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Cumulative risk assessment toolbox: methods and approaches for the practitioner.

1. Introduction

The public has become increasingly aware of the wide variety of chemicals present--not just in the environmental media to which they are exposed (such as air, water, and soil) but also in the food they eat and the products they use. As access to relevant information continues to grow, notably via the Internet, many communities have voiced concerns about health effects associated with the multiple chemicals in their daily lives. To address these concerns, many organizations have responded with approaches, guidelines, focused workshops, and illustrative applications to better assess cumulative risks. These organizations include the US Environmental Protection Agency (EPA), National Institute for Occupational Safety and Health (NIOSH), Agency for Toxic Substances and Disease Registry (ATSDR), World Health Organization (WHO), California Environmental Protection Agency (Cal/EPA), the Environmental Justice (EJ) community, and

professional organizations such as the Society of Toxicology.

Cumulative risk assessment (CRA) explicitly considers the combined fate and effects of multiple contaminants from multiple sources through multiple exposure pathways. The goal of CRA is to address more realistic conditions than those addressed under the classic approach of the 1983 National Research Council (NRC) "red book" on Risk Assessment in the Federal Government [1], which agencies historically implemented by evaluating one chemical at a time. Reflecting advances in scientific knowledge since that time, which made more detailed and integrated analyses possible, EPA outlined its Framework for Cumulative Risk Assessment [2]in 2003 that considered joint exposure to multiple chemical, physical, and biological stressors. A number of organizations have published additional cumulative risk reports over the past decade [3-9]. Despite the increase in relevant analyses and reports, the translation of a more fully integrated approach to practice has lagged behind the science. With various groups and individual community members unaware of available tools that could be used to assess cumulative risk, explicit applications have been relatively modest.

The concept of a "cumulative risk toolbox" emerged soon after the EPA framework was published, during the early stages of developing a companion report to support evaluations at contaminated sites. The purpose of this CRA toolbox was to overcome the "awareness" hurdle and serve as a practical resource for cumulative risk assessors and other interested parties. Recognizing that cumulative risk encompasses many different kinds of stressors ranging from chemical and physical to biological and psychological ones, the CRA toolbox compilation that began in 2004 targeted a specific scope, namely, health risks from exposure to multiple anthropogenic chemicals as well as to elevated concentrations of chemicals that occur naturally. The main objectives of the CRA toolbox were to (1) consolidate resources for conducting cumulative risk assessments, (2) provide coverage for the main elements of the assessment process, and (3) offer practical notes to help assessors understand the strengths and limitations of a given approach or model for cumulative risk applications.

The original CRA toolbox was published as an appendix to the 2007 Agency report, Concepts, Methods, and Data Sources for Cumulative Health Risk Assessment of Multiple Chemicals, Exposures, and Effects: A Resource Document [10]. It was recently reevaluated to determine if the descriptions and electronic web links for the individual entries were current or needed to be updated. This paper highlights relevant excerpts from the CRA toolbox with interpretive context for CRAs at contaminated sites, with updates as indicated; it also identifies several additional resources not included in the original CRA toolbox.

2. Methods

The CRA toolbox was developed in three phases: (1) identification of information resources related to CRA, (2) assessment of their relevance to contaminated sites and facilities, and (3) categorization of the relevant resources to facilitate their use in analyses. In searching the scientific literature and other online materials for information related to CRA, the resources pursued included conceptual approaches, models, and other tools related to assessing health risks posed by multiple chemicals in multiple environmental media via multiple exposure routes. In addition, risk analysts from several agencies, universities, and the private sector were informally invited to identify methods and models they had found useful for assessing multiple contaminants, exposures, and effects as part of their environmental projects and programs.

Some information evaluated in the second phase was designed to assess ecological effects, while other material addressed acute and shorter-term human exposures; however, the primary emphasis of the CRA toolbox was on approaches and tools for evaluating health effects from chronic to lifetime exposures. An example of this type of resource is the NIOSH approach for worker protection that accounts for exposures to chemical mixtures [11]. The resources considered less well suited than others to this type of application were screened out at this stage, as were resources that essentially duplicated content that had already been compiled. In the third phase, the resources selected for inclusion were collectively evaluated to identify common themes. The purpose of this last phase was to define a manageable set of categories to serve as the organizational structure of the CRA toolbox. This toolbox was not intended to be comprehensive; rather, it was developed to provide a suite of resources, including guidelines, approaches, and models, that could be applied to assess cumulative health risks associated with contaminated sites. For this reason, three basic documents guided the determination of the CRA toolbox categories: the 1983 NRC risk assessment paradigm [1],the 1989 EPA Risk Assessment Guidance for Superfund [12], and the 2003 EPA Framework for Cumulative Risk [2].

