Appendix D
Environmental Protection Agency Response to Recommendations from Selected NRC Reports: Policy, Activity, and Practice

Table D-1 was developed as an information resource to illustrate the kinds of policies and activities that the Environmental Protection Agency (EPA) has undertaken in response to previous National Research Council recommendations (NRC 1983, 1994, 1996) for the list of bulleted topics presented below. This is not a comprehensive review. Rather, it presents representative recommendations from these key National Research Council reports, beginning with the so-called Red Book; related EPA policies as reflected in guidance documents and other materials; and related implementation activities, along with an assessment of some of these guidance documents and implementation activities as summarized in a 2006 report from the Government Accountability Office (GAO).

Many of the individual National Research Council reports and EPA documents address the risk-assessment issues below repeatedly and with some variations in a single report. As a result, passages quoted or summarized in the table are highly selected “snapshots” and are not the only examples for the indicated topic in a given report. In addition, the “response” to recommendations in the table is considered somewhat loosely, as it simply considers whether EPA addressed the issue at some point in time. For a full picture on any topic of interest, the committee advises readers to begin with pages cited in the table and to look beyond those citations for related information. Note also that several National Research Council recommendations and EPA policy statements cover multiple topics (such as both “risk characterization” and “uncertainty” or both “models” and “defaults”). Several issues are therefore discussed under several topic headings.1,2

1

Empty cells indicate only that the committee could not easily identify and isolate a representative quotation, not that related policies or implementation activities do not exist.

2

As explained in Chapter 2, the report cited as “NRC 1994” (Science and Judgment in Risk Assessment) gave special attention to issues arising under the Clean Air Act Amendments of 1990, and many of the recommendations in that report focused on air issues. A recommendation directed mainly to the air program is designated by “(Directed to Air Program).” Similarly, a recommendation directed mainly to the IRIS program is designated by “(Directed to IRIS Program).”



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Appendix D Environmental Protection Agency Response to Recommendations from Selected NRC Reports: Policy, Activity, and Practice Table D-1 was developed as an information resource to illustrate the kinds of policies and activities that the Environmental Protection Agency (EPA) has undertaken in response to previous National Research Council recommendations (NRC 1983, 1994, 1996) for the list of bulleted topics presented below. This is not a comprehensie reiew. Rather, it presents representative recommendations from these key National Research Council reports, begin- ning with the so-called Red Book; related EPA policies as reflected in guidance documents and other materials; and related implementation activities, along with an assessment of some of these guidance documents and implementation activities as summarized in a 2006 report from the Government Accountability Office (GAO). Many of the individual National Research Council reports and EPA documents address the risk-assessment issues below repeatedly and with some variations in a single report. As a result, passages quoted or summarized in the table are highly selected “snapshots” and are not the only examples for the indicated topic in a given report. In addition, the “response” to recommendations in the table is considered somewhat loosely, as it simply considers whether EPA addressed the issue at some point in time. For a full picture on any topic of interest, the committee advises readers to begin with pages cited in the table and to look beyond those citations for related information. Note also that several National Research Council recommendations and EPA policy statements cover multiple topics (such as both “risk characterization” and “uncertainty” or both “models” and “defaults”). Several issues are therefore discussed under several topic headings.1,2 1 Empty cells indicate only that the committee could not easily identify and isolate a representative quotation, not that related policies or implementation activities do not exist. 2 As explained in Chapter 2, the report cited as “NRC 1994” (Science and Judgment in Risk Assessment) gave special attention to issues arising under the Clean Air Act Amendments of 1990, and many of the recommenda- tions in that report focused on air issues. A recommendation directed mainly to the air program is designated by “(Directed to Air Program).” Similarly, a recommendation directed mainly to the IRIS program is designated by “(Directed to IRIS Program).” 2

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300 SCIENCE AND DECISIONS: ADVANCING RISK ASSESSMENT • Aggregate and Cumulative Risk • Default Assumptions and Options • Distinguishing and Linking Risk Assessment and Risk Management • Distinguishing Science and Science Policy • Exposure Assessment (and Methods Validation) • Health-Risk and Toxicity Assessment for Cancer and Other End Points • Inference Guidelines • Interagency and Outside Collaboration • Iterative Approach to Risk Assessment • Models and Model Validation • Peer Review and Expert Panels • Priority-Setting and Data-Needs Management • Problem Formulation and Ecologic Risk Assessment • Public Review and Comment; Public Participation • Risk Characterization • Risk Communication in Relation to Risk Management • Uncertainty Analysis and Characterization • Variability and Differential Susceptibility

