assessment, designed to support risk management
    decision making. Human health and ecological risk assessments occur during
    step five, the Remedial Investigation/ Feasibility Study stage.

     For human health risk assessments, Superfund procedures approximate the
    NAS paradigm, using the following four stages. 1. A data collection and
    evaluation stage that involves:

     gathering and analyzing site data relevant to the human health evaluation,
    and

     identifying substances present at the site that are the focus of the risk
    assessment process. 2. An exposure assessment that involves:

     analyzing contaminant releases,

     identifying exposed populations,

     identifying potential exposure pathways and estimating exposure
    concentrations for pathways, and

     estimating contaminant intakes for pathways. 3. A toxicity assessment
    stage that considers:

     types of adverse health effects associated with chemical exposures,

     relationships between magnitude of exposure and adverse effects,

     related uncertainties such as the weight evidence of a particular
    chemical?s carcinogenicity in humans, and

     existing toxicity information developed through hazard identification and
    dose- response assessment. 4. A risk characterization that involves:

     characterizing potential for adverse health effects (cancer or noncancer)
    to occur,

     evaluating uncertainty, and

     summarizing risk information.

     For ecological risk assessments, EPA?s guidelines suggest that Superfund
    remedial actions generally should not be designed to protect organisms on an
    individual basis, but should protect local populations and communities of
    biota. 38 Furthermore, except for a few very large sites, Superfund
    ecological risk assessments typically do not address effects on entire
    ecosystems. Instead, they gather data regarding the effects on individuals
    in order to predict or postulate potential effects on local wildlife, fish,
    invertebrate, and plant populations and communities that occur or that could
    occur in specific habitats at sites (e. g., a wetland, floodplain, stream,
    estuary, or grassland). Specifically, the guidelines recommend that
    ecological risk assessments performed

    at every site follow an eight- step process: 1. Screening- level problem
    formulation and ecological effects evaluation:

     site history,

     site visit,

     problem formulation, and

     ecological effects evaluation. 2. Screening- level exposure estimate and
    risk calculation:

     exposure estimate, and

     risk calculation. 3. Baseline risk assessment problem formation:

     ecotoxicity literature review,

     exposure pathways,

     assessment endpoints and conceptual model, and

     risk questions. 4. Measurement endpoints and study design. 5. Verification
    of field sampling design. 6. Site investigation and data analysis. 7. Risk
    characterization. 8. Risk management.

     OERR uses a tiered approach for Superfund risk assessments, in which the
    agency employs more conservative methods and assumptions in the initial
    screening phases, followed by a more rigorous, multistage risk assessment if
    screening results indicate the need. Under Superfund,

    38 An exception would be actions affecting designated protected status
    resources that could be exposed to site releases. Such resources include
    treaty- protected species and species that are listed as or candidates for
    threatened or endangered status.

    decisions generally are made on a site- by- site basis. According to agency
    officials, early activities at Superfund sites are often based on initial
    tier screening. However, they pointed out that the remedial cleanup decision
    is supported by a site- specific risk assessment that is usually quite
    detailed with either site- specific exposure assumptions or

    national default assumptions appropriate to the site which result in ?high-
    end? reasonable risk estimates. Although the Superfund program initially
    employed an approach of using a hypothetical ?worst case? scenario for
    exposure assessments, EPA?s exposure assessment guidance now emphasizes use
    of a more realistic upper- bound exposure

    scenario. The EPA guidelines emphasize that this exposure scenario should be
    in the range of plausible real exposures, and also call for a central
    tendency case. In addition, guidelines put forth by the Superfund program
    office emphasize streamlining the process and reducing the cost and time
    required, focusing on providing information necessary to justify action and
    select the best remedy for a Superfund site. In doing so, Superfund
    guidelines suggest using standardized assumptions, equations, and values
    wherever appropriate.

     The Superfund program uses extensive additional program- specific guidance
    documents addressing human health and ecological risk assessments, as well
    as analytical tools, such as probabilistic analysis. These documents
    supplement applicable EPA- wide guidelines. The Superfund guidelines for
    human health risk assessment, for example, cover developing a baseline risk
    assessment (Part A), developing or refining preliminary remediation goals
    (Part B), performing a risk evaluation of remedial alternatives (Part C),
    and standardizing, planning, reporting, and completing a review (Part D).
    There are also

    other headquarters and regional office documents that further supplement the
    program- specific guidelines and manuals.

    Office of Solid Waste The Office of Solid Waste, like OERR, is part of
    OSWER. OSW regulates the management of solid waste and hazardous waste
    through federal programs established by the Resource Conservation and
    Recovery Act of 1976, as amended (RCRA). 39 Congress enacted RCRA to protect
    human health and the environment from the potential hazards of waste
    disposal, conserve

    energy and natural resources, reduce the amount of waste generated, and
    ensure that wastes are managed in a manner that is protective of human
    health and the environment. The act defines solid and hazardous waste,

    39 42 U. S. C. 6901- 6991k.

    authorizes EPA to set standards for facilities that generate or manage
    hazardous waste, and establishes a permit program for hazardous waste
    treatment, storage, and disposal facilities. The RCRA hazardous waste
    program has a ?cradle to grave? focus, regulating facilities that generate,
    transport, treat, store, or dispose of hazardous waste from the moment it is
    generated until its ultimate disposal or destruction.

    RCRA regulations interact closely with other environmental statutes,
    especially CERCLA. EPA notes that both programs are similar in that they are
    designed to protect human health and the environment from the dangers of
    hazardous waste, but each has a different regulatory focus.

    RCRA mainly regulates how wastes should be managed to avoid potential
    threats to human health and the environment. On the other hand, according to
    EPA, CERCLA is relevant primarily when mismanagement occurs or has occurred,
    such as when there has been a release or a substantial threat of a release
    in the environment of a hazardous substance. Regulatory activity under RCRA
    focuses primarily on specifying procedures and technology to be used to
    ensure proper handling and disposal of wastes, but risk assessments play a
    role in several supporting tasks, particularly those involving hazardous
    waste regulation under RCRA Subtitle C. For example, risk assessment
    information may be used in the processes for defining (and delisting)
    substances as hazardous wastes, evaluating the hazards posed by waste
    streams, assessing the need for

    corrective action at disposal sites, and granting waste disposal permits
    (such as incinerator permits). In its RCRA Orientation Manual, OSW expressed
    an increasing emphasis on making the RCRA hazardous waste program more risk
    based (with the intention of ensuring that the

    regulations correspond to the level of risk posed by the hazardous waste
    being regulated). Major features and characteristics of risk assessment for
    hazardous waste regulation are summarized below.

     Making the determination of whether a substance is a hazardous waste is a
    central component of the waste management program. The Subtitle C program
    includes procedures to facilitate this identification and classification of
    hazardous waste. Under the RCRA framework, hazardous wastes are a subset of
    solid wastes. 40 In RCRA sect.1004( 5), Congress defined hazardous waste as a
    solid waste, or combination of 40 Despite the name, solid wastes actually
    may be solids, semi- solids, liquids, or sludges.

    solid wastes, which because of its quantity, concentration, or physical,
    chemical, or infectious characteristics may:

     cause, or significantly contribute to, an increase in mortality or an
    increase in serious irreversible, or incapacitating reversible, illness; or

     pose a substantial present or potential hazard to human health or the
    environment when improperly treated, stored, transported, or disposed of, or
    otherwise managed.

    EPA developed more specific criteria for defining hazardous waste using two
    different mechanisms: (1) listing certain specific solid wastes as hazardous
    and (2) identifying characteristics (physical or chemical properties) which,
    when exhibited by a solid waste, make it hazardous.

    The agency has done so, and risk assessment information may be used to
    support both mechanisms. 41

    ? Listed wastes? are wastes from generic industrial processes, wastes from
    certain sectors of industry, and unused pure chemical products and
    formulations. EPA uses four criteria to decide whether or not to list a
    waste as hazardous.

    1. The waste typically contains harmful chemicals (and exhibits other
    factors, such as risk and bioaccumulation potential) which indicate that it
    could pose a threat to human health and the environment in the

    absence of special regulation. Such wastes are known as toxic listed wastes.

    2. The waste contains such dangerous chemicals that it could pose a threat
    to health or the environment even when properly managed. These wastes are
    fatal to humans and animals even in small doses and are known as acute
    hazardous wastes.

    3. The waste typically exhibits one of the four characteristics of hazardous
    waste: ignitability, corrosivity, reactivity, and toxicity. 4. EPA has cause
    to believe that, for some other reason, the waste

    typically fits within the statutory definition of hazardous waste. 41 In
    addition, there are some wastes that are specifically excluded from Subtitle
    C regulation and wastes that may be exempted when recycled.

    Listed hazardous wastes can exit Subtitle C regulation through a
    sitespecific delisting process initiated by a petition from a waste handler
    to an EPA region or a state. The petition must demonstrate that, even though
    a particular waste stream generated at a facility is a listed hazardous
    waste, it does not pose sufficient hazard to merit RCRA regulation.

    ? Characteristic wastes? are wastes that exhibit measurable properties that
    indicate they pose enough of a threat to deserve regulation as hazardous
    wastes. EPA established four hazardous waste characteristics.

    1. Ignitability identifies wastes that can readily catch fire and sustain
    combustion.

    2. Corrosivity identifies wastes that are acidic or alkaline. Such wastes
    can readily corrode or dissolve flesh, metal, or other materials. 3.
    Reactivity identifies wastes that readily explode or undergo violent

    reactions (e. g., when exposed to water or under normal handling
    conditions).

    4. Toxicity is used in a rather narrow and specific sense under this program
    to identify wastes that are likely to leach dangerous concentrations of
    chemicals into ground water if not properly managed (and thus expose users
    of the water to hazardous chemicals and constituents). EPA developed a
    specific lab procedure, known as the Toxicity Characteristic Leaching
    Procedure, to predict whether any particular waste is likely to leach
    chemicals into ground water at dangerous levels. In this procedure, liquid
    leachate created from hazardous waste samples is analyzed to determine
    whether it contains any of 40 different common

    toxic chemicals in amounts above specified regulatory levels. The regulatory
    levels are based on ground water modeling studies and toxicity data that
    calculate the limit above which these toxic compounds and elements will
    threaten human health and the environment.

     For OSW, the task of identifying and assessing hazardous wastes is made
    more difficult because waste may be in the form of a mixture of
    constituents, some of which may be hazardous and some not. (This is also a
    common issue for the Superfund program.) The EPA- wide guidelines on
    assessments of chemical mixtures therefore could come

    into play in OSW risk assessments.

     For dose- response data on the toxicity and potency of hazardous
    substances, OSW largely relies on information from other EPA sources. For
    example, OSW may use the chemical- specific assessments prepared by ORD,
    data in EPA?s IRIS database, and regulatory standards from

    other EPA program offices, in particular the Office of Water. However, OSW
    combines this information with its own exposure analyses.

     Rhomberg categorized exposure assessment by OSW as either hypothetical or
    site specific. He noted that hypothetical exposures principally come into
    play when the agency is defining hazardous wastes and evaluating disposal
    options. These exposure analyses cover hypothetical waste- handling and
    disposal practices anywhere in the

    nation, and OSW focuses on the question of whether such practices might
    cause undue risks to individuals, not on characterizing the actual
    distribution of exposures across the population. One of the principal
    concerns in OSW exposure assessments is leaching to groundwater, but

    OSW evaluates other exposure pathways from virtually all treatment and
    disposal practices, with the specific pathways for any particular analysis
    being decided on a case- by- case basis. Site- specific exposure assessments
    might be needed when OSW is making regulatory decisions regarding actual
    waste disposal facilities, as when assessing the need for remedial action at
    a given site or permitting incineration or other disposal activities. In
    such cases, the office can focus exposure estimates on the off- site
    migration of the particular toxic compounds associated with that location.
    In general, an important part of OSW?s

    exposure assessments is evaluating the ?relative contribution? of hazardous
    wastes to the overall exposure to a hazardous chemical (which is very
    similar to assessments by EPA?s Office of Water).

     In exposure assessments, OSW?s deterministic analyses follow EPA?s risk
    characterization guidance by setting only two sensitive parameters at high-
    end values, with the rest of the parameters being set at their central
    tendency values. According to OSW, this approach is meant to produce a risk
    estimate above the 90 th percentile of the risk distribution

    but still on the actual distribution. Chemical Emergency

    CEPPO is also part of OSWER. It provides leadership, advocacy, and
    Preparedness and Prevention assistance to: (1) prevent and prepare for
    chemical emergencies; (2) Office

    respond to environmental crises; and (3) inform the public about chemical
    hazards in their community. To protect human health and the environment,

    CEPPO develops, implements, and coordinates regulatory and nonregulatory
    programs. It carries out this work in partnership with EPA regions, domestic
    and international organizations in the public and private sectors, and the
    general public.

    CEPPO is responsible for the risks associated with accidental chemical
    releases. Under the Emergency Planning and Community Right- to- Know Act
    (EPCRA) in Title III of the Superfund Amendments and Reauthorization Act of
    1986, CEPPO must evaluate, develop, and maintain a list of chemicals and
    threshold quantities that are subject to reporting for emergency planning.
    In addition, CEPPO develops the emergency reporting and planning
    requirements, guidance for industry, and guidance

    and tools for use of the reporting information by Local Emergency Planning
    Committees. These reporting and planning requirements serve to provide the
    necessary information to be used at the local level to manage the risks

    associated with accidental chemical releases. CEPPO is also responsible for
    accidental chemical release prevention. Under Section 112( r) of the Clean
    Air Act, as amended by the Clean Air Act Amendments of 1990, CEPPO must
    evaluate chemicals for acute adverse health effects, likelihood of
    accidental release, and magnitude of exposure to develop a list of at least
    100 substances that pose the greatest risk of causing death, injury, or
    serious adverse effects to human health or the

    environment from accidental releases. Each listed substance must have a
    threshold quantity that takes into account the chemical?s toxicity,
    reactivity, volatility, dispersability, combustibility, or flammability.

    Facilities handling a listed substance above its threshold quantity must
    implement a risk management program and develop a risk management plan. The
    risk management program must address a hazards analysis, prevention program,
    and emergency response program. According to CEPPO officials, they scaled
    these regulatory requirements according to the risk posed by the wide range
    of facilities subject to the requirements- the greater the risk, the greater
    the risk management responsibilities. The facilities submit their risk
    management plans to EPA and to state and local officials for use in
    emergency planning and local risk management and reduction. CEPPO
    investigates chemical accidents, conducts research, and collects information
    about chemical and industrial process hazards to issue Chemical Safety
    Alerts and other publications to raise awareness about chemical accident
    risks. CEPPO also develops tools, methods, and

    guidance necessary to identify and assess the risks to human health from
    accidental releases.

    Major features and characteristics of CEPPO?s risk assessment procedures are
    summarized below.

     The chemical risk assessments conducted by CEPPO are unique from the risk
    assessments conducted by other EPA offices. CEPPO?s procedures do not follow
    the NAS four- step risk assessment approach, but are similar to the chemical
    risk assessment approach used by the Department of Transportation?s (DOT)
    Research and Special Programs

    Administration (RSPA) in that hazards are identified and a measure of
    exposure (or consequence) is determined to yield a ?threat? associated with
    an accidental release. While RSPA focuses on risks associated with accidents
    involving unintentional releases of hazardous materials during
    transportation, CEPPO focuses on risk associated with accidental releases
    from a fixed facility. According to CEPPO, for accidental release risks,
    because these events are high consequence and low probability, the hazard
    and exposure typically can be estimated with some degree of confidence.
    However, the likelihood or probability of an

    accidental release is very uncertain. Consequently, likelihood is addressed
    only in a limited way and the ?threat? is judged to be a surrogate for risk.

     CEPPO?s approaches with respect to chemical accident risk are published
    mainly in two rulemakings-? List of Regulated Substances and Thresholds for
    Accidental Release Prevention and Risk Management Programs for Chemical
    Accident Release Prevention,? 59 FR 4478 (Jan. 31, 1994) and ?Accidental
    Release Prevention Requirements: Risk Management Programs under the Clean
    Air Act, Section 112( r)( 7),? 61 FR 31668 (June 20, 1996)- and in
    guidelines,

    especially ?Technical Guidance for Hazards Analysis, Emergency Planning for
    Extremely Hazardous Substances,? which was issued jointly by EPA, DOT, and
    the Federal Emergency Management Agency (Dec. 1987).

     For hazard identification, CEPPO identifies the hazards that pose a risk
    to human health and the environment from an analysis of chemical accidents
    and of the physical/ chemical properties of substances that make them more
    likely to cause harm as a result of an accidental chemical release. For
    example, the catastrophic chemical release in Bhopal, India, in December
    1984 involved methyl isocyanate, a chemical that is toxic when inhaled.
    CEPPO identified the criteria necessary to

    identify those substances that are so toxic that, upon exposure (i. e.,
    inhalation, dermal contact, or ingestion) to a small amount, they cause

    death or serious irreversible health effects in a short time (acute
    toxicity). CEPPO also has developed criteria to identify other substances,
    such as highly flammable substances that can trigger a

    vapor cloud explosion harming the public and environment. CEPPO is also
    working to understand the long- term (chronic) effects that might be
    generated by a single acute exposure.

     As part of its identification of hazards, CEPPO also evaluates the
    quantity of a chemical that would need to be released and travel off- site
    to establish a threshold quantity. 42 If a facility handles more than this
    quantity, there is a presumption of risk triggering some action by the
    facility?s owner( s) and operator( s). The hazardous chemicals and threshold
    quantities identified by CEPPO are published in rulemakings.

     According to CEPPO, the exposure assessment (or consequence analysis)
    phase of a chemical accident release assessment is somewhat unique from the
    classical risk assessment approaches and procedures. The actual exposure to
    humans after an accidental release is often not known. In addition, the
    amount and rate of chemical released and the

    precise conditions (e. g., weather) are usually not known. However, these
    parameters can be estimated using engineering calculations and mathematical
    models to generate the concentration likely to have been present or that
    could be present in a certain type of accidental release. Using these
    techniques, chemicals that possess the physical/ chemical properties most
    likely to harm the public or the environment can be

    evaluated to estimate the degree of ?threat? that they may pose in an
    accidental release.

     CEPPO uses these exposure assessment (consequence analysis) techniques to
    understand the potential magnitude of exposure associated with a variety of
    hazardous chemicals. In addition, CEPPO publishes the techniques in
    guidelines and as software to assist facilities in their assessment of
    accidental release risk. According to CEPPO, industry has a fundamental
    responsibility to understand the risks associated with chemical accidents.
    In addition, the Risk Management

    Plan requirements under section 112( r) of the Clean Air Act require that
    this information be made available to the public so that industry and the 42
    A CEPPO official pointed out that his agency?s focus is the general public
    and environment outside the bounds of an industrial facility. The
    Occupational Safety and Health Administration is responsible for risk within
    the bounds of an industrial facility.

    community can work together to manage the risks that might be present.

     CEPPO may characterize the risks associated with accidental releases using
    a number of parameters, such as the presence of a large quantity of a highly
    hazardous substance in proximity to a large facility that has had a number
    of accidental releases in the past. CEPPO uses these

    parameters to place more responsibility on such facilities (e. g., greater
    accidental release prevention measures under the Risk Management Program
    requirements), to investigate the underlying reasons for their accidental
    releases, or to assist in audits and inspections of their accident
    prevention programs.

    Office of Air and Radiation OAR oversees the air and radiation protection
    activities of the agency. Radiation risk assessments conducted by OAR are
    outside the scope of this report, but chemical risk assessments do have a
    part in OAR?s efforts to preserve and improve air quality in the United
    States. 43 Such air quality concerns are the primary mission of OAR?s Office
    of Air Quality Planning and Standards (OAQPS), which, among other
    activities, compiles and reviews air pollution data and develops regulations
    to limit and reduce air pollution. The Risk and Exposure Assessment and the
    Health and Ecosystem Effects Groups within OAQPS provide the scientific and
    analytical expertise to conduct and support human health and ecological risk
    assessments in this area, in coordination with ORD.

    The Clean Air Act, as amended, provides the statutory basis for air- related
    risk assessments by OAR. 44 The CAA requires EPA to establish national
    standards for air quality, but it gives states the primary responsibility
    for assuring compliance with the standards. Chemical risk assessments are

    primarily associated with regulation of (1) criteria air pollutants and (2)
    hazardous air pollutants, also referred to as ?air toxics.? 45 43 See
    Radiation Standards: Scientific Basis Inconclusive, and EPA and NRC

    Disagreement Continues (GAO/ RCED- 00- 152, June 30, 2000) for information
    regarding some of the procedures used by EPA in setting radiation standards.

    44 42 U. S. C. 7401- 7626. 45 There are other distinct programs within OAR-
    for example, focusing on the regulation of mobile sources (including fuels
    and fuel additives), acid rain, and global climate change- that also include
    consideration of chemicals.

    The CAA requires EPA to set health- based air quality standards (National
    Ambient Air Quality Standards, or NAAQS) for criteria pollutants, which are
    common throughout the United States and mostly the products of combustion.
    46 Under the CAA, EPA is also required to review the scientific data upon
    which the standards are based and revise the standards, if necessary, every
    5 years. The criteria pollutants are particulate matter,

    carbon monoxide, sulfur oxides, nitrogen dioxide, ozone, and lead. Of these
    pollutants, ozone is not directly emitted by a source, but rather is the
    product of the interaction of nitrogen oxide, volatile organic compounds,
    and sunlight. Therefore, regulations targeting ozone focus on controlling
    emissions of nitrogen oxide and volatile organic compounds. The CAA requires
    EPA to set health- based standards with an ?adequate margin of safety,? but
    according to EPA it is not required to set air quality standards at a zero-
    risk level to achieve an adequate margin of safety, but simply at a

    level that avoids unacceptable risks. EPA therefore sets the standards to
    protect the substantial part of the national population, including sensitive
    or at- risk populations, but not necessarily the most sensitive or exposed

    individuals. The CAA also contains provisions, first added in 1970, for the
    regulation of emissions to the atmosphere of hazardous air pollutants- toxic
    chemicals other than the six criteria pollutants. The 1970 amendments to the
    CAA

    required EPA to identify and control hazardous air pollutants so as to
    achieve ?an ample margin of safety.? However, Congress passed another major
    set of amendments, the Clean Air Act Amendments of 1990 (CAAA), which
    revised the hazardous air pollutant provisions and substantially affected
    the application of risk assessment regarding air toxics. The amendments
    explicitly wrote into the act a list of 189 hazardous air pollutants to be
    regulated. In addition, the amendments replaced the

    former health- based criterion for standards with a criterion that is
    primarily technology based, mandating the maximum achievable control
    technology (MACT) for the specified list of chemicals. 47 The act further
    mandates that EPA evaluate residual risks remaining after implementation

    46 The states are responsible for establishing procedures to attain and
    maintain the standards. They prepare State Implementation Plans (SIPs) on
    these procedures that are submitted to EPA for approval.

    47 All new or existing sources of these pollutants are to require the use of
    MACT, which is judged to be ?the best of the best? for new sources and at
    the top end (best 12 percent) of current emissions control performance for
    existing sources.

    of the MACT standards to determine if additional standards are needed to
    protect the public health with an ample margin of safety.

    Additional information on the major features and characteristics of chemical
    risk assessments related to these air quality protection activities is
    presented below.

    Criteria air pollutants

     There are several unique features that affect risk assessments for
    criteria air pollutants. Compared to many other agents assessed by EPA, the
    agency generally has extensive human data available on health effects at
    relevant exposure levels. Therefore, risk assessments for criteria air
    pollutants require little extrapolation across species or to low doses and
    few default assumptions. These are the least likely of EPA?s risk
    assessments to use precautionary or conservative methods and assumptions,
    and the results are intended to be unbiased estimates without any built- in
    conservatism.

     For criteria air pollutants, ?hazard identification? information on health
    effects appears primarily in air quality criteria documents prepared by ORD
    and staff papers prepared by OAQPS to support the review and development of
    national ambient air quality standards. These documents are intended to
    reflect the available scientific evidence on toxicity endpoints of concern.
    The definition of what responses constitute ?adverse? outcomes is ultimately
    left to the Administrator?s judgment, informed by staff recommendations,
    advice from the Clean Air Scientific Advisory Committee (part of EPA?s
    Science Advisory Board), and public comments.

     EPA?s principal concern regarding criteria pollutants is for noncancer
    health effects. In contrast to most other EPA noncancer risk assessments,
    however, EPA does not apply a threshold approach in the case of criteria
    pollutants. Instead, the agency models response curves as though they have
    no threshold, recognizing that, as a practical matter,

    at least some members of the general population will have their thresholds
    exceeded at or near the lowest exposure levels. EPA characterizes these
    response relationships without any conservative upper- bound methods.
    However, probabilistic methods are used to characterize uncertainty in the
    fitted exposure- response relationships. In addition, there is temporal
    variation in pollution concentrations, so characterization of exposure- time
    relationships is also an important

    component of EPA?s assessments of criteria pollutants.

     Although EPA?s exposure assessments (and risk characterization) for
    criteria pollutants focus on population risks, rather than individual risks,
    the agency does consider effects on more sensitive or exposed populations.
    Exposure assessments are also affected by the need to establish air quality
    standards for both annual and daily concentrations for some pollutants. The
    annual standards are intended to provide

    protection against typical day- to- day exposures as well as longer- term
    exposures, while the daily standards are intended to provide protection
    against days with high peak concentrations of pollutants. EPA?s exposure
    assessments therefore need to address these types of variations. Rhomberg
    noted that, because of the long history of analysis of standard pollutants,
    EPA?s exposure modeling has been continually improved and expanded,
    resulting in sophisticated models with

    capabilities well beyond models used in other situations that do not have
    the benefit of decades of experience and application.

     Finally, it is important to recognize that one of the most important uses
    of risk assessments regarding criteria air pollutants is to characterize the
    population exposure levels and health effects that would be expected given
    various specified air quality criteria. In other words, one of the primary
    uses of risk assessment is to estimate what the effects would be if
    standards were set at various specified levels, rather than using the tool
    simply to estimate what health risks these pollutants pose.

    Hazardous air pollutants (air toxics)

     Although the Clean Air Act Amendments of 1990 shifted the focus in
    hazardous air pollutant regulation to technology- based controls, several
    activities may still involve risk assessments, including

     listing and delisting of hazardous air pollutants, which depends on
    whether a chemical may present a threat of adverse effects to humans and the
    environment;

     de minimis delisting of source categories, which requires sources be
    listed unless they pose less than a 10 -6 risk to the maximally exposed
    individual (MEI);

     triggering the consideration of further regulation to address residual
    risks that remain after applying MACT standards (triggered if the MEI
    suffers a 10 -6 or greater lifetime risk); and

     offset trading of one pollutant for another based on whether the increase
    in emissions is offset by an equal or greater decrease in a

    ?more hazardous? air pollutant.

     According to section 112( o) of the amended CAA, prior to the promulgation
    of any residual risk standard, EPA shall revise its guidelines for
    carcinogen risk assessment or provide an explanation of the reasons
    regarding any NAS report section 112( o)( 4) recommendations that have not
    been implemented.

     The amended act also had a major impact on hazard identification for air
    toxics. The amendments defined hazardous air pollutants as air pollutants
    listed pursuant to section 112( b) of the act. Section 112( b) included an
    initial list of 189 compounds incorporated by reference into the law.

     Dose- response analysis for air toxics has in the past been done largely
    through Health Assessment Documents produced by ORD for the air office,
    according to the methods discussed in the earlier section on EPAwide risk
    assessment procedures. Carcinogen potency calculations for

    de minimis delisting and residual risk determination will be done under the
    revised carcinogen assessment guidelines, once they are finalized. EPA
    addresses noncancer risks for hazardous air pollutants with its usual
    methodologies (e. g., NOAEL/ LOAEL, benchmark dose, or others).

     With the 1990 amendments, exposure assessments for air toxics will focus
    on assessing the residual risk for the most exposed individual after MACT
    has been applied. OAR uses a population- based risk assessment to generate
    estimates of how risks are distributed within the population, not just for
    specific conservative scenarios. According to Rhomberg (and confirmed by OAR
    officials), OAR?s intent is to define the actual most exposed person in the
    population, rather than a

    hypothetical person with an unrealistically high estimated exposure. EPA has
    adopted a tiered approach to analyzing residual risk consistent with the
    recommendations from NAS and the Presidential/ Congressional Commission. 48
    In the screening phase, default conservative assumptions are used to ensure
    that risks will not be underestimated. Sources and hazardous air pollutants
    that exceed

    some benchmark in the screening analysis will be evaluated further.
    According to OAR, the more refined assessments will utilize more
    sitespecific information and more realistic assumptions, especially as they
    relate to exposure. EPA estimates exposures to air toxics using a general-
    purpose model largely based on fate and transport considerations for stack
    emissions. 49 OAR officials noted that they are updating their modeling
    methodology, updating their Human Exposure

    Model with the current state- of- the- art dispersion model (ISCST3), and
    will be updating the census data they use with the 2000 Census numbers when
    they become available.

    Office of Water OW is responsible for the agency?s water quality activities,
    including development of national programs, technical and science policies,
    regulations, and guidance relating to drinking water, water quality, ground
    water, pollution source standards, and the protection of wetlands, marine,
    and estuarine areas. Chemical risk assessments are associated, in
    particular, with EPA?s ambient water quality criteria, under the CWA, and
    drinking water quality regulations, under the SDWA. 50

    The goal of CWA is to maintain and improve the cleanliness and biological
    integrity of the nation?s waters, including lakes, rivers, and navigable
    waters. Under CWA, EPA publishes water quality criteria defining the 48 See
    Residual Risk Report to Congress, U. S. EPA (March 1999). 49 Fate and
    transport models are mathematical descriptions of the movement and
    transformation of substances through various media, such as air, soil, and
    water.