3. Results and Discussion

3.1. Illustrative Information Resources. The online searches and interactions with risk practitioners produced more than 100 methods and tools relevant to CRAs at contaminated sites. Not all explicitly target multiple contaminants, exposures, or effects. That is, many were developed for general risk assessment purposes, but they were found to be either directly useful or adaptable for population-specific CRAs, or the underlying approach was found to offer useful insights for such analyses. Many of the materials addressed one or two components of a CRA, while others addressed multiple elements or the overall concept. Although certain resources clearly consider multiple exposures to multiple chemicals, such as the standard Agency guidance for risk assessment at contaminated sites [12], only a fraction are explicitly defined as cumulative risk tools. Relatively few specifically focus on exposure groupings or joint toxicity, or on a given population group for CRA, such as children (e.g., see (4.1) in Table 4 and (6.7) in Table 6). Although many focus on contaminant sources or affected environmental media, as has been the historical practice, they can also be applied to more complex cumulative risk analyses. Similarly, various resources can be helpful for evaluating subsets of an overall cumulative risk assessment, such as cumulative hazards, threats, exposures, or impacts, including health impact analyses.

The resources compiled for the CRA toolbox are available on websites managed by a variety of organizations, including (1) federal agencies and institutes such as the EPA, US Nuclear Regulatory Commission, US Department of Energy (DOE), and US Department of Health and Human Services, including NIOSH and ATSDR within the Centers for Disease Control and Prevention (CDC), as well as the National Institutes of Health (NIH), including the National Institute of Environmental Health Sciences (NIEHS); (2) national scientific organizations such as the National Academies, including the National Academy of Sciences and National Research Council; (3) other federal entities such as the National Environmental Justice Advisory Council; (4) national organizations in other countries, including Canada (Health Canada, Environment Canada, and the Quebec worker protection institute IRSST, Institut deRecherche Robert-Sauve en Sante et en Securite du Travail) and The Netherlands (Organization for Applied Scientific Research, Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek (TNO) Nutrition and Food Institute); (5) international bodies, such as the European Commission and WHO; (6) private nonprofit organizations such as the International Institute of Indigenous Resource Management (IIIRM); (7) state agencies, such as the Cal/EPA Office of Environmental Health Hazard Assessment (OEHHA) and Air Resources Board (ARB); (8) industry organizations such as the American Chemistry Council (ACC); (9) scientific groups at universities and national laboratories; and (10) local community advisory boards at contaminated sites and facilities, such as site-specific, restoration, and citizen advisory boards (SSABs, RABs, and CABs).

3.2. CRA Toolbox Categories. The CRA toolbox is divided into five sections as described in Table 1 and illustrated in Figure 1, with some sections further subdivided to identify specific content. (The resource count in Table 1 refers to the number of tools highlighted in tables for each topic.)

3.3. Resource Highlights. The resources highlighted in this section focus on those identified in the original CRA toolbox (which was developed in 2004), with limited updates. Several additional tools that include more recent content are noted in Section 3.5. While several tools apply to multiple categories, they are generally listed with the first CRA toolbox category for which they are particularly useful. (Note that planning and scoping for CRAs continues iteratively throughout the assessment process.) Each section begins with a topical introduction, followed by text bullets highlighting selected resources, and concluding

with a table that summarizes the following for a larger number of entries: (1) title, author/organization, and access information (e.g., web link), where available; (2) purpose and scope; (3) remarks on application to CRA. Nearly 80 resources are summarized across the five tables combined, with additional resources highlighted in the accompanying text.

3.3.1. Category 1: Resources for Planning, Scoping, and Problem Formulation (Table 2). Topics addressed during planning, scoping, and problem formulation include the purpose and breadth of the assessment (considering multiple chemicals, population groups, exposures, and effects), the type of product needed from the assessment to inform a decision, the data to be collected and synthesized, the general assessment approach, and stakeholder involvement. CRAs can involve a very large number of potential combinations of chemicals and interactions inherent to the environmental setting. During this initial and iterative phase of the process, common questions include which chemicals are most likely to contribute significantly to risks, whether they might interact, and what the nature of those interactions could be. The Internet has become a valuable tool for promoting and enhancing stakeholder involvement, and successful programs often combine traditional methods (ranging from one-on-one to town hall meetings and printed newsletters or other information sent in regular mail) with electronic approaches to take advantage of the unique benefits of each. Selected resources that can be used to support planning, scoping, and problem formulation for CRAs, including stakeholder involvement, are presented in Table 2; several specific resources are highlighted below.

Planning and Scoping. In 1997, EPA released its Guidance on Cumulative Risk Assessment, Part 1, Planning and Scoping ((2.1) in Table 2) that presented broad-based approaches that considered (1) multiple endpoints, sources, pathways, and routes of exposure; (2) community-based decision making; (3) flexibility in achieving goals; (4) case-specific responses; (5) all environmental media; and (6) holistic risk reduction. The companion Lessons Learned on the Planning and Scoping of Environmental Risk Assessments ((2.2) in Table 2)followed in 2002, presenting case studies to illustrate organizing principles for CRAs. The following year, the Agency published its Framework for Cumulative Risk Assessment ((2.3) in Table 2) that outlines an umbrella structure for CRAs, identifies key issues, and defines common terms. Neither a procedural guide nor a regulatory requirement, the Framework document summarizes key elements of the CRA process as part of a flexible structure rather than identifying prescriptive protocols. Providing the basic information about important aspects of cumulative risk, that framework continues to serve as a key foundation for CRA reports. One example of a tool based on the framework is EJView ((2.4) in Table 2), a GIS-based module jointly designed by the EPA Offices of Environmental Information (OEI) and Environmental Justice (OEJ). Combining environmental, socioeconomic, and health indicators in statistical tables, this tool was initially developed to evaluate potential EJ issues. For community based approaches, this and other ranking and prioritization tools can help identify the problems warranting consideration in a CRA. Note that although it is presented here within the planning/problem formulation stage to support front-end scoping, this and other such tools are also very useful for other phases of the CRA process, including risk characterization.