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TAbLE D-1 Environmental Protection Agency Response to National Research Council Recommendations of 1983-2006: Policy, Activity, and Practice Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc Aggregate and NRC 1994 at 240: “EPA should consider EPA 1997a Science Policy Council EPA 2003a: Human Health Research Cumulative Risk using appropriate statistical (e.g., Monte Memorandum: “This guidance directs each Strategy at E-2: “ORD’s research program on Carlo) procedures to aggregate cancer risks office to take into account cumulative risk aggregate and cumulative risk will address from exposure to multiple compounds.” issues in scoping and planning major risk the fact that humans are exposed to mixtures assessments and to consider a broader of pollutants from multiple sources. Research scope that integrates multiple sources, will provide the scientific support for effects, pathways, stressors and populations decisions concerning exposure to a pollutant for cumulative risk analyses in all cases for by multiple routes of exposure or to multiple which relevant data are available.” pollutants having a similar mode of action. ORD will also develop approaches to study EPA1997b Cumulative Risk Assessment how people and communities are affected guidance: “Agency managers need to following exposure to multiple pollutants place special emphasis on cumulative that may interact with other environmental risk (that is, the potential risks presented stressors.” by multiple stressors in aggregate). The specific elements of risk evaluated need Also: The research strategy identified the to be determined as an explicit part of following research objectives related to the Planning and Scoping (PS) stage of cumulative risk: “(1) Determine the best and each risk assessment. . . . The Agency most cost effective ways to measure human will support research to improve our exposures in all relevant media, including understanding of cumulative risks and pathway-specific measures of multimedia to develop methods to account for the human exposures to environmental multiple elements of risks that affect contaminants across a variety of relevant humans, animals, plants and their microenvironments and exposure durations environment. In addition, the Science and conditions; (2) Develop exposure models Policy Council will support workshops and methods suitable for EPA and the for risk assessors and managers to public to assess aggregate and cumulative discuss implementation opportunities and risk, including mathematical and statistical problems, and solutions.” relationships among sources of environmental contaminants, their environmental fate, and EPA 2000a Supplementary guidance for pathway specific concentrations; models Conducting Health Risk Assessment of linking dose and exposure from biomarker Chemical Mixtures at xiv: This guidance data; and approaches to assess population- updates the 1986 agencywide guidance on based cumulative risk, including those chemical mixtures and “describes more involving exposure to stressors other than 301 continued

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TAbLE D-1 Continued 302 Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc detailed procedures for chemical mixture pollutants; and (3) Provide the scientific basis assessment using data on the mixture to predict the interactive effects of pollutants of concern, data on a toxicologically in mixtures and the most appropriate similar mixture, and data on the mixture approaches for combining effects and risks component chemicals. [It] is organized from pollutant mixtures.” according to the type of data available to the risk assessor, ranging from data rich gAO 2006 at 50: “The extent to which to data poor situations. . . . An evaluation program offices assess the effects of of the data may lead the user to decide cumulative and aggregate exposures is that only a qualitative analysis should be related to the regulatory responsibilities of performed. This generally occurs in cases each office and by the availability of data. where data quality is poor, inadequate For example, the hazardous air pollutant quantitative data are available, data on office routinely analyzes a mix of chemicals a similar mixture cannot be classified as from various emitting sources, such as “sufficiently similar” to the mixture of petroleum refineries, to regulate hazardous concern, exposures cannot be characterized air pollutants. Similarly, as mentioned above, with confidence, or method-specific the Office of Pesticide Programs is required to assumptions about the toxicologic action consider exposure to pesticides from various of the mixture or of its components cannot pathways, such as food, drinking water, and be met. When this occurs, the risk assessor residential uses, and various routes, such as can still perform a qualitative assessment eating, breathing, and contact with skin.” that characterizes the potential human health impacts from exposure to that Note: The Toxic Substances Control Act mixture.” does not require the Office of Pollution Prevention and Toxics to assess the risks EPA 2003b Framework for Cumulative of a new chemical that may occur through Risk Assessment at xvii: “a simple, flexible its interaction with other chemicals. The structure for conducting and evaluating office also assesses the risks of existing cumulative risk assessment within the chemicals but cannot conduct cumulative risk EPA. . . . The framework describes assessment for classes of chemical that share three main phases to a cumulative risk a common mode of action because no data assessment: (1) planning, scoping, and exist. problem formulation, (2) analysis, and (3) risk characterization…Research and gAO 2006 at 49: “The branch of the Office development needs are also discussed, of Air Quality Planning and Standards that including understanding the timing of regulates hazardous air pollutants employs exposure and its relationship to effects; the Multiple Pathways of Exposure model to

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understanding the composition and toxicity assess and predict the movement and behavior of mixtures; applying the risk factor of chemicals in the environment. [It] includes approach; using biomarkers; considering procedures to estimate human exposures and hazards presented by nonchemical stressors; health risks that result from the transfer of methods for combining different types of pollutants from the air to soil and surface risk; and development of default values water bodies and the subsequent uptake of for cumulative risk assessments, among the pollutant by plants, animals, and humans. others.” The model specifically addresses exposures from breathing; consuming food, water, and EPA 2001 and 2002: general Principles for soil; and contact with skin.” Performing Aggregate Exposure and Risk Assessments: This document “focus[es] gAO 2006 at 49: EPA developed the Total on describing principles to guide the way Risk Integrated Methodology (TRIM) and in which aggregate exposure and risk created the TRIM Fate, Transport, and assessment may be performed when more Ecological Exposure model that describes extensive distributional data and more the movement of air pollutants emitted from sophisticated exposure assessment, methods any type of stationary source as well as their and tools are available. . . . [The guidance] transformation over time in water, air and looks beyond the Interim Guidance to soil. encompass the use of distributional data for all pathways of exposure when data are available. A distributional data analysis (as opposed to a point estimate approach) is preferred because this tool allows an aggregate exposure assessor to more fully evaluate exposure and resulting risk across the entire population, not just the exposure of a single, high-end individual.” (EPA 2001, p. 4) The 2002 guidance (EPA 2002a, p. ii) “provides guidance to OPP scientists for evaluating and estimating the potential human risks associated with such multichemical and multipathway exposures to pesticides.” 64 Fed. Reg. 38705[1999]: The Integrated Urban Air Toxics Strategy includes guidance on assessing cumulative risks on both the national and the urban- 303 continued