    50 CWA is codified generally as 33 U. S. C. 1251- 1387 and SDWA as 42 U. S.
    C. 300f- 300j.

    degree of water quality that is compatible with intended uses and states of
    different water bodies. The criteria are health based, but they are not
    rules and are themselves unenforceable. States use these criteria as
    guidance for developing state water quality standards and setting
    enforceable limits in permits for facilities that discharge pollutants into
    surface waters. CWA distinguishes ?conventional? from ?toxic? pollutants.
    Toxic water pollutants are evaluated as exposures to toxic chemicals
    (similar to EPA?s

    treatment of hazardous air pollutants). The goal of SDWA is to protect the
    quality of public drinking water systems. The law focuses on all waters
    actually or potentially designed for drinking use, whether from above ground
    or underground sources. SDWA requires

    EPA to set drinking water standards to control the level of contaminants in
    drinking water provided by public water systems, which the water systems are
    required to meet. 51 Congress passed extensive amendments to SDWA through
    the Safe Drinking Water Act Amendments of 1996 (PL 104- 182). Among other
    key changes, the amendments increased regulatory flexibility, focused
    regulatory efforts on contaminants posing the greatest health risks, and
    added risk assessment and risk communication provisions to

    SDWA. There are several risk- related mandates in these acts.

     Under CWA, EPA is to establish criteria for water quality solely on the
    basis of health and ecological effects and ?accurately reflecting the latest
    scientific knowledge on the kind and extent of all identifiable effects on
    health and welfare.? CWA defines a toxic pollutant as one that after
    discharge and upon exposure, ingestion, inhalation, or

    assimilation into any organism, either directly from the environment or
    indirectly by ingestion through food chains, will, on the basis of
    information available to the Administrator, cause death, disease, behavioral
    abnormalities, cancer, genetic mutations, physiological malfunctions
    (including malfunctions in reproduction), or physical

    deformities in such organisms or their offspring. Federal water quality
    criteria are unenforceable, but states develop enforceable permit limits 51
    Drinking water standards apply to public water systems that provide water to
    at least 15 connections used by year- round residents or regularly serve at
    least 25 year- round residents. Private water wells serving fewer than 25
    persons are not covered by these federal standards. EPA also sets Secondary
    Drinking Water Regulations, which are nonenforceable guidelines for
    contaminants that may cause cosmetic or aesthetic effects.

    based on them.

     In contrast to the unenforceable federal water quality criteria, CWA also
    provides for the promulgation of enforceable federal performance standards
    for sources of effluent (waste discharged into a river or other water body)
    that do include consideration of technological and economic feasibility.
    Since 1977, establishment of effluent standards for toxic pollutants has
    been based on the best available technology (BAT)

    economically achievable by particular source category. The compounds to be
    regulated are specified in a list, and there are provisions for additions
    and deletions to the list. Standards must be at that level which the
    Administrator determines provides ?an ample margin of safety,? so that
    standards more stringent than BAT may be named at EPA discretion.

     Under SDWA, the EPA Administrator is to ?promulgate national primary
    drinking water regulations for each contaminant which may have any adverse
    effect on the health of persons and which is known or anticipated to occur
    in public water systems.? An important feature of such regulations, however,
    is that a standard specifies two levels of

    contamination. First, a maximum contaminant level goal (MCLG) is set solely
    on health grounds ?at a level at which no known or anticipated adverse
    effects on the health of persons occur and which allows an adequate margin
    of safety.? For each such goal there is also a maximum contaminant level
    (MCL). This MCL is to be as close to the MCLG ?as is feasible,? where
    feasible means ?with the use of the best technology, treatment techniques
    and other means which are available (taking cost into consideration).? The
    MCL is the enforceable standard.

     The 1996 amendments to SDWA added several provisions that increased the
    importance of risk assessment and risk communication in EPA?s regulation of
    drinking water quality. For example, the amendments

     Require EPA, when developing regulations, to (1) use the best available,
    peer- reviewed science and supporting studies and data and (2) make publicly
    available a risk assessment document that discusses estimated risks,
    uncertainties, and studies used in the assessment.

     Require EPA to conduct a cost- benefit analysis for every new standard to
    determine whether the benefits (health risk reduction) of a drinking water
    standard justify the costs.

     Permit consideration of ?risk- risk? issues by authorizing EPA to set a
    standard other than the feasible level if the feasible level would lead

    to an increase in health risks by increasing the concentration of other
    contaminants or by interfering with the treatment processes used to comply
    with other SDWA regulations.

     Require EPA to review and revise, as appropriate, each national primary
    drinking water regulation promulgated by the agency at least every 6 years.
    Of particular relevance to the use of risk assessment information, any
    revisions must ?maintain, or provide for greater, protection of the health
    of persons.?

     Require EPA to identify subpopulations at elevated risk of health effects
    from exposure to contaminants in drinking water and to conduct studies
    characterizing health risk to sensitive populations from contaminants in
    drinking water.

    Additional information on major features and characteristics of chemical
    risk assessments related to water quality protection activities is presented
    below.

     The various offices within OW- the Office of Ground Water and Drinking
    Water; Office of Science and Technology; Office of Wastewater Management;
    and Office of Wetlands, Oceans, and

    Watersheds- have developed extensive technical and analytical guidance on
    water quality monitoring and the development of water quality criteria. One
    recently finalized document particularly relevant for describing OW?s
    current risk assessment procedures is the revision to the methodology for
    deriving ambient water quality criteria (AWQC) for the protection of human
    health. 52 Published pursuant to section 304( a)( 1) of the CWA, OW noted
    that this revised methodology supersedes EPA?s 1980 guidelines and
    methodology on this subject. In addition to describing OW?s approach to
    developing new and revising existing AWQC, it defines the default factors
    that EPA will use in evaluating and determining consistency of state water
    quality standards with the requirements of the CWA.

     Although there are different statutory bases and risk mandates for the
    regulation of ambient and drinking water, OW?s risk assessment procedures in
    support of CWA and SDWA are mostly similar. 52 Methodology for Deriving
    Ambient Water Quality Criteria for the Protection of Human

    Health, also referred to as the ?2000 Human Health Methodology,? EPA- 822-
    B- 00- 005 (October 2000). The agency is also in the process of revising its
    methodology for deriving AWQC for the protection of aquatic life.

    However, risk assessments in support of CWA consider not just human health
    effects but also the ecological effects associated with exposure to
    pollutants. With regard to human health risks, perhaps the most notable
    difference between the ambient water and drinking water parts of OW is the
    additional focus, during exposure assessments for CWA purposes, on exposures
    to contaminated water through consumption of contaminated fish or shellfish.
    (This is a primary reason for potential differences in the resulting
    drinking water and ambient water quality criteria or standards for the same

    chemical.)

     OW?s Office of Science and Technology does all of the risk assessments for
    SDWA maximum contaminant level goals and CWA?s AWQC. For cancer risk
    evaluation, OW has been applying the principles in EPA?s proposed revision
    of the carcinogen guidelines.

     For hazard identification purposes, SDWA originally had specified a list
    of compounds to be regulated as toxic pollutants and required EPA to
    regulate an additional 25 contaminants every 3 years. However, the 1996
    amendments eliminated that requirement and

    revised OW?s approach for listing, reviewing, and prioritizing the drinking
    water contaminant candidate list. The new risk- based contaminant selection
    process provides EPA the flexibility to decide whether or not to regulate a
    contaminant after completing a required review of at least five contaminants
    every 5 years. EPA must use three risk- related criteria to determine
    whether or not to regulate:

    (1) that the contaminant adversely affects human health; (2) it is known or
    substantially likely to occur in public water systems with a frequency and
    at levels of public health concern; and (3) regulation of the contaminant
    presents a meaningful opportunity for health risk reduction. The 1996
    amendments also included specific requirements to assess health risks and
    set standards for arsenic,

    sulfate, radon, and disinfection byproducts.

     There are a number of important features regarding OW?s exposure
    assessments in support of CWA and SDWA regulations.

     OW?s primary exposure question during the criteria/ standard- setting
    process for drinking or ambient water is hypothetical: What health effects
    might be expected if people consumed water and/ or finfish and shellfish
    contaminated at the level of a candidate standard? The main function of
    exposure assessment is to link criteria or water

    concentrations to doses of chemicals and the associated health effects that
    might be projected.

     For its exposure assessments, OW uses estimates of water and food
    ingestion in the United States based on a variety of surveys and studies.
    One of the major sources of per capita water and fish ingestion is the
    Department of Agriculture?s Continuing Survey of Food Intakes by Individuals
    (CSFII), which presents results for the general population and for certain
    subpopulations (e. g., pregnant and lactating women, children). 53

     For assessing standards under SDWA, the linking of water concentration to
    dose is conducted through standardized consumption values. For example, the
    default exposure scenario of lifetime consumption by individuals is 2 liters
    of water per day. However, OW uses other default values to address
    consumption by sensitive subpopulations, especially children and infants.
    For assessing AWQC under the CWA, EPA uses the same water consumption rate
    as under SDWA. In addition, though, the agency adds the dose resulting from
    the daily average consumption of 17.5

    grams of fish.  An important change in EPA?s approach for developing AWQC,
    reflected in the 2000 Human Health Methodology, has been the move toward use
    of a bioaccumulation factor (BAF) to estimate potential human exposure to
    contaminants via the consumption of contaminated fish and shellfish. BAFs
    reflect the accumulation of chemicals by aquatic organisms from all
    surrounding media (e. g., water, food, and sediment). EPA?s 1980 method used
    a bioconcentration factor that reflected only absorption directly out of the
    water column, and therefore tended to underestimate actual contaminant
    levels in fish and shellfish. EPA?s revised methodology also gives
    preference to the use of high- quality field data over laboratory or model-
    derived estimates of BAFs.

     OW considers indirect exposures to a substance from sources other than
    drinking water (e. g., food and air) when establishing AWQC. This is
    particularly important for noncarcinogens, where the fact that 53 The CSFII
    is a complex multistage probability sample of the entire United States
    conducted to survey food and beverage intake.

    several exposure sources might individually be below the RfD level does not
    mean that collectively the exposure is below this presumably safe level. OW
    has revised and expanded its policy on accounting for nonwater sources of
    indirect exposures known as the ?relative source contribution.? The
    procedures for calculating the

    relative source contribution vary depending on the adequacy of available
    exposure data, levels of exposure, sources and media of exposure relevant to
    the pollutant of concern, and whether there are multiple health- based
    criteria or standards for the same pollutant.

    (See table 5 in the next section for a more detailed description of these
    assumptions.) Risk Assessment

    EPA?s risk assessment guidelines and other related documents identify
    Assumptions and many default assumptions, standardized data factors, and
    methodological choices that may be used in chemical risk assessments. As
    pointed out by Methodological NAS, assumptions and professional judgment are
    used at every stage of a

    Choices risk assessment, because there are always uncertainties in risk

    assessments that science can not directly answer. For the most part, these
    assumptions and choices are intended to address various types of
    uncertainties- such as an absence or limited amount of available data,

    model uncertainty, and gaps in the general state of scientific knowledge- or
    variability in the population. They are also intended to provide some
    consistency and transparency to agency risk assessments. Defaults are
    generally used in the absence of definitive information to the contrary, but
    also reflect policy decisions.

    In its guidelines, EPA characterizes many of its choices as conservative or
    public- health protective in that they are intended to help the agency avoid
    underestimating possible risks. Agency guidelines often cited the scientific
    studies and other evidence that supported the agency?s choice and the
    plausibility of the resulting risk estimates. In our recent report on EPA?s
    use of precautionary assumptions, we identified three major factors
    influencing the agency?s use of such assumptions: (1) EPA?s mission to
    protect human health and safeguard the natural environment (including
    specific requirements in some of the underlying environmental statutes),

    (2) the nature and extent of relevant data, and (3) the nature of the risk
    being evaluated. 54 54 Environmental Protection Agency: Use of Precautionary
    Assumptions in Health Risk Assessments and Benefits Estimates (GAO- 01- 55,
    Oct. 16, 2000).

    EPA?s program offices commonly employ tiered risk assessment approaches that
    progress from rough screening assessments (for which only limited data may
    be available) through increasingly detailed and rigorous analyses, if
    needed. EPA?s guidelines and program- specific documents indicate that
    conservative default assumptions are most often

    used during initial screening assessments, when the primary task is to
    determine whether a risk might exist and further analysis is called for.
    Such screening assessments may use ?worst case? assumptions to determine
    whether, even under those conditions, risk is low enough that a potential
    problem can be eliminated from further consideration. According to
    guidelines and related descriptive materials from the program offices,
    conservative assumptions are used less often in later tiers, as the agency
    attempts to gather and incorporate more detailed data into its analyses.

    Several circumstances may lead to conservative choices playing a less
    prominent role in EPA risk assessments. For example, the development of more
    complex and sophisticated models for cancer and noncancer effects places
    more emphasis on using the full range of available data and characterizing
    the full range of potential adverse outcomes and effects. Similarly, the
    increased use of probabilistic analytical methods to derive

    parameter values will tend to reduce the ?compounding? effect of picking
    conservative point values for each factor. As noted above, the use of tiered
    risk assessment approaches may also limit the use of default assumptions if
    more rigorous and case- specific analysis is done beyond initial screening
    assessments. However, all of these developments may require substantial
    additional effort and the availability of considerable data, which might not
    be possible in many cases.

    Although not intended to be comprehensive, table 5 illustrates in detail
    some of the specific assumptions, default data values, or methodological
    choices that are used in EPA chemical risk assessments. The table
    concentrates primarily on default choices from EPA?s various agencywide risk
    assessment guidelines. However, to also provide a sense of how default
    choices are used at the program level, we have included examples of standard
    assumptions and values employed by two of EPA?s program offices. One set of
    examples illustrates assumptions and choices used by OPP. The second set
    presents more detailed descriptions of the standard assumptions and choices
    identified in OW?s risk assessment methodology

    for deriving AWQC for the protection of human health. OW?s policy reflects
    many of the same basic choices that would apply to assessments conducted
    across the agency, such as the use of uncertainty factors when estimating an
    RfD.

    To the extent that EPA?s documents identified for each of these assumptions
    or choices a reason for its selection, when it would be applied in the risk
    assessment process, and its likely effect on risk assessment results, we
    have reported that information. However, it is important to recognize that
    there is no requirement that agencies provide such

    information in their guidelines (or even that they have guidelines). In
    particular with regard to the ?likely effects? column, EPA officials
    cautioned that it is not always appropriate to characterize a single
    assumption separate from the rest and that it is not always possible to

    quantify the effect of each default assumption. They noted that, in general,
    their default assumptions are intended to be public- health protective.

    The information presented in table 5 was taken primarily from EPA risk
    assessment guidelines and related documents but also reflects additional
    comments provided by EPA officials. (GAO notes and comments appear in
    parentheses.)

    Table 5: EPA Risk Assessment Assumptions and Methodological Choices When the
    assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    1. Agencywide (ORD) proposed carcinogen risk assessment guidelines

    A carcinogen is a substance or agent that produces or incites cancerous
    growth. The following items reflect major assumptions or choices identified
    in the 1999 version of EPA?s proposed revision to its 1986 carcinogen risk
    assessment guidelines.

    1.1 (The discussion setting up this (General framework outlined for

    (Not identified in the The guidelines use a combination of

    framework refers to reports by the determining whether or not to use
    proposed guidelines.)

    principles and process to describe a National Academy of Sciences? default
    assumptions.)

    general framework for the application NRC. In particular, the guidelines of,
    or departure from, default note that, in 1994, NRC supported assumptions.

    continued use of default assumptions as a reasonable way The proposed
    guidelines state that the to deal with uncertainty about decision to use a
    default, or not, is a

    underlying mechanisms in choice considering available selecting methods and
    models for information on an underlying scientific use in risk assessment
    but also process and agent- specific data, recommended that EPA should
    depending on which kind of data it is.

    consider attempting to give Generally, greater formality to its criteria for
    a departure from default options.)

     If a gap in basic understanding exists, or if agent- specific data are
    missing,

    The framework of default the default is used without pause.

    assumptions allows risk assessment to proceed when

     If data are present, their evaluation current scientific theory or may
    reveal inadequacies that also available case- specific data do not lead to
    use of the default.

    provide firm answers in a particular case.

     If data support a plausible alternative to the default, but no more
    strongly than they support the default, both

    the default and its alternative are carried through the assessment and
    characterized by the risk manager.

     If the alternative to the default is strongly supported by data, the
    alternative may be used in place of the default.

    (Continued From Previous Page)

    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    1.2 (Not identified in the proposed

    When determining whether the The guidelines caution When cancer effects in
    exposed guidelines, but this is a standard

    presence or absence of effects that studies either humans are attributed to
    exposure to assumption in risk assessment.)

    observed in a human population is attributing cancer an exogenous agent, the
    default predictive of an agent posing a effects in humans to assumption is
    that such data are

    carcinogenic hazard to other exogenous agents or

    predictive of cancer in any other exposed humans. reporting no effects
    exposed human population.

    are often studies of occupationally exposed humans and,

    therefore, not representative of the general population exposed
    environmentally to the same agents. Therefore, the guidelines state that

    this assumption does not err on the side of public- health conservatism,
    because it could still underestimate the response of certain sensitive human
    subpopulations.

    1.3 Epidemiologic studies usually

    When determining whether the (Not identified in the When cancer effects are
    not found in have low power to detect and presence or absence of effects
    proposed guidelines.) an exposed human population, this attribute responses
    and typically observed in a human population is information by itself is not
    generally

    evaluate cancer potential in a predictive of an agent posing a sufficient to
    conclude that the agent restricted population (e. g., by age, carcinogenic
    hazard to other poses no carcinogenic hazard to this or occupation, etc.).

    exposed humans. other populations of potentially exposed humans, including
    sensitive subpopulations.

    (Continued From Previous Page)

    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    1.4 The assumption is supported by When determining whether the This
    assumption is a Positive effects in animal cancer

    the fact that nearly all of the presence or absence of effects public-
    health

    studies indicate that the agent under agents known to cause cancer in
    observed in an animal population

    conservative policy, study can have carcinogenic potential humans are
    carcinogenic in is predictive of an agent posing a and it is both in humans.

    animals in tests with adequate carcinogenic hazard to exposed appropriate
    and protocols [citations provided].

    humans, if no adequate human necessary given that  To demonstrate that a
    response in

    Moreover, almost one- third of data are present. we do not test for

    animals is not relevant to any human human carcinogens were carcinogenicity
    in situation, adequate data to assess identified subsequent to animal

    Available mode of action humans. the relevancy issue must be testing
    [citations provided]. information is studied for its available.

    Further support is provided by implications in both hazard and research on
    the molecular biology

    dose- response assessment and its of cancer processes, which has effect on
    default assumptions. shown that the mechanisms of control of cell growth and
    differentiation are remarkably homologous among species and

    highly conserved in evolution.

     (Relevancy issue) There may be instances in which the use of an animal
    model would identify a

    hazard in animals that is not truly a hazard in humans [citation provided].
    1.5

    Animal studies are conducted at When determining whether the (Not identified
    in the Effects seen at the highest dose tested high doses in order to
    provide presence or absence of effects guidelines.) are appropriate for
    assessment, but it statistical power, the highest dose observed in an animal
    population is necessary that the experimental being one that is minimally
    toxic. is predictive of an agent posing a conditions be scrutinized.

    Consequently, the question often carcinogenic hazard to exposed arises
    whether a carcinogenic humans, if no adequate human

     If adequate data demonstrate that the effect at the highest dose may be
    data are present. effects are solely the result of a consequence of cell
    killing with excessive toxicity rather than compensatory cell replication or
    of This is a matter of expert carcinogenicity of the tested agent general
    physiological disruption, judgment, considering all of the

    per se, then the effects may be rather than inherent data available about
    the agent, regarded as not appropriate to carcinogenicity of the tested
    including effects in other toxicity include in assessment of the potential

    agent. There is little doubt that studies, structure- activity for human
    carcinogenicity of the

    this may happen in some cases, relationships, and effects on agent. but
    skepticism exists among some growth control and differentiation. scientists
    that it is a pervasive problem [citations provided].

    (Continued From Previous Page)

    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    1.6 (Not identified in the guidelines. When determining whether the The
    guidelines note When cancer effects are not found in Instead, the discussion
    focuses on

    presence or absence of effects that this default well- conducted animal
    cancer studies

    the limitations of this default observed in an animal population assumption
    about lack in two or more appropriate species and assumption. EPA notes, for

    is predictive of an agent posing a of cancer effects has other information
    does not support the

    example, that it is recognized that carcinogenic hazard to exposed
    limitations. For

    carcinogenic potential of the agent, animal studies and epidemiologic
    humans, in the absence of human example, in some these data provide a basis
    for

    studies have very low power to data to the contrary. situations, the tested
    concluding that the agent is not likely detect cancer effects and, in some
    animal species may to possess human carcinogenic

    situations, the tested animal not be predictive of potential, in the absence
    of human

    species may not be predictive of effects in humans. data to the contrary.

    effects in humans (e. g., arsenic).) Therefore, the guidelines discuss the
    importance of using supplementary data to support conclusions

    that negative results in animal studies indicate a lack of human hazard. 1.7

    Target organs of carcinogenesis When determining whether the This is a
    public- health Target organ concordance is not a for agents that cause
    cancer in presence or absence of effects conservative science prerequisite
    for evaluating the

    both animals and humans are observed in an animal population policy.

    implications of animal study results for most often concordant at one or

    is predictive of an agent posing a humans.

    more sites [citations provided]. carcinogenic hazard to exposed However,
    concordance by site is humans.

     An exception to the basic default of not uniform. not assuming site
    concordance exists ?It is appropriate under these in the context of
    toxicokinetic

    guidelines to consider the modeling. Site concordance is influences of route
    of exposure, inherently assumed when these

    metabolism, and, particularly, models are used to estimate hormonal modes of
    action that delivered dose in humans based on may either support or not
    support animal data.

    target organ concordance between animals and humans. When data allow, these
    influences are considered in deciding whether the default remains
    appropriate in individual instances.?

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    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    1.8 This default is consistent with the When determining whether the This is
    a science policy The default is to include benign tumors

    approach of the National presence or absence of effects decision that is
    observed in animal studies in the

    Toxicology Program and the observed in an animal population somewhat more

    assessment of animal tumor incidence International Agency for Research is
    predictive of an agent posing a conservative of public if they have the
    capacity to progress to

    on Cancer and is somewhat more carcinogenic hazard to exposed health than
    not

    the malignancies with which they are protective of public health than not

    humans. including benign

    associated. including benign tumors in the

    tumors in the assessment. This treats the In assessing findings from animal
    assessment. benign and malignant tumors as studies, a greater proportion of
    representative of related

    malignancy is weighed more responses to the test agent, which heavily than a
    response with a is scientifically appropriate greater proportion of benign

    [citation provided]. tumors.

    1.9 (Not identified in the proposed

    When determining whether the (Not identified in the Benign tumors that are
    not observed to guidelines.) presence or absence of effects proposed
    guidelines.) progress to malignancy are assessed observed in an animal
    population on a case- by- case basis.

    is predictive of an agent posing a carcinogenic hazard to exposed humans.

    1.10 (Not identified in the proposed

    When extrapolating from animal (Not identified in the There is a similarity
    of the basic

    guidelines.) studies and considering how proposed guidelines.) pathways of
    metabolism and the metabolic pathways relate across occurrence of
    metabolites in tissues in species.

    regard to the species- to- species extrapolation of cancer hazard and risk.
    1.11

    This adjustment factor is used When estimating human (Not identified in the
    For oral exposure, a human equivalent because it represents scaling of

    equivalent doses in extrapolating proposed guidelines. dose for adults is
    estimated from data metabolic rate across animals of

    from animal studies. However, from other

    on another species by an adjustment different sizes. (Also see reason
    sources, this is of animal applied oral dose by a

    cited under next assumption, and Because the factor adjusts for a

    generally considered scaling factor of body weight to the note that an
    interagency parameter that can be improved on to provide the midpoint 0. 75
    power. committee recommended this and brought into more

    of plausible values.) scaling factor as a default sophisticated
    toxicokinetic

     The same factor is used for children. approach for federal agencies.)

    modeling, when such data become available, the default assumption

     The same factor is used for of 0. 75 power can be refined or

    children because it is slightly replaced. more protective than using
    children?s body weight.

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    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    1.12 This default assumption, like the

    When extrapolating from animal Health conservatism is For inhalation
    exposure, a humanequivalent one with oral exposure, is selected studies and
    considering how not an element in dose for adults is estimated in part
    because it lays a

    toxicokinetic processes relate choosing the default. by default
    methodologies that provide

    foundation for incorporating better across species. estimates of lung
    deposition and of data. The use of information to internal dose.

    improve dose estimation from applied, to internal, to delivered  Because of
    the differences for infants dose is encouraged, including use and children,
    for gases and aerosols,

    of toxicokinetic modeling instead an adjustment is made for their of any
    default, where data are breathing rate and their body weight.

    available.

     The guidelines point out that the processes of absorption, distribution,
    and elimination have important differences among infants and adults
    [citation provided].

    1.13 The rationale is that for internal When extrapolating from one route
    This is a qualitative

    For a route- to- route exposure tumors an internal dose is of exposure to
    another route and

    assumption and is extrapolation, the default assumption is significant no
    matter what the considering how toxicokinetic

    considered to be that an agent that causes internal route of exposure.
    Additionally, processes relate across species.

    public- health tumors by one route of exposure will be the metabolism of the
    agent will be conservative. carcinogenic by another route if it is
    qualitatively the same for an This is a qualitative assumption. absorbed by
    the second route to give internal dose.

    The issue of quantitative an internal dose. extrapolation of the dose-
    response relationship from one route to another is addressed case by case.
    Adequate data are

    necessary to demonstrate that an agent will act differently by one route
    versus another route of exposure.

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    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    1.14 While no standard biologically When assessing the correlation of (See
    more specific If sufficient data are available, a

    based models are in existence, the observed dose- response assumptions
    biologically based model for both the

    one may be developed if extensive relationship to the relationship at
    described below.)

    observed range and extrapolation data exist in a particular case and lower
    doses. [Low- dose

    below that range may be used. the purpose of the assessment extrapolation
    during doseresponse

    justifies the investment of assessment.] When a biologically based model is
    not

    resources needed. used,

    In the absence of data supporting

     The default procedure for the (See more specific assumptions a
    biologically based model for observed range of data is to use a described
    below for rationales extrapolation outside of the curve- fitting model for
    incidence data.

    regarding extrapolation when a observed range, the choice of  For
    extrapolation outside of the

    biologically based model is not approach is based on the view of

    observed range, the choice of used.) the mode of action of the agent

    approach is based on the view of arrived at in the hazard mode of action of
    the agent arrived at assessment. in the hazard assessment (covered by items
    1.15 through 1.17 below).

    1.15 (Although not mentioned in the

    Low- dose extrapolation during This approach is When the mode of action
    information is proposed guidelines, the dose- response assessment, in the

    generally considered supportive of linearity or mode of assumption of
    linearity for absence of data supporting a to be public- health action is
    not understood, the basic suspected carcinogens biologically based model.

    conservative. The default is to assume linearity and use a

    traditionally has been a standard linear default is linear default approach.
    default assumption for EPA.)

    thought to generally produce an upper The linear approach is to draw a The
    LED 10 is the lower 95- percent

    bound on potential risk straight line between a point of limit on a dose
    that is estimated to at low doses. This departure from observed data,

    cause a 10- percent response. upper bound is thought generally, as a
    default, the LED 10 , and

    This level is chosen to account to cover the range of the origin (zero
    incremental dose, zero (conservatively) for experimental human variability
    incremental response). Other points of variability. Additionally, it is
    although, in some departure may be more appropriate for chosen because it
    rewards

    cases, it may not certain data sets; these may be used experiments with
    better designs in completely do so. EPA instead of the LED 10 .

    regard to number of doses and considers the linear

    dose spacing, since these default to be inherently generally will have
    narrower

    conservative of public confidence limits. It is also an health, without
    appropriate representative of the addition of another lower end of the
    observed range factor for human because the limit of detection of
    variability. studies of tumor effect is about 10 percent.

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    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    1.16 In the nonlinear approach, the

    Low- dose extrapolation during (Not identified in the When adequate data on
    mode of

    margin that exists between a dose- response assessment, in the

    proposed guidelines.) action show that linearity is not

    human exposure of interest and absence of data supporting a plausible, and
    provide sufficient

    the point of departure is examined biologically based model. evidence to
    support a nonlinear mode

    for adequacy to protect public of action for the general population and
    health. A margin of exposure As noted in the first column, this any
    subpopulations of concern, the analysis may be used as the basis

    default is to be used when default changes to a different to consider the
    protectiveness of a adequate data on mode of action approach- a margin of
    exposure possible environmental criterion

    (1) show that linearity is not analysis- which assumes that

    for regulation or to judge whether plausible and (2) provide sufficient
    nonlinearity is more reasonable. (A an existing exposure might

    evidence to support a nonlinear margin of exposure analysis compares present
    risk.

    mode of action. The guidelines the dose at the point of departure with also
    state that a sufficient basis to the dose associated with the According to
    the guidelines, the support this nonlinear procedure environmental exposure(
    s) of interest NOAEL/ LOAEL procedures are will include data on responses
    that by computing the ratio between the used with continuous data

    are key events integral to the two.) because modeling approaches for

    carcinogenic process. This means deriving a point of departure from that the
    point of departure mostly The departure point is again generally continuous
    data are not yet

    will be from these precursor data the LED 10 when incidence data are

    available. rather than tumor incidence data. modeled. When the data
    available are continuous data, such as blood levels of hormones or organ
    weight, a

    NOAEL/ LOAEL procedure is typically used. 1.17 (No additional discussion in
    the

    Low- dose extrapolation during (No additional When the mode of action
    information proposed guidelines. See

    dose- response assessment, in the discussion in the

    indicates that the dose response may previous assumptions regarding absence
    of data supporting a proposed guidelines. be adequately described by both a
    linear and nonlinear approaches.)

    biologically based model. See previous linear and a nonlinear approach, then
    assumptions regarding the default is to present both the linear

    As noted in the first column, this linear and nonlinear and margin of
    exposure analyses.

    default is to be used when mode of approaches.)

    action information indicates that both a linear and a nonlinear approach may
    adequately describe the dose response. 1.18

    This assumes that a high dose of When assessing the correlation of This is
    thought to be a A default assumption is made that

    such an agent over a shorter the observed dose- response

    relatively public- health cumulative dose received over a period of time is
    equivalent to a relationship to the relationship at conservative lifetime,
    expressed as a lifetime low dose spread over a lifetime.

    lower doses. [Low- dose assumption.

    average daily dose, is an appropriate This assumption has empirical
    extrapolation during doseresponse

    measure of dose (exposure to a support [citation provided].

    assessment.] carcinogen).