Stakeholder Involvement. A number of tools have been developed to support stakeholder involvement in CRAs, particularly for contaminated sites. Ranging from guidance for EPA's Superfund and EJ programs to project-specific field activities (see the second section of Table 2, (2.5) through (2.10)), these resources chronicle approaches taken to solicit inputs from multiple stakeholders and incorporate them into the assessment plans. A number of examples from DOE legacy waste sites reflect inputs of long-standing community advisory boards, from the DOE Savannah River Site in Georgia to the DOE Hanford Site in Washington. Practical insights can also be gained from the Risk Analysis, Communication, Evaluation, and Reduction (RACER) project at the DOE Los Alamos National Laboratory (LANL) in New Mexico. Led by the Risk Assessment Corporation (RAC) team, extensive stakeholder involvement has been a hallmark of that effort ((2.8) in Table 2).

Data Quality Objectives. The EPA has developed a series of guidance documents to help ensure that all data collection, including at contaminated sites, is appropriate for the intended use, which is particularly important for CRAs given the typical complexity of these analyses. These documents outline a systematic process for developing performance criteria to collect, evaluate, and use environmental data. Statistical and analytical tools underlie data quality objectives (DQOs), as highlighted in the last section of Table 2 ((2.11) through (2.17)).

3.3.2. Category 2: Resources for Environmental Fate and Transport Analyses (Table 3). Alarge number of tools have been developed to assess the environmental fate and transport of chemicals, and many of these can be used to support CRAs, as highlighted below and in Table 3. These tools include computer models available from the EPA Center for Subsurface Modeling Support (CSMoS), as well as resources for physicochemical constants and guidance for determining background concentrations in soil.

Fate and Transport. Risk assessments for contaminated sites and also for urban environments and other settings impacted by multiple pollutant sources commonly simulate the behavior of multiple chemicals in the environment because of the relatively high costs (in terms of both manpower and dollars) to conduct measurements. Hundreds of computer models have been developed to model contaminant fate and transport in the environment. Some are very general and conceptual, while others address specific media characteristics and setting conditions. The use and suitability of individual models vary widely depending on the project objectives and data required, so it is important for the selected model to be appropriate for the given evaluation. CSMoS is a key resource for these tools; the center maintains an online database of publicly available ground water and vadose zone fate and transport models, a number of which are included in Table 3 (see entries (3.13)-(3.23)). Selected tools are also highlighted below.

Physicochemical Constants. Several online resources provide information on the chemical, physical, and biological properties of substances, including industrial products and byproducts. Resources highlighted in the original toolbox include the EPA ChemBioFinder Database ((3.1) in Table 3)and Soil Screening Guidance ((3.2) in Table 3), which includes an extensive set of environmental and physical constants and parameters that can be used to model the fate and transport of chemicals in soil. The chemical-specific properties used to derive EPA Regional Screening Levels are also available online (see related discussion for Table 5). Information about these properties can be used to predict that chemicals will likely share a similar environmental fate to support exposure groupings for CRAs.

Background Concentrations. Concentrations that represent natural background or ambient conditions are location specific and provide valuable context for assessing chemical fate and transport as well as incremental risk. The EPA has outlined an approach for characterizing background concentrations, including protocols for determining whether site measurements are statistically elevated, in Guidelines for Characterizing Background Chemicals in Soil at Superfund Sites ((3.3) in Table 3). Data on background concentrations of inorganic chemicals can be found in several sources that provide baseline context for community-based environmental risk assessments. Information sources include ATSDR toxicological profiles ((5.4) in Table 5) and technical reports from the US Geological Survey, as illustrated by a report on constituents of ambient surface soil in Chicago that was prepared in cooperation with the City of Chicago [13]. Similar regional data can be found in state-specific resource reports, such as from the Massachusetts Department of Environment [14]as well as the Texas Commission on Environmental Quality (TCEQ) [15], regarding background levels of polycyclic aromatic hydrocarbons (PAHs) and other constituents in soil. (Also, see related TCEQ entry (6.5) in Table 6.)

Vapor Intrusion. Vapor intrusion can be an important exposure pathway for multiple chemicals when volatile organic compounds are in the subsurface (e.g., soil and groundwater) and can migrate to indoor air. Contributions from vapor intrusion are commonly combined with estimates from other indoor air pathways (e.g., inhalation of volatiles during showering) to quantify aggregate exposures and risks for single chemicals (e.g., benzene) and cumulative risks for groups of chemicals (e.g., chlorinated solvents). This pathway has historically been evaluated using a model based on the equation published by Johnson and Ettinger in 1991 [16]. The model is a one-dimensional spread sheet that estimates convective and diffusive transport of chemical vapors to indoor air from sources near a building's perimeter. Attenuating factors such as biological degradation were not included in the original model, and the source was assumed to be infinite over the exposure duration assessed (e.g., 25 years for a commercial or industrial worker). The EPA provided a detailed description of this earlier vapor intrusion model in its draft guidance issued in 2002, and since that time, the Agency and others have continued to strengthen the modeling approach ((3.11) in Table 3). Following the early Johnson and Ettinger model, several US states have adopted simple equations based on this method to conduct screening evaluations of indoor air ((3.11) in Table 3). The indoor air concentrations calculated by these models across multiple chemicals can be combined to estimate cumulative exposures and corresponding risks.