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TAbLE D-1 Continued 304 Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc neighborhood scales. It provides “an overview of EPA’s national effort to reduce air toxics, including stationary and mobile source standards, cumulative risk initiatives, assessment approaches, and education and outreach.” The “national air toxics program includes activities under multiple Clean Air Act (Act) authorities to reduce air toxics emissions from all sources, including major industrial sources, smaller stationary sources, and mobile sources such as cars and trucks. By integrating activities under different parts of the Act, EPA can better address cumulative public health risks and adverse environmental impacts posed by exposures to multiple air toxics in areas where the emissions and risks are most significant.” EPA 2004a: Air Toxics Risk Assessment Reference Library at 14-1: The guidance states that “multipathway risk assessment may be appropriate generally when air toxics that persist and which also may bioaccumulate and/or biomagnify are present in releases. These generally will focus on the persistent bioaccumulative hazardous air pollutant (PB-HAP) compounds (Exhibit 14-1), but specific risk assessments may need to consider additional chemicals that persist and which also may bioaccumulate and/or biomagnify. For these compounds, the risk assessment generally will need to consider exposure pathways other than inhalation—in particular, pathways that involve deposition of air toxics onto soil and plants and

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into water, subsequent uptake by biota, and potential human exposures via consumption of contaminated soils, surface waters, and foods. Substances that persist and bioaccumulate readily transfer between the air, water, and land. Some may travel great distances, and linger for long periods of time in the environment.” The guidance provides information on planning, scoping, problem formulation, data analysis, and risk characterization. EPA 2002a guidance on cumulative risk assessment of pesticide chemicals that have a common mechanism of toxicity: Provides “guidance to OPP scientists for evaluating and estimating the potential human risks associated with such multichemical and multipathway exposures to pesticides. . .” (p. ii). “Cumulative risk assessments may play a significant role in the evaluation of risks posed by pesticides, and will enable OPP to make regulatory decisions that more fully protect public health and sensitive subpopulations, including infants and children. . . . The purpose of this guidance is to set forth the basic assumptions, principles, and analytical framework that are recommended for use by OPP risk assessors in conducting cumulative risk assessments. It is also intended to inform decision makers and the public of the principles and procedures generally followed in the conduct of cumulative risk assessments on pesticide chemicals” (p. 7). 30 continued

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TAbLE D-1 Continued 306 Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc Default NRC 1994 at 8: “EPA should continue EPA 2005a Carcinogen Risk Assessment gAO 2006 at 41: “To a large degree, the use Assumptions to regard the use of default options as a guidelines, Appendix A (71 FR 17809-12): of defaults is intertwined with EPA’s ability and Options reasonable way to deal with uncertainty The guideline “covers [five] major default to get the data it needs. As was discussed (see also Risk about underlying mechanisms in selecting options commonly employed when data previously, EPA has targeted research, both Characterization, methods and models for use in risk are missing or sufficiently uncertain in a within EPA and through its grant programs, Models, assessment.” cancer risk assessment. . . . These options to understand variability and uncertainty in Uncertainty are predominantly inferences that can help the data derived from studies of laboratory Analysis) use the data observed under empirical animals, and this research may further reduce conditions in order to estimate events and EPA’s need to rely on default options.” outcomes under environmental conditions.” NRC 1994 at 8: “EPA should explicitly EPA 2004b at 51: “EPA’s current gAO 2006 at 40: “The majority of IRIS identify each use of a default option in risk practice is to examine all relevant and assessments completed since 1997 describe assessments.” available data first when performing a the defaults used in the analysis and any risk assessment. When the chemical- and/ departures from those defaults. NRC 1994 at 8: “EPA should clearly state or site-specific data are unavailable (i.e., the scientific and policy basis for each when there are data gaps) or insufficient to “Despite the increased focus on more default option.” estimate parameters or resolve paradigms, transparency in the use of defaults, EPA EPA uses a default assumption in order to acknowledges it could more consistently continue with the risk assessment. Under describe how the default was developed and this practice EPA invokes defaults only explain why it is a reasonable assumption. after the data are determined to be not In its staff paper, EPA acknowledges it needs usable at that point in the assessment—this to ensure that the defaults are supported is a different approach from choosing by the best available data and should look defaults first and then using data to depart for opportunities to increase certainty and from them. The default assumptions confidence in the defaults and extrapolations are not chemical- or site-specific, but used.” are relevant to the data gap in the risk assessment. They are based on peer EPA 2004a: The Office of Air Quality reviewed studies and extrapolation to Planning and Standard’s Air Toxics Risk address specific data gaps. These defaults Assessment Reference Library (EPA 2004a) are based on published studies, empirical discusses defaults that should be used when observations, extrapolation from related preparing risk assessments. This is discussed, observations, and/or scientific theory.” for example, when conducting screening analyses: “For complete or potential exposure EPA 1996 Proposed Carcinogen Risk pathways identified in the exposure pathway Assessment guidelines at 61 FR 18000: evaluation, the screening analysis may involve