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    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    2. Agencywide (ORD) guidelines for neurotoxicity risk assessment
    Neurotoxicity is an adverse change in the structure or function of the
    central and/ or peripheral nervous system following exposure to a chemical,
    physical, or biological agent. 2.1

    This assumption is based on the When extrapolating data from These
    assumptions

    It is assumed that an agent that comparisons of data for known animal
    studies to humans.

    are ?plausibly

    produces detectable adverse human neurotoxicants [citations conservative? in
    that neurotoxic effects in experimental

    provided], which indicate that Generally applied in the absence they are
    protective of animal studies will pose a potential

    experimental animal data are of data on the relevance of effects public
    health and are hazard to humans. frequently predictive of a

    to potential human risk. also well founded in neurotoxic effect in humans.

    scientific knowledge about the effects of concern. 2.2

    In the past, the tendency has been When extrapolating data from (See general
    It is assumed that behavioral, to consider only neuropathological animal
    studies to humans.

    statement about these neurophysical, neurochemical, and

    changes as endpoints of concern. assumptions cited neuroanatomical
    manifestations are of Based on data on agents that are

    Generally applied in the absence above.) concern.

    known human neurotoxicants of data on the relevance of effects [citations
    provided], there is at to potential human risk. A biologically significant
    increase in

    least one experimental species any of the manifestations is considered that
    mimics the types of effects indicative of an agent?s potential for seen in
    humans, but in other disrupting the structure or function of

    species tested, the neurotoxic the human nervous system. effect may be
    different or absent.

    2.3 The fact that every species may

    When extrapolating data from (See general It is assumed that the neurotoxic
    not react in the same way is animal studies to humans.

    statement about these effects seen in animal studies may not probably due to
    species- specific assumptions cited always be the same as those produced
    differences in maturation of the

    Generally applied in the absence above.) in humans. Therefore, it may be
    nervous system, differences in of data on the relevance of effects difficult
    to determine the most timing of exposure, metabolism, or to potential human
    risk.

    appropriate species in terms of mechanisms of action. predicting specific
    effects in humans. 2.4

    This is based on the assumption When extrapolating data from Provides a

    It is also assumed that, in the absence that humans are as sensitive as
    animal studies to humans. conservative estimate of data to the contrary, the
    most the most sensitive animal species of sensitivity. (Also

    sensitive species is used to estimate tested. This provides a Generally
    applied in the absence see general statement human risk.

    conservative estimate of of data on the relevance of effects about these
    sensitivity for added protection to to potential human risk.

    assumptions cited the public. above.)

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    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    2.5 Although there may be a threshold

    When extrapolating data from (See general As with other noncancer endpoints,
    it is for neurotoxic effects, these are animal studies to humans.

    statement about these assumed that there is a nonlinear

    often difficult to determine assumptions cited dose- response relationship
    for

    empirically. Therefore, a nonlinear Generally applied in the absence above.)
    neurotoxicants.

    relationship is assumed to exist for of data on the relevance of effects
    neurotoxicants.

    to potential human risk.

    3. Agencywide (ORD) guidelines for reproductive toxicity risk assessment

    Reproductive toxicity focuses on toxic effects regarding the male and female
    reproductive systems, including outcomes of pregnancy and lactation.

    3.1 This assumption is based on

    When extrapolating data from (Not identified in the An agent that produces
    an adverse

    comparisons of data for agents experimental animal studies to

    guidelines.) reproductive effect in experimental that are known to cause
    human humans, in the absence of animals is assumed to pose a potential

    reproductive toxicity [citations adequate human data threat to humans.

    provided]. In general, the experimental animal data indicated adverse
    reproductive effects that are also seen in humans.

    3.2 Because similar mechanisms can

    When extrapolating data from (Not identified in the Effects of xenobiotics
    on male and

    be identified in the male and experimental animal studies to guidelines.)

    female reproductive process are female of many mammalian humans, in the
    absence of

    assumed generally to be similar unless species, effects of xenobiotics on
    adequate human data. demonstrated otherwise.

    male and female reproductive processes are assumed generally For
    developmental outcomes, the

    to be similar across species, specific effects in humans are not unless
    demonstrated otherwise. necessarily the same as those seen in the
    experimental species. However, The assumption for developmental adverse
    developmental outcomes in outcomes is made because of the laboratory
    mammalian studies are possibility of species- specific presumed to predict a
    hazard for

    differences in timing of exposure adverse developmental outcome in relative
    to critical periods of humans. development, pharmacokinetics (including
    metabolism), developmental patterns, placentation, or modes of action.

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    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    3.3 It is assumed that the most

    When extrapolating data from (Not identified in the In the absence of
    information to

    sensitive species is most experimental animal studies to guidelines.)

    determine the most appropriate appropriate because, for a humans, in the
    absence of

    experimental species, data from the majority of agents known to cause

    adequate human data, and in the most sensitive species should be used.

    human reproductive toxicity, absence of sufficient information humans appear
    to be as or more (e. g., pharmacokinetic data) to sensitive than the most
    sensitive

    determine the most appropriate animal species tested, based on experimental
    species. data from studies that determined dose on a body weight or air

    concentration basis [citations provided]. 3.4

    This assumption for reproductive When extrapolating data from (Not
    identified in the In the absence of information to the risk assessment is
    based on three experimental animal studies to

    guidelines.) contrary, an agent that affects considerations:

    humans, in the absence of reproductive function in one sex is 1. For most
    agents, the nature of adequate human data. assumed to adversely affect the
    testing and data available reproductive function in the other sex.

    are limited, reducing In the absence of information to confidence that the
    potential the contrary.

    for toxicity to both sexes and their offspring has been examined equally. 2.
    Exposures of either males or

    females have resulted in developmental toxicity. 3. Many of the mechanisms
    controlling important aspects of reproductive system function are similar in
    females

    and males, and therefore could be susceptible to the same agents.

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    When the assumption/ choice would be applied (step in the Assumption or
    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    3.5 This is based on known

    When extrapolating data from (Not identified in the A nonlinear dose-
    response curve is homeostatic, compensatory, or experimental animal studies
    to

    guidelines.) assumed for reproductive toxicity.

    adaptive mechanisms that must humans, in the absence of be overcome before a
    toxic adequate human data. endpoint is manifested and on the rationale that
    cells and organs of In a quantitative dose- response the reproductive system
    and the analysis, mode of action, developing organism are known to
    pharmacokinetic, and

    have some capacity for repair of pharmacodynamic information

    damage. should be used to predict the

    shape of the dose- response curve Although a threshold may exist for

    when sufficient information of that endpoints of reproductive toxicity,
    nature is available. When that it usually is not feasible to information is
    insufficient, it has distinguish empirically between a

    generally been assumed that there true threshold and a nonlinear

    is a nonlinear dose response for low- dose relationship.

    reproductive toxicity.

    4. Agencywide (ORD) guidelines for developmental toxicity risk assessment
    Developmental toxicity risk assessment focuses on risk to human development,
    growth, survival, and function because of exposure to environmental agents
    prior to conception, prenatally, or to infants and children. 4.1

    This assumption is based on the When extrapolating data from (Not identified
    in the

    It is assumed that an agent that comparisons of data for agents

    animal studies to humans for guidelines.)

    produces an adverse developmental known to cause human hazard
    identification/ doseresponse

    effect in experimental animal studies developmental toxicity [citations
    analysis.

    will potentially pose a hazard to provided] which indicate that, in humans
    following sufficient exposure almost all cases, experimental Generally
    applied in the absence during development. animal data are predictive of a

    of adequate human data. developmental effect in humans.

    4.2 In the past, there has been a

    When extrapolating data from (Not identified in the It is assumed that all
    of the four tendency to consider only

    animal studies to humans for guidelines.)

    manifestations of developmental malformations or malformations hazard
    identification/ doseresponse

    toxicity (death, structural and death as endpoints of

    analysis. abnormalities, growth alternations, and

    concern. From data on agents functional deficits) are of concern. A that are
    known to cause human Generally applied in the absence biologically
    significant increase in any developmental toxicity [citations of adequate
    human data.

    of the four manifestations is considered provided], there is usually at
    least indicative of an agent?s potential for one experimental species that
    disrupting development and producing

    mimics the types of effects seen in a developmental hazard. humans, but in
    other species tested, the type of developmental perturbation may be
    different.

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    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    4.3 This assumption is made because

    When extrapolating data from (Not identified in the It is assumed that the
    types of

    it is impossible to determine which animal studies to humans for

    guidelines.) developmental effects seen in animal

    will be the most appropriate hazard identification/ doseresponse studies are
    not necessarily the same species in predicting the specific

    analysis. as those that may be produced in types of effects seen in humans.
    humans.

    The fact that every species may Generally applied in the absence not react
    the same way could be of adequate human data.

    due to species- specific differences in critical periods, differences in
    timing of exposure, metabolism, developmental patterns, placentation, or
    mechanisms of action.

    4.4 This assumption is based on

    When extrapolating data from (Not identified in the The most appropriate
    species is used

    observations that humans are as animal studies to humans for

    guidelines.) to estimate human risk when data are

    sensitive or more so than the most hazard identification/ doseresponse
    available (e. g., pharmacokinetics). In sensitive animal species tested for

    analysis. the absence of such data, it is the majority of agents known to
    assumed that the most sensitive

    cause human developmental Generally applied in the absence species is
    appropriate for use. toxicity [citations provided].

    of adequate human data. 4.5

    This is based on the known When evaluating the doseresponse (Not identified
    in the

    In general, a threshold is assumed for capacity of the developing
    relationship. guidelines.)

    the dose- response curve for agents organism to compensate for or to that
    produce developmental toxicity.

    repair a certain amount of damage at the cellular, tissue, or organ level.
    In addition, because of the multipotency of cells at certain

    stages of development, multiple insults at the molecular or cellular level
    may be required to produce an effect on the whole organism.

    4.6 (Not identified in the guidelines.) When doing dose- response (Not
    identified in the

    For developmental toxic effects, a evaluation. guidelines.)

    primary assumption is that a single exposure at a critical time in
    development may produce an adverse developmental effect, i. e., repeated
    exposure is not a necessary prerequisite for developmental toxicity to be
    manifested.

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    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    4.7 (Not identified in the guidelines, When doing dose- response (Not
    identified in the

    If absorption [of the administered dose but this assumption is a variation

    evaluation using data from animal guidelines.)

    of an agent] in the experimental on the inference assumption studies.
    species has been determined, but

    identified under item 4. 4, and human absorption is not known, other related
    EPA guidelines are human absorption is generally referenced as well.)
    assumed to be the same as that for the species with the greatest degree of
    absorption.

    4.8 (Not identified in the section on When determining the reference

    (Not identified in the When determining the reference dose RfD and RfC, but
    the assumptions dose or concentration for

    guidelines.) or reference concentration for regarding use of the most
    developmental toxicity (the RfD DT developmental toxicity:

    sensitive effect and most or RfC DT ) a level at or below which

    appropriate and/ or sensitive it is assumed that no significant  The most
    sensitive developmental species are variations on risk occurs.

    effect from the most appropriate inference assumptions described and/ or
    sensitive mammalian species above.) is used for determining the NOAEL,
    LOAEL, or benchmark dose.

     Uncertainty factors for developmental and maternal toxicity generally
    include a 10- fold factor for interspecies variation and a 10- fold factor
    for intraspecies variation. Additional factors may be applied to account for
    other uncertainties or additional information that may exist in the
    database. In general, an uncertainty factor is not applied to account for
    duration of exposure.

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    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    5. Agencywide (ORD) guidelines for health risk assessment of chemical
    mixtures (1999 draft of supplemental guidance)

    5.1 Several studies have Used in dose- response (Not identified in the

    For the component chemicals that demonstrated that dose (or

    assessment. guidelines.)

    show similar toxicity, dose addition is concentration) addition often
    recommended. (When the effect of the

    predicts reasonably well the Dose addition is the default combination is the
    effect expected from toxicities of mixtures composed of

    approach in situations where the the equivalent dose of an index a
    substantial variety of both similar dose for each individual chemical, the
    equivalent dose is the and dissimilar compounds component is at a level at
    which sum of the component doses scaled by (citations provided).

    effects are not expected to occur, their potency relative to the index be
    observable, or be of concern. chemical. This sum of the exposure The
    assessment of multiple However, when the doses are levels is a weighted
    sum.) toxicant exposure has been

    combined, effects of concern are addressed by the American then expected or
    observed in Dose addition is different from Conference of Governmental
    response to the higher dose level response addition because two Industrial
    Hygienists, OSHA, the of the mixture.)

    assumptions are made: that all of the World Health Organization, and
    components have similar uptake,

    the NRC (citations provided). pharmacokinetics, and toxicologic

    Although the focus and purpose of processes, and that the (log probit) each
    group was somewhat dose- response curves of the different, all of the
    recommended components are parallel.

    approaches included some type of dose- additive model.

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    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    5.2 Dose- additive models may not be Used in dose- response (Not identified
    in the

    For the component chemicals in a the most biologically plausible assessment.

    guidelines.) mixture that show dissimilar toxicity, approach if the
    compounds do not response addition is recommended.

    have the same mode of toxicologic Response addition is the default

    (Under response addition, the general action. approach when the component

    procedure is to first determine the risks chemicals are functionally per
    exposure for the individual independent. It is most often components; the
    mixtures risk is then applied when an effect that is of estimated by adding
    the individual concern is expected to be present

    risks together.) at low- dose levels for each of the

    component chemicals, even Response addition is different from though it is
    highly unlikely to be dose addition in that it does not observable at these
    low levels in assume similar kinetics or a similar either epidemiologic or
    toxicologic mode of action and does not assume studies. parallel dose-
    response curves. It assumes that the components of the

    Because response addition does mixture are considered to be not require a
    similar mode of action functionally independent of one

    across the chemicals in the another at low- exposure levels, so that
    mixture, it allows for combining the risks may be added together. (This

    risks across different types of sum of the effects of the individual

    endpoints. chemicals is a conditional sum.)

    5.3 (Not identified in the guidelines.) Used in dose- response (Not
    identified in the

    If interactions data are available, the assessment. guidelines.) default
    recommendation is that they be incorporated into the risk assessment either
    by using the interactions based hazard index or by including a qualitative
    assessment of the direction and magnitude of the impact of the interaction
    data.

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    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    6. Agencywide (ORD) guidelines for ecological risk assessment

    These guidelines focus on exposures to one or more anthropogenic chemical,
    physical, or biological stressors that may result in adverse ecological
    effects. In comparison to the NAS risk paradigm, the information here
    reflects the novel approaches and methodological choices advocated by EPA in
    ecological risk assessments. Only a subset of the primary methodological
    choices are presented- rather than specific default assumptions, reflecting
    the level of specificity in EPA?s ecological risk assessment guidance
    document.

    6.1 Allows determinations regarding

    Applied in most ecological risk Precautionary EPA advocates tiering
    ecological risk how extensive a risk assessment assessments. approach
    maintaining assessments such that conservative should be, taking into a
    higher degree of approaches are first employed in both

    consideration risk management conservatism in the data and model use,
    followed by a

    goals. risk assessment.

    more detailed assessment process (if warranted).

    The underlying assumptions and the risk scenarios can be carried When a risk
    has been identified,

    through to risk characterization subsequent tiers use additional data to
    phase in a first- tier risk address the uncertainties of the initial
    assessment, allowing their

    assessment( s). plausibility to be discussed and

    reevaluated. Examples of methodological choices in first tier of a
    ecological risk assessment:

     use simple rather than complex models;

     analyze uncertainty propagation and how uncertainty in individual
    parameters can affect the overall

    uncertainty in the results (e. g., calculate error bounds on a point
    estimate); and

     conduct tests designed to evaluate effects such as lethality and
    immobility.

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    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    6.2 Better characterization of stressorassessment General data
    considerations Data choice( s) can Methodological choices regarding data

    endpoint during early first- and subsequenttier effect a risk issues:

    relationships and better ability to risk assessment stages of assessment in
    a accurately formulate and address problem formulation phase-

    variety of ways, for  When existing data are few and new risk hypotheses:
    particularly when data or example: data cannot be collected, consider
    relationships cannot be defined in extrapolation from existing data when
    Extrapolation of data collected a traditional laboratory setting or

     More accurate characterizing effects of stressors on from other locations
    or on

    where assessments of multiple conclusions in assessment endpoints. organisms
    where similar

    stressors or site- specific factors laboratory settings

     Employ field- observational studies circumstances exist can be a
    significantly influence exposure.

    may be possible; that represent exposures and effects useful proxy-
    particularly when however, laboratory better than estimates generated from
    obtaining original data is Studies that minimize the amount controls may
    limit the laboratory studies or theoretical unachievable.

    of extrapolation are preferred. range of responses

    models. and/ or may not  Use statistical tests (e. g., correlation,

     Field- observational studies reflect responses in clustering, factor
    analysis) or indices

    (surveys) are necessary to the environment. to measure and evaluate effects.

    measure biological changes in  Directly measure environmental uncontrolled
    situations that best

     Results can be media (or a combination of modeling mimic the relationship
    between

    presented as a and direct measurement) if stressors assessment endpoint and

    series of point have already been released into the

    stressor [citations provided]. estimates with environment, if possible.

    different aspects of  Use point estimate/ descriptor

     Large- scale ecological uncertainty reflected approach when there is not
    enough

    processes are difficult to detect in each (e. g., information to describe a
    distribution. in laboratory settings.

    classical statistical methods such as confidence limits, or percentiles, can
    be employed).

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    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    6.3 Allows for the establishment of a

    Determination of dose in analysis (Not indicated in Generally, potential
    dose of a chemical standardized approach in deriving phase. guidelines.) is
    quantified as the amount of chemical values of exposure for ingested
    ingested, inhaled, and/ or applied media (food or soil).

    dermally. Specifically, potential average daily dose for ingested media is a
    function of:

     average contaminant concentration in the type of food (using modeled or
    measured values);

     fraction of intake of the food type that is from the contaminated area;

     normalized ingestion rate of the food type on a wet- weight basis;

     number of contaminated food types.

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    methodological

    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    6.4 EPA advocates such Production of a summary exposure

    (Not indicated in In creating an exposure profile, methodological choices
    regarding profile during analysis phase that:

    guidelines.) estimates of exposure should be

    exposure profiles in order to allow considered, at a minimum, along three a
    risk assessor to best estimate

     identifies the receptor (i. e., the dimensions: intensity, time, and
    space. risks. The exposure profile, in exposed ecological entity); These,
    and other exposure guidelines,

    turn, is combined with an effects are outlined below: profile to estimate
    risks.

     describes the course a stressor takes from the source to the

     Intensity may be expressed as the receptor (i. e., the exposure amount of
    chemical contacted per

    pathway); and day or the number of pathogenic organisms per unit area.

     describes the intensity and spatial and temporal extent of cooccurrence

     The temporal dimension of exposure or contact. is best addressed with the
    parameters of duration, frequency, and timing.

     In its simplest form, a stressor is quantified as a concentration, with
    the assumption that the chemical is well mixed or that the organism moves
    randomly through the medium.

    ? High end? exposure should refer to estimates that are expected to fall
    between the 90 th and 99. 9 th percentile of the exposure distribution.

     Bounding estimates should refer to those higher than any actual exposure.

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    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    6.5 Quotient method is commonly When performing activities of risk (Not
    indicated in

    When sufficient data are available to used for chemical stressors,
    characterization phase (i. e., risk guidelines.) quantify exposure and
    effects where reference or benchmark estimation, risk description,
    estimates, the simplest approach for

    toxicity values are widely reporting risk).

    comparing the estimates is a ratio (or available.

    quotient). Principal reasons for selecting A quotient addition approach
    assumes quotient method: that toxicities are additive or

     It is simple and quick to use and approximately additive (this risk
    assessors and managers assumption may be mostly applicable

    are familiar with its application. when the modes of action of chemicals

     It provides an efficient, in a mixture are similar).

    inexpensive means of identifying high- or low- risk situations that can
    allow risk management decisions to be made without the need for further
    information.

     Quotients can be used to integrate risks of multiple chemical stressors.

    The following sections illustrate the types of additional, program- specific
    assumptions and choices identified by individual program offices within EPA.
    We only provide examples from two of EPA?s offices- the Office of Pesticide
    Programs and the Office of Water. However, other offices can also have their
    own preferences with regard to risk assessment assumptions and methods tied
    to the particular exposures of concern to their programs.

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    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    7. Office of Pesticide Programs science policy papers and guidance documents
    regarding risk assessments for pesticides

    OPP has published an expanding series of over 20 science policy papers- many
    still at the draft stage- on various issues related to regulation of
    pesticides in response to the Food Quality Protection Act of 1996. The
    following rows illustrate some of the major assumptions or choices described
    within those science policy papers or guidance documents.

    7.1 Statutory provision of the FQPA, in (This is primarily a ?risk (The
    intent of this Applying the FQPA tenfold safety factor

    section 408( b)( 2)( C). management? issue when EPA is additional ?safety
    ?establishing, modifying, leaving in factor? is The FQPA requires EPA to
    apply, in the (In draft policy papers on this effect, or revoking a
    tolerance or precautionary- to give case of threshold effects, an additional

    subject, EPA cited a number of exemption for a pesticide chemical special
    consideration tenfold margin of safety for the reasons regarding the
    agency?s

    residue.? However, it affects risk with respect to pesticide chemical
    residue and other preference for making a case- bycase assessment by OPP in
    that it calls exposure and toxicity

    sources of exposure for infants and determination of an for a determination
    of whether the

    to infants and children to take into account potential

    appropriate safety factor. The available data are reliable and a children.)

    pre- and postnatal toxicity and agency pointed out, in particular,

    different ?margin of safety? will be completeness of data with respect to
    that because OPP?s approach to safe for infants and children.) exposure and
    toxicity to infants and

    estimating exposure in the children. The Administrator of EPA absence of
    extensive, specific may use a different margin of safety for data is
    typically very conservative, the pesticide chemical residue only if, OPP can
    usually conclude, with a on the basis of reliable data, such a high degree
    of confidence, that its margin will be safe for infants and

    approach adequately protects children. infants and children. EPA is also
    revising its toxicology and Where reliable data are available, OPP exposure
    data requirements in favors an approach that attempts to response to the
    FQPA.) make a specific case- by- case determination as to the size of the
    additional factor rather than rely on the tenfold default value.

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    7.2 The tiered approach is used to When assessing dietary exposures (EPA
    characterizes the Dietary exposure estimates (draft):

    conserve limited resources. to pesticides. Analysis proceeds initial tiers,
    especially through more rigorous tiers, as the

    tier 1, as producing For regulatory purposes, acute and overall risk
    assessment situation

    conservative exposure chronic dietary exposure to pesticides requires, when
    data exist. estimates. The higher in foods are estimated using indirect
    level tiers are modeling approaches that consider characterized as pesticide
    residues in food and the producing more

    amount of food consumed. EPA accurate, and less

    assesses dietary exposure using a conservative, tiered approach, proceeding
    from exposure conservative to more refined assessments.)

    assumptions and varying by acute (short- term) and chronic (long- term)
    assessments. Initially, EPA uses deterministic assessments based on

    various assumptions about the concentration of pesticide residue in the
    food. For more refined dietary

    assessments, EPA uses probabilistic exposure assessments. (See details for
    these various tiers in rows 7.2.1 through 7. 2.4 below.] 7.2. 1

    The tiered approach is used to When assessing dietary exposures Tolerance
    levels for Tier 1 approach to estimating dietary

    conserve limited resources. to pesticides. Analysis proceeds residues used
    in Tier 1

    risk from pesticides in foods (draft): through more rigorous tiers, as the

    dietary exposure overall risk assessment situation estimates are not  Both
    acute and chronic assessments requires, when data exist.

    expected to accurately use deterministic values (point reflect actual
    residues estimates) for exposure, assuming in ready- to- eat foods; residues
    on foods to be at maximum rather, they are legal tolerance levels and that
    100 intended to provide percent of the crop is treated with the inputs for
    ?worst- case? pesticide.

    exposure estimates. Residue data for Tier 1 assessments meet the criterion
    for conservative exposure factors.

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    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    7.2. 2 The tiered approach is used to When assessing dietary exposures
    Assessments are

    Tier 2 approach to estimating dietary conserve limited resources. to
    pesticides. Analysis proceeds

    refined in Tier 2 using risk from pesticides in foods (draft): through more
    rigorous tiers, as the

    more realistic values overall risk assessment situation for pesticide
    residues.

     Acute assessments use deterministic requires, when data exist. values for
    exposure and assume that (In its guidance for residues on single- serving
    size items

    performing aggregate are at maximum legal tolerance

    exposure levels, residues for blended assessments, OPP commodities are based
    on average noted that field trial residue from field trials or monitoring
    data, which are data, and 100 percent of the crop is traditionally the
    treated with the pesticide. primary source of residue data in foods,
    Chronic assessments use

    overestimate the deterministic values and assume residues that are likely
    residues are at tolerance levels, but to occur in foods as use actual
    percentage of the crop actually consumed. treated. According to the agency,
    this is because they reflect

    the maximum application rate and shortest pre- harvest interval, and
    represent residue levels ?at the farm gate.? OPP

    pointed out that data more reflective of residues on foods as consumed are
    often available from monitoring data in which food samples are obtained
    closer to the dinner table in the chain of commerce and analyzed.)

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    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    7.2. 3 The tiered approach is used to When assessing dietary exposures In
    Tiers 3 and 4,

    Tier 3 approach to estimating dietary conserve limited resources. to
    pesticides. Analysis proceeds

    pesticide residue data risk from pesticides in foods (draft):

    through more rigorous tiers, as the are combined with overall risk
    assessment situation

    assumptions on actual  Acute assessments use probabilistic requires, when
    data exist.

    pesticide application values (distributional estimates), an rates,
    stability, etc., to empirical distribution frequency from refine further
    residue field trials for single- serving items, estimates in foods as
    average residue data from field trials they are consumed.

    or monitoring data for blended commodities, and actual percentage (See note
    on field trial of the crop treated. These and monitoring data in assessments
    also consider food row 7.2.2 above.)

    processing factors.

     Chronic assessments use deterministic values, average residue data from
    field trials or monitoring data for both blended and singleserving

    commodities, and actual percentage of the crop treated. Again, food
    processing factors are

    considered. 7.2. 4

    The tiered approach is used to When assessing dietary exposures In Tiers 3
    and 4, Tier 4 approach to estimating dietary

    conserve limited resources. to pesticides. Analysis proceeds pesticide
    residue data

    risk from pesticides in foods (draft): through more rigorous tiers, as the

    are combined with overall risk assessment situation assumptions on actual
    Acute assessments use probabilistic requires, when data exist.

    pesticide application values, market basket survey data on rates, stability,
    etc., to consumption, actual percentage of

    refine further residue the crop treated, and consider

    estimates in foods as cooking, residue decline, residue they are consumed.
    degradation, and other factors that may affect residues in foods as they are
    consumed.

     Chronic assessments use the same types of data as acute assessments, but
    with deterministic values.

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    7. 3 Assessing Residential Exposures This conservatism adds an extra

    When assessing risks associated EPA said that when measure of safety when
    regulating with residential exposures to

    scientists have studied EPA notes that although its residential pesticides.

    (residential uses of) pesticides. people in the real exposure assessments
    ?are designed world (including the

    to be as realistic as possible,? the Explanations for the specific children
    of assessments also are ?generally

    assumptions include: farmworkers) they conservative.? Specific assumptions
    have generally found a

    include: a. The highest reasonably person?s exposure to

    a. Assume high amounts of pesticide possible transfer rate must be be less
    than that residues will transfer to a person. assumed for safety.

    predicted by EPA?s (EPA generally assumes 20- 50 exposure percent of the
    residues will b. Dissipation rate is based on assessments.

    transfer.) many factors (heat, sunlight,

    and rain, etc.) so EPA says it (In other guidance b. Assume no residue
    dissipation. In must include the conservative documents, EPA other words,
    all the residues prospect that in a given case points out that its available
    initially are available there is no residue

    residential SOPs are throughout the time a person is dissipation. by nature
    designed to exposed. produce screeninglevel c. Assumed because little or no
    assessments that c. Assume that a person has no clothing is a possible
    realistic

    are intentionally clothing on to protect from scenario in some conservative
    in exposure. circumstances.

    nature.) d. Assume 2 to 8 hours of continuous

    d. (No additional explanation contact. provided.)

    (Note that EPA was reviewing and considering whether to update some of the
    detailed exposure scenario assumptions in its standard operating procedures
    (SOPs) for residential assessments.)

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    risk assessment process or Likely effect on risk choice Reason( s) for
    selection circumstances) assessment results

    7.4 Guidance for Performing (EPA revised its approach to When performing
    aggregate (Not directly Aggregate Exposure and Risk aggregate exposure and
    risk exposure and risk assessments addressed in the

    Assessment assessment in response to the

    general discussion in FQPA?s requirement that the the revised guidance.
    Aggregate exposure and risk agency consider aggregate The inference from
    assessment involves the analysis of a exposure in its decision making.)