3.3.3. Category 3: Resources for Exposure Analysis (Table 4). Many exposure models are well suited to assessing multiple chemicals by multiple routes, although this is generally performed by combining predictions made for individual chemicals. Tools range from relatively straightforward screening models to comprehensive multimedia models, as highlighted below and further illustrated in Table 4. Certain models also support other portions of the risk assessment process. For example, models for subsurface vapor migration described earlier are often tapped for multimedia exposure assessments because they consider both soil and groundwater inputs. In addition, several technical reports identify exposure factors, their bases, and parameters commonly used to estimate cumulative exposures. This category includes resources linked to fate and transport models, in some cases to account for the time lag between release and exposure considering the movement of chemicals from source to receptor. The analysis of changing chemical exposures over time is also an important concept for grouping chemicals, and models that incorporate this factor are included in Table 3 (e.g., see (3.7), (3.14), and (3.15)).

Exposure Factors. Risk assessments commonly rely on exposure models to capture receptor-specific factors that influence chemical intakes. For example, factors that address exposure duration, time involved in certain activities, body weight and surface area, intake rates (e.g., inhalation, or ingestion of food, soil, or water), and many others parameters needed to estimate potential risks from multiple exposures are available from the EPA 2011 Exposure Factors Handbook and 2008 Child-Specific Exposure Factors Handbook (see (4.1) in Table 4). To support the evaluation of potentially vulnerable or susceptible subgroups, EPA's 1999 report on Sociodemographic Data Used for Identifying Potentially Highly Exposed Populations ((4.2) in Table 4) provides information to help identify subsets of the general population who may be at greater risk for negative health consequences, which can be incorporated into CRAs. An additional valuable resource is the National Human Exposure Assessment Survey (NHEXAS, (4.3) in Table 4), which was developed by EPA in the early 1990s to compile information on human exposures to chemicals at the community and regional scales, with an emphasis on associating these exposures with personal activities. The NHEXAS database is also noted in Table 4.

Multipathway Releases and Exposures. The 3MRA model ((4.4) in Table 4) is a multimedia, multipathway, multireceptor exposure and risk assessment model developed by EPA to assess releases from land-based waste management units. After simulating releases from disposal units, modules model fate and transport through the environment, estimate exposure to receptors, and calculate distributions of risks to receptors. The 3MRA methodology uses a Monte Carlo scheme to quantify uncertainty (e.g., from natural variability or based on selection of representative sites). The Exposure and Fate Assessment Screening Tool (E-FAST, (4.5) in Table 4) is another computer-based model that can provide screening-level estimates for general population, consumer, and environmental exposures to chemicals released to air, surface water, or landfills and those released from consumer products. Potential inhalation, dermal, and ingestion doses resulting from these releases are estimated, with the modeled concentrations and doses designed to reasonably overestimate exposures for use in screening-level assessments. States have also developed tools to assess exposures via the air pathway, such as California's Air Toxics "Hot Spots" Program that requires stationary air emission sources in the state to report the types and quantities of certain substances routinely released to air and also to estimate potential exposures to surrounding populations. A software package was developed to support these evaluations ((4.10) in Table 4).

Dietary Exposures. The Dietary Exposure Potential Model (DEPM) ((4.12) in Table 4) estimates dietary exposure to multiple chemicals based on data from several national, government-sponsored food intake surveys and chemical residue monitoring programs. The DEPM includes recipes developed specifically for exposure analyses that link consumption survey data for prepared foods to the chemical residue information, which is normally reported for raw food ingredients, to estimate daily dietary exposure. The summary databases are aggregated in a way that allows the analyst to select appropriate demographic factors, such as age/sex groups, geographical regions, ethnic groups, and economic status. The model also includes modules for evaluating chemical exposures from residues, soil, and tap water.

3.3.4. Category 4: Resources for Toxicity Analyses (Table 5). Resources that can be used to support toxicity analyses for CRAs are highlighted here and summarized in Table 5. Topics include (1) resources for toxicity reference values for various exposure routes and durations; (2) development of toxicity factors, including for whole mixtures; (3) identification of toxicity criteria for similar or surrogate compounds or mixtures to represent a mixture or its components; and (4) joint toxicity of the components of a mixture.