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Risk characterization includes “risk comparing media concentrations at points estimates and their attendant uncertainties, of exposure to ‘screening’ values (based on including key uses of default assumptions protective default exposure assumptions) when data are missing or uncertain.” and estimating exposure doses based on study area-specific exposure conditions. The Also at 17966-17970ff: Explaining the assessor then compares estimated doses with scientific and policy bases of five “major” health-based guidelines to identify substances default options. requiring further evaluation.” Also at 17964ff: “Pursuant to [the National Research Council recommendation related to criteria for departure from defaults] the following discussion presents . . . general policy guidance on using and departing from defaults in specific risk assessments.” NRC 1994 at 8: “The agency should EPA 2005a Carcinogen Risk Assessment consider attempting to give greater guidelines at 71 FR 17770ff: “Rather than formality to its criteria for a departure viewing default options as starting points from default options, in order to give from which departures may be justified by greater guidance to the public and to lessen new scientific information, these cancer the possibility of ad hoc, undocumented guidelines iew a critical analysis of all of departures from default options that the aailable information that is releant would undercut the scientific credibility to assessing the carcinogenic risk as the of the agency’s risk assessments. At the starting point from which a default option same time, the agency should be aware of may be inoked if needed to address the undesirability of having its guidelines uncertainty or the absence of critical evolve into inflexible rules.” information [emphasis in original].” Also Appendix A at 17809ff: Discusses default options and alternative approaches. EPA 2000b Risk Characterization Handbook at 21: Directs risk assessors to “describe the uncertainties inherent in the risk assessment and the default positions used to address these uncertainties or gaps in the assessment.” 30 continued

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TAbLE D-1 Continued 308 Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc Also at 41: “Risk assessors should carefully consider all available data before deciding to rely on default assumptions. If defaults are used, the risk assessment should reference the Agency guidance that explains the default assumptions or values.” NRC 1994 at 186: “EPA sometimes EPA 2005a Carcinogen Risk Assessment Note: Although both the 1996 and 2005 attempts to ‘harmonize’ risk-assessment guidelines at 70 FR 17808: “Important guidelines refer to the scaling-factor issue (at procedures between itself and other features [of the risk characterization] 61 FR 17968 and 71 FR 17796, respectively), agencies, or among its own programs, include the constraints of available data it is not clear whether EPA has addressed by agreeing on a single common model and the state of knowledge, significant interagency harmonization to the extent assumption, even though the assumption scientific issues, an significant science and recommended. chosen might have little more scientific science policy choices that were made plausibility than alternatives (e.g., replacing when alternative interpretation of data FDA’s body-weight assumption and EPA’s exist [citations omitted]. Choices made surface-area assumption with body weight about using data or default options in the to the 0.75 power). . . . Rather than assessment are explicitly discussed in the ‘harmonizing’ risk assessments by picking course of the analysis, and if a choice is one assumption over others when several a significant issue, it is highlighted in the assumptions are plausible and none of summary.” the assumptions is clearly preferable, EPA should maintain its own default assumption for regulatory decisions but indicate that any of the methods might be accurate and present the results as an uncertainty in the risk estimate or present multiple estimates and state the uncertainty in each. However, ‘harmonization’ does serve an important purpose in the context of uncertainty analysis—it will help, rather than hinder, risk assessment if agencies cooperate to choose and validate a common set of uncertainty distributions.”