    EPA?s comparison to single chemical exposure by multiple the interim
    guidance is pathways of exposure (i. e., food, EPA noted in the guidance
    that that the revised drinking water, and residential, aggregate exposure
    assessments

    practices should result nonoccupational), and all relevant built individual
    by individual,

    in less conservative routes of exposure (i. e., oral, dermal, culminating in
    a total exposure to estimates than the and inhalation). EPA?s revised the
    population, may allow for interim practices. guidelines support an approach
    in probabilistic treatment of data

    However, the revised which an analyst assesses exposure

    incorporating all pathways of guidance also on an individual- by- individual
    basis, exposure, (i. e., food, drinking emphasizes the use of culminating in
    a representative water, and residential).

    ?reasonable population of interest. This approach assumptions that do
    differs from EPA?s interim guidelines. Distributional data analysis is not
    underestimate (According to the interim guidelines, preferred as this tool
    allows an exposure? when data aggregate assessments most aggregate exposure
    assessor to are not available, so frequently added the ?high- end? or more
    fully understand the

    there still may be a upper- bound point estimates from the uncertainty and
    variability inherent

    precautionary drinking water and residential

    in the data set. element.)

    exposure pathways to a point on the distribution of food ingestion exposure,
    e. g., the 99. 9 th percentile.) Aggregate exposure and risk assessments
    will be more realistic to the extent that the appropriate

    temporal, spatial, and demographic factors that affect exposure to an
    individual are understood and accounted for. When these data are not
    available, reasonable assumptions that do not underestimate exposure can be
    used. Once an aggregate exposure and risk assessment is completed for one
    individual and repeated for many individuals, population and subpopulation
    distributions of total exposures and risk may be constructed by
    probabilistic techniques. Distributional data analysis is preferred.

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    8. Office of Water Risk Assessments

    OW has published a collection of guidance documents relating to water
    quality issues, based primarily on mandates derived from the Clean Water Act
    (CWA) and Safe Drinking Water Act (SDWA). For illustrative purposes,
    emphasis here is on assumptions and methodological choices taken from
    Methodology for Deriving Ambient Water Quality Criteria for the Protection
    of Human Health, EPA822-

    B- 00- 005 (October 2000). This document provides detailed guidance on
    developing Ambient Water Quality Criteria (AWQC), with organized procedures
    for evaluating cancer risk, noncancer health effects, human exposure, and
    bioaccumulation potential in fish. In this guidance, EPA states that
    protective assumptions are made regarding potential human exposure intakes
    at an appropriate level of conservatism where uncertainties exist.
    Furthermore, criteria are derived to be protective, not predictive, of an
    exact percentile of the

    total population that is protected. 8.1

    Body weight, water intake, and Used in the derivation of AWQC,

    Conservative EPA has identified a number of fish intake are default
    parameters and also, to be consistent with

    assumptions in standard or default exposure factors: specific to target
    populations that

    Section 101( a) of CWA which choosing exposure  All drinking water consumed
    is are considered important when specifies possible water body uses
    parameters support contaminated at the criteria level.

    determining AWQC values. (e. g., consumption of fish).

    the goal of protecting  All fish consumed is contaminated at the majority
    of the the criteria level and all fish may Drinking water and fish intake
    population. come from one water body.

    values are 90 th percentile  Body weight of a child ages 1 to 3 is
    estimates, based on most recent 13 kg (when the age group is ages 1

    USDA survey data reflecting the to 14, body weight is 30 kg).

    90 th percentile of the general

     Body weight of an adult is 70 kg. population (1994- 96 CSFII data),  Body
    weight of a woman of and are percentiles selected to

    childbearing age is 67 kg. ensure protection of the majority

     Daily untreated surface water of consumers of drinking water consumed is 2
    liters.

    and fish.

     Daily fish consumption is 17. 5 g for general adult population and
    (average) sport fishers; 142. 4 g for

    subsistence fishers.

     Criteria generally represent ambient pollutant concentrations that are
    acceptable based on a lifetime (70 years) of exposure.

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    8.2 Uncertainty factors listed in the Deriving water quality criteria for
    Conservative In setting RfDs for noncarcinogens,

    previous column are used to more the protection of human health

    approach resulting in EPA advocates the use of uncertainty

    accurately determine an RfD by from noncancer effects (i. e., lower RfD
    values. factors and, if needed, a modifying more closely identifying and

    noncarcinogenic chemicals) via factor to account for areas of scientific
    incorporating, respectively:

    the determination RfDs. uncertainty in toxicity databases. EPA recommends a
    default of 10 for

    a. interhuman variability (to Specifically, the RfD is used with

    uncertainty factors and a default of 1 account for variation in additional
    information regarding

    for modifying factors when lacking sensitivity among the exposure and the
    bioaccumulation

    other information. members of the human potential of the substance to derive
    population);

    an AWQC for noncancer effects. Specifically, EPA recommends b. experimental
    animal- tohuman applying a 1-, 3-, or 10- fold uncertainty

    extrapolation According to EPA, the ?[ c] hoice of factor when:
    (interspecies variation); appropriate uncertainty factors and a.
    extrapolating from valid data in c. subchronic to chronic modifying factors
    must be a caseby- studies using long- term exposure extrapolation (to
    account for

    case judgment by experts and to average healthy humans; uncertainty in
    extrapolating

    should account for each of the b. extrapolating from valid results of from
    less- than- chronic applicable areas for uncertainty long- term studies on
    experimental NOAELs or LOAELs to and nuances in the available data animals
    when results of studies of chronic NOAELs);

    that impact uncertainty.? human exposure are not available

    d. database completeness (to or inadequate;

    account for the inability of any c. extrapolating from less- thanchronic
    single study to adequately

    results on experimental address all possible adverse

    animals when there are no useful outcomes); and long- term human data; or

    e. LOAEL- to- NOAEL d. deriving an RfD from an extrapolation.

    ?incomplete? database. A modifying factor is to be used EPA recommends a 3-
    or 10- fold when the areas of scientific uncertainty factor when:

    uncertainty addressed with e. deriving an RfD from a LOAEL, uncertainty
    factors do not instead of a NOAEL.

    represent all of the uncertainties in the estimation of a RfD. EPA advocates
    using professional judgment in determining the modifying factor, the
    magnitude of which is greater than zero and less than or equal to 10, being
    dependent on assessment of uncertainties of relevant studies and databases.

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    8.3 Such values reflect appropriate (None given.) (None given.)

    EPA identified both 10 -6 and 10 -5 as target risk levels for health
    appropriate cancer target risk levels, protection of the general and said
    that highly exposed

    population. populations should not exceed a 10 -4 cancer risk level.

    The cancer risk levels increase the degree of consistency between Cancer
    risk level of 10 -6 is based on a the drinking water program, fish intake
    rate of 17. 5 g/ day for

    ambient water program, and other general population and sport anglers, a EPA
    programs. fish intake rate of 142.4 g/ day for subsistence fishers, and a
    drinking water intake rate of 2 liters per day for each of these groups.

    8.4 This methodological choice offers

    Where either new risk assessment AWQC may increase Under some circumstances,
    it may be some flexibility for site- specific or studies or site- specific
    information

    or decrease. appropriate to use a point within an

    contaminant- specific situations but support derivation of an AWQC RfD range
    as the basis for deriving remains protective of public from a point within
    RfD range.

    AWQC, rather than the single point health. default estimate of the RfD, when
    the uncertainty factor is 100 or greater and the range is either a quarter
    or half log unit to either side of the calculated RfD.

    8.5 In deriving RfD, use of RSC allows Derivation or revision of an AWQC
    Conservative and

    Consideration of nonwater sources of for assessing total human based on RfDs
    or nonlinear

    protective approach exposure (e. g., ingestion and/ or exposure to a
    contaminant and

    carcinogen PODs. when known or inhalation exposure) is recommended
    apportions the RfD among the

    anticipated nonwater when determining a relative source media of concern.
    sources of exposure contribution (RSC) factor to apply to a are anticipated.
    nonlinear carcinogen point- ofdeparture

     Use of ?Exposure Decision Tree? (POD) or a RfD. approach allows for use of
    either subtraction or percentage Apply an estimate of the RSC factor
    methods, depending on (between 20 and 80 percent) to the

    chemical circumstances, within RfD when adequate exposure data do the 20- to
    80- percent range. not exist, using an exposure decision tree approach.

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    8.6 This change was made in order to BAF values are used in

    The ambient water EPA recommends using a

    reflect the uptake of a contaminant calculations of AWQC for

    quality criteria for bioaccumulation factor (BAF) rather by aquatic
    organisms from all

    carcinogens (in both linear and highly bioaccumulative than a
    bioconcentration factor as sources (e. g., water, food, nonlinear
    approaches) and for

    pollutants may be up previously set forth in the 1980 sediment) rather than
    just from the noncarcinogens. to 2 orders of Methodology.

    water column. magnitude lower than

    criteria derived with bioconcentraton factors.

    Source: Compiled from GAO review of EPA risk assessment guidelines and
    related documents and from additional comments provided by agency officials.

    Risk Characterization As with exposure assessment, the program offices
    typically are responsible for completing the risk characterization. EPA
    does, however, have several documents that provide agencywide guidance on
    how such characterization is to be done. The guidance includes a February
    26, 1992, memorandum from the EPA Deputy Administrator entitled, ?Guidance
    on Risk Characterization for Risk Managers and Risk Assessors,? and a March
    21, 1995, document issued by the EPA Administrator entitled, ?Policy for
    Risk Characterization at the U. S. Environmental Protection Agency.? EPA
    also has developed a Risk Characterization Handbook to provide more detailed
    guidance to agency staff. In the statement accompanying its 1994 report
    Science and Judgment in

    Risk Assessment, NRC said that although EPA?s overall approach for assessing
    risks was fundamentally sound, the agency ?must more clearly establish the
    scientific and policy basis for risk estimates and better describe the
    uncertainties in its estimates of risk.? In March 1995, the EPA
    Administrator issued the agency?s risk characterization policy and guidance,
    which reaffirmed the principles and guidance in the agency?s 1992 policy.
    EPA?s guidance document defined risk characterization as the final step in
    the risk assessment process that (1) integrates the individual
    characterizations from the hazard identification, dose- response, and

    exposure assessments; (2) provides an evaluation of the overall quality of
    the assessment and the degree of confidence the authors have in the
    estimates of risk and conclusions drawn; (3) describes the risks to
    individuals and populations in terms of extent and severity of probable
    harm; and (4) communicates the results of the risk assessment to the risk

    manager. Discussing ?guiding principles? for risk characterization, EPA
    emphasized that the integration of information from the three earlier stages
    of risk assessment, discussion of uncertainty and variability, and
    presentation of information to risk managers requires the use of both
    qualitative and quantitative information. For example, when assumptions are
    made in exposure assessment, EPA said that the source and general

    logic used to develop the assumptions should be described, as well as the
    confidence in the assumptions made and the relative likelihood of different
    exposure scenarios. In the 1995 policy statement, EPA said that risks should
    be characterized in a manner that is clear, transparent, reasonable, and
    consistent with other risk characterizations of similar scope. EPA said that
    all assessments ?should identify and discuss all the major issues associated
    with determining the nature and extent of the risk and provide commentary on

    any constraints limiting fuller exposition.? The policy also said risk
    characterization should (1) bridge the gap between risk assessment and risk
    management decisions; (2) discuss confidence and uncertainties involving
    scientific concepts, data, and methods; and (3) present several types of
    risk information (i. e., a range of exposures and multiple risk

    descriptors such as high ends and central tendencies). The policy stated
    that each risk assessment used in support of decision making at EPA should
    include a risk characterization that follows the principles and reflects the
    values outlined in the policy. However, the policy statement went on to say
    that it and the associated guidance did not establish or affect legal rights
    or obligations.

    Some of EPA?s other risk assessment guidelines also discuss and recommend
    certain approaches to the risk characterization phase. For example, EPA?s
    proposed guidelines for carcinogen risk assessment call for greater emphasis
    on the preparation of ?technical? characterizations to summarize the
    findings of the hazard identification, dose- response assessment, and
    exposure assessment steps. The agency?s risk assessors

    are then to use these technical characterizations to develop an integrative
    analysis of the whole risk case. That integrative analysis is in turn used
    to prepare a less extensive and nontechnical Risk Characterization Summary
    intended to inform the risk manager and other interested readers. EPA
    identified several reasons for individually characterizing the results of
    each analysis phase before preparing the final integrative summary. One is
    that the analytical assessments are often done by different people than
    those who do the integrative analysis. The second is that there is very
    often a lapse of time between the conduct of hazard and dose- response
    analyses

    and the conduct of the exposure assessment and integrative analysis. Thus,
    according to EPA, it is necessary to capture characterizations of
    assessments as the assessments are done to avoid the need to go back and
    reconstruct them. Finally, several programs frequently use a single hazard
    assessment for different exposure scenarios. The guidelines also point out
    that the objective of risk characterization is to call out any significant

    issues that arose within the particular assessment being characterized and
    inform the reader about significant uncertainties that affect conclusions,
    rather than to recount generic issues that are covered in agency guidance
    documents.

    In another example, EPA?s ecological risk guidelines emphasize that risk
    characterization is a means for clarifying relationships between stressors,
    adverse effects, and ecological entities. In addition, this phase of the
    risk assessment process is a time to reach conclusions regarding the
    occurrence of exposure( s) and the adversity of existing or anticipated
    effects. Specifically, EPA guidance describes three ecological risk
    characterization activities: (1) risk estimation (i. e., integrating
    exposure and effects data and evaluating uncertainties); (2) risk
    description (i. e.,

    interpreting and discussing available information about risks to the
    assessment endpoints); and (3) risk reporting (i. e., estimating risks
    indicating the overall degree of confidence in such estimates, citing lines
    of

    evidence to support risk estimates, and addressing assumptions and
    uncertainties). Similar to EPA- wide guidance on risk characterization,
    EPA?s ecological risk characterization guidelines emphasize open

    communication with risk managers and other interested parties to clearly
    convey information needed for decision making in a risk management context.

    It is also EPA?s policy that major scientifically and technically based work
    products related to the agency?s decisions normally should be peer reviewed
    to enhance the quality and credibility of the agency?s decisions.

    With regard to EPA?s chemical risk assessments, peer review can be used for
    evaluating both specific assessments and the general methods EPA uses in its
    risk assessments. Peer review generally takes one of two forms: (1) internal
    peer review by a team of relevant experts from within EPA who have no other
    involvement with respect to the work product that is to be evaluated or (2)
    external peer review by a review team that consists primarily of independent
    experts from outside EPA. In December 2000,

    EPA released a revised edition of its Peer Review Handbook for use within
    the agency.

    Chemical Risk Assessment at the Food and

    Appendi x II I Drug Administration The Food and Drug Administration (FDA)
    within the Department of Health and Human Services regulates the safety of a
    large number and wide variety of consumer products, including foods,
    cosmetics, human and animal medicines, medical devices, biologics (such as
    vaccines and blood products), and radiation- emitting products (such as
    microwave ovens). Chemical risk assessments are primarily conducted by three
    of FDA?s five product- oriented centers- the Center for Food Safety and
    Applied Nutrition (CFSAN), the Center for Veterinary Medicine (CVM), and the
    Center for Devices and Radiological Health (CDRH). The chemical risk
    assessment activities of these centers vary depending on factors such as

    the underlying statutory requirements, the substances being regulated,
    whether cancer or noncancer effects are of concern, and whether a product is
    under pre- or postmarket scrutiny. FDA officials said that the agency
    generally follows the National Academy of Sciences? (NAS) fourstep risk
    assessment process, although it has not developed written internal
    guidelines. FDA often incorporates conservative assumptions into its
    assessments when information essential to a risk assessment is not known,
    but such assumptions are supposed to be scientifically plausible and
    consistent with agency regulations or policies. For example, CFSAN

    assumptions are expected to be reasonably protective of human health. FDA
    does not have an official policy on how risk assessment results should be
    characterized and communicated to policymakers and the public. However, FDA
    officials said that, in practice, they use a standard approach

    that typically highlights the assumptions with the greatest impact on the
    results of an analysis, states whether the assumptions used were
    conservative, and shows the implications of different choices.

    Context for FDA FDA?s regulatory authority is primarily derived from the
    Federal Food, Chemical Risk

    Drug, and Cosmetic Act, as amended (FFDCA), although several related public
    health laws (e. g., the Food and Drug Administration Modernization
    Assessment

    Act of 1997, or FDAMA) provide additional authority. FDA administers its
    regulatory responsibilities through its five product- oriented centers: (1)
    CFSAN, (2) CVM, (3) CDRH, (4) the Center for Drug Evaluation and Research,
    and (5) the Center for Biologics Evaluation and Research. FDA officials said
    that, although each of these five product centers conducts some type of risk
    assessments, the first three primarily conduct the

    chemical risk assessments that are the focus of this report. 1 Each of these
    centers has different responsibilities, authorities, and constraints on its
    regulatory and risk assessment activities. 1 Some of the offices focused on
    in this appendix also conduct other, nonchemical, types of risk assessments.
    For example, the Center for Devices and Radiological Health also uses risk
    assessments to determine the carcinogenic, genetic, and/ or reproductive
    health risks associated with radiation- emitting products. The Center?s
    reviews of medical devices are also likely to consider engineering risk
    assessments and the potential adverse effects of exposure to microbial
    contamination. The Center for Veterinary Medicine and the Center for Food
    Safety and Applied Nutrition also carry out microbiological risk
    assessments.

     CFSAN is responsible for the regulation of food additives, color additives
    used in food, and cosmetic additives. 2 Under the FFDCA, the regulation of
    substances intentionally added to food or used in contact with food must be
    based solely on the safety of the substances for their

    intended uses (i. e., consideration of benefits and costs is not allowed). A
    food containing an unapproved food or color additive is considered

    ?unsafe? unless FDA issues a regulation approving its use or, in the case of
    a food contact substance, there exists an effective notification. 3 To
    obtain an authorizing regulation or an effective notification, the sponsor
    of a food or color additive must show that it is safe for its intended use.

    FDA regulations under the FFDCA define a product as safe if there is ?a

    reasonable certainty in the minds of competent scientists that the substance
    is not harmful under the intended conditions of use.? 4 For food additives
    and color additives that are not themselves carcinogenic but contain
    carcinogenic impurities, CFSAN uses a quantitative risk

    assessment to determine whether the risk posed by a carcinogenic impurity is
    acceptable (i. e., a lifetime risk below one per million) under the FFDCA?s
    general safety clause of ?reasonable certainty of no harm.? Nevertheless, if
    the food or color additive itself is a known carcinogen, under the ?Delaney
    Clause? amendments to FFDCA, it cannot be deemed safe and is prohibited from
    use in food. 5 CFSAN is also involved with substantial activities in the
    area of postmarket concerns with contaminants and naturally occurring
    toxicants. For example, in

    the past year, CFSAN participated in a number of major, international
    chemical risk assessments in the areas of dioxins and various mycotoxins.

    2 FDA?s responsibility in the food area covers all food except meat,
    poultry, and egg products, which are under the authority of the U. S.
    Department of Agriculture. Generally, FDA regulates food products sold in
    interstate commerce, whereas products made and sold entirely within a state
    are regulated by that state.

    3 Section 309 of FDAMA of 1997. 4 21 CFR 170.3( i). 5 21 U. S. C. 348 (c)(
    3)( A) on food additives and 379e( b)( 5)( B) on color additives. The Food
    Quality Protection Act of 1996 eliminated application of the Delaney proviso
    to pesticides.

     CVM?s primary role is to implement the FFDCA requirement that animal drugs
    and medicated feeds are safe and effective for their intended uses and that
    food from treated animals is safe for human consumption. Under the FFDCA,
    the regulation of residues of animal drugs that become a part of food
    because of the use of the animal drug must be based solely on health factors
    (i. e., consideration of benefits and costs is not allowed). A carcass or
    any of its parts that contain residues of an unapproved drug, or residues of
    an approved drug above approved levels, is considered to be unsafe and the
    carcass is considered adulterated. CVM uses risk assessment to help develop
    safe

    concentration levels in edible tissues, residue tolerances for postmarket
    monitoring, and withdrawal periods for slaughter following drug treatment.
    For noncancer effects, the applicable safety standard under

    FFDCA is that that these concentrations, tolerances, and withdrawal periods
    should represent a ?reasonable certainty of no harm.? FFDCA includes
    provisions that permit FDA to authorize extralabel uses of an animal drug
    that would pose a ?reasonable probability? of risk to human health if
    residues of the drug are consumed. The agency may establish a safe level for
    the residue and require that the drug sponsor provide an analytical method
    for detecting residues of such a compound. 6 However, the act prohibits use
    in food- producing animals of any

    compound found to induce cancer when ingested by people or animals unless it
    can be determined that ?no residue? of that compound will be found in the
    food produced from those animals under conditions of use

    reasonably certain to be followed in practice. 7 FDA has interpreted the
    intention of the ?no residue? language in the statute as meaning that any
    remaining residues should present an insignificant risk of cancer to people.
    As a matter of policy, FDA accepts a lifetime risk below one per million as
    an insignificant level.

    6 21 U. S. C. 360b( a)( 4)( B). 7 21 U. S. C. 360b( d)( 1)( I) on new animal
    drugs. This is known as the DES (diethylstilbestrol) proviso to the Delaney
    Clause. The Center for Veterinary Medicine?s regulation found in 21 CFR
    500.80 outlines how the center regulates carcinogenic drugs and feed
    additives under the DES proviso.

     CDRH administers the medical device provisions of FFDCA, and assesses
    risks posed by chemicals that might leach out from medical devices (e. g.,
    breast implants) into surrounding tissue. The center?s

    basic mission is to protect the public health by ensuring that there is
    reasonable evidence of the safety and effectiveness of medical devices
    intended for human use. CDRH usually evaluates risks in the context of a
    premarket review system, and the decision to clear or approve a product to
    treat a specific condition is based on a benefit- risk analysis for the
    intended population and use (not just on the basis of safety or

    human health as in the case of food regulation). Because all medical
    products are associated with risks, CDRH considers a medical product to be
    safe if it has reasonable risks given the magnitude of the benefit

    expected and the alternatives available. 8 Another unit of FDA, the National
    Center for Toxicological Research (NCTR), has an important supporting role
    in the risk- related activities of the product centers. NCTR conducts much
    of the agency?s methodological research on risk assessment methods and helps
    to develop and modify FDA?s quantitative methods, in conjunction with
    experts from the various product centers. NCTR also provides toxicology
    research supporting all components of FDA. It performs fundamental and
    applied research designed specifically to define biologic mechanisms of
    action underlying

    the toxicity of products regulated by FDA. 8 This applies to all medical
    products, including drugs and biological products, not just to devices.

    Risk Assessment Although FDA has long been a pioneer in the development of
    risk assessment methods, the agency has not developed written internal
    Procedures

    guidance specifically on conducting risk assessments. 9 FDA officials noted
    that much of their work is done before products are placed on the market
    and, in those instances, the burden of proof is on sponsors seeking FDA
    approval for new products. 10 In keeping with this requirement, FDA produces
    extensive external guidance documents that are primarily directed at those
    sponsors. 11 The documents are meant to represent the agency?s current
    thinking on the scientific data and studies considered appropriate for
    assessing the safety of a product. However, the guidance documents are not
    legal requirements and do not preclude the use of

    alternative procedures or practices by either FDA or external parties. Some
    of these guidelines include detailed descriptions of risk assessment methods
    deemed appropriate to satisfy FDA?s reviews under various statutory
    provisions. FDA has also adopted a number of domestic and international
    consensus standards that prescribe certain risk assessment methods (e. g.,
    approaches for assessing the safety of medical devices and default
    consumption values for meat products).

    9 FDA published ?Procedures for the Appraisal of Toxicity of Chemicals in
    Food,? the agency?s first guidance to industry, in 1949. In the 1950s, FDA
    initially developed the general NOAEL (or NOEL)/ safety factor approach to
    noncancer risk assessment that has been used by most regulatory bodies (e.
    g., EPA?s reference dose approach). 10 This is not true with regard to
    dietary supplements. The Dietary Supplement Health and Education Act of 1994
    created a new framework for FDA?s regulation of dietary supplements, which
    do not have to undergo preapproval by FDA to determine their safety or
    efficacy. FDA officials said they currently have no standard procedures for
    dietary supplement risk assessment. 11 Examples of such guidelines include
    ?Redbook 2000: Toxicological Principles for the Safety of Food Ingredients,?
    ?Estimating Exposure to Direct Food Additives and Chemical Contaminants in
    the Diet,? and ?General Principles for Evaluating the Safety of Compounds
    Used in Food- Producing Animals.?

    FDA risk assessment procedures have also been described by individuals and
    organizations from within and outside of the agency in scientific and
    professional journal articles. For example, a 1997 journal article written
    by a panel of officials from across FDA summarized the risk assessment
    approaches of each of FDA?s product centers. 12 A 1996 report on federal
    agencies? chemical risk assessment methods described CFSAN?s methods, but
    did not describe the approaches used by the other centers within FDA. 13
    FDA?s food safety risk assessment procedures were also described in
    ?Precaution in U. S. Food Safety Decisionmaking: Annex II to the United
    States? National Food Safety System Paper,? which was prepared for the
    Organization for Economic Cooperation and Development in March 2000. 14 FDA
    officials said that the agency generally follows the four- step risk

    assessment process identified by NAS: hazard identification, dose- response
    assessment (which FDA prefers to call ?hazard characterization?), exposure
    assessment, and risk characterization. They said that they also rely on past
    precedent and other seminal works on risk assessment, such

    as the 1985 Office of Science and Technology Policy guidance document on
    cancer risk assessment. However, they emphasized that FDA does not presume
    there is a ?best way? of doing a risk assessment and is continually updating
    its procedures and techniques with the goal of using the ?best available
    science.? Differences in Risk

    FDA officials also said that there are variations in the risk assessment
    Assessment Among FDA approaches used among the agency?s different product
    centers and, in Product Centers

    some cases, within those centers. In general, those variations are traceable
    to differences in the following factors:

     the substances being regulated, 12 D. W. Gaylor, J. A. Axelrad, R. P.
    Brown, J. A. Cavagnaro, W. H. Cyr, K. L. Hulebak, R. J. Lorentzen, M. A.
    Miller, L. T. Mulligan, and B. A. Schwetz, ?Health Risk Assessment Practices
    in the U. S. Food and Drug Administration,? Regulatory Toxicology and
    Pharmacology 26 (1997).

    13 Lorenz R. Rhomberg, A Survey of Methods for Chemical Health Risk
    Assessment Among Federal Regulatory Agencies, a report prepared for the
    National Commission on Risk Assessment and Risk Management (1996).

    14 Hereinafter referred to as Precaution in U. S. Food Safety
    Decisionmaking. This paper also addresses risk assessment practices of other
    federal agencies involved in food safety, such as the Department of
    Agriculture and EPA.

     the nature of the health risks involved (particularly carcinogens versus
    noncarcinogens),

     statutory and regulatory requirements,

     whether the risk assessment is part of the process to review and approve a
    product before it can be marketed and used (premarket) or whether the
    assessment is for risks that might arise during monitoring

    of a product once it is being used (postmarket), and

     the nature and extent of the scientific information available. The nature
    and extent of scientific information varies on a case- by- case basis. The
    other factors, however, are more generic, and table 6 illustrates how they
    are similar or different across CFSAN, CVM, and CDRH. The subsections
    following the table describe more specifically how CFSAN, CVM, and CDRH
    conduct the first three stages of risk assessment.

    Table 6: Differences in FDA Chemical Risk Assessment Factors Nature of
    chemical Stage of product health risk Statutory/ regulatory requirements
    review

    (Endpoint of Substances being Risk assessment

    (Premarket/ Product center concern) regulated Safety standard mandated?
    Postmarket review)

    CFSAN Office of Noncancer Food contact

    Reasonable Mandatory Primarily premarket

    Food Additive Safety toxicological substances, direct certainty of no harm
    endpoints and indirect food additives, color

    additives, and impurities

    CFSAN Office of Various toxicological

    Industrial and May render injurious

    Mandatory for new Postmarket for foods Food Additive Safety endpoints,
    including naturally occurring to health

    dietary ingredients and Office of cancer

    chemical Premarket for new Nutritional Products, contaminants,

    In addition, for Discretionary for dietary ingredients in Labeling and
    Dietary dietary supplements

    dietary supplements, other food dietary supplements

    Supplements significant or

    unreasonable risk of illness or injury

    Nature of chemical Stage of product

    health risk Statutory/ regulatory requirements review (Endpoint of
    Substances being

    Risk assessment (Premarket/

    Product center concern) regulated Safety standard mandated? Postmarket
    review)

    CFSAN Cancer Cancer Direct and indirect For additives, Assessment for
    Primarily premarket, Assessment

    food additives, food Delaney clause carcinogenicity is but can (and has
    Committee and

    contact substances, applies (carcinogens

    mandatory as part of been) used for Quantitative Risk color additives, and
    prohibited)

    the premarket postmarket issues Assessment

    impurities approval process, Committee

    For others, but a risk reasonable certainty assessment is of no harm
    standard

    discretionary applies

    CVM Various noncancer Residues of new Reasonable

    Mandatory Primarily premarket, toxicological animal drugs and certainty of
    no harm but can (and has endpoints

    feed additives been) used for

    postmarket issues CVM Cancer Residues of new Reasonable

    Mandatory Primarily premarket, animal drugs, feed certainty of no harm but
    can (and has additives, or their

    with inclusion of been) used for impurities

    Delaney clause and postmarket issues DES proviso

    CDRH Cancer and Chemical Reasonable Mandatory for

    Primarily premarket, noncancer endpoints compounds released assurance that
    the certain types of but also could occur (leaching) from device is safe
    under devices (Class III), per postmarket medical devices the conditions of
    use

    discretionary for surveillance

    prescribed, others

    recommended, or suggested in the labeling thereof In addition, regarding
    Class III premarket approval, unreasonable risk of illness or injury

    Source: Compiled from information provided by FDA.