Toxicity Reference Values. The EPA Integrated Risk Information System (IRIS) ((5.7) in Table 5) is a key source of information on chronic toxicity reference values, including reference doses (RfDs), reference concentrations (RfCs), and oral slope factors, unit risks, and corresponding risk-based concentrations [17] (see (5.7) in Table 5). Chronic toxicity values are also available in IRIS for certain mixtures (such as the RfC for diesel exhaust and cancer toxicity values for polychlorinated biphenyls). Note that if a standard toxicity value is not available in IRIS, a Provisional Peer-Reviewed Toxicity Value (PPRTV; derived for use in the Superfund Program) may be available ((5.8) in Table 5). PPRTVs are derived using the same methods, data sources, and EPA guidance used to derive IRIS values but undergo a comparatively more rapid scientific review [18]. If a relevant PPRTV is not available, some states have also developed selected toxicity values that may be found in summary tables of EPA Regional Screening Levels ((5.11) in Table 5). Recent IRIS assessments commonly include data on effects other than the critical effect used to derive a toxicity value; these effects (sometimes called secondary effects) can be used to at least qualitatively assess joint toxicity (usually via dose or response addition) of combined chemical exposures. The information provided in EPA's RfD arrays also could be used to support estimates of target organ toxicity doses based on secondary effects [19]. The ATSDR has developed toxicological profiles for many individual chemicals that identify the effects of the given chemical, as well as primary environmental and metabolic transformation products to support grouping by specific target organs and systems. A smaller set of interaction profiles has also been developed that assesses joint toxicity [3] (see (5.4) in Table 5).

Chemical Mixtures and Pesticides: Common Mode of Action. In 2000, EPA updated its 1986 guidelines for chemical mixtures ((5.1) in Table 5). This supplemental guidance describes risk assessment approaches that depend on the type, nature, and quality of available data, and it includes equations, definitions, discussions of toxicological interactions and pharmacokinetic models, and approaches for assessing whole mixtures, surrogate mixtures, and individual mixture components. The whole-mixture discussion includes the derivation of whole-mixture toxicity values (RfDs, RfCs, cancer slope factors, and inhalation unit risks), as well as consideration of comparative potency and environmental transformations. The component discussion includes dose addition, the hazard index (HI), interaction-based HI, relative potency factors (RPFs), and response addition.

In 2002, EPA published guidance for assessing the cumulative risk of pesticides with a common toxic mechanism to address requirements set forth in the Food Quality Protection Act of 1996 [20](see(5.2) in Table 5); that guidance was updated in 2006 [21]. Note that common mechanism was interpreted by EPA as common mode of action [20]. The initial guidance considered potential exposures to 30 organophosphate pesticides via food, drinking water, and residential uses, and it applied methods to account for variable exposures per different ages, seasons, and geographic factors.

EPA scientists in the National Center for Environmental Assessment collaborated with colleagues in the National Toxicological Research Center of the Food and Drug Administration to develop additional component approaches for assessing the cumulative risk posed by exposures to multiple chemicals by evaluating three scenarios [22, 23]. They explored a simple scenario in which it was certain that all chemicals being considered shared a common toxic mode of action, so a dose-additive approach could be applied. In the second scenario, modes of action for the chemicals in the mixture were known and could be used to divide the chemicals into independent mode-of-action subclasses; dose addition and response addition were then integrated to assess the risk. In the third scenario, the mode or modes of action were uncertain for the chemicals in the mixture, so a joint dose-response modeling procedure was developed that created arrange of risk estimates.

Physiologically Based Models and Chemical Mixtures Toxicology Research. Statistically based methods and computer tools that can model interactions and effects associated with multiple chemicals continue to be developed and refined. A main area of study involves applying physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models to chemical mixtures. Reaction network modeling is an example of a computer-based approach that has been used in petroleum engineering to predict chemical reaction rates, products, and outcomes based on various statistical methods (including Monte Carlo-type analysis). A molecular-based model (BioMOL) was designed to use the reaction network modeling approach to predict effects of chemicals in complex biological systems [24].

Joint toxicology studies have also improved the understanding of potential health effects of chemical mixtures with different modes of action. For example, the TNO Nutrition and Food Research Institute of The Netherlands has evaluated the use of mechanistic models to describe interactions between mixture components expected to act by different modes of action. In a pilot study funded by the American Chemistry Council Long-Range Research Initiative (see (5.10) in Table 5), the TNO team applied PBPK models to assess possible toxicokinetic interactions between compounds in an applied mixture and compared those estimates to empirical dose-response modeling of observed pathological changes in the liver, blood, and kidney. The aim of such research is to develop and refine methods to be applied to other chemical mixtures. Other TNO studies have developed and applied statistical methods combining multivariate data analysis and modeling in in vitro and in vivo studies on various chemical mixtures such as petroleum hydrocarbons, aldehydes, food contaminants, industrial solvents, and mycotoxins [25, 26].

Similarly, NIH/NIEHS has sponsored studies on mixtures toxicology and environmental health, including as part of the National Toxicology Program (NTP), for which related reports and fact sheets are available from the NIEHS website [27]. A search engine on this website can be used to tap research and tools for specific applications, including those related to cumulative risk. NIEHS also publishes Environmental Health Perspectives, a monthly journal that often reports on studies relevant to chemical mixtures, with some issues and supplements entirely dedicated to mixtures. Also, NIH maintains the National Library of Medicine and other databases (see (5.9) in Table 5). In addition to the organizations highlighted in Table 5, others have also been assessing mixtures to support CRAs during the past decade. For example, the Health Canada Toxic Substances Research Initiative (TSRI) assessed cumulative effects of environmental toxics to both human and ecological receptors [28, 29]. Cal/EPA conducted a health assessment in the 1990s that focused on a representative complex mixture, diesel particulate matter (DPM) [30]. The scientific review panel for this study used the analyses of epidemiological data from workers to develop a unit risk estimate for diesel particulates, which was then used to derive an inhalation slope factor. This approach offered insights not only for assessments involving diesel exhaust but also for other chemical mixtures.