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NRC 1994 at 241: “EPA’s guidelines EPA 2005a Carcinogen Risk Assessment should clearly state a default option guidelines at 70 FR 17811: “The linear of nonthreshold low-dose linearity for approach is used when a view of the mode genetic effects on which adequate data of action indicates a linear response, for (e.g., data on chromosomal aberrations example, when a conclusion is made that or dominant or X-linked mutations) an agent directly causes alterations in might exist. This default option allows a DNA, a kind of interaction that not only reasonable quantitative estimate of, for theoretically requires one reaction but example, first-generation genetic risk due also is likely to be additive to ongoing, to environmental chemical exposure.” spontaneous gene mutation.” Distinguishing NRC 1983 at 7: “Regulatory agencies EPA 1984 at 3: “Scientists assess a risk Administrators William Ruckelshaus and Lee Linking Risk should take steps to establish and maintain to find out what the problems are. The Thomas mandated and funded a series of Assessment a clear conceptual distinction between process of deciding what to do about the training programs for (1) the entire SES corps and Risk assessment of risks and the consideration problems is ‘risk management.’ . . . The and other senior management and (2) agency Management of risk management alternatives; that is, distinction between the two activities staff in all program and regional offices. The (see also the scientific findings and policy judgments has become an attractive means for training materials were based in materials Problem embodied in risk assessments should be understanding and improving upon the developed initially by Bernard Goldstein and Formulation) explicitly distinguished from the political, two fundamental processes involved in Jack Moore. There was a heavy financial economic, and technical considerations environmental decision-making.” investment in the program, which ran for that influence the design and choice of about 5 y (approximately 1987-1992), with regulatory strategies.” EPA 1984 at 30: “First, we want to obtain remnants and updates continuing sporadically a better and more consistent information even today. NRC 1983 at 49: “Two kinds of policy base for making decisions about the can potentially affect risk assessment: that control of risk. Second, we want to use the which is inherent in the assessment process various analytic methods associated with itself and that which governs the selection risk management whenever appropriate in of regulatory options. The latter, risk developing environmental policy; we also management policy, should not be allowed want to place more emphasis on figuring to control the former, risk-assessment out what we have achieved in terms of policy.” risk reduction through past efforts and on locating and efficiently managing the serious risks remaining. Third, we must communicate to the public what we are doing, why we are doing it in risk management terms, and how the risk management approach will improve the way that EPA carries out its mission.” EPA 1986 guidelines for Carcinogen Risk 30 Assessment at 51 FR 33993: “Regulatory continued

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TAbLE D-1 Continued 36 Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc in a risk assessment be reported in a EPA 2000b Risk Characterization written risk-assessment document.” Handbook at A-3: “Key scientific concepts, data and methods (e.g., use of animal or human data for extrapolating from high to low doses, use of pharmacokinetics data, exposure pathways, sampling methods, availability of chemical-specific information, quality of data) should be discussed. To ensure transparency, risk characterizations should include a statement of confidence in the assessment that identifies all major uncertainties along with comment on their influence on the assessment, consistent with the Guidance on Risk Characterization.” (See “Risk Characterization” section above for other relevant policy statements in EPA risk-assessment guidelines and other sources.) NRC 1994 at 12: “EPA should conduct EPA 1997c guiding Principles for Monte formal uncertainty analyses, which can Carlo Analysis at 1: “Such probabilistic show where additional research might analysis techniques as Monte Carlo resolve major uncertainties and where it analysis, given adequate supporting data might not.” and credible assumptions, can be viable statistical tools for analyzing variability NRC 1994 at 12: “EPA should consider in and uncertainty in risk assessments and its risk assessments the limits of scientific presents an initial set of principles to guide knowledge, the remaining uncertainties, the agency in using probabilistic analysis and the desire to identify errors of either tools.” overestimation or underestimation.” NRC 1994 at 12: “Despite the advantages EPA 1996 Proposed guidelines on EPA did not adopt this recommendation in of developing consistent risk assessments Carcinogen Risk Assessment at 125: “The the 1996 guidelines. between agencies by using common rationale for adopting the oral scaling assumptions (e.g., replacing surface area factor of body weight to the 0.75 power

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with body weight to the 0.75 power), EPA has been discussed above in the explanation should indicate other methods, if any, that of major defaults. The empirical basis might be more accurate.” is further explored in Federal Register 57(109): 24152 [1992]. The more accurate approach is to use a toxicokinetic model when data become available or to modify the default when data are available as encouraged under these guidelines. As the EPA [57 Fed. Reg. 24152 [1992] discussion explores in depth, data on the differences among animals in response to toxic agents are basically consistent with using a power of 1.0, 0.75, or 0.66. The Federal agencies chose the power of 0.75 for the scientific reasons given in the previous discussion of major defaults; these were not addressed specifically in the NRC report. It was also considered appropriate, as a matter of policy, for the agencies to agree on one factor. Again, the default for inhalation exposure is a model that is constructed to become better as more agent-specific data become available.” NRC 1994 at 12: “When ranking risks, EPA 2004b at 16: “Since uncertainty and EPA should consider the uncertainties in variability are present in risk assessments, each estimate, rather than ranking solely EPA usually incorporates a ‘high-end’ on the basis of point estimate value. Risk hazard and/or exposure level in order to managers should not be given only a single ensure an adequate margin of safety for number or range of numbers. Rather, they most of the potentially exposed, susceptible should be given risk characterizations that population, or ecosystem. EPA’s high- are as robust (i.e., complete and accurate) end levels are around 90% and above—a as can be feasibly developed.” reasonable approach that is consistent with the NRC discussion (NRC 1994). This policy choice is consistent with EPA’s legislative mandates (e.g., adequate margin of safety). Even with a high-end value, there will be exposed people or environments at greater risk and at lower 3 risk. In addition to the high-end values, continued