    CFSAN Risk Assessment CFSAN?s procedures for hazard identification and dose-
    response Procedures assessment vary depending on whether noncancer or cancer
    risks are at issue. For noncancer effects, CFSAN starts with the largest
    dose in a

    chronic animal study that did not appear to lead to an increase in toxic
    effects above the level measured in unexposed control animals- the ?no

    observed adverse effect level? or NOAEL. 15 CFSAN then divides this NOAEL by
    one or more safety factors to arrive at an ?acceptable daily intake? (ADI)
    intended to be an amount that can be ingested daily for a lifetime without
    harm. For example, CFSAN typically divides the NOAEL by 10 to allow for the
    possibility that humans might be more sensitive to a chemical than the
    experimental animals and then by another 10 to account

    for the possibility that some individuals might have greater sensitivity
    than others might. Therefore, for ADIs derived from long- term animal
    studies, CFSAN commonly uses a combined safety factor of 100. Additional
    safety factors may also be applied to account for long- term effects versus
    shortterm experiments, inadequacies of the experimental data, or other
    factors. 16 For cancer effects, CFSAN uses two different hazard assessment/
    doseresponse

    approaches, depending on the nature of the products being regulated.

    15 FDA often determines a no observed effects level (NOEL) rather than a
    NOAEL because many significantly altered, standard toxicological endpoints
    are assumed to be adverse to animals and/ or humans even in the absence of
    data affirming that assumption.

    16 For example, Lorenz Rhomberg noted that, for developmental toxicity, the
    Center for Food Safety and Applied Nutrition may use a combined safety
    factor of 1, 000 for severe, irreversible health effects.

     For food and color additives that are themselves known carcinogens, the
    Delaney provisions in FFDCA make risk assessment rather straightforward. If
    a petition to market a food ingredient contains an adequately conducted
    animal cancer study, and if results of that study indicate that the food
    ingredient produces cancer in animals, CFSAN

    identifies the substance as a carcinogen under the conditions of the study.
    No further corroboration or weight- of- evidence analysis is required, and
    there is no need for a detailed dose- response assessment, exposure
    assessment, or risk characterization for the purpose of determining a
    specific level of the carcinogenic substance in food that may be considered
    to be safe. 17

     CFSAN uses more elaborate procedures for known or suspected carcinogenic
    impurities in food additives. The center?s method for lowdose cancer risk
    estimation is similar to EPA?s method (presented in app. II) on
    extrapolation for carcinogens (see fig. 3). On the doseresponse

    curve of tumor incidence versus dose for a chemical, CFSAN chooses a point
    below which the data are no longer considered reliable, usually in the range
    of a tumor incidence of 1 percent to 10 percent. A straight line is drawn
    from the upper- confidence limit on the estimated risk at that point to the
    origin (i. e., zero incremental dose/ zero incremental response). This
    provides the slope of the line used to provide upper- bound estimates of
    cancer risk at low doses. CFSAN

    does not specify a particular mathematical form for the dose- response
    relationship in the experimental dose range; the only requirement is an
    adequate fit to the data. According to FDA officials, CFSAN risk assessors
    use one of two different methods in animal- to- human scaling when
    extrapolating this dose- response curve to the estimation of upper bounds on
    human risk. In one of the methods, CFSAN assumes that cancer risks are equal
    in animals and humans when doses are similar on a lifetime- averaged
    milligram/ kilogram/ day basis (i. e., body weight scaling). In the other
    method, CFSAN bases its interspecies dose scaling on body weight to the �
    power (in the absence of information to the contrary). Although the

    literature suggests that scaling methods can have a significant impact on
    risk assessment results, FDA officials said that using one approach versus
    the other makes relatively little difference. Also, because tumor rates can
    be biased by intercurrent mortality in animal studies (i. e., some animals
    die 17 FDA may do a detailed assessment for other purposes, such as helping
    to determine

    regulatory priorities.

    during the study from causes other than the tumor type being investigated),
    CFSAN uses a statistical procedure to make adjustments for intercurrent
    mortality in testing and estimating tumor rates. CFSAN procedures for
    exposure assessments to food and color additives are largely driven by the
    FFDCA requirement that the safety of a chemical compound be assessed in
    terms of the total amount of the compound in the diet. Therefore, to
    determine exposure, CFSAN risk assessors must consider all potential uses of
    the compound being reviewed. Similarly, in defining the allowable limits,
    the assessors must conclude that the sum total of all of these uses is
    within safe limits. CFSAN generally assumes in its exposure assessments that
    the compound is present at its maximum proposed use level in all foods in
    which it may be used, that any contaminants are present at residue levels
    established through chemical analysis, and that consumers are exposed to the
    additive every day. Although most of the agency?s focus is on chronic (long-
    term) exposures,

    the agency must also sometimes focus on very short- term, or even single,
    exposures, especially for contaminants associated with acute toxic effects.

    The first component in CFSAN?s exposure assessment for food safety is the
    determination of the concentrations (i. e., use levels or residue levels, in
    the case of a chemical contaminant) of a chemical in foods. In the premarket
    approval process, the sponsor of the petition or notification provides this
    information. For postmarket assessments, information may come from

    focused field surveys or from established monitoring programs such as the
    Total Diet Study, which has provided data since 1961 on dietary intakes of a
    variety of food contaminants, including pesticides, industrial chemicals,
    toxic and nutritional elements, and vitamins and radionucleides. Analyses
    are performed on foods prepared for consumption in order to provide a

    realistic measure of human intake.

    The second component of CFSAN?s exposure assessment is determining the
    extent of consumption of different foods. In this process, CFSAN primarily
    relies on multiple- day national food consumption surveys, and focuses on
    the upper end of the food intake distribution (i. e., the heaviest consumers
    of particular foods). CFSAN assumes that, within demographic

    subgroups, all variation in the survey data represents variation among
    individuals. That is, the average daily consumption of a food during the
    survey period is assumed to apply to that person for his or her whole life,
    and the intakes for different survey participants are assumed to reflect
    differences from one person to the next in each person?s lifetime
    consumption. This default assumption has acknowledged biases that result in
    both overestimating high- end chronic exposures and

    underestimating the proportion of the population ever consuming particular
    foods. 18 To complete the exposure assessment, levels of an additive or
    contaminant

    in each food type are combined with estimates of daily consumption of each
    food type to give a total estimated daily intake. FDA may calculate
    exposures for various demographic groups, attempting to characterize both a
    mean exposure and an exposure for the heavy consumer (typically consumers at
    the 90 th percentile of the intake distribution). FDA officials

    also pointed out that the exposure models they use for direct food additives
    are very different from those for food- contact substances (e. g.,
    packaging). 19 For the latter, they said that the bottom line is usually a
    mean exposure.

    18 EPA?s pesticide office uses an alternative assumption- that surveyed
    variation represents day- to- day variation. Using this assumption, the
    exposure estimate represents average chronic consumption, but fails to
    estimate high- end exposures. 19 See CFSAN?s ?Guidance for Industry:
    Preparation of Premarket Notifications for Food Contact Substances:
    Chemistry Recommendations.?

    FDA officials said that for risk management purposes they may attempt to
    show the implications of different scenarios used to estimate risk. FDA
    noted that a computer program that employs Monte Carlo techniques has been
    developed to study the effects of variability and uncertainty of potency and
    exposure estimates on estimates of risk. 20 Such complex

    analyses have been applied principally to contaminants rather than in the
    premarket evaluations for food and color additives.

    CVM Risk Assessment CVM uses risk assessment in both the premarket approval
    process and

    Procedures postmarket surveillance. Risk assessments support risk management
    decisions such as the development of safe concentration values and

    residue tolerances for these drugs in foods. The primary human health
    concern in chemical risk assessment for CVM is animal drug residues in food.
    Residue is defined as any compound present in edible tissues (including milk
    and eggs) of the food- producing animal that results from the use of the
    chemical compound, including the compound, its metabolites, or other
    substances formed in or on food because of the use of the compound. Like
    CFSAN, CVM?s risk assessment procedures vary based on whether noncancer or
    cancer risks are at issue. According to FDA officials, the center?s risk
    assessment procedures for noncarcinogens are similar to those used by the
    rest of FDA, and are based on laboratory animal data, estimated daily food
    consumption, drug and metabolite residue data, and

    appropriate safety factors. CVM?s guidelines for industry note that the
    agency will calculate the ADI from the results of the most sensitive study
    in the most sensitive species. The center will normally use different safety
    factors depending on the type of study supporting the ADI calculation. When
    using the ADI to calculate the ?safe concentration? for an animal drug
    product, CVM uses standard values for residues of veterinary drugs in edible
    tissues for the weight of an average adult and the amount and

    proportion of meat products, milk, and eggs consumed per day. CVM officials
    pointed out that the consumption values in their guidelines for industry are
    standard values used by the Joint Expert Committee on Food Additives,
    sponsored by the World Health Organization and Food and

    20 Monte Carlo analysis involves a repeated random sampling from the
    distribution of values for each of the parameters in a calculation (such as
    average daily exposure) to derive a distribution of estimates of exposures
    for a population. According to FDA, because Monte Carlo modeling is a
    probabilistic technique that can use all the available food intake and
    concentration data, it will result in more accurate estimates at upper
    percentiles of exposure than those obtained using point values from consumer
    surveys.

    Agriculture Organization, that provides food safety recommendations to the
    Codex Committee on Residues of Veterinary Drugs in Foods. For carcinogen
    risk assessments, CVM uses a nonthreshold, conservative, linear- at- low-
    dose extrapolation procedure to estimate an upper limit of low- dose risk
    (as described under CFSAN). Cancer risk estimates are

    generally based on animal bioassays, and upper 95- percent confidence limits
    of carcinogenic potency are used to account for inherent experimental
    variability. FDA officials noted that some elements and assumptions of its
    dose- response analysis procedures are likely to overestimate risk by an
    unknown amount. Similarly, some of its assumptions on exposure may also
    overestimate cancer risks. For example, CVM?s risk assessment procedures
    assume that the concentration

    of residue in the edible product is at the permitted concentration and that
    consumption is equal to that of the 90 th percentile consumer. In addition,
    the agency assumes that all marketed animals are treated with the
    carcinogen. While acknowledging that all of these assumptions result in
    multiple conservatisms, FDA also states that they are prudent because of the
    uncertainties involved.

    CDRH Risk Assessment Medical devices, supplies, and implants may contain
    chemicals that can Procedures

    leach out of the devices into surrounding tissues. Risks from these types of
    chemical contaminants are considered during the premarket review of the
    material safety of a device, but concerns may also arise during CDRH?s
    postmarket surveillance activities. 21 According to FDA officials, the
    concentrations of such leachants in human tissues are generally small and
    amenable to typical safety risk assessment procedures.

    21 As an example of a postmarket quantitative risk assessment, FDA cited its
    assessment of cancer risk posed by patient exposure to 2, 4- toluenediamine
    released from polyurethane foam- covered breast implants.

    CDRH has issued guidance for the preclinical (premarket) biological safety
    evaluation of medical devices. 22 In that guidance, CDRH recognizes and uses
    a number of domestic and international consensus standards that have been
    developed to address aspects of medical device safety, including risks posed
    by exposure to compounds released from medical devices. However, CDRH
    officials pointed out that they and medical device approval applicants may
    use approaches other than those described in the

    consensus standards to conduct risk assessments. They said the standard that
    comes closest to describing CDRH?s approach for chemical risk assessment is
    International Organization for Standardization (ISO)/ FDIS 10933- 17. 23
    CDRH officials noted that, although this international standard is still in
    draft and has not been formally recognized by the center, the

    methods that it describes represent the primary procedures used by CDRH to
    assess the risk posed by patient exposure to compounds released from medical
    devices. They also pointed out that this standard is unique among risk
    assessment guidelines in that it provides methods to derive healthbased

    exposure levels for local effects such as irritation, which often ?drive?
    the risk assessment for compounds released from implanted devices. According
    to CDRH, hazards posed by patient exposure to a device are typically
    determined after subjecting the device to a series of tests defined by the
    preclinical evaluation guidance. Evaluation of potential toxicity is
    supposed to cover a number of adverse effects, including local or systemic
    effects, cancer, and reproductive and developmental effects. Unless
    justification is otherwise provided, CDRH assumes that the results

    obtained in animal studies are relevant for humans. One notable exception
    for medical device risk assessment, according to CDRH, is that implantation-
    site sarcomas (malignant tumors) found in rodents are not assumed to be
    relevant for humans.

    One option available to applicants is to use a risk assessment approach
    involving: (1) characterization of the chemical constituents released from a
    22 The Center for Devices and Radiological Health?s Office of Device
    Evaluation ?Blue Book? memorandum #G95- 1, ?Use of International Standard
    ISO- 10993, ?Biological Evaluation of Medical Devices Part- 1: Evaluation
    and Testing. ??

    23 Biological evaluation of medical device Part 17: Methods for the
    establishment of allowable limits for leachable substances. The
    International Organization for Standardization is a nongovernmental
    federation of national standards bodies from about 140 countries. Its work
    results in international agreements that are published as international
    standards.

    device; (2) derivation of a tolerable intake (TI) value for the compound;
    and (3) comparing the dose of each constituent received by a patient to its
    respective TI value. A TI value is a dose of a compound that is not expected
    to produce adverse effects in patients following exposure to the compound
    for a defined period. According to CDRH, it is conceptually similar to EPA?s
    reference dose, but different TI values can be derived for a

    compound depending on the route and duration of exposure to the medical
    device. CDRH?s procedures recommend establishing TI values for noncancer
    adverse effects using standard uncertainty factors in order to account for
    interspecies and inter- individual differences in sensitivity. However, CDRH
    permits flexibility in the event that data are available to characterize
    these

    uncertainties more accurately. CDRH also uses a lumped uncertainty factor to
    adjust for limitations in data quality such as (1) the use of short- term
    studies in the absence of long- term studies, (2) the absence of supporting
    studies, and (3) use of studies involving different routes or rates of
    exposure. According to CDRH, this lumped uncertainty value typically

    does not exceed 100, but can exceed 100 when acute (short- term) toxicity
    data are the only basis of the calculation of a TI value for permanent
    exposure. CDRH considers this provision especially important for medical
    device risk assessment because of the paucity of long- term toxicity data
    for

    many of the compounds released from medical devices. For carcinogenic
    leachants, FDA often uses low- dose linear extrapolation techniques. For a
    device- released compound that has been determined to be a carcinogen, CDRH
    uses a weight- of- the- evidence approach to

    determine the likelihood that it exerts its carcinogenic effect via a
    genotoxic mechanism. 24 If the evidence suggests that the compound is
    genotoxic, then CDRH uses quantitative risk assessment to estimate a TI
    consistent with a risk level of 1 per 10,000. No specific quantitative risk
    assessment approaches have been identified as better than others for

    conducting the cancer risk assessment. If, however, the weight- of-
    theevidence test suggests that the compound is a nongenotoxic carcinogen,
    the uncertainty factor approach described above should be employed to derive
    the TI.

    24 A genotoxic carcinogen is one that initiates cancer through a direct
    effect on genetic material. It is capable of causing heritable changes or
    damage leading to heritable changes in genetic material.

    Once the TI is derived for each compound released from a device, it is then
    converted to a tolerable exposure value by taking into account the body
    weight of the patient and the usage patterns of the device that releases the
    compound. Overall, the agency noted that one of the most challenging
    problems in risk assessments for devices is determining the level of
    exposure to leached chemicals.

    Risk Assessment As previously noted, FDA does not require the use of a
    specific risk Assumptions and assessment protocol or of specific default
    assumptions. However, the

    summary of FDA procedures also demonstrated that assumptions and
    Methodological methodological choices are an integral part of a risk
    assessment. FDA Choices

    officials noted that they employ many default assumptions or choices by
    precedent. In particular, FDA officials and several reference documents on
    FDA risk assessment procedures pointed out that the agency routinely
    incorporates conservative assumptions into its assessments in the face of
    uncertainty. The report on the U. S. food safety system emphasized that
    precaution is embedded in the underlying statutes and the actions of
    regulatory agencies to ensure acceptable levels of consumer protection. 25
    Therefore, precautionary approaches are very much a part of the agency?s

    risk analysis policies and procedures. Although not intended to be
    comprehensive, the following table illustrates in detail some of the
    specific assumptions or methodological choices that are used in FDA as a
    whole and within particular FDA product centers.

    The information in the table was taken primarily from FDA documents, but
    also reflects additional comments provided by FDA officials. (GAO notes and
    comments appear in parentheses.)

    25 Precaution in U. S. Food Safety Decisionmaking.

    Table 7: FDA Risk Assessment Assumptions and Methodological Choices When the
    assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    (Methodological assumptions According to FDA officials, According to FDA
    officials, the

    (Not applicable to this generic and choices in general.) ?reasons? always
    include the circumstances under which

    information.) following three general items:

    these assumptions would be used always include that data

     information essential to a risk indicating the assumption may assessment
    is not known; be invalid for a particular  the assumption, selected by
    circumstance are not available.

    FDA to substitute for that information, is scientifically plausible; and

     the effect of using the assumption is consistent with agency regulations
    or policy (e. g., for CFSAN, an assumption is expected to be

    reasonably protective of human health).

    1. CFSAN general procedures regarding food safety 1.1

    This is a fundamental When there are no data or For chemicals that are human
    Animal studies are useful for assumption of quantitative risk inadequate
    data on human

    carcinogens, animal data may human risk assessment, with assessment,
    accepted as a

    outcomes. underestimate human risk by up appropriate uncertainty factors

    basic precedent according to to one order of magnitude and (i. e., you can
    extrapolate human FDA officials. They noted that, in overestimate risk by up
    to three effects from animal data). general, adequate information

    orders of magnitude [citations from human studies is preferred provided]. to
    adequate data from animal studies. However, when human data are not
    available, or when such data are judged to be

    relatively insensitive to moderate- or low- level risks and difficult to
    quantify, FDA makes the assumption that animal studies can be used for human
    risk assessment. FDA officials also said that the application of appropriate
    uncertainty factors

    to data from animal studies makes this assumption reasonably protective of
    human health.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    1.2 (Not identified in the FDA

    When choosing which animal (Not specifically identified, but Use the most
    sensitive animal

    documents that we reviewed study data to use for hazard

    FDA officials commented that species, unless you have describing risk
    assessment identification and dose- response risk assessment literature
    information to the contrary. procedures. However, FDA

    estimation, when the most identifies the ?usual? range of officials
    explained that appropriate animal model for

    toxicological responses among comparative absorption,

    humans is not known. animal models for this metabolism, distribution, and

    assumption.) elimination data could identify the most appropriate animal
    model for extrapolating results

    from animals to humans. They also stated that FDA has determined that use of
    this assumption is reasonably protective of human health.)

    1.3 FDA officials identified this When doing low- dose

    (Not explicitly identified. FDA You can extrapolate low- dose

    assumption as another extrapolation because low- dose officials explained
    that the effects from high- dose effects. fundamental assumption, similar

    effects were not directly literature on this subject shows to 1. 1 above,
    noting that, in measured in available human or

    ?very large? variability among general, low- dose effects cannot animal
    studies and the

    predictions of low- dose effects be directly measured in human

    mechanism of action at low using different modeling epidemiology studies or
    in doses is not known to be assumptions. They also stated animal toxicity
    and

    different than the mechanism at that, because they do not know
    carcinogenicity studies. They higher doses. the correct relationship between
    said that, in such circumstances,

    high- and low- dose effects for a the mechanism of action at low substance,
    they do not know doses is assumed to be the how much conservatism is same as
    that operating at higher associated with the use of this doses, which makes
    the related assumption.) assumption that one can extrapolate effects at low
    doses from effects at high doses scientifically plausible. FDA has

    determined that such an assumption is reasonably protective of human health.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    1.4 Not specifically identified, but When doing low- dose

    This linear extrapolation provides Low- dose cancer risk estimation FDA
    noted in general that, extrapolation for carcinogens. upper- bound estimates
    of cancer is done using a linear, nothreshold because it is not possible to
    risk at low doses.

    approach. determine the accuracy and

    precision of low- dose cancer The point of departure for this estimates, the
    agency employs linear extrapolation is the upperconfidence conservative risk
    assessment

    limit on risk at a point procedures to compensate for on the dose- response
    curve

    weaknesses in scientific rigor. below which the data no longer appear to be
    reliable. However, The agency did provide specific the agency does not
    specify any

    citations for various low- dose particular mathematical form for
    extrapolation procedures. the dose- response relationship in the
    experimental dose range,

    just that there is an adequate fit to the data.

    A more specific, but related, string of assumptions is that genotoxic
    carcinogens do not have thresholds, and the appropriate low- dose
    extrapolation is linear.

    1.5 The � power approach was When extrapolating equivalent (Not addressed in
    FDA

    Dose scaling across species is recommended in a 1992 doses of a carcinogen
    from materials, but other sources based on body weight to the � proposed
    rule by an interagency

    animals to humans, in the indicated that the ?body weight � power (an
    adjustment factor for committee [citation provided].

    absence of information to the power? approach is considered calculating the
    dose at which contrary.

    to produce the midpoint of cancer risks are equal in rodents plausible
    values from among the and humans)

    common alternative approaches for interspecies dose scaling, (In meetings
    with CFSAN while ?body weight? scaling is officials, we were informed that
    considered to produce the least the agency?s risk assessors may

    conservative values. A CFSAN also use the default that cancer official
    stated that this choice risks are presumed equal when makes little
    difference in the daily amounts of a chemical results.) agent are scaled in
    proportion to a species? body weight.)

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    1.6 (Note that the underlying statute

    Risk assessments for noncancer The resulting ADI is an estimate FDA/ CFSAN
    uses a basic no specifically directs the use of endpoints estimating an ADI

    with uncertainty spanning observed effect level (NOEL) safety factors.) from
    the results of animal

    perhaps an order of magnitude safety factor approach for experiments.

    of a daily exposure that is likely noncancer effects. The agency to be
    without appreciable risk of generally uses standard safety

    deleterious effects during a factors to account for lifetime. uncertainty:
    a. A safety factor of 10 is used to account for the possible increased
    sensitivity of humans compared to test animals.

    b. Another safety factor of 10 is used to account for the increased
    sensitivity of some humans. c. Additional safety factors are

    often employed to account for long- term effects based on short- term
    experiments, use of a LOAEL instead of a NOEL/ NOAEL, and other

    inadequacies of the experimental data.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    1.7 a. Empirical: based on food Assumptions about consumption FDA officials
    told us that these CFSAN uses a series of consumption survey data.

    used when estimating human assumptions provide a publichealth

    assumptions about food b. Concern that the mean

    exposure to chemical conservative estimate of consumption:

    exposure is not sufficiently substances (i. e., additives, exposure for
    comparison with

    public- health conservative. residues) in foods.

    the ADI. a. The agency assumes that c. The method for estimating the average
    total diet of a

    the 90 th percentile in the 60- kg adult generally absence of other data is
    consists of 1500 grams (g)

    based on observations from of solid food and 1500 g of dietary survey
    distribution liquid per day.

    data for a variety of b. For calculating exposure to products. additives or
    contaminants, CFSAN frequently uses the 90 th percentile of consumption to
    represent

    intake of heavy consumers. c. In the absence of the distribution of intakes
    among individuals in a

    population and a direct measure of the 90 th percentile, the 90 th
    percentile is estimated to be

    two to three times the average intake.

    1.8 FDA officials said they use this When basing exposure

    According to the Rhomberg The agency usually assumes assumption because only
    shortterm estimates on food intake report, the effect of this that, within
    demographic groups, food intake surveys are

    surveys. assumption is an acknowledged food intake survey variation

    available. overestimation of high- end

    represents differences in chronic chronic exposures and an consumption among
    individuals. underestimation of the

    The average daily consumption proportion of the population ever by an
    individual of a food during

    consuming particular foods. the survey period is assumed to apply to that
    person for his or her

    whole life.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    1.9 FDA officials said that they use

    When doing exposure FDA officials said these The agency generally assumes

    these public- health conservative assessments. assumptions were public-
    health that all foods in which a chemical assumptions because of the lack
    conservative. additive is proposed or permitted of scientifically sound for
    use will bear it at the information that would permit maximum proposed or

    their relaxation. permissible use level.

    The agency also assumes that consumers are exposed to an additive every day
    for a lifetime.

    1.10 The agency noted that its intent

    When doing risk assessments The intent is to be conservative.

    When dealing with mixtures of is to be conservative, and it cited

    involving mixtures of chemicals carcinogens, the agency usually research on
    the estimation of

    (with dose levels for each considers that interactions are upper- confidence
    limits on component below those having not likely and uses some estimates of
    risk for mixtures.

    measurable effects for that standard assumptions:

    compound). a. It is assumed that

    carcinogens are acting independently. Therefore, the risk of cancer from a
    mixture may be obtained by summing the individual risk. b. It is generally
    assumed that

    all carcinogenic components are at their tolerance concentrations.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    2. CVM procedures regarding animal drug residues in food 2.1

    In general, FDA noted that all of When conducting cancer risk This set of
    assumptions was As a matter of policy regarding

    the assumptions identified in this assessments. identified generically as
    potential risks from residues of section on the DES Proviso (see ?resulting
    in multiple carcinogenic animal drugs in following rows 2.2 through 2.5),

    conservatisms.? foods consumed by humans (per

    ?result in multiple conservatisms, the DES Proviso to the Delaney but are
    prudent because of the Clause), FDA accepts a lifetime uncertainties.? risk
    below one per million as an insignificant level.

    ?Thus, adoption of a [residue] concentration associated with a cancer risk
    of one per million is likely to be well below that level

    of risk and to satisfy the FDA?s responsibility under the statute [FFDCA] to
    ensure to a reasonable certainty that the public will not be harmed.?

    2.2 (No additional information

    Choosing data sets to use for (See previous row.)

    Regulation is based on the target provided, but see row 2.1 for cancer risk
    assessments. tissue site exhibiting the highest

    general rationale.) potential for cancer risk for each carcinogenic
    compound.

    If tumors are produced at more than one tissue site, the minimum
    concentration that produced a tumor is used.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    2.3 Upper 95- percent confidence

    When doing low- dose The process of linearly Cancer risk estimates are

    limits are used to account for extrapolation from animal

    extrapolating from the high generally based on animal inherent experimental
    variability.

    bioassay data in the absence of doses used in animal bioassays bioassays,
    using upper 95percent information establishing the

    to concentrations of residues is confidence limits of The low- dose
    extrapolation

    mechanism of carcinogenesis of likely to overestimate risk by an
    carcinogenic potency.

    procedure estimates an upper a compound.

    unknown amount. limit on low- dose risk. Low- dose extrapolation is done
    using a nonthreshold,

    In its general principles for conservative, linear- at- low- dose industry
    (guideline #3), CVM procedure (modified GaylorKodell). notes that none of
    the mathematical procedures for

    extrapolation has a fully adequate biological rationale, because the
    mechanism of carcinogenesis is not sufficiently understood.

    2.4 (No additional information

    In cancer risk assessments From rather limited data It is assumed that the

    provided, but see row 2.1 for when doing low- dose comparing human and
    animal

    carcinogenic potency in humans general rationale.) extrapolation from animal

    cancer potencies of compounds, is the same as that in animals.

    bioassay data. animal results are likely to

    overestimate human cancer risk but could underestimate risk by an order of
    magnitude (citations provided).

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    2.5 (See row 2.1 for general Used for exposure assessments These assumptions
    on Multiple assumptions are used in rationale. Note that item d is for
    cancer risks. exposures also overestimate the

    carcinogen exposure taken from CVM?s guidance for risk. assessments:

    industry.) a. The concentration of

    residue in the edible product is at the permitted concentration. b.
    Consumption is equal to that of the 90 th percentile consumer.

    c. All marketed animals are treated with the carcinogen. d. In the absence
    of information about the

    composition of the total residue in edible tissue, assume that the entire

    residue is of carcinogenic concern.

    2.6 FDA officials said this In noncancer risk assessment, (Not identified,
    but the intent of For noncancer toxicological

    assumption was used because when calculating the ADI based

    this calculation is to provide endpoints, the agency will of historical
    precedent back to at upon animal studies and in the

    protective, public- health calculate the ADI from the NOEL least 1954,
    because, in the

    absence of data suggesting that conservative estimates.)

    of the most sensitive effect in an absence of data (e. g., an alternative
    approach is animal study of the most

    physiologically based scientifically justified.

    sensitive sex and species. pharmacokinetic or other data) suggesting that
    another species is more appropriate to use for

    extrapolating to humans, using the most sensitive endpoint in the most
    sensitive species and sex is still considered to be protective of public
    health.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    2.7 These are identified as In noncancer risk assessment

    (Not identified, but the intent of The agency will normally use the
    ?appropriate? safety factors. when calculating the ADI by such factors is
    usually to provide following safety factors, dividing the NOEL from an
    protective, public- health depending on the type of study animal study by
    safety factors.

    conservative estimates.) supporting the ADI estimate:

    a. chronic study (factor of 100), b. reproduction/ teratology study (100 for
    a clear

    indication of maternal toxicity; 1000 for other effects), and c. 90- day
    study (1000).