Benchmark Dose Software (BMDS) and Categorical Regression (CatReg). The EPA developed the BMDS to fit mathematical models to toxicological dose-response data for a particular toxic effect ((5.6) in Table 5). The user evaluates results of this statistical software to select a benchmark dose (BMD) associated with a predetermined benchmark response (BMR), such as a 10% increase in the incidence of a particular lesion or a 10% decrease in bodyweight. A goal of the BMD approach is to define a point of departure to derive an RfD or RfC that is more independent of study design than the traditional method based on a single experimental dose, such as the no-observed-adverse-effect level (NOAEL). The HI uses RfDs or RfCs in a formula that is based on dose addition to scale the exposure levels in a mixture, producing an indicator of the extent of concern for toxicity. The BMD values used with dose addition could estimate a BMD for the mixture, allowing the mixture dose to be interpreted in terms of the risk of a particular effect. BMD modeling could also be applied to whole mixture dose-response data.

The categorical regression tool CatReg was developed to conduct dose-response modeling of data on diverse endpoints across multiple toxicological studies by categorizing effects into different severity levels, such as no-effect and

adverse-effect levels ((5.3) in Table 5). The EPA has suggested that categorical regression results for a single chemical can yield benchmark doses (e.g., a 10% effective dose or ED10) or risk estimates that reflect the probability of observing a severity level of (nonspecific) response [10]. Once this is done for each component of a mixture, risk assessment methods for chemical mixtures such as the HI or response addition approach can then be applied to yield an indication of risk for the mixture. For CRAs, CatReg can be applied to evaluate grouped chemicals considering multiple effects. Therefore, this tool could be helpful for both the toxicity assessment and risk characterization components of an integrated risk analysis.

Risk-Based Screening Levels. Risk-based screening concentrations have been developed for environmental media (including soil, drinking water, and air) by several organizations, including EPA. For example, EPA Regions 3, 6, and 9 previously developed risk-based concentrations (RBCs), medium-specific screening levels (MSSLs), and preliminary remediation goals (PRGs), respectively; these similar values were subsequently combined to produce regional screening levels (RSLs) for assessing contaminated sites ((5.11) in Table 5). These screening values can be used to narrow the focus of assessments on key contributors to risks; they are based on conservative default assumptions for exposure and environmental parameters, and they reflect toxicity values from IRIS and other sources (e.g., Cal/EPA).

3.3.5. Category 5: Resources to Characterize Risk and Uncertainty and Present Results (Table 6). Many assumptions are made when assessing health risks from environmental exposures to multiple chemicals. Thus, it is important for the risk estimates and associated uncertainties to be well characterized and clearly presented so this information can be interpreted appropriately to guide sound decisions. This final phase of the CRA process has come to rely on issue-specific summaries and graphical tools to display statistical and spatial information, as highlighted here and in Table 6. Spatial Analysis and Decision Assistance Tool (SADA). The SADA tool was jointly developed by the EPA, US Nuclear Regulatory Commission, and University of Tennessee as an integrated software package to support human and ecological CRAs (see (6.1) of Table 6). Like many other tools (including the RSLs),the human health module of SADA includes equations from the standard Superfund guidance [12]and accommodates different land use scenarios and exposure pathways. These can be combined to estimate overall exposures for the selected receptors. This tool emphasizes the spatial distribution of contaminant data, and individual modules cover visualization, geospatial analysis, statistical analysis, sampling design, and decision analysis. Outputs can be tabular or graphical, and they can be used to identify where estimated risks exceed target values. Although the input data for these pathways can be tailored to reflect site-specific conditions, interactions are not considered.

Probabilistic Methods and Tools. Risk assessments commonly present human health risks as single-point estimates (e.g., 1 x [10.sup.-5]) in accordance with standard guidance for contaminated sites [12]. Such estimates provide little information about the underlying uncertainty or variability. For example, Monte Carlo simulation tools can be used to consider the effect of uncertainty and variability, with results approximating a full range of reasonably possible outcomes that are typically plotted as graphs (e.g., frequency distributions) or tabulated. While these probabilistic approaches have not yet been widely implemented in environmental health risk analyses for contaminated sites, such simulations can help assessors represent uncertainty and variability in the risk results (see (6.7) in Table 6). Extensive research in probabilistic analysis relevant to CRAs has been conducted at a number of universities, including North Carolina State University (C. Frey and colleagues) and the University of Washington (A. Cullen and colleagues). These evolving tools incorporate distributions of parameter values that may be more appropriate for a given assessment than point estimates, and they are particularly well suited for CRAs.