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TAbLE D-1 Continued 38 Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc EPA programs typically estimate central tendency values for risk managers to evaluate. This provides a reasonable sense of the range of risk that usually lies on the actual distribution.” NRC 1994 at 242: “The distinction EPA 2000b Risk Characterization between uncertainty and individual Handbook at 40: “The risk assessor should variability ought to be maintained strive to distinguish between variability rigorously at the level of separate risk- and uncertainty to the extent possible assessment components (e.g., ambient (see 3.2.8 for a discussion of uncertainty). concentration, uptake, and potency) as variability arises from true heterogeneity well as at the level of an integrated risk in characteristics such as dose-response characterization.” differences within a population, or differences in contaminant levels in the environment. The values of some variables used in an assessment change with time and space, or across the population whose exposure is being estimated. Assessments should address the resulting variability in doses received by members of the target population. Individual exposure, dose, and risk can vary widely in a large population. Central tendency and high end individual risk descriptors capture the variability in exposure, lifestyles, and other factors that lead to a distribution of risk across a population (e.g., see Guidelines for Exposure Assessment).” variability and NRC 1994 at 11: “Federal agencies EPA 1997d Exposure Factors Handbook: gAO 2006 at 47: “Another way EPA Differential should sponsor molecular, epidemiological, Risk assessors have used the Exposure addresses variability is through research. One Susceptibility and other types of research to examine Factors Handbook to account for variation of ORD’s four strategic research directions the causes and extent of interindividual in exposure. The purposes of the handbook in its Human Health Research Strategy variability in susceptibility to cancer and are to “(1) summarize data on human is designed to improve the understanding the possible correlations between behaviors and characteristics which affect of why some people and groups are more exposure to environmental contaminants, susceptible and highly exposed than others.

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susceptibility and such covariates as age, and (2) recommend values to use for these According to this strategy, ORD’s research race, ethnicity, and sex.” factors” (p. 1-1). The document includes on subpopulations will focus on three over 150 data tables with information factors—life stage, genetic factors, and pre- on exposure scenarios. It also discusses existing diseases—that have been identified by variability and attempts to characterize the a program office and the scientific community variability of each of the exposure factors as having a high priority for risk assessment. “(1) as tables with various percentiles In 2000, ORD released its Strategy for or ranges of values; (2) as analytical Research on Enironmental Risks to Children distributions with specified parameters; to strengthen the scientific foundation of and/or (3) as a qualitative discussion” risk assessment and management decisions (p. 1-5). The handbook discusses how that affect children and guide EPA’s research risk assessors can identify the types of needs and priorities over the following 5 to variability and ways that variability can be 10 years. Approximately 75 percent of the analyzed. funding for this strategy will be dedicated to research grants under the STAR program, such as those designed to evaluate children’s exposure to pesticides.” gAO 2006 at 46: “To further its understanding of variability in exposure, EPA has undertaken a number of research projects. For example, one of ORD’s laboratories conducted the National Human Activity Pattern Survey to provide detailed human exposure information for specific populations and allow EPA to better understand actual human exposure to pollutants in real-world situations. The survey results are stored in the Consolidated Human Activity Database to help risk assessors estimate the time that exposed people spend in various environments and their inhalation, ingestion, and dermal absorption rates while in those environments. This laboratory also conducts research to define, quantify, and reduce the uncertainty associated with the exposure and risk assessments, to develop improved methods to more accurately measure exposure and dose, and to develop technical information 3 continued

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TAbLE D-1 Continued 360 Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc and quantitative tools to predict the nature and magnitude of human exposures to environmental contaminants. A recent EPA study was designed to identify chemicals commonly used in homes or day care centers, and whether children in these environments encountered the chemicals in the course of their daily activities. The research sought to identify the major routes (i.e., breathing and ingestion) and sources (i.e., dust, food, air, soil, and water) through which children come into contact with chemicals. “variability also exists with regard to susceptibility to adverse affects because of inherent differences among humans.” NRC 1994 at 11: “EPA should adopt EPA 1996 Proposed guidelines for a default assumption for differences in Carcinogen Risk Assessment at 125: susceptibility among humans in estimating “The issue of a default assumption for individual risks.” human differences in susceptibility has been addressed under the major defaults discussion in section 1.3 with respect to margin of exposure analysis. The EPA has considered but decided not to adopt a quantitative default factor for human differences in susceptibility when a linear extrapolation is used. In general, the EPA believes that the linear extrapolation is sufficiently conservative to protect public health. Linear approaches (both LMS and straight line extrapolation) from animal data are consistent with linear extrapolation on the same agents from human data (Goodman and Wilson 1991; Hoel and Portier 1994). If actual data on human variability in sensitivity are

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available they will, of course, be used.” EPA 2005a guidelines for Cancer Risk Assessment at 17802: “The dose-response estimate strives to derive separate estimates for susceptible populations and lifestages so that these risks can be explicitly characterized. For a susceptible population, higher risks can be expected from exposures anytime during life, but this applies to only a portion of the general population. . . . In contrast, for a susceptible lifestage, higher risks can be expected from exposures during only a portion of the lifetime, but everyone in the population may pass through those lifestages.” Also at 17811: “As a default for oral exposure, a human equivalent dose for adults is estimated from data on another species by an adjustment of animal applied oral dose by a scaling factor based on body weight to the ¾ power. The same factor is used for children because it is slightly more protective than using children’s body weight (see sec. 3.1.3).” NRC 1994 at 11: “The distinction between EPA 2000b Risk Characterization gAO 2006 at 45: “All program offices uncertainty and individual variability Handbook at 40: “The risk assessor should address exposure variability in their risk should be maintained rigorously in each strive to distinguish between variability and assessments, although they do so in different component of risk assessment.” uncertainty to the extent possible.” ways. For example, risk assessors in the Office of Air Quality Planning and Standards EPA 2000b Risk Characterization who set certain air quality standards for Handbook at 40: “The risk assessor should six principal pollutants said they consider strive to distinguish between variability and individual activity patterns for sensitive uncertainty to the extent possible (see 3.2.8 populations like children or asthmatics in for a discussion of uncertainty). variability exposure modeling by including a distribution arises from true heterogeneity in of breathing rates to reflect variability 361 continued