    2.8 CVM officials noted that the

    Exposure analysis for noncancer (Not identified, but the intent of The
    agency uses a series of

    standard consumption factors risk assessments. Consumption such factors is
    usually to provide standard values and (e. g., 300 grams of muscle) were

    values applied to determine the protective, public- health assumptions to
    estimate an established by the Joint Expert safe concentration for most new
    conservative estimates.)

    individual?s daily food Committee on Food Additives animal drug products,
    unless an consumption: (sponsored by the World Health appropriate scientific
    justification Organization and the Food and

    supports alternative a. edible muscle (300 grams); Agriculture Organization
    of the

    consumption values. b. liver (100 g);

    United Nations). c. kidney (50 g); d. fat (50 g); e. assume that when an

    individual consumes a full portion of a meat product from one species, he or
    she will not consume a full portion of a meat product from another species;
    f. assume a person consumes a full portion of milk (1. 5

    liters) in addition to the full portion of edible muscle or organ tissue;
    and g. assume that a person consumes a full portion of eggs (100 g) in
    addition to

    the consumption of muscle or organ tissue.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    2.9 CVM officials said this CVM officials said that this CVM officials said
    the

    The agency assumes the weight assumption is used because of assumption is
    applied in all assumption should protect of an average adult is 60 kg
    historical precedent and

    circumstances. women, growing adolescents, when calculating the safe because
    the 60- kg person is and the elderly.

    concentration of a compound in likely to cover the exposure of edible tissue
    of a food- producing women, growing adolescents, animal. and the elderly. 3.
    CDRH procedures regarding medical devices (For purposes of this report,
    limited to chemical leachants. Does not include engineering or radiation
    risk assessments.)

    3.1 (Not specifically addressed in During hazard identification. (Not
    mentioned.)

    CDRH assumes that the results the material provided by CDRH, obtained in
    animal studies are although the first part is a relevant for humans, but
    with one

    standard assumption of notable exception for medical quantitative risk
    assessment.) device risk assessment implantation- site malignant

    tumors found in rodents are not assumed to be relevant for humans.

    3.2 To provide a safety factor. During hazard identification. (Not
    specifically identified, but Extractions of medical devices

    the intent of such factors is (to test for adverse effects) are usually to
    provide protective, typically carried out using

    public- health conservative rigorous but not exhaustive estimates.)
    conditions to provide a ?safety factor? for the hazard identification phase.

    When the assumption/ choice would be applied (step in the Assumption or risk
    assessment process or Likely effect on risk methodological choice Reason( s)
    for selection circumstances) assessment results

    3.3 The first two factors are standard

    Used when calculating TI values (Not specifically identified, but The
    following uncertainty factors uncertainty factors for noncancer effects of
    chemical the intent of such factors is are typically used for adverse

    recommended in the scientific compounds, unless case data usually to provide
    protective,

    effects other than cancer: literature.

    are available to characterize public- health conservative these
    uncertainties more estimates.) a. a factor to adjust for

    The lumped uncertainty factor accurately. interspecies differences in takes
    into account: sensitivity to toxic compounds;

    1. use of short- term studies in b. a factor to adjust for the absence of
    long- term interindividual differences in studies;

    sensitivity to toxic 2. having only a LOAEL

    compounds; and instead of a NOAEL;

    c. a ?lumped? factor to adjust 3. absence of supporting for limitations in
    data quality.

    studies; 4. route- to- route extrapolation of dose, when needed;

    5. rate of exposure; and 6. confidence in the data base.

    CDRH noted that the lumped factor typically does not exceed 100, but can
    exceed this value when acute toxicity data are the only basis for the
    calculation of a TI value for permanent exposure.

    Source: Compiled from GAO review of FDA risk assessment guidelines and
    related documents and from additional comments provided by agency officials.

    Risk Characterization Unlike EPA, FDA does not have an official policy on
    how the results of the agency?s risk assessments should be characterized to
    decision makers and

    the public. However, FDA officials said that, in practice, the agency uses a
    standard approach for risk characterization that is similar to EPA?s
    official policy. They said that FDA?s general policy is to reveal the risk
    assessment assumptions that have the greatest impact on the results of the
    analysis, and to state whether the assumptions used in the assessment were
    conservative. FDA officials also said that their risk assessors attempt to

    show the implications of different distributions and choices (e. g., the
    results expected at different levels of regulatory intervention). As noted
    earlier, FDA may employ methods such as Monte Carlo techniques to provide
    additional information on the effects of variability and uncertainty on
    estimates of risk.

    There are some differences in FDA risk characterization procedures depending
    on the products being regulated and the nature of the risks involved. For
    food ingredients (direct and indirect food additives, color additives used
    in food, and substances generally recognized as safe) and animal drug
    residues that are not carcinogenic, risk characterization under the FFDCA
    focuses on whether the mandate of reasonable certainty of no harm will be
    achieved given the proposed limits on use and permissible residues. The main
    issue is whether the higher end (the 90 th percentile) of

    the distribution of estimated daily intakes is below the ADI calculated from
    toxicity data. The statutory mandate is interpreted as requiring that, for a
    food additive to be declared safe, heavy consumers of particular foods

    should be reasonably assured of protection even if residues were at the
    maximum level allowed. For carcinogenic impurities, FDA?s focus is also on
    characterizing whether there is reasonable certainty of no harm. However,
    because of the Delaney clause, risk characterization is not needed for
    carcinogenic food ingredients. Residues of carcinogenic animal drugs are
    also evaluated separately under the DES proviso.

    CDRH officials pointed out that the draft ISO/ FDIS 10933- 17 international
    standard explicitly addresses one risk characterization issue- how sensitive
    subpopulations should be taken into account when setting allowable limits
    for compounds released from devices. Although it states that ?idiosyncratic
    hypersusceptibility? should not normally be the basis of the tolerable
    exposure or allowable limit, the ISO standard does not preclude setting
    standards in this manner. Furthermore, the standard says that limits should
    be based on the use of the device by the broadest segment of the anticipated
    user population. Therefore, if a device is intended for a specific
    population, such as pregnant women, estimates

    should be based on that population.

    Chemical Risk Assessment at the Occupational Safety and Health

    Appendi x V I Administration Although the Occupational Safety and Health
    Administration (OSHA) generally follows the standard four- step National
    Academy of Sciences? (NAS) paradigm for risk assessment, there are several
    distinguishing characteristics of its assessments. Under its statutory
    mandate, OSHA has a specific and narrow focus on the potential risks to
    workers in an occupational setting. Further, the underlying statute and
    court decisions interpreting the statute have required the agency to focus
    on

    demonstrating, with substantial evidence, that significant risks to workers
    exist before it can regulate. In addition to presenting its own best
    estimates of risk, OSHA may present estimates based on alternative methods
    and assumptions.

    Context for OSHA Much of what is distinct about risk assessment at OSHA can
    be traced to

    Chemical Risk statutory provisions, court decisions, and the nature of
    workplace

    exposures to chemicals. OSHA, an agency within the Department of Labor,
    Assessment

    was created by the Occupational Safety and Health Act of 1970 (the OSH Act).
    1 The central purpose of the act is to ensure safe and healthful working
    conditions. As one of the primary means of achieving this goal, the act
    authorizes the Secretary of Labor to promulgate and enforce mandatory
    occupational safety and health standards. 2 Certain provisions

    in the act stipulate both the nature and the manner in which these standards
    should be established. For example:

     Under section 3( 8) of the OSH Act, a safety or health standard is defined
    as a standard that requires conditions, or the adoption or use of one or
    more practices, means, methods, operations, or processes, reasonably

    necessary or appropriate to provide safe or healthful employment or places
    of employment.

     According to OSHA, a standard is reasonably necessary or appropriate
    within the meaning of section 3( 8) if it eliminates or substantially
    reduces significant risk and is economically feasible, technologically
    feasible, cost effective, consistent with prior OSHA action or supported by
    a reasoned justification for departing from prior OSHA actions, supported by
    substantial evidence on the record as a whole, and is 1 29 U. S. C. 651 et
    seq.

    2 Safety standards are generally designed to reduce on- the- job injuries.
    Health standards are usually directed at limiting the risk of workers
    developing occupational diseases from exposure to hazardous chemical or
    physical agents.

    better able to effectuate the act?s purposes than any national consensus
    standard it supersedes.

     Section 6( b)( 5) of the act states that ?The Secretary, in promulgating
    standards dealing with toxic materials or harmful physical agents shall set
    the standard which most adequately assures, to the extent feasible, on the
    basis of the best available evidence, that no employee will suffer material
    impairment of health or functional capacity even if such employee has
    regular exposure to the hazard dealt with by such standard for the period of
    his working life.? A significant factor influencing the interpretation of
    the OSH Act provisions and OSHA?s approach to risk assessment is the Supreme
    Court ruling in its 1980 ?Benzene? decision that, before issuing a standard,
    OSHA must demonstrate that the chemical involved poses a ?significant risk?
    under workplace conditions permitted by current regulations and that the new

    limit OSHA proposes will substantially reduce that risk. 3 This decision
    effectively requires OSHA to evaluate the risks associated with exposure to
    a chemical and to determine that these risks are ?significant? before
    issuing a standard. However, the court provided only general guidance on
    what level of risk should be considered significant. The court noted that a

    reasonable person might consider a fatality risk of 1 in 1000 (10 -3 ) to be
    a significant risk and a risk of one in one billion (10 -9 ) to be
    insignificant. Thus, OSHA considers a lifetime risk of 1 death per 1, 000
    workers to

    represent a level of risk that is clearly significant. The court also stated
    that ?while the Agency must support its findings that a certain level of
    risk exists with substantial evidence, we recognize that its determination
    that a particular level of risk is significant will be based largely on
    policy considerations.? 4

    Later Court of Appeals decisions have interpreted the Supreme Court?s

    ?Benzene? decision to mean that OSHA must quantify or explain the risk for
    each substance that it seeks to regulate unless it can demonstrate that a
    group of substances share common properties and pose similar risks. 5
    Although this decision does not require OSHA to quantitatively estimate the

    risk to workers in every case, it does preclude OSHA from setting new 3
    Industrial Union Dept. v. American Petroleum Inst., 448 U. S. 607, 642
    (1980). 4 448 U. S. at 655- 56 n. 62. 5 AFL- CIO v. OSHA, 965 F. 2d 962 (11
    th Cir. 1992), International Union, UAW v. Pendergrass,

    878 F. 2d 389 (D. C. Cir. 1989).

    standards without explaining how it arrives at a determination that the
    standard will substantially reduce a significant risk. According to OSHA
    officials, the other important contextual influence on OSHA risk assessment
    is the very nature of workplace exposures to chemicals. Generally, workplace
    exposures to chemicals are at higher

    levels than most environmental exposures to chemicals experienced by the
    general public. Workers are often exposed to many chemical agents at levels
    not much lower than those used in experimental animal studies.

    According to agency officials, this is one of the unique features of OSHA?s
    chemical risk assessments. Also, OSHA frequently has relevant human data
    available on current exposures, in contrast to most other agencies
    regulating toxic substances.

    Risk Assessment Procedures

    General Approach OSHA currently has no formal internal risk assessment
    guidance. Instead, OSHA has primarily described its general risk assessment
    methods, as well as the rationale for specific models and assumptions
    selected, in the record

    of each risk assessment and regulatory action. One reason for this,
    according to agency officials, is that OSHA performs risk assessments only
    for its standards. Overall, they said the agency only publishes two or three
    proposed or final rules per year, and not all of these rules involve a
    chemical risk assessment. The officials also emphasized the incremental
    nature of advances in risk assessment methods and science, with successive
    assessments establishing precedents for methods that may be used for
    succeeding analyses.

    Like EPA and FDA, OSHA uses the basic NAS four- step process for risk
    assessment. Another fundamental source for OSHA?s (and EPA?s and FDA?s)
    methods was the 1985 document on chemical carcinogens produced by the Office
    of Science and Technology Policy. 6 OSHA often refers to the reference
    sources of other entities, including other federal agencies, in 6 Office of
    Science and Technology Policy, Executive Office of the President, ?Chemical
    Carcinogens: A Review of the Science and Its Associated Principles, February
    1985,? 50 FR 10372 (Mar. 14, 1985).

    both specific rulemakings and as general technical links to its on- line
    information on occupational risks. Despite these common elements and
    procedures, several features of OSHA?s approach differ from those of other
    federal agencies. Because OSHA does not currently have written internal
    guidance on its risk

    assessment procedures, the information in the following sections is derived
    primarily from an examination of OSHA?s chemical risk assessments. 7 We also
    relied on secondary sources, such as Lorenz Rhomberg?s report on

    federal agencies? risk assessment methods. 8 Hazard Identification In OSHA?s
    risk assessments, the hazard identification step results in a determination
    that an exposure to a toxic substance causes, is likely to cause, or is
    unlikely or unable to cause, one or more specific adverse health effects in
    workers. According to OSHA, this step also shows which studies have data
    that would allow a quantitative estimation of risk. OSHA defines hazardous
    and toxic substances as those chemicals present in the workplace that are
    capable of causing harm. In this definition, the term chemicals includes
    dusts, mixtures, and common materials such as paints, fuels, and solvents.
    OSHA currently regulates exposure to approximately 400 such substances. In
    the workplace environment, chemicals pose a wide range of health hazards (e.
    g., irritation, sensitization, carcinogenicity, and noncancer acute and
    chronic toxic effects) and physical hazards (e. g., ionizing and nonionizing
    radiation, noise, and vibration).

    7 Because OSHA?s methylene chloride standard is the most recent hazardous
    chemical rulemaking, most of the specific examples cited come from OSHA?s
    methylene chloride rulemaking: ?Occupational Exposure to Methylene
    Chloride,? 62 FR 1494 (Jan. 10, 1997). 8 Lorenz R. Rhomberg, A Survey of
    Methods for Chemical Health Risk Assessment Among Federal Regulatory
    Agencies, a report prepared for the National Commission on Risk Assessment
    and Risk Management (1996).

    Most of OSHA?s chemical risk assessments have addressed occupational
    carcinogens. In assessing potential carcinogens, OSHA may consider the
    formal hazard classification or ranking schemes of other entities as part of
    the available evidence on a particular chemical. Ultimately, though, OSHA

    makes its own determinations on the risk posed by particular compounds and
    their classification as potential occupational carcinogens. OSHA?s chemical
    risk assessments may also discuss noncancer hazards. For example, in the
    final rule on methylene chloride the agency discussed the evidence regarding
    central nervous system, cardiac, hepatic (liver), and reproductive toxicity,
    as well as carcinogenicity. Similarly, the agency?s rulemaking on 1,3-
    butadiene addressed adverse health effects such as developmental and
    reproductive toxicity and bone marrow effects in addition to the evidence on
    carcinogenicity. 9 OSHA quantifies the risks of

    noncancer effects if it determines that there are adequate data on exposure
    and response for the substance of interest. OSHA officials also noted that
    OSHA has a hazard communication standard, which requires manufacturers,
    shippers, importers, and employees to inform their employees of any
    potential health hazard when handling these chemicals. This is usually done
    through container labeling and material safety data sheets. Although this
    standard does not address

    specific risks posed by individual chemicals, it is a comprehensive hazard
    information standard for nearly all chemicals in commerce.

    Dose- Response Assessment Carcinogens OSHA?s general procedures for dose-
    response assessment are similar to

    those of EPA and FDA, especially in the choice of data sets to use for
    quantitative assessments. However, OSHA probably uses a linear low- dose
    extrapolation model less often than is the case for other agencies. OSHA
    differs from the other federal regulatory agencies also in being less
    conservative in setting its target risk levels when conducting low- dose
    extrapolation. As previously noted, the main points of OSHA?s risk

    assessments for regulatory purposes are to determine whether significant
    risks exist and to demonstrate in a broad sense the degree to which the
    standard would reduce significant risk. The specific choice of where to set

    9 ?Occupational Exposure to 1, 3- Butadiene? 61 FR 56746 (Nov. 4, 1996).

    the standard is tempered by the statutory mandate that standards must be
    technologically and economically feasible.

    Like other agencies, OSHA states that, all things being equal,
    epidemiological data are preferred over data from animal studies whenever
    good data on human cancer risks exist. More often than some other agencies
    regulating exposures to toxic substances, OSHA may have relevant human data
    on adverse health effects available for consideration in its risk
    assessments. However, the rulemaking examples we reviewed also illustrate
    that these epidemiological data may be considered inadequate for
    quantitative dose- response assessment, while animal data may provide more
    precise and useful dose- response information. In both

    the methylene chloride and 1,3- butadiene dose- response assessments, for
    example, OSHA had both epidemiological and animal data available, but based
    its quantitative estimates on data from rodent models. However,

    OSHA did use its analysis of the epidemiological data when examining the
    consistency of the results derived from animal studies.

    When faced with the choice of several animal data sets, OSHA tends not to
    combine tumor sites but to choose the data set showing the highest
    sensitivity (i. e., most sensitive sex, species, and tumor site). The agency
    will, however, frequently present information from alternative data sets and
    analyses. The agency is likely to include benign tumors with the potential
    to progress to malignancy along with malignant tumors in the data set used
    for its quantitative assessments. OSHA cited the Office of Science and
    Technology Policy?s views on chemical carcinogens in support of this
    practice, as well as noting that other federal agencies, including EPA and

    FDA, have also included benign responses in their assessments. Because
    occupational exposures tend to be closer to the range of experimentally
    tested doses in animal studies, extrapolation may pose less of a challenge
    for OSHA than for other regulatory agencies. OSHA?s

    preferred model for quantitative analysis of animal cancer dose- response
    data and for extrapolation of these data to low doses is the ?multistage
    model,? which is based on the biological assumption that carcinogens

    induce cancer through a series of independent ordered viable mutations, and
    that cancer develops through stages. Unlike EPA and FDA, however, OSHA tends
    to focus on the maximum likelihood estimate (MLE) of the fitted dose-
    response curve rather than on an upper bound, although the

    agency also provides estimates for the 95- percent upper confidence limit
    (UCL) of the dose- response function. This procedure generally leads to a
    less conservative risk estimate than the procedures used by EPA or FDA.

    Like EPA and FDA, OSHA generally assumes no threshold for carcinogenesis. In
    contrast to the other agencies, OSHA?s default dosemetric for interspecies
    extrapolation is body weight scaling (mg/ kg/ day i. e., risks equivalent at
    equivalent body weights). According to OSHA, this default is used to be
    consistent with prior chemical risk assessments, but it also reflects a
    conscious policy decision that its methodology should not be

    overly conservative. OSHA says it may in the future move to � -power
    scaling, as agreed to by EPA, FDA, and the Consumer Product Safety
    Commission some years ago. OSHA also says it is currently considering
    developing a different form of the multistage model, which will provide more
    stable MLE estimates than does the current form. OSHA also considered data
    from physiologically based pharmacokinetic (PBPK) models in the risk
    assessment examples we reviewed. 10 PBPK models provide information on
    target organ dose by estimating the time distribution of a chemical or its
    metabolites through an exposed subject?s system. 11 OSHA noted that PBPK
    modeling can be a useful tool for describing the distribution, metabolism,
    and elimination of a compound of interest under conditions of actual
    exposure and, if data are adequate, can allow extrapolation across dose
    levels, routes of exposure, and species. In particular, pharmacokinetic
    information is useful in modeling the relationship between administered
    doses and effective doses as a function of the exposure level. 12 However,
    PBPK models are complicated and require substantial data, which may not be
    available for most chemicals. OSHA pointed out in the methylene chloride
    rule that differences in the risk

    estimates from alternative assessments (including those submitted by outside
    parties) were not generally due to the dose- response model used, but to
    whether the risk assessor used pharmacokinetic modeling to 10
    Pharmacokinetics is the study of the absorption, distribution, metabolism,
    and elimination

    of chemicals in humans and animals. It is the basis for developing more
    realistic and accurate models of the movement and interactions of a chemical
    with blood, tissues, and organs once it enters the body, including
    consideration of the body?s ability to repair damage caused by a chemical.
    PBPK models are based on the physiology of the exposed subjects, in

    contrast to more general compartmental pharmacokinetic models that do not
    necessarily represent effects on real anatomic regions/ compartments of the
    body. 11 Once in the body, a chemical may be chemically altered to form
    metabolites. Either the chemical itself or its metabolites may produce toxic
    effects. Therefore, both may need to be considered in assessing the
    potential harm associated with a given chemical. 12 The administered dose is
    the amount of a substance given to an animal or human (e. g., through diet,
    drinking water, or ambient air). The effective dose is the amount that
    actually reaches a target organ or tissue.

    estimate target tissue doses and what assumptions were used in that
    modeling. In the methylene chloride standard, OSHA developed a set of 11
    criteria to judge whether available data are adequate to permit the agency
    to rely on PBPK analysis in place of administered exposure levels when
    estimating human equivalent doses. Although it is beyond the scope of this
    appendix to provide a full technical explanation of the following criteria,
    they do illustrate the complex nature of PBPK analysis and, more generally,
    the types of issues that risk assessors consider in weighing the available
    data.

    1. The predominant as well as all relevant minor metabolic pathways must be
    well described in several species, including humans.

    2. The metabolism must be adequately modeled. 3. There must be strong
    empirical support for the putative mechanism of

    carcinogenesis. 4. The kinetics for the putative carcinogenic metabolic
    pathway must

    have been measured in test animals in vivo and in vitro and in corresponding
    human tissues at least in vitro. 13 5. The putative carcinogenic metabolic
    pathway must contain metabolites

    that are plausible proximate carcinogens. 6. The contribution to
    carcinogenesis via other pathways must be

    adequately modeled or ruled out as a factor. 7. The dose surrogate in target
    tissues used in PBPK modeling must correlate with tumor responses
    experienced by test animals.

    8. All biochemical parameters specific to the compound, such as blood: air
    partition coefficients, must have been experimentally and reproducibly
    measured. This must especially be true for those parameters to which the
    PBPK model is sensitive.

    13 The term in vivo refers to tests carried out within living organisms,
    while in vitro refers to tests outside the organism (e. g., using cells
    taken from an animal or human).

    9. The model must adequately describe experimentally measured physiological
    and biochemical phenomena.

    10. The PBPK models must have been validated with other data (including
    human data) that were not used to construct the models. 11. There must be
    sufficient data, especially data from a broadly

    representative sample of humans, to assess uncertainty and variability in
    the PBPK modeling. In the 1,3- butadiene standard, which came out after the
    methylene chloride standard, OSHA used these same 11 criteria to judge the
    adequacy of the 1,3- butadiene PBPK models for dose- response assessment. In
    the butadiene case, the PBPK models did not meet all of these criteria.

    For dose- response analyses from human cancer data, OSHA tends to use
    similar methodologies to the other regulatory agencies. Mostly these are
    simple linear models, such as relative risk models, and estimates of risk
    are based on the MLE.

    Noncancer Effects No specific approach or procedure for the assessment of
    noncancer effects was evident in the examples of OSHA rulemakings we
    reviewed. However, OSHA clearly considered a range of noncancer toxic
    effects in its analyses.

    In its rulemakings, OSHA focused on describing and analyzing a variety of
    relevant studies, case reports, and other information found in the
    scientific literature. Rhomberg noted that, in the past, OSHA used methods
    that were

    comparable to those of other agencies. However, the federal court in the

    AFL- CIO v. OSHA case questioned the use of standard safety factors, noting
    that ?application of such factors without explaining the method by which
    they were determined is clearly not permitted.? 14 OSHA has produced
    quantitative risk estimates for reproductive and

    developmental effects (glycol ethers, 1993), heart disease and asthma
    (environmental tobacco smoke, 1994), Hepatitis B virus infection (bloodborne
    pathogens, 1992), tuberculosis, and kidney toxicity from cadmium exposure.
    OSHA is currently working on quantitative risk assessments for such adverse
    health effects as cardiovascular disease

    mortality, neural effects, asthma, and respiratory tract irritation for a
    number of substances. OSHA states that new methodology has been used 14 965
    F. 2d at 978.

    for these assessments, but review drafts were not yet ready and we cannot
    comment further. Exposure Assessment Under the OSH Act, OSHA has a
    relatively specific and narrow focus on exposure assessment. OSHA?s primary
    focus is estimating the risk to workers exposed to an agent for a working
    lifetime. This risk is calculated

    in terms of a person exposed at a constant daily exposure level for 45 years
    at 5 days per workweek and 8 hours per workday. The goal is to set
    standards, in the form of permissible exposure limits (PELs), so workers
    would suffer no impairment during the course of their lifetime under a
    continuous exposure scenario. Although this is a hypothetical exposure
    scenario, Rhomberg observed that it is not conservative compared with the
    actual distribution of exposures in the workplace. He also noted that, in

    assessing the exposures and risks associated with the new proposed standard,
    OSHA assumes that the standard is applied to newly exposed workers who will
    work under the new standard for their entire working lives. No allowance is
    made for the fact that current workers may already have had exposures higher
    than the new standard.

    Despite the primary focus on long- term working lifetime exposures, there
    may also be some risks posed by acute, short- term exposures. Therefore,
    although part of OSHA?s risk assessment could focus on longer- term risks
    and deal with 8- hour time- weighted average (TWA) exposure, the agency?s
    analysis may also cover short- term exposure effects. In the methylene
    chloride rule, for example, OSHA set the 8- hour TWA PEL primarily to reduce
    the risk of employees developing cancer, while the 15- minute shortterm
    exposure limit (STEL) was primarily designed to protect against noncancer
    risks, such as negative effects on the central nervous system.

    Finally, Rhomberg pointed out the following distinct features of
    occupational exposure assessments: Compared to environmental exposures,
    exposures in the workplace tend to be much better defined. The workplace is
    a confined setting within which practices and behaviors tend to be
    standardized. Exposure levels are often high enough to be easily measured,
    and many workplaces have ongoing monitoring of environmental levels of
    compounds. 15

    15 Rhomberg (1996), p. 36.

    Risk Assessment As previously noted, OSHA?s risk assessment procedures,
    including its

    Assumptions and default assumptions and methodological preferences, tend to
    be established through the precedents of prior rulemakings. In contrast to
    Methodological EPA and FDA, OSHA also appears to choose somewhat less
    conservative

    Choices options, even though the agency notes that Congress and the courts
    have

    permitted and even encouraged it to consider ?conservative? responses to
    both uncertainty and human variability. The Supreme Court?s Benzene
    decision, in particular, affirmed that ?the Agency is free to use
    conservative assumptions in interpreting the data with respect to
    carcinogens, risking error on the side of over- protection rather than under
    protection.? 16 On the other hand, OSHA explicitly stated in rulemakings
    that it takes various

    steps to be confident that its risk assessment methodology is not designed
    to be overly conservative (in the sense of erring on the side of
    overprotection). Although not intended to be comprehensive, table 8

    illustrates some of the specific assumptions or methodological choices used
    by OSHA. It also illustrates the overt balancing of more and less
    conservative choices that characterizes OSHA?s approach to risk assessment.
    The information presented in table 8 was taken primarily from OSHA risk
    assessment documents but also reflects additional comments provided by OSHA
    officials. (GAO notes and comments appear in parentheses.)

    Table 8: OSHA Risk Assessment Assumptions and Methodological Choices When
    the assumption/ choice would be applied (step in the risk assessment process
    or Likely effect on risk Assumption or

    circumstances) assessment results methodological choice Reason( s) for
    selection

    1. Avoids the uncertainty of crossspecies Choice of data set for

    (Not identified.) Most things being equal, extrapolation. Also,

    quantitative cancer risk epidemiologic data are preferred most human studies
    on nondrug assessment (hazard to data from animal studies

    chemicals come from identification and dose- response whenever good data on
    human occupational exposures. assessment) risks exist.

    16 448 U. S. at 656.

    (Continued From Previous Page)

    When the assumption/ choice would be applied (step in the risk assessment
    process or Likely effect on risk Assumption or circumstances) assessment
    results methodological choice Reason( s) for selection

    2. Virtually all of the toxic

    Choice of data set for qualitative (Not specifically identified, but It is
    reasonable to suspect that substances that have been

    and quantitative cancer risk OSHA did note that it is possible substances
    that cause cancer in demonstrated to be carcinogenic assessment (hazard

    that a substance may be multiple animal species and at in humans are also
    carcinogenic identification and dose- response carcinogenic in a laboratory
    multiple target organ sites would

    in laboratory animals. assessment) in the absence of species but not in
    humans.

    be carcinogenic to humans. sufficiently powerful negative OSHA officials
    also pointed out

    Therefore, OSHA relies on wellconducted, epidemiological studies or that, as
    part of its risk high- quality animal mechanistic studies assessment, OSHA
    examines all

    bioassays as the primary basis demonstrating that the purported

    relevant toxicity data to for cancer hazard identification carcinogenic
    mechanism of determine the appropriateness and often for quantitative risk
    action of the substance is of relying on extrapolation from assessment.

    irrelevant to humans. animal studies.)

    3. To protect workers from Analysis of epidemiological and

    (Not identified.) If human (epidemiological) data

    significant risk. animal data for quantitative are equivocal, or the cancer
    risk assessment (hazard epidemiologic study is not identification and dose-
    response sufficiently sensitive to identify assessment) when animal an
    increased risk predicted by a studies indicate a positive well- conducted
    animal bioassay, response to a particular it is necessary to consider the

    chemical and epidemiological animal data to protect workers

    studies of exposures to the same from significant risk. chemical fail to
    exhibit a statistically significant increase

    in risk. 4.

    (Not identified.) Choice of animal- to- human dose (Not identified, but this
    is In the absence of equivalence for quantitative risk generally considered
    to be a pharmacokinetic information

    assessment (dose- response conservative approach.)

    satisfying OSHA?s criteria for assessment). acceptance of PBPK models, OSHA
    relies on a default mg/ kg/ day species conversion factor. 5.

    (Not explicitly identified. Per Choice of data set for

    OSHA cited this as an instance OSHA uses site- specific tumor comments from
    OSHA it reflects,

    quantitative cancer risk where the agency does not use incidence, rather
    than pooled

    in part, a policy choice to be assessment (dose- response the most
    conservative approach.

    tumor response, in determining conservative, but not overly assessment).

    the dose- response function for a conservative.)

    chemical agent. OSHA estimates excess risks to humans based on the most
    sensitive species- sex- tumor site.