Community-Based Air Pathway Modeling and Other Joint Exposure-Risk Resources. The EPA Region 6 Regional Air Impact Modeling Initiative (RAIMI) was originally designed as a GIS-based system that could tap a number of emissions data sources to assess potential impacts at the community level ((6.3) in Table 6). This system also supports source attribution analyses, and early findings indicated that a small number of sources were responsible for most of the impact. Initially implemented at a pilot scale that focused on risks from direct inhalation exposures, RAMI was subsequently expanded to assess indirect exposures resulting from airborne releases, thus increasing the relevance for additional CRA applications. Tools identified with the exposure assessment phase that consider the spatial scale of various impacts (e.g., (4.7) in Table 4) can also be valuable resources for the risk characterization phase of CRAs. Similarly, disease registries that provide context for exposure assessments (see (4.15) in Table 4)also serve as resources for risk characterization by presenting health data that can be considered in concert with modeled or measured chemical data to assess potential influences of multiple exposures (including population-specific or location-specific patterns) and to calibrate risk models.

3.4. Review Findings. This reevaluation of the original toolbox (as described in EPA's 2007 report, Concepts, Methods, and Data Sources for Cumulative Health Risk Assessment of Multiple Chemicals, Exposures, and Effects: A Resource Document [10]) found that only half the web links were still valid, as most websites and models have been updated since the original toolbox was published. However, most information is still available in some form, and only a few web pages no longer exist. The web links presented in this overview of the original toolbox reflect the updated web addresses as of early 2013.

The review of the original toolbox also found that many compilations, approaches, and models have been updated, and additional resources are now available online. For example, a targeted search produced more than twice the number of resources reflected in the original toolbox. Additional organizations represented in this ongoing update of the CRA toolbox include the US Army Corps of Engineers, US Geological Survey, and US Department of Agriculture.

Both new and updated models can be found via a number of EPA (and other) websites, including the Center for Exposure Assessment Modeling (CEAM), National Center for Environmental Assessment (NCEA), and National Exposure Research Laboratory (NERL), as well as the Council for Environmental Regulatory Modeling (CERM). Most of these additional resources focus on the broad topic of exposure, including environmental fate and transport, but some address toxicity and risk characterization resources. Selected examples are provided in the following section.

3.5. Selected CRA Resources in addition to Those Listed in the Original Toolbox. Several cumulative risk meetings held within the last several years have produced compilations in a manner similar to the effort undertaken for the original

toolbox in 2004 to support the EPA CRA resource document (which was published in 2007). These include workshops organized by EPA that involved external scientists, as well as an internal EPA workshop that convened cumulative risk experts and EPA Program and Regional project leads in July 2009 to share insights from recent and ongoing applications. The models and other resources compiled from some of these meetings are available in the scientific literature and online [31-33]. Furthermore, the NRC published two studies relevant to cumulative risk [7, 8], one in 2008 that focused on a specific class of chemicals (Phthalates and Cumulative Risk Assessment: The Task Ahead), and the other in 2009 that focused on how current risk analysis approaches could be improved (Science and Decisions: Advancing Risk Assessment). In addition, after an extensive process of collaborative workshops and soliciting input from interested parties, in late 2010 Cal/EPA OEHHA released its report on Cumulative Impacts: Building a Scientific Foundation [6].

For the exposure category, a key resource not included in the original toolbox is the CDC's National Health and Nutrition Examination Survey (NHANES) database. This database contains information on the health and nutritional status of adults and children, and it is unique in its incorporation of data from both interviews and physical examinations. NHANES is also a source of information on the distribution of some contaminant concentrations in human tissues drawn from samples collected in the US population. Valuable research findings have been made possible by this unique database, including recent evaluations of cadmium exposures and effects in children that inform risk assessments for contaminated products from overseas [34]. Information about the NHANES program and research publications can be found online via the CDC website [35].

For the toxicity category, in addition to the recent online availability of the EPA PPRTVs [18], the IRIS database [17] now provides additional toxicity information that can be used to assess chemical mixtures. For example, information is included from recent toxicological reviews that evaluate common modes of action and common target organs and systems, which can be considered in evaluating secondary effects and establishing toxicity groupings for CRAs. NCEA has also developed a new database of the toxicity literature for a number of chemicals, called Health and Environmental Research Online (HERO), which provides information underlying recent risk-related EPA analyses and can also be mined to support CRAs [36].

The International Toxicity Estimates for Risk Assessment (ITER) database is another toxicity resource [37], which was created and is maintained by the nonprofit scientific organization Toxicology Excellence for Risk Assessment (TERA). Its tabulated data include toxicity values and cancer classifications for more than 600 chemicals, with synopses that explain data differences and web links to the source organizations for further information.

Progress also continues on the international front, spanning each key element of a CRA. In 2009, the WHO released its draft report for public review, Risk Assessment of Combined Exposures to Multiple Chemicals: A WHO/IPCS Framework [4]. Also that year, the European Commission moved forward with its ongoing initiative, NoMiracle (Novel Methods for Integrated Risk Assessment of Cumulative Stressors in Europe), including making a toolbox available to support these analyses [9].

Only a few of the recent resources have been highlighted here. Many more continue to be developed and refined to support CRAs, as the science evolves to meet the demands of the broader community for more realistic assessments that can guide effective risk management decisions. Resource toolboxes such as this one can support more integrated compilations to help address the need for increased awareness and access to practical approaches for cumulative risk assessors. CRAs that tap resources in this toolbox--which extend from EPA's cumulative risk framework and resource document to conceptual models, exposure factor handbooks, and toxicity databases, together with census data, specific fate models, community involvement processes, and new visualization tools--are being reflected in the growing literature on this topic (e.g., see [32, 38-44]).