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TAbLE D-1 Continued 362 Topic NRC Report: Recommendationa EPA Response: Stated Policyb EPA Response: Implementation Activityc characteristics such as dose-response inherent in the population. Furthermore, by differences within a population, or modeling to protect the most sensitive or differences in contaminant levels in the at-risk groups, they are assured of protecting environment. The values of some variables the rest of the population. variability in used in an assessment change with time exposure to the six principal pollutants is and space, or across the population whose generally described qualitatively in scientific exposure is being estimated. Assessments summaries for each pollutant. The Office of should address the resulting variability in Water includes an analysis of risks to various doses received by members of the target subpopulations and a narrative discussion of population. Individual exposure, dose, and the strengths and weaknesses of the studies risk can vary widely in a large population. it used to estimate exposure, but generally Central tendency and high end individual does not include a quantitative analysis. The risk descriptors capture the variability Office of Pesticide Programs considers 24 in exposure, lifestyles, and other factors different population subgroups in its exposure that lead to a distribution of risk across a estimates, including differences in age, gender, population (e.g., see Guidelines for Exposure ethnicity, and geographic dispersion. When Assessment).” data allow, the Office of Pesticide Programs develops a distribution of exposures and risks EPA 2003b Framework for Cumulative for its more refined risk assessments.” Risk Assessment at 65: “NRC (1994) notes a clear difference between uncertainty and variability and recommends that the distinction between these two be maintained: A distinction between uncertainty (i.e., degree of potential error) and interindividual variability (i.e., population heterogeneity) is generally required if the resulting quantitative risk characterization is to be optimally useful for regulatory purposes, particularly insofar as risk characterizations are treated quantitatively. The distinction between uncertainty and individual variability ought to be maintained rigorously at the level of separate risk assessment components (e.g., ambient concentration, uptake, and potency) as well as at the level of an integrated risk characterization.”

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NRC 1994 at 220: “If there is reason EPA 2005b Supplemental guidance for gAO 2006 at 46: “Legislation can also to believe that risk of adverse biological Assessing Susceptibility from Early-Life require EPA to consider potentially effects per unit dose depends on age, EPA Exposure to Carcinogens at 1: “The susceptible populations and life stages. should present separate risk estimates for National Research Council (NRC, 1994) For example, the Safe Drinking Water Act adults and children. When excess lifetime recommended that ‘EPA should assess risks Amendments mandate that EPA consider risk is the desired measure, EPA should to infants and children whenever it appears risks to groups within the general population compute an integrated lifetime risk, taking that their risks might be greater than those that are at greater risk of adverse health into account all relevant age-dependent of adults.’ This document focuses on cancer effects, including children, the elderly, and variables. risks from early-life exposure compared people with serious illnesses. In addition, with those from exposures occurring later the Food Quality Protection Act contains “EPA does not usually explore or consider in life. Evaluating childhood cancer and special provisions for the consideration of interindividual variability in key biologic childhood exposures resulting in cancer risks to children from pesticides. In 1995, parameters when it uses or evaluates later in life are related, but separable, EPA’s Science Policy Council called for EPA various physiologic or biologically based issues.” to consider the risks to infants and children risk-assessment models (or else evaluates consistently and explicitly as part of its risk some data but does not report on this EPA 2004b at 42: “Consideration of the assessments. In 1997, the White House issued in its final public documents). In some variability among humans is a critical an executive order that required EPA and other cases, EPA does gather or review aspect of risk assessment. It is the goal other federal agencies to identify and assess data that bear on human variability, but of EPA risk assessments to identify all environmental health and safety risks that tends to accept them at face value without potentially affected populations, including may disproportionately affect children and ensuring that they are representative of the human populations (e.g., gender, nutritional to ensure that policies, programs, activities, entire population. As a general rule, the status, genetic predisposition) and life- and standards address such disproportionate larger the number of characteristics with stages (e.g., childhood, pregnancy, old risks.” an important effect on risk or the more age) that may be more susceptible to toxic variable those characteristics are, the larger effects or are highly or disproportionately the sample of the human population needed exposed.” to establish confidently the mean and range of each of those characteristics.” Also at 43: “When data are available to describe toxicological differences for a susceptible population or life-stage, then those data are summarized and analyzed, and the decisions based on this information are presented. It is preferable to have population- and chemical-specific data to describe a susceptibility to toxic effects.” aExample of recommendation from NRC 1983, 1994, or 1996. bExample of EPA policy bearing on issues raised in the recommendation in the form of written guidelines, reports, or policy memoranda. cCommentary, practice, or activities related to issues raised in the National Research Council recommendation and related EPA guidance. 363 dThese guidelines were not specifically in response to the National Research Council report but reflect agency policy related to this topic.