    (Continued From Previous Page)

    When the assumption/ choice would be applied (step in the risk assessment
    process or Likely effect on risk Assumption or circumstances) assessment
    results methodological choice Reason( s) for selection

    6. Evidence suggests that such Choice of data set for

    (Not specifically identified in the OSHA combines benign tumors

    tumors should be interpreted as quantitative cancer risk risk assessments we
    reviewed, with the potential to progress to

    representing a potentially assessment (dose- response

    but according to OSHA officials malignancies with malignant

    carcinogenic response. assessment).

    is almost always conservative.) tumors occurring in the same tissue and the
    same organ site.

    (In support of this position, OSHA cited the views of the Office of Science
    and Technology Policy on chemical carcinogenesis [citation provided]. OSHA
    also pointed out that other federal agencies-

    EPA, FDA, the Consumer Product Safety Commission, and the National Institute
    for Occupational Safety and Health- have also included benign responses in
    their

    assessments.) 7.

    (Not explicitly identified, but the Dose- response assessment. (Not
    identified.)

    OSHA relies on low- dose assumption that you can extrapolation to estimate
    risks

    extrapolate low- dose effects associated with exposure levels

    from high- dose effects is a of interest; however, because standard
    assumption of risk occupational exposures are assessment.) typically much
    higher than those encountered in the general environment, OSHA?s risk
    assessments do not extrapolate

    as far beyond the range of observed toxicity as might be necessary to
    characterize environmental risks.

    (Continued From Previous Page)

    When the assumption/ choice would be applied (step in the risk assessment
    process or Likely effect on risk Assumption or circumstances) assessment
    results methodological choice Reason( s) for selection

    8. OSHA stated that it believes that

    Cancer dose- response The multistage model is For low- dose animal- to-
    human the multistage model conforms assessment. generally considered to be a
    cancer risk extrapolation, most closely to what is known

    conservative model because it is OSHA?s preference is to use the about the
    etiology of cancer,

    approximately linear at low maximum likelihood estimate including the fact
    that linear- atlow- doses and because it assumes (MLE) in the Crump- Howe
    dose behavior is expected no threshold for carcinogenesis,

    reparameterization of the for exogenous agents, which

    although there are other

    ?multistage model.? increase the risk of cancer

    plausible models of already posed by similar carcinogenesis which are more
    This model is based on the "background? processes. OSHA conservative at low
    doses. biological assumption that noted that there is no evidence
    carcinogens induce cancer that the multistage model is (OSHA officials also
    pointed out through a series of independent

    biologically inappropriate, that the algorithm that OSHA viable mutations in
    a series of especially for genotoxic uses to compute MLE estimates stages,
    and that each mutation carcinogens, and that the

    is less conservative because it rate is linearly related to dose.

    overwhelming scientific may lead to models that are consensus is that
    genotoxins sublinear at low doses.) The multistage model used by follow low-
    dose linear functions. the agency also assumes no However, OSHA officials
    also threshold for carcinogenesis.

    pointed out that the CrumpHowe algorithm that OSHA uses can yield nonlinear
    models.

    OSHA?s preference is consistent with the position of the Office of Science
    and Technology Policy, which recommended that ?when data and information are
    limited, models or procedures that

    incorporate low- dose linearity are preferred when compatible with limited
    information? [citation provided].

    9. In part, this appears to reflect a Cancer dose- response OSHA cited this
    as an instance OSHA?s default choice is to policy choice. OSHA cited this
    assessment. where the agency does not use

    select the MLE of the choice as one of the steps it has a conservative (or
    the most parameterized dose- response taken that make it fairly confident

    conservative) approach. function, rather than the upper

    its risk assessment methodology 95- percent confidence limit. is not
    designed to be overly ?conservative,? in the sense of erring on the side of

    overprotection.

    (Continued From Previous Page)

    When the assumption/ choice would be applied (step in the risk assessment
    process or Likely effect on risk Assumption or circumstances) assessment
    results methodological choice Reason( s) for selection

    10. In its risk assessments, OSHA During dose- response

    OSHA notes that the body For interspecies dose scaling, points out that
    there are several assessment, when estimating weight extrapolation approach
    OSHA assumes that equivalent plausible options for

    the equivalent human dose that it generally uses tends to be doses in mg/
    kg/ day (body weight extrapolating human risks from based upon an
    experimental significantly less conservative scaling) would lead to
    equivalent animal data via interspecies

    dose in animals. than other plausible risks.

    scaling factors [citations methodologies and most likely is provided]. OSHA
    states that its less conservative even than the (OSHA?s Director of Health
    selection of body weight scaling central tendency of the plausible Standards
    noted that the agency

    is one of the steps it takes that values. might also move to consideration
    make the agency fairly confident of �- power scaling, as agreed to that its
    risk assessment The agency also notes that,

    by EPA, FDA, and the Consumer methodology is not

    across the series of plausible Product Safety Commission, or

    ?conservative? in the sense of values, its body weight

    to develop a probability erring on the side of

    extrapolation approach is distribution for the power.) overprotection.

    generally considered the least conservative, (body weight) 2/ 3 In addition,
    to convert mg/ kg/ day (No particular basis cited for [surface area scaling]
    the most doses to parts per million (ppm), using the specific breathing rate
    conservative, and (body OSHA uses a human breathing and body weight figures,
    just that weight) 3/ 4 the midpoint value.

    rate of 9.6 m 3 /workday and they are OSHA?s preferred

    human body weight of 70 kg. values.)

    11. The focus on working lifetime Exposure assessment. OSHA notes that this
    reflects a

    OSHA assumes that workers will exposure comes from the ?more conservative?
    choice. be exposed to a chemical at the statutory mandate under the maximum
    permissible level for

    OSH Act to protect an employee 45 years.

    ?even if such employee has regular exposure to the hazard The standard
    values used for

    for the period of his working life.? assessing exposures over a working
    lifetime are:

    The choice of 45 years is based a. 45 years per working

    on a worker beginning work at lifetime, age 20 and retiring at age 65. b. 5
    workdays per week, and c. 8 hours per workday.

    (Continued From Previous Page)

    When the assumption/ choice would be applied (step in the risk assessment
    process or Likely effect on risk Assumption or circumstances) assessment
    results methodological choice Reason( s) for selection

    12. The general boundary is directly Policy for evaluating ?significant (No
    direct effect on the risk The general boundary within attributed to the
    Supreme

    risk.? estimates, but this general policy which acceptable versus Court?s
    1980 Benzene decision.

    does serve as an underlying unacceptable risk falls is focus in conducting
    risk between an insignificant fatality assessments.)

    risk of one in one billion (10 -9 ) and a significant risk of 1 in one
    thousand (10 -3 ).

    More explicitly, OSHA stated in one of its rulemakings that risks at or
    above 10 -3 (1 per 1000) are always significant by any empirical, legal, or
    economic

    argument available. Source: Compiled from GAO review of OSHA risk assessment
    documents and from additional comments provided by agency officials.

    Risk Characterization Although OSHA does not have written risk
    characterization policies, recent OSHA rulemakings showed that the agency
    emphasized (1) comprehensive characterizations of risk assessment results;
    (2) discussions of assumptions, limitations, and uncertainties; and (3)
    disclosure of the data and analytic methodologies on which the agency
    relied. Rhomberg noted

    that OSHA?s usual practice is to present the results and methodological
    bases of outside parties? risk assessments for a chemical in addition to
    OSHA?s own assessment, and to feature several possible bases for risk
    calculation in its characterization of risks. In checking examples of recent
    OSHA rulemakings, we also observed this emphasis on showing a range of
    alternative assessments, both those of external parties and OSHA?s own
    sensitivity analyses.

    At least three factors help to explain this proclivity to characterize risks
    using different data sets, assumptions, and analytical approaches, all of
    which are rooted in the statutory context for OSHA standards setting. First,
    the agency?s statutory mandate, reinforced by the Supreme Court?s Benzene
    decision, is that it must demonstrate ?significant? risk from workplace
    exposure to a chemical with ?substantial evidence.? Second, the OSH Act
    directs OSHA to base health standards on the ?best available

    evidence? and consider the ?latest scientific data.? The third factor is
    that the standard selected will be limited by consideration of its
    technological and economic feasibility and cost effectiveness. Together,
    these provisions

    provide ample incentive to show that a compound presents a significant risk
    even when using a range of alternative estimates and scientific evidence.
    (This does not preclude the agency from focusing on one analysis as the most
    appropriate to support its final estimate of risk at a particular level of
    exposure.) The bottom line is that OSHA uses risk assessment to justify a
    standard by showing, in general, that significant risks exist and that
    reducing exposure as proposed in the agency?s standard will reduce those
    risks.

    In recent OSHA rulemakings, the agency devoted considerable effort to
    addressing uncertainty and variability in its risk estimates. Such efforts
    included performing sensitivity analyses, providing the results produced by

    alternative analyses and assumptions, and using techniques such as Monte
    Carlo and Bayesian statistical analyses. In its risk characterizations, OSHA
    provided both estimates of central tendency (such as the mean) and upper
    limits (such as the 95 th percentile of a distribution). In the methylene

    chloride rule, OSHA noted that, in its past rulemakings, it had frequently
    estimated carcinogenic potencies via the MLE of the multistage model
    parameters. However, in this particular rule it chose for its final risk
    estimate to couple one measure of central tendency (the MLE of the
    doseresponse parameters) with a somewhat conservative measure of its PBPK
    output (the 95 th percentile of the distribution of human internal dose).
    OSHA concluded that this combination represented ?a reasonable attempt

    to account for uncertainty and variability.?

    Chemical Risk Assessment at the Department of Transportation?s Research and
    Special

    Appendi x V

    Programs Administration The chemical risk assessments conducted by the
    Department of Transportation?s (DOT) Research and Special Programs
    Administration (RSPA) focus primarily on acute (short- term) risks
    associated with potential accidents involving unintentional releases of
    hazardous materials (HAZMAT) during transportation. 1 As such, they are very
    different from risk assessments that focus on chronic health risks.
    According to agency officials, RSPA?s assessments are done using a flexible,
    criteria- based system. RSPA?s HAZMAT transportation safety program begins
    with a hazard analysis that results in material classification. There are
    international standards on the transportation and labeling of dangerous

    goods that classify the type of hazard associated with a given substance (e.
    g., whether it is flammable, explosive, or toxic) and the appropriate type
    of packaging. Once a hazard is classified, RSPA?s analysis focuses on
    identifying the potential circumstances, probability, and consequences of

    unintentional releases of hazardous material during its transportation. DOT
    has written principles on how the results of its risk or safety assessments
    should be presented. Those principles emphasize

    transparency regarding the methods, data, and assumptions used for risk
    assessments and encourage DOT personnel to not only characterize the range
    and distribution of risk estimates, but also to put the risk estimates into
    a context understandable by the general public.

    Context for RSPA According to DOT officials, chemical risks may be an
    element of almost Chemical Risk any departmental risk assessment. For
    example, they said that one of the

    alternatives they explored regarding air bags involved potential exposure
    Assessment

    to chemicals used in the inflation mechanism. They also noted that Federal
    Aviation Administration (FAA) safety analyses include some elements related
    to potential exposures to the chemicals that are always found in aircraft
    mechanisms. However, DOT?s risk assessment most commonly focus on chemical
    risks when considering the transportation of hazardous materials.
    Unintentional releases of hazardous materials during transportation, whether
    due to packaging leaks or transportation accidents, may pose risks to human
    health and safety, the environment, and property. The potential consequences
    of such incidents include deaths or 1 DOT uses the term ?risk assessment?
    narrowly to refer to risk characterization, specifically the determination
    of risk context and acceptability, often by comparison to other similar
    risks. However, to be consistent with the rest of this report, we are using
    the term in this appendix to refer to the entire process of identifying,
    analyzing, and characterizing risks.

    injuries caused by an explosion, fire, or release of gases that are toxic
    when inhaled. Under the Federal Hazardous Materials Transportation Act, as
    amended, the Secretary of Transportation has the regulatory authority to
    provide adequate protection against risks to life and property inherent in
    transporting hazardous materials in commerce. 2 DOT officials pointed out
    that, because this act tends to be more general than those relevant to other

    agencies? regulation of risks from chemicals, it gives DOT more flexibility
    to define what is ?adequate? to address potential risks. The statute directs
    the DOT Secretary to designate a material or group or class of materials as
    hazardous when he or she decides that transporting the material in commerce
    in a particular amount and form may pose an unreasonable risk to health and
    safety or property. The Secretary is also directed to issue regulations for
    the safe transportation of such materials. The hazardous materials
    regulations apply to interstate, intrastate, and foreign transportation in
    commerce by aircraft, railcars, vessels (except most bulk

    carriage), and motor vehicles. The Secretary has delegated authority for
    implementing these hazardous materials responsibilities to various
    components within DOT. In particular, RSPA issues the Hazardous Materials
    Regulations and carries out related regulatory functions, such as issuing,
    renewing, modifying, and terminating

    exemptions from the regulations. The Superfund Amendments and
    Reauthorization Act of 1986 mandated that RSPA also list and regulate under
    the Hazardous Materials Regulations all hazardous substances designated by
    EPA. According to DOT officials, RSPA conducts most of the department?s risk
    assessments regarding the transportation of chemical hazardous materials.
    RSPA and the modal administrations in DOT- FAA,

    the United States Coast Guard, the Federal Motor Carrier Safety
    Administration, and the Federal Railroad Administration- share enforcement
    authority for hazardous materials transportation. RSPA?s Office of Hazardous
    Materials Safety (OHMS) has the primary responsibility for managing the
    risks of hazardous materials transportation

    within the boundaries of the United States, unless such materials are being
    transported via bulk marine mode (in which case the Coast Guard is
    responsible). Overall, OHMS notes that its Hazardous Materials Safety
    Program and resulting regulations (1) are risk based; (2) use data,

    2 49 U. S. C. 5101 et seq.

    information, and experience to define hazardous materials and manage the
    risk hazardous materials present in transportation; and (3) are prevention
    oriented. Therefore, the analysis of risk is an important element of OHMS?
    responsibilities. Within OHMS, the Office of Hazardous Materials Technology
    (OHMT) provides scientific, engineering, radiological, and risk analysis
    expertise. Other entities may also be involved in conducting transportation-
    related chemical risk and safety assessments. For example, OHMS sponsored a
    quantitative threat assessment by the John A. Volpe National Transportation
    Systems Center (the Volpe Center), which is operated by RSPA, to determine
    the probability that a life- threatening incident would

    occur as a result of transporting hazardous materials in aircraft cargo
    compartments. 3 OHMS also sponsored a multiyear research effort by the
    Argonne National Laboratory to characterize the risk associated with
    transportation of selected hazardous materials on a national basis. 4

    One of the most distinctive aspects regarding the regulation of hazardous
    materials transportation is the role that is played by international
    agreements and definitions. Criteria for classifying and labeling dangerous
    chemicals being transported have been internationally harmonized through the
    United Nations Recommendations on the Transport of Dangerous Goods. 5 This
    UN classification system is internationally recognized, and

    RSPA has essentially adopted the UN recommendations into the domestic
    hazardous materials regulations. (A more detailed description of this
    classification system appears in the following section.) 3 Threat Assessment
    of Hazardous Materials Transportation in Aircraft Cargo Compartments, U. S.
    Department of Transportation, Research and Special Programs Administration,
    John A. Volpe National Transportation Systems Center, Final Report (December
    1999). 4 A National Risk Assessment for Selected Hazardous Materials
    Transportation, Decision and Information Sciences Division, Argonne National
    Laboratory (December 2000). The Argonne National Laboratory is operated by
    the University of Chicago under contract for the U. S. Department of Energy.
    5 The United States and other countries are attempting to develop a Globally
    Harmonized System (GHS) for the classification and labeling of chemicals.
    However, while criteria have been internationally harmonized for purposes of
    transportation, harmonized requirements have not yet been established for
    purposes of environmental, worker, or consumer safety regulations. RSPA
    participates, along with other federal agencies, in these GHS activities.

    Risk Assessment Because of the particular regulatory context in which it
    operates- in

    Procedures particular, its focus on acute (short- term) risks associated
    with transportation accidents- RSPA does not follow the four- step risk

    assessment paradigm identified by NAS and used by EPA, FDA, and OSHA.
    However, RSPA?s procedures do address similar generic questions, such as
    whether a particular material or activity poses a threat and the likelihood

    and consequences of potential accidents. The agency uses a criteria- based
    system to assess the hazards to human health and safety, property, and the
    environment that are associated with potential accidents during hazardous
    materials transportation. Chemicals are identified and classified as hazards
    according to a classification system in the Hazardous Materials

    Regulations that is largely harmonized with internationally recognized
    criteria. The risk analyses by RSPA then focus on assessing the potential
    circumstances under which exposure could occur during transportation,

    their causes, consequences, and probability of occurrence. Guidance The
    general risk assessment procedures applicable to RSPA are found within DOT-
    wide policies on conducting regulatory analyses and also in descriptive
    materials about the agency?s Hazardous Materials Safety

    Program. DOT included general guidelines for conducting a risk assessment as
    part of its broader Methods for Economic Assessment of Transportation
    Industry Regulations (Office of the Assistant Secretary for Policy and
    International Affairs, June 1982). The DOT guidelines for risk assessment
    are grouped under three major topics:

     procedural guidelines that recommend formats for presentation of risk
    analyses, formats for conducting risk analyses, and reporting of assumptions
    and limits of analyses;

     methodology guidelines that discuss some of the more frequently used risk
    methods and their applicability; and

     data guidelines that discuss data sources, collection and presentation of
    data, and raw and derived statistics.

    The primary focus of the DOT- wide risk assessment methodology and
    guidelines is on estimating the risk reduction attributable to proposed
    transportation safety regulations. DOT?s guidelines are intended to be

    applicable to risk assessment of hazardous material transport by any mode as
    well as assessment of other types of transportation risk. However, DOT
    stated that the guidelines are not intended to be a ?cookbook,? or a
    prescriptive methodology, specifying each step in a risk assessment. DOT

    pointed out in the guidelines that such an approach is not desirable,
    because there is no single ?correct? set of methods for assessing
    transportation risk.

    In addition to the DOT- wide guidelines, RSPA has produced written materials
    specifically on the Hazardous Materials Safety Program. These materials
    describe the role of risk assessment in the management of risks associated
    with transportation of hazardous materials and the general

    process used for analysis of risks, and they define risk assessment and
    management terms for purposes of hazardous materials safety. 6 There also
    are a number of general guidance documents and reports on various aspects of
    hazardous materials transportation safety that provide additional insights
    into the identification and assessment of risks.

    Risk Assessment Approach RSPA does not apply the same NAS four- step
    paradigm for risk assessment as generally used by EPA, FDA, and OSHA.
    According to RSPA officials, the main reason for this difference between
    their risk assessments and most of those conducted by the other three
    agencies is the focus of RSPA?s assessments. RSPA?s concerns relative to
    hazardous materials transportation are primarily directed at short- term or
    acute health risks due to relatively high exposures from the unintentional
    release of hazardous materials. The officials said that, in contrast, the
    four basic steps of the NAS paradigm were intended to focus on chronic
    health risks due to longterm,

    low- level background chemical exposure. 7 The main exceptions to this
    difference in general risk assessment procedures occur when other agencies?
    assessments are similarly directed at risks associated with unintentional
    releases of chemicals. In particular, RSPA officials said that there are
    parallels between their risk assessment and management efforts and those of
    EPA and OSHA programs that are directed at chemical accidents. (See, for
    example, the description of the risk assessment procedures for EPA?s
    Chemical Emergency Preparedness and Prevention Office in app. II.)

    6 DOT?s definitions sometimes vary from the definitions of those terms in
    other risk assessment settings. Items in the glossary of this report
    identify some of these different definitions. 7 Note, however, that the
    general risk assessment procedures of the other three agencies cover both
    chronic and acute risks.

    In sharp contrast to most of the risk assessment procedures we described for
    EPA, FDA, and OSHA, toxicity is simply one of several potentially dangerous
    properties of a hazardous material of concern to RSPA. Where

    toxicity is a factor, RSPA?s risk assessments tend to center on exposure
    levels that pose an immediate health hazard. This focus is reflected in the
    types of chemical toxicity information that RSPA helps develop. For example,
    RSPA actively participates on a National Advisory Committee developing Acute
    Exposure Guideline Levels for chemicals. In specific

    cases where chronic toxicity or environmental values play a role in RSPA
    analyses, agency officials said that they rely on what EPA, FDA, OSHA, and
    other agencies have developed. Despite such differences, RSPA?s risk
    assessments address similar basic

    issues as the chemical risk assessments of the other three agencies (e. g.,
    whether a particular material or activity poses a threat and the severity
    and likelihood of potential exposures). The DOT- wide risk assessment
    guidelines primarily discuss ?consequence? and ?probability? analyses, but
    also describe a preliminary step for defining scenarios of concern

    (essentially part of a hazard identification step) and a final step to
    summarize results and conclusions from the preceding analyses (essentially a
    risk characterization). The Hazardous Materials Safety Program materials
    outline a similar risk assessment process that progresses from the
    identification of hazards to an evaluation of incident causes, frequencies,
    and consequences.

    Identifying Hazards RSPA begins with a hazard analysis that results in
    material classification. In RSPA risk assessments, hazardous materials are
    chemical, radioactive, or infectious substances or articles containing
    hazardous materials that can

    pose a threat to public safety or the environment during transport.
    Hazardous materials pose this threat through chemical, physical, nuclear, or
    infectious properties that can make them dangerous to transport workers or
    the public. For example, RSPA is concerned with the potential for the
    unintentional release of hazardous materials to lead to adverse

    outcomes such as explosions, fires, or severely enhanced fires that can
    cause deaths, injuries, or property damage. The agency is also concerned
    with the potential toxic, corrosive, or infectious effects of released
    materials on humans and the environment.

    According to DOT officials, their hazard classification approach is a
    criteria- based system that provides them considerable flexibility in their
    analysis and regulation of potential hazards. They noted that their criteria

    are geared more toward the hazard a material may pose in an accident

    scenario than toward a chronic health risk. The Director of the Office of
    Hazardous Materials Technology characterized this hazard classification
    approach as a more open system than used in other agencies (e. g., EPA). He
    explained that, in this system, any new chemical or substance that fits
    within RSPA?s matrix of hazard criteria falls under the hazardous materials

    transportation regulations. Hazard identification for these assessments is
    based largely on international agreements regarding transportation of
    dangerous goods. Of particular importance, there is an internationally
    recognized system for the classification, identification, and ranking of all
    types of hazardous

    materials that was created by the UN Committee of Experts on the Transport
    of Dangerous Goods. This system is revised biennially and published as the
    ?United Nations Recommendations on the Transport of Dangerous Goods.? Under
    this classification system, all hazardous materials are divided into nine
    general classes according to physical,

    chemical, and nuclear properties. The system also specifies subdivisions and
    packing group designations (that indicate a relative level of hazard) for
    some classes. (See table 9.)

    Table 9: UN Classification System for Transport of Dangerous Goods Packaging
    performance Hazard class Description Subdivisions specified requirements
    specified

    1 Explosives and pyrotechnics X 2 Compressed and liquefied gases X 3
    Flammable liquids X 4 Flammable solids (including self- reactive liquids) X
    X 5 Oxidizers and peroxides X X 6 Toxic (poisonous) and infectious materials
    X X 7 Radioactive materials 8 Corrosive materials (acidic or basic) X 9
    Miscellaneous dangerous substances and articles

    Packing groups

    1 Great danger 2 Medium danger 3 Minor danger

    Source: Research and Special Programs Administration, Department of
    Transportation.

    These are broad categories that may include large numbers of diverse
    materials. For example, the air cargo threat assessment noted that there
    were 535 different flammable liquid entries in the hazardous materials table
    and more than 700 toxic material entries. Because there are hazardous
    materials with multiple dangerous properties, these classes and

    subdivisions are not mutually exclusive. Compressed or liquefied gases, for
    example, also may be toxic or flammable. The UN Committee of Experts created
    more than 3, 400 possible identification numbers, proper

    shipping descriptions, and hazard classes to be assigned to various
    hazardous material compounds, mixtures, solutions, and devices. There are
    also generic ?not otherwise specified? identification numbers and

    shipping descriptions that allow the material to be classed by its defined
    properties.

    RSPA uses essentially the same framework as the UN recommendations for the
    hazard classes and packing requirements of its Hazardous Materials
    Regulations. Table 10 shows the hazard classification system in the
    regulations.

    Table 10: Hazard Classification System of RSPA?s Hazardous Materials
    Regulations Class/ division number Description

    None Forbidden materials a None Forbidden explosives b Class 1

    Explosives

     Division 1.1

     Explosives with a mass explosion hazard

     Division 1.2

     Explosives with a projection hazard

     Division 1.3

     Explosives with predominantly a fire hazard

     Division 1.4

     Explosives with no significant blast hazard

     Division 1.5

     Very insensitive explosives; blasting agents

     Division 1.6

     Extremely insensitive detonating articles Class 2

    Gases

     Division 2.1

     Flammable gas

     Division 2.2

     Nonflammable compressed gas

     Division 2.3

     Poisonous (toxic by inhalation) gas Class 3 Flammable and combustible
    liquid Class 4

    Flammable solids; spontaneously combustible materials; and dangerous when
    wet materials

     Division 4.1

     Flammable solid

     Division 4.2

     Spontaneously combustible material

     Division 4.3

     Dangerous when wet material

    (Continued From Previous Page)

    Class/ division number Description

    Class 5 Oxidizers and organic peroxides

     Division 5.1

     Oxidizer

     Division 5.2

     Organic peroxide Class 6

    Poisonous (toxic) materials and infectious substances

     Division 6.1

     Poisonous (toxic) materials

     Division 6.2

     Infectious substance (etiologic agent) Class 7 Radioactive material Class
    8 Corrosive material Class 9 Miscellaneous hazardous material None Other
    regulated material a 49 CFR Section 173.21 defines the materials that shall
    not be offered for transportation or

    transported. b 49 CFR Section 173.54 defines the explosives that shall not
    be offered for transportation or

    transported. Source: 49 CFR section 173.2.

    The classification system in these regulations can be very detailed for some
    subjects. For example, the regulations specifically identify the types of
    toxicity tests and data that should be used to determine whether something

    would be classified as poisonous material (class 6, division 6. 1). The
    regulations define poisonous material as a material, other than a gas, which
    is known to be so toxic to humans as to afford a hazard to health during
    transportation, or which, in the absence of adequate data on human toxicity,

     is presumed to be toxic to humans because it falls within one of several
    specified categories for oral, dermal, or inhalation toxicity when tested on
    laboratory animals; or  is an irritating material, with properties similar
    to tear gas, which causes extreme irritation, especially in confined spaces.

    Of particular relevance to comparisons with chemical risk assessments of
    other agencies, the regulations contain precise definitions of what
    constitutes oral, dermal, or inhalation toxicity for purposes of the
    Hazardous Materials Regulations. For example, one threshold for

    inhalation toxicity is defined as a dust or mist with an LC 50 for acute
    toxicity on inhalation of not more than 10 mg per liter of air. 8 (A
    different definition applies to the inhalation toxicity of a vapor.) The
    regulations also address other testing requirements and conversion factors.
    The regulations state that, whenever possible, animal test data that have
    been reported in the chemical literature should be used.

    The Hazardous Materials Regulations include an extensive Hazardous Material
    Table with itemized information about specific hazardous materials. The
    number of HAZMAT table entries corresponds closely with the number created
    by the UN. RSPA officials noted that the number of specific chemicals
    covered by the regulations is many multiples of the

    more than 3,400 entries, though, because of the generic nature of the ?not

    otherwise specified? descriptions. The table includes, but is not limited
    to, information such as the material?s description, hazard class or
    division, identification number, packing group, label codes, limits to the
    quantity of the material permitted in a single package, and special
    provisions

    concerning its transportation. Allyl chloride, for example, is identified as
    a class 3 material (flammable and combustible liquid), is in packing group I
    (indicating great danger), is forbidden on passenger aircraft and rail, and

    has two special provisions regarding the tanks used for transporting this
    substance. A material that meets the definition of more than one hazard
    class or division, but is not specifically listed in the table, is to be
    classed according to the highest applicable hazard class or division
    according to a descending order of hazard. For example, the division of
    poisonous gases is ranked as a greater hazard than the division of flammable
    gases.

    According to OHMS, the process of classifying a material in accordance with
    these hazard classes and packing groups is itself a form of hazard analysis.
    Another important feature of this process is that the regulations require
    the shipper to communicate the material?s hazards through the use of the
    hazard class, packing group, and proper shipping name on the shipping paper
    and the use of labels on packages and placards on the

    8 In this case, LC for acute toxicity on inhalation means that concentration
    of dust or mist 50 which, administered by continuous inhalation for 1 hour
    to both male and female young adult albino rats, causes death within 14 days
    in half of the animals tested.

    transport vehicle. Therefore, the shipping paper, labels, and placards
    communicate the most significant findings of the shipper?s hazard analysis
    to other parties. This communication aspect is particularly important in

    emergency response situations if an accident occurs during transport of
    these materials.