4. Conclusions

A number of existing methods and tools can be applied to assess cumulative risks for contaminated sites, and progress continues in developing and refining such resources. Most of the tools in the original CRA toolbox have been updated, and others have become available. Nevertheless, explicit CRA applications are not yet widespread as issues related to general awareness and integration of relevant tools persist. Meanwhile, programs continue to evolve that are well suited to CRA approaches, which could help enhance the understanding of, and guide measures to address, combined stressors before they become a problem. Thus, the need exists for a broadly accessible toolbox that can serve as a practical foundation for cumulative risk practitioners across agencies, academia, and the private sector, as well as for interested members of the general public. Plans designed to address this need include the following:

(i) Strengthen the online accessibility of CRA toolbox resources;

(ii) Provide additional practical context from case studies; and

(iii) Incorporate further tools that extend to nonchemical stressors and other applications, to address emerging themes including sustainable communities.

Conflict of Interests

The authors have no direct financial relations with any trademarks mentioned in this paper.

http://dx.doi.org/10.1155/2013/310904

Acknowledgments

The authors would like to thank their many colleagues who have contributed to this research area over the past decade and beyond, including those whose approaches and tools are reflected in the CRA toolbox. The views expressed in this paper are those of the author(s) and do not necessarily reflect the views or policies of the US Environmental Protection Agency (EPA). Argonne National Laboratory's work was supported by the EPA under interagency agreement, through US Department of Energy Contract no. DE-AC02-06CH11357.

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Margaret M. MacDonell, (1) Lynne A. Haroun, (2) Linda K. Teuschler, (3) Glenn E. Rice, (3) Richard C. Hertzberg, (4) James P. Butler,1 Young-Soo Chang, (1) Shanna L. Clark, (5) Alan P. Johns, (6) Camarie S. Perry, (7) Shannon S. Garcia, (8) John H. Jacobi, (1) and Marcienne A. Scofield (1)

(1) Environmental Science Division, Argonne National Laboratory, Argonne, IL 60439, USA

(2) ENVIRON International Corporation, Emeryville, CA 94608, USA

(3) US Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH 45268, USA

(4) Biomathematics Consulting and Department of Environmental and Occupational Health, Emory University, Atlanta, GA 30322, USA

(5) Synergy Toxicology, Boerne, TX 78006, USA

(6) Baker Hughes, Tulsa, OK 74107, USA

(7) ToxStrategies, Austin, TX 78759, USA

(8) TEAM Integrated Engineering, Inc., San Antonio, TX 78216, USA

Correspondence should be addressed to Margaret M. MacDonell; macdonell@anl.gov

Received 27 September 2012; Accepted 13 November 2012

Academic Editor: Orish Ebere Orisakwe

TABLE 1: Five categories and example resources from
the CRA toolbox tables.

                        Resource
Topic                     count     Resource highlights

                                    Includes resources for the main
Planning, scoping,                  category shown as well as for the
and problem                18       subcategories of stakeholder
formulation                         involvement and data quality; it
                                    also includes a geographic
                                    assessment tool for Environmental
                                    Justice (EJ) applications and
                                    other prioritization tools,
                                    together with project-specific
                                    examples.

                                    Includes resources for
Environmental              24       physicochemical constants,
fate and                            guidance for determining

transport analysis                  background concentrations in
                                    soil, soil screening, and
                                    selected models available from
                                    the EPA Center for Subsurface
                                    Modeling Support (CSMoS).

                                    Includes resources linked to fate
Exposure analysis                   and transport that also extend to
(extending to                       human activities, such as
human factors)             15       technical information and models
                                    to predict dispersion of airborne
                                    contaminants released from
                                    industrial facilities and waste
                                    sites. It also includes resources
                                    for exposure factors,
                                    sociodemographic data, and the
                                    human exposure assessment
                                    database.

                                    Includes resources for toxicity
Toxicity analysis          12       reference values for specific
                                    exposure routes and durations,
                                    criteria for determining similar
                                    chemicals or surrogates for
                                    assessing mixtures, and
                                    approaches for assessing joint
                                    toxicity.

Risk and uncertainty                Includes a cumulative risk index
characterization and       10       analysis, a spatial analysis and
presentation                        decision assistance tool, and
of results                          other geographic information
                                    system (GIS)-based tools, as well
                                    as probabilistic approaches and a
                                    method for developing an
                                    environmental load profile.

TABLE 2: Selected resources for planning, scoping,
and problem formulation.

Resource and access         Purpose and scope

Resources for planning,
scoping, and problem
formulation

                            Published in 1997, this guidance outlines
                            EPA policy for planning and scoping for
                            CRAs. The guidance directs each office of
                            the EPA to take into account cumulative
                            risk issues in scoping and planning major
(2.1) Guidance on           risk assessments and to consider
Cumulative Risk             a broader scope that integrates multiple
Assessment-Part 1,          sources, effects, pathways, stressors,
Planning and Scoping        and populations for cumulative risk
(EPA); http://              analyses in all cases for which relevant
www.epa.gov/OSA/spc/pdfs/   data are available. This guidance also
cumrisk2