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364 SCIENCE AND DECISIONS: ADVANCING RISK ASSESSMENT REFERENCES EPA (U.S. Environmental Protection Agency). 1984. Risk Assessment and Management: Framework for Decision Making. EPA 600/9-85-002. Office of the Administrator, U.S. Environmental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency). 1986. Guidelines for Carcinogen Risk Assessment. EPA/630/R-00/004. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http:// cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=54933 [accessed June 3, 2007]. EPA (U.S. Environmental Protection Agency). 1989a. Exposure Factors Handbook. EPA/600/8-89/043. NTIS PB90-106774/AS. Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency). 1989b. Risk Assessment Guidance for Superfund: Volume I—Human Health Evaluation Manual (Part A). Interim Final. EPA-540/1-89/002. Office of Emergency and Remedial Response, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/ oswer/riskassessment/ragsa/pdf/rags-vol1-pta_complete.pdf [accessed Oct. 16, 2007]. EPA (U.S. Environmental Protection Agency). 1992a. Guidelines for Exposure Assessment. EPA/600/Z-92/001. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. May 1992 [online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=15263 [accessed Oct. 10, 2007]. EPA (U.S. Environmental Protection Agency). 1992b. Guidance on Risk Characterization for Risk Managers and Risk Assessors. Memorandum to Assistant Administrators, and Regional Administrators, from F. Henry Habicht, Deputy Administrator, Office of the Administrator, Washington, DC. February 26, 1992 [online]. Available: http://www.epa.gov/oswer/riskassessment/pdf/habicht.pdf [accessed Oct. 10, 2007]. EPA (U.S. Environmental Protection Agency). 1994a. Model Validation for Predictive Exposure Assessments. U.S. Environmental Protection Agency, Washington, DC. July 4, 1994 [online]. Available: http://www.epa.gov/ord/ crem/library/whitepaper_1994.pdf [accessed Oct.15, 2007]. EPA (U.S. Environmental Protection Agency). 1994b. Report on the Workshop on Cancer Risk Assessment Guide- lines Issues. EPA/630/R-94/005a. Office of Research and Development, Risk Assessment Forum, Washington, DC. EPA (U.S. Environmental Protection Agency). 1994c. Peer Review and Peer Involvement at the U.S. Environmental Protection Agency. Memorandum to Assistant Administrators, General Counsel, Inspector General, Associate Administrators, Regional Administrators, and Staff Office Directors, from Carol M. Browner, Administrator, U.S. Environmental Protection Agency. June 7, 1994 [online]. Available: http://www.epa.gov/osa/spc/pdfs/ perevmem.pdf [accessed Oct. 16, 2007]. EPA (U.S. Environmental Protection Agency). 1995a. Policy for Risk Characterization at the U.S. Environmental Protection Agency. Memorandum from Carol M. Browner, Office of the Administrator, U.S. Environmental Protection Agency, Washington, DC. March 21, 1995 [online]. Available: http://64.2.134.196/committees/ aqph/rcpolicy.pdf [accessed Oct. 10, 2007]. EPA (U.S. Environmental Protection Agency). 1995b. Guidance for Risk Characterization. Science Policy Council, U.S. Environmental Protection Agency. February 1995 [online]. Available: http://www.epa.gov/osa/spc/pdfs/ rcguide.pdf [accessed Oct. 15, 2007]. EPA (U.S. Environmental Protection Agency). 1996. Proposed Guidelines for Carcinogen Risk Assessment. EPA/600/P-92/003C. Office of Research and Development, U.S. Environmental Protection Agency, Washing- ton, DC. April 1996 [online]. Available: http://www.epa.gov/ncea/raf/pdfs/propcra_1996.pdf [accessed Oct. 15, 2007]. EPA (U.S. Environmental Protection Agency). 1997a. Cumulative Risk Assessment Guidance—Phase I Planning and Scoping. Memorandum to Assistant Administrators, General Counsel, Inspector General, Associate Administrators, Regional Administrators, and Staff Office Directors, from Carol M. Browner, Administrator, and Fred Hansen, Deputy Administrator, Office of Administrator, U.S. Environmental Protection Agency, Washington, DC. July 3, 1997 [online]. Available: http://www.epa.gov/swerosps/bf/html-doc/cumulrsk.htm [accessed Oct. 15, 2007]. EPA (U.S. Environmental Protection Agency). 1997b. Guidance on Cumulative Risk Assessment. Part 1. Planning and Scoping. Science Policy Council, U.S. Environmental Protection Agency, Washington, DC. July 3, 1997 [online]. Available: http://www.epa.gov/osa/spc/pdfs/cumrisk2.pdf [accessed Oct. 10, 2007]. EPA (U.S. Environmental Protection Agency). 1997c. Guiding Principles for Monte Carlo Analysis. EPA/630/R- 97/001. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/NCEA/pdfs/montcarl.pdf [accessed June 3, 2007].

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