    The classification system, by itself, is not sufficient for all risk
    assessment purposes. For example, RSPA and OHMS still need to identify
    potential scenarios in which transportation accidents, spills, and leaks
    could occur. As evidenced by the air cargo threat assessment, such scenarios
    include the possibility that hazardous materials might be transported in a
    manner not in compliance with current regulations. 9 Also, as emphasized in
    a November 2000 report for RSPA, the hazardous materials transport system is
    highly heterogeneous and complex. 10 The report pointed out that this system
    involves not only many different materials posing a variety of

    hazards (as reflected in the classification system outlined in table 9) but
    also:

     a chain of events involving multiple players having different roles in the
    process of moving hazardous materials (such as shippers, carriers, packaging
    manufacturers, freight forwarders, and receivers of shipments) and the
    possibility of multiple handoffs of a material from one party to another
    during transport;

     several different modes of transport (principally highway, rail, waterway,
    and air), with some shipments that switch from one mode to another during
    transit; and

     multiple possible routes of transit. 9 The threat assessment project was,
    in fact, initiated following the crash of ValuJet Flight 592 near Miami, FL
    in May 1996, which had been linked to hazardous material devices (chemical
    oxygen generators) shipped in violation of DOT regulations.

    10 ?Risk Management Framework for Hazardous Materials Transportation,?
    prepared by ICF Consulting for the U. S. Department of Transportation,
    Research and Special Programs Administration (Nov. 1, 2000). RSPA officials
    noted that this framework provides a structure for their efforts and serves
    as a tool for all parties involved in hazardous materials

    transportation to consider in fostering continuous safety improvement.

    All of these complex features might need to be considered in identifying
    hazard scenarios. However, in identifying (and analyzing) potential hazard
    scenarios, RSPA and OHMS benefit from being able to use data, information,
    and experience on hazardous materials transportation

    incidents. For example, risk assessors can review data from sources such as
    the DOT Hazardous Materials Information System (HMIS) that catalogues
    transportation- related incidents that involve a release of

    hazardous materials. An OHMS official pointed out that the agency also uses
    fairly sophisticated models in analyzing various scenarios. He said that
    such models were used, for example, to provide a scientific basis for

    determining evacuation zones when developing the 2000 Emergency Response
    Guidebook. 11 Analyzing the Consequences and In contrast to the other
    agencies covered in this report, determining the

    Probabilities of Risks toxicity of a particular chemical (dose- response
    assessment) is not a

    central focus of risk assessment in RSPA and OHMS. Toxicity is only one of
    many risk factors under consideration (and should already be addressed
    through the hazard classification system). Instead, the primary focus of
    analysis is on the potential for hazardous materials to (1) spill or leak
    while in transit or (2) cause, contribute to, or multiply the consequences
    of a

    transportation- related accident. Analysis regarding the first item is
    primarily concerned with the packaging and containers used for
    transportation of hazardous materials, while analysis of the second item
    also considers other elements, such as the modes and routes of
    transportation for these materials. As the DOT risk assessment guidelines
    state, ?Hazardous materials accidents generally are transportation accidents
    in which hazardous materials happen to be present.?

    DOT documents use a variety of terms to describe and refer to the analysis
    of hazards or risks of concern to the department and its component offices
    (e. g., hazard analysis, risk analysis, threat assessment). However, the
    core of the analysis remains the same- an evaluation of the causes, 11 The
    2000 Emergency Response Guidebook was developed jointly by DOT, Transport

    Canada, and the Secretariat of Communications and Transportation of Mexico.
    It is intended primarily to guide firefighters, police, and other emergency
    personnel who may be the first to arrive at the scene of a transportation
    incident involving a hazardous material in (1) quickly identifying the
    specific or generic classification of the material( s) involved in the
    incident, and (2) protecting themselves and the general public during the
    initial response phase of the incident. According to RSPA, the 2000 revision
    of this guidebook was based on risk principles and analyses, and the
    technical basis and derivation of the values in the guidebook?s Table of
    Initial Isolation and Protective Action Distances are available on the RSPA
    website.

    consequences, and likelihood of transportation incidents involving hazardous
    materials. The general model in DOT?s guidelines for risk assessment of
    transportation activities or operations partitions the analysis of risk into
    two main parts:

     prediction of possible consequences in terms of loss from accidents (or,
    more broadly, incidents) while transporting materials in a specified way;
    and

     estimation of the probabilities or frequencies of occurrence of the
    consequences of such accidents (e. g., the likelihood or expected number of
    accidents occurring that would result in the above loss).

    For purposes of estimating the risk reduction attributable to transportation
    safety regulations, the expected loss or ?risk? is computed by summing the
    products of each possible loss multiplied by its probability. (In other

    words, risk in this context is the probability- weighted average loss.)
    According to DOT definitions, consequence analysis is the evaluation of the
    severity and magnitude of impacts associated with the occurrence of
    postulated accident scenarios. For purposes of analysis, the DOT

    guidelines recommend partitioning this evaluation into three segments: (1)
    initiating events (i. e., causes of an accident that can result in loss),
    (2) effects (i. e., the possible mechanisms by which an initiating event
    might result in injury or damage); and (3) consequences (i. e., the loss of
    life,

    injuries, property damage, or other losses expected from the effects). The
    evaluation of consequences reflects many factors, including the
    characteristics of the agent involved, the type of packaging or container

    used, the amount of material being transported, and the particular modes and
    routes of transportation (which also affect the extent of potential exposure
    by the public and environment). DOT defines probability analysis as the
    evaluation of the likelihood of individual accident scenarios and outcomes
    of adverse events. The likelihood of a particular hazard might be expressed
    either as a frequency or probability.

    The analyses of consequences and probabilities are based on a variety of
    data sources, including, to the extent possible, ?experience? data. Among
    the sources of information identified in OHMS materials to address
    consequences and probabilities are:

     data from the Hazardous Materials Information System (HMIS);

     commodity flow surveys;

     chemical substance manufacturing, use, and transportation studies;

     special analyses (such as the National Transportation Risk Analysis and
    Air Cargo reports mentioned earlier in this appendix, as well as shipment
    counts); and

     public comments on rulemakings. Such sources can provide valuable
    information for risk assessment in general and the statistical analysis of
    hazardous material transportation incidents in particular. The HMIS database
    provides a good illustration of the types of baseline data available. This
    database provides incident counts according to time, transportation phase
    (i. e., en route from origin to destination, loading or unloading, and
    temporary storage), and

    transportation mode (e. g., air, highway, and rail). For each incident, the
    database includes information on the hazardous materials involved, including
    the name of the chemical shipped, container type and capacity, number of
    containers shipped, number of containers that fail, and the

    amount of material released. The database also contains information
    concerning the occurrence of fire, explosion, water immersion, environmental
    damage, and the numbers of deaths, major and minor injuries, and persons
    evacuated.

    However, because DOT?s risk assessments are often used to estimate the

    ?risk impact? of proposed regulations, the DOT guidelines caution that lack
    of directly applicable experience data for assessing the impacts is probably
    the rule rather than the exception. This is because the controls provided by

    the proposed regulations constitute changes from present conditions, and
    experience data, by definition, relate to present conditions. The guidelines
    also emphasize that, to evaluate the impact on risk of a proposed regulation

    or its alternatives, it is necessary to perform a ?with and without? type of
    assessment, considering the potential effects on any or all of the elements
    of the risk model.

    As was the case with the classification of hazardous materials and
    packaging, the agency may employ criteria- based classifications of the
    consequences of potential adverse events and their likelihood of occurrence.
    A 1995 guidance document illustrates how consequence and

    frequency categories were combined into a ?risk assessment matrix? to assist
    decision makers in their risk management decisions. 12 (See table 11 below.)

    Table 11: Example of a Hazardous Materials Risk Assessment Matrix
    Consequence of occurrence categories Frequency of occurrence categories
    Catastrophic Critical Marginal Minor Negligible

    Frequent U U U C- MDR A- MRR Probable U U C- MDR A- MRR A- MRR Occasional U
    C- MDR A- MRR A- MRR A Remote C- MDR A- MRR A- MRR A A Improbable A- MRR A-
    MRR A A A

    Risk index: U - Unacceptable C- MDR - Conditional management decision
    required A- MRR - Acceptable management review required A - Acceptable
    Source: Adapted from ?Procedure for Removal of Nonconforming Hazardous
    Materials Packagings from Service, 7- 13- 95,? Office of Hazardous Materials
    Safety.

    12 In a nonchemical risk assessment context, DOT?s Federal Transit
    Administration (FTA) and the American Public Transit Association recommend
    the use of very similar matrices for analysis of rail systems? safety. See
    FTA?s State Safety Oversight, Issue 6 (Fall 1999).

    As was the case with the three other agencies covered by our review, some of
    the chemical risk assessments produced by or for DOT have begun using more
    sophisticated methods and models. For example, the Director of OHMT
    characterized the National Transportation Risk Assessment study

    prepared for OHMS by the Argonne National Laboratory as using state- ofthe-
    art risk assessment techniques to characterize risks associated with the
    transportation of selected hazardous materials on a national basis. The
    consequence assessments in this study employed the Chemical Accident
    Statistical Risk Assessment Model that predicts distributions of hazard

    zones (i. e., areas in which a threshold chemical concentration is exceeded)
    resulting from hazardous material release. 13 That model, in turn, reflected
    the input of other physical models on subjects such as hazardous material
    release rates of toxic- by- inhalation materials. The Director noted that
    his

    office believed this study to be the first comprehensive application of
    these techniques in this arena for this purpose. Risk Assessment

    Although generally very structured and criteria based, RSPA?s risk
    Assumptions and assessments for hazardous materials transportation also use
    assumptions. DOT- wide guidance documents provide a general framework for
    the use of Methodological assumptions. In general, DOT guidance recognizes
    that assumptions may Choices

    be made when data are lacking or uncertain, or when it is necessary to limit
    the scope of an analysis. However, the assumptions, while not empirically
    verifiable, are supposed to be reasonable, logically credible, and
    supportable in comparison with alternative assumptions. The DOT risk
    assessment methodology guidance specifically states that every assessment
    should include a list of the major assumptions, conditions, and limitations
    of the risk analysis, as well as the reasons why the assumptions

    were made. As noted earlier in this appendix, RSPA has access to a number of
    sources of directly relevant data and statistics on the transportation of
    hazardous materials. However, there are limitations to these systems and
    data. For example, the authors of the national transportation risk
    assessment for selected hazardous materials cautioned that the information
    in DOT?s data systems was not always sufficient or detailed enough to
    directly support a

    quantitative risk assessment. For example, incidents involving most 13
    Rather than specifying a deterministic measure of risk, this model
    determines the distribution of possible outcomes, allowing the probability
    of a particular consequence to be identified within the limits of the
    statistical data used.

    hazardous materials (other than gasoline- truck accidents) typically occur
    too infrequently to provide statistically reliable data for directly
    projecting future risks. In his introduction to the study, the Director of
    OHMT also

    stated that the quantitative results of this study should be used with
    caution. Specifically, he noted, ?While the model of the hazardous materials
    transportation system employed in this study is sophisticated, the accuracy
    of the data used in the model is often less precise. Estimates, assumptions,
    and aggregate numbers have been used in many cases.?

    Some of the topics that might require assumptions or choices during a
    hazardous materials transportation assessment include:

     the probability of the release of a hazardous material, depending on the
    nature of the accident, type of material being transported, and the
    containers used;

     the amount of material released in an accident, depending again on factors
    such as the severity of the accident, nature of the material, and type of
    container, but also depending on assumptions about the size of holes in
    containers;

     commodity flows of the materials (e. g., modes of transportation used,
    classes of rail tracks, types of highways, routing through urban and rural
    areas and related population density);

     the dispersion of released hazardous material, including assumptions about
    climate and meteorological conditions and the type of surface that a liquid
    might ?pool? on if spilled;

     the probability of a fire or explosion being ignited (both as a
    consequence of a release or as a cause of a release); and

     the extent to which humans potentially exposed to released materials would
    be sheltered or protected (both within a given mode of transportation, such
    as an aircraft, or external to the carrier).

    In addition to these topics, RSPA sometimes uses a factor to adjust data in
    the HMIS database to address underreporting. However, RSPA officials noted
    that, for certain purposes, it might be inappropriate to extrapolate

    information in the database. Although assumptions may be needed in RSPA
    assessments, RSPA officials said that they do not have default assumptions
    for their risk assessments. According to the officials, assumptions must be
    developed and described as part of each risk assessment and are specific to
    the risk assessment. RSPA officials also noted that they do not use ?safety
    factors? in risk assessments, but rather base their assessments on expected
    levels or

    ranges of performance. Therefore, unlike in the appendices on EPA, FDA, and
    OSHA, we have not included a table in this DOT appendix to identify major
    default choices, the reasons for their selection, when they would be used in
    the process, and their likely effects on risk assessment results. However,
    with regard to some of the case- specific assumptions or choices we
    identified during our review, we did observe that DOT?s assessments
    typically discussed the reasons for particular choices (as with the other
    agencies, often citing an interpretation of related research studies). In
    some instances, information was also provided on the likely effect (e. g.,
    that a particular value represented a conservative estimate or an upper
    limit) or level of uncertainty (e. g., that a particular parameter value
    might be high by a factor of 3 to 10 times the results from another study)

    associated with choices made by the analysts. Risk Characterization DOT has
    explicit, written principles regarding how the results of its risk or safety
    assessments should be presented. The department?s policies

    emphasize the principle of transparency and encourage agency personnel to
    not only characterize the range and distribution of risk assessment
    estimates, but also to put risk estimates into a context understandable by
    the general public. For example, DOT?s ?risk assessment principles? state
    that the risk assessment should:

     make available to the public data and analytic methodology on which the
    agency relied in order to permit interested entities to replicate and
    comment on the agency?s assessment;

     state explicitly the scientific basis for the significant assumptions,
    models, and inferences underlying the risk assessment, and explain the
    rationale for these judgments and their influence on the risk assessment;

     provide the range and distribution of risks for both the full population
    at risk and for highly exposed or sensitive subpopulations, and encompass
    all appropriate risks, such as acute and chronic risks, and cancer and
    noncancer risks, to health, safety, and the environment;

     place the nature and magnitude of risks being analyzed in context,
    including appropriate comparisons with other risks that are regulated by the
    agency as well as risks that are familiar to, and routinely encountered by,
    the general public, taking into account, for example, public attitudes with
    respect to voluntary versus involuntary risks, wellunderstood

    versus newly discovered risks, and reversible versus irreversible risks; and

     use peer review where there are issues with respect to which there is
    significant scientific dispute to ensure that the highest professional
    standards are maintained. The DOT risk assessment guidelines also state that
    every risk analysis should present information on (1) quantitative estimates
    of risk (over the entire range of plausible values of the developed
    variables, and with a ?base case? loss to provide a point of reference); (2)
    insights gained from performing the analysis into the factors that most
    affect risk assessment

    results; and (3) assumptions, conditions, and limitations of the analysis.
    With regard to the third item, the guidelines specifically state that
    reasons why the assumptions were made, and why the limitations of the
    analysis do not significantly impact the risk estimate, should be provided.
    The guidelines also suggest two methods for treating uncertainty in a risk
    analysis:

     sensitivity analysis (DOT?s preferred method for treating and reporting
    the impact of uncertainty), which should be conducted for each scenario in a
    risk analysis; and

     bounding analysis involving error propagation (requiring that each model
    parameter be expressed as a distribution, or at least a variance, to trace
    the implication of uncertainty for the risk estimate).

    Glossary Acceptable daily intake

    The maximum dose of a hazardous substance that can be consumed daily (ADI)

    without causing adverse health effects over a lifetime. Acute effect An
    effect that results from a brief exposure or shortly after an acute exposure
    (possibly at high levels) of duration measured in minutes, hours,

    or days. Additive dose- response

    A dose- response model in which the health effects attributable to exposure
    model to particular levels of two or more risk agents are equal to the sum
    of the responses predicted for each agent alone.

    Aggregate risk The risk resulting from the combined exposure of an
    individual or defined population to a single agent or stressor via all
    relevant routes, pathways, and sources.

    Ambient concentration The average amount of a substance in a particular
    environmental medium, such as air or water.

    Ambient water quality Numeric values limiting the amount of chemicals
    present in our nation?s

    criteria (AWQC) waters. Developed under section 304( a) of the Clean Water
    Act (CWA) and periodically updated, they are determined by assessing the
    relationship

    between pollutants and their effect on human health and the environment.
    These recommended criteria provide guidance for states and tribes in
    adopting water quality standards under section 303( c) of the CWA and to
    ultimately provide a basis for controlling discharges or releases of
    pollutants. Benchmark dose An exposure level that corresponds to a
    statistical lower bound on a

    standard probability of an effect, such as 10 percent of people affected.
    Bioaccumulation factor Bioaccumulation is a process whereby the
    concentration of certain (BAF) substances in organisms increases as the
    organisms breathe contaminated air, drink contaminated water, or eat
    contaminated food. The BAF is the

    ratio of a substances' concentration in an organism?s tissue to its
    concentration in the medium where the organism lives. BAFs measure a
    chemical's potential to accumulate in tissue through exposure to both food
    and water.

    Bioassay The use of living organisms to measure the effect of a risk agent
    or condition- for example, a test for carcinogenicity in laboratory animals
    that includes near- lifelong exposure to the agent under test. Used
    interchangeably with animal test.

    Biologically based dose A model that describes biological processes at the
    cellular and molecular

    response model level linking the target organ dose to the adverse effect.

    Cancer A group of diseases characterized by abnormal, disorderly, and
    potentially unlimited new tissue growth.

    Carcinogen Any chemical or physical agent possessing the ability to induce
    cancer in living organisms. Chronic health effects Diseases occurring as a
    result of repeated or persistent exposures. Chronic exposure An exposure
    (usually of low concentration) of long duration, e. g., months

    or years. Consequence The direct effect of an event, incident, or accident.
    It is expressed as a health effect (e. g., death, injury, exposure),
    property loss, environmental effect, evacuation, or quantity spilled.

    Contaminant( s) Chemicals, microorganisms, or radiation found in air, soil,
    water, or food that are not normally constituents of these environmental
    media.

    Cumulative risk The combined risk from aggregate exposures to multiple
    agents or stressors.

    Dose The amount of a substance available for interactions with metabolic
    processes or biologically significant receptors after crossing the outer
    boundary of an organism. A potential dose is the amount ingested, inhaled,
    or applied to the skin. An applied dose is the amount presented to an
    absorption barrier and available for absorption (although not necessarily
    having yet crossed the outer boundary of the organism). An

    absorbed dose is the amount crossing a specific absorption barrier (e. g.,
    the exchange boundaries of the skin, lung, and digestive tract) through
    uptake processes. An internal dose denotes the amount absorbed without
    respect to specific absorption barriers or exchange boundaries. A

    delivered or biologically effective dose is the amount of the chemical
    available for interaction by any particular organ or cell.

    Dose- response assessment The determination of the relationship between the
    magnitude of administered, applied, or internal dose and a specified
    biological response.

    Dose- response relationship The relationship between exposure level and the
    incidence of adverse effects. Ecological risk assessment A process used to
    estimate the likelihood of adverse effects on plants or animals from
    exposure to stressors, such as chemicals or the draining of wetlands. The
    process includes problem formulation, characterization of exposure,
    characterization of ecological effects, and risk characterization.

    Effluent Treated or untreated waste material discharged into the
    environment. Generally refers to wastes discharged to surface waters.
    Emission Pollution discharged into the atmosphere from smokestacks, other
    vents,

    and surface areas of commercial or industrial facilities; residential
    chimneys; and motor vehicle, locomotive, or aircraft exhausts.

    Environmental fate The distribution and transformation of a chemical from
    its first release until its ultimate removal from or recycling through the
    environment.

    Epidemiology The study of diseases as they affect populations, including the
    distribution of disease, or other health- related states and events in human
    population;

    the factors (e. g., age, sex, occupation, economic status) that influence
    this distribution; and the application of this study to assess and control
    health risk. It involves investigating the causes and risk factors of
    disease and

    injury in populations and the potential to reduce such disease burdens.
    Exposure Contact of a chemical, physical, or biological agent with the outer
    boundary of an organism. Exposure is quantified as the concentration of the
    agent in the medium over time.

    Exposure assessment The process of developing a description of the relevant
    conditions and characteristics of human and other exposures to risk agents
    produced or released by a specified source of risk. This usually involves
    the determination or estimation of the magnitude, frequency, duration, and
    route of exposure.

    Exposure pathway( s) The physical course or means by which risk agents are
    transmitted- e. g., the route by which a given population, individual,
    species, or setting is exposed to a toxic substance (e. g., via drinking
    water, air, or dermal

    contact). Exposure route The way an environmental agent enters an organism
    (e. g., ingestion,

    inhalation, or dermal absorption). Extrapolation Prediction of the value of
    a variable outside the range of observation. This involves making inferences
    about the unknown by projecting or extending

    known information, using models and assumptions. Genotoxic Capable of
    causing heritable changes or damage leading to heritable changes in genetic
    material (i. e., altering the structure of DNA). A

    genotoxic carcinogen is one that initiates cancer through a direct effect on
    genetic material.

    Hazard A (potential) source of risk that does not necessarily produce risk.
    A hazard is the inherent characteristic of a material, condition, or
    activity that has the potential to cause harm to people, property, or the
    environment and

    produces risk only if an exposure pathway exists and if exposures create the
    possibility of adverse consequences. Hazard analysis The identification of
    material properties, system elements, or events that lead to harm or loss.
    The term hazard analysis may also include evaluation of consequences from an
    event or incident. Incidence The rate at which an event occurs. In
    toxicology, the number of new cases

    of a disease within a specified period of time, often expressed per 100,000
    individuals per year. Interspecies extrapolation The act of applying a set
    of data or an individual test result from one

    species, under certain conditions and subject to particular dose levels of a
    toxic substance and application method, to another population of a different
    species under perhaps different conditions, dose levels, and application
    method.

    LC 50 The concentration of a substance in air that when administered by
    inhalation to all animals in a test (over a specified time period) is lethal
    to 50 percent of the animals. LD 50 The dose that when administered to all
    animals in a test (over a specified

    time period) is lethal to 50 percent of the animals. Likelihood Expressed as
    either a frequency or a probability. Frequency is a measure of the rate at
    which events occur over time (e. g., events per year, incidents per year,
    deaths per year). Probability is a measure of the rate of a possible

    event expressed as a fraction of the total number of events (e. g. 1/
    1,000,000).

    Lowest effective dose (LED) The lowest dose of a chemical that produced a
    specified level of an adverse effect when it was administered to animals in
    a toxicity study. For

    example, the LED 10 is the lowest effective dose that produced an effect in
    10 percent of the exposed animals. Lowest observed adverse

    The lowest exposure at which there is a statistically or biologically effect
    level (LOAEL)

    significant increase in the frequency of an adverse effect when compared
    with a control group.

    Margin of exposure A ratio defined by EPA as a dose derived from a tumor
    bioassay, epidemiologic study, or biologic marker study, such as the dose
    associated

    with a 10- percent response rate, divided by an actual or projected human
    exposure.

    Mechanism of action/ mode The mechanism of action is the complete sequence
    of biological events of action

    that must occur to produce the toxic effect. The mode of action is a
    lessdetailed description of the mechanism of action in which some but not
    all of the sequence of biological events leading to a toxic effect is known.

    Monte Carlo analysis The computation of a probability distribution over
    consequences by means of a random sampling method analogous to the game of
    roulette. Combinations of events and outcomes that yield possible
    consequences are randomly selected according to a specified probability
    distribution. The resulting consequences are counted and used to estimate
    other probability distributions.

    Multistage models Dose- response models that assume a given number of
    biological stages occur following exposure to a risk agent (e. g.,
    metabolism, covalent

    binding, DNA repair) before manifestation of the effect in question is
    possible.

    Mutagen Any substance that can cause a change in genetic material. Mutagens
    have the ability to induce adverse, heritable changes in the genetic
    material of

    living organisms. No observed adverse effects

    The highest dose at which there is no statistically or biologically
    significant level (NOAEL) increase in the frequency of an adverse effect
    when compared with a control group. No observed effects level The highest
    dose at which there is no statistically or biologically significant (NOEL)
    increase in the frequency of any effect, adverse or not, compared with a

    control group. Order of magnitude An expression often used in reference to
    calculations of environmental quantities of risk. Order of magnitude means a
    factor of 10. For example,

    20 (2 x 10) is 1 order of magnitude greater than 2; 200 (2 x 10 x 10) is 2
    orders of magnitude greater than 2; and so forth.

    Permissible exposure limit PELs are time- weighted average (TWA) air
    concentrations that must not be (PEL) exceeded during any 8- hour work shift
    of a 40- hour workweek as defined by OSHA.

    Pharmacokinetics Study of the absorption, distribution, metabolism, and
    excretion of chemicals and the genetic, nutritional, behavioral, and
    environmental factors that modify these parameters.

    Pharmacokinetic models Dose- response models based on the principle that
    biological effects are the result of biochemical interaction between foreign
    substances or metabolites and parts of the body.

    Physiologically based A model that estimates the dose to a target tissue or
    organ by taking into pharmacokinetic (PBPK)

    account the rate of absorption into the body, distribution among target
    model organs and tissues, metabolism, and excretion.

    Probabilistic approaches Evaluating a range of possible risk estimates and
    their likelihood, tied to various mathematical models of the likely
    distribution of potential values, instead of relying on single numbers or
    point estimates.

    Reference concentration A reference concentration is an estimate of a
    continuous inhalation

    (RfC)/ reference dose (RfD) exposure to the human population (including
    sensitive subgroups) that is likely to be without an appreciable risk of
    deleterious noncancer effects during a lifetime. EPA uses a reference dose
    to express a conservative threshold value for a dose- response relationship
    for noncarcinogenic effects. It is an estimate of a daily dose to the human
    population (including

    sensitive subgroups) that is likely to be without an appreciable risk of
    deleterious noncancer effects during a lifetime. Residual risk The health
    risk remaining after risk- reduction actions are implemented, such as risks
    associated with sources of air pollution that remain after the
    implementation of maximum achievable control technology. Risk The
    probability that a substance or situation will produce harm under

    specified conditions. Risk is a combination of two factors: the probability
    that an adverse event will occur and the consequences of its occurrence (e.
    g., a specific disease or type of injury).

    Risk assessment The systematic, scientific description of potential adverse
    effects of exposures to hazardous agents or activities. According to NAS, it
    involves the four steps of hazard identification, dose- response assessment,
    exposure assessment, and risk characterization. The product of the risk
    assessment is a statement regarding the probability that populations,
    individuals, or environmental entities so exposed will be harmed and to what
    degree.

    Risk characterization The process of organizing, evaluating, and
    communicating information about the nature, strength of evidence, and the
    likelihood of adverse health or ecological effects from particular
    exposures.

    Risk management The process of analyzing, selecting, implementing, and
    evaluating actions to reduce risk.

    Screening risk assessment A risk assessment performed using few data and
    many assumptions to identify exposures that should be evaluated more
    carefully for their

    potential risks. Sensitivity analysis A method used to examine the behavior
    of a model by systematically measuring the deviation in its outputs produced
    as each input, parameter, or assumption is varied from its nominal or base-
    case value.

    Synergistic effects A term used to describe when the combined biological
    effects of two risk agents are greater than the sum of the effects of each
    agent acting alone.

    Target organ The specific organ affected by a dose of a toxic substance,
    which is not necessarily the organ receiving the highest concentration.

    Threshold The level of exposure above which adverse health effects are
    thought to occur, and below which no adverse effect is thought to occur.

    Threshold dose Minimum application of a given risk agent required to produce
    a measurable response.

    Threshold effect An effect for which there is some dose below which the
    probability of an individual's responding is zero. Tiered approach A series
    of assessments of increasing complexity. Toxicity A measure of the degree of
    harm caused by a specified exposure of human,

    animal, or plant life to a chemical substance.

    Toxicokinetics The mechanism by which chemical or physical change causes
    toxic effects. Toxicology The study of adverse effects of chemicals on
    living organisms. Tumor Any abnormal growth of tissue in which growth is
    uncontrolled and

    progressive. Uncertainty factor One of several factors used to calculate an
    exposure level that will not

    cause toxicity from experimental data. Uncertainty factors are used to
    account for the variation in susceptibility among humans, the uncertainty in
    extrapolating from experimental animal data to humans, the uncertainty in
    extrapolating from data from studies in which agents are given for less than
    a lifetime, and other uncertainties such as using LOAEL data instead

    of NOAEL data. Variability A population's natural heterogeneity or
    diversity, particularly that which contributes to differences in exposure
    levels or in susceptibility to the

    effects of chemical exposures.

    (410543) Lett er

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    Appendix I

    Appendix I Objectives, Scope, and Methodology

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    Appendix I Objectives, Scope, and Methodology

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    Appendix I Objectives, Scope, and Methodology

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    Appendix I Objectives, Scope, and Methodology

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    Appendix II

    Appendix II Chemical Risk Assessment at the Environmental Protection Agency

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    Appendix II Chemical Risk Assessment at the Environmental Protection Agency

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    Appendix II Chemical Risk Assessment at the Environmental Protection Agency

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    Appendix II Chemical Risk Assessment at the Environmental Protection Agency

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    Appendix II Chemical Risk Assessment at the Environmental Protection Agency

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    Appendix II Chemical Risk Assessment at the Environmental Protection Agency

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    Appendix III

    Appendix III Chemical Risk Assessment at the Food and Drug Administration

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    Appendix III Chemical Risk Assessment at the Food and Drug Administration

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    Appendix III Chemical Risk Assessment at the Food and Drug Administration

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    Appendix III Chemical Risk Assessment at the Food and Drug Administration

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    Appendix III Chemical Risk Assessment at the Food and Drug Administration

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    Appendix III Chemical Risk Assessment at the Food and Drug Administration

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    Appendix IV

    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Administration

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    Appendix IV Chemical Risk Assessment at the Occupational Safety and Health
    Administration

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    Administration

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    Administration

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    Administration

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    Administration

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    Administration

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    Administration

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    Appendix V

    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special Programs Administration

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

    Programs Administration Page 203 GAO- 01- 810 Chemical Risk Assessment

    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

    Programs Administration Page 204 GAO- 01- 810 Chemical Risk Assessment

    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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    Appendix V Chemical Risk Assessment at the Department of Transportation?s
    Research and Special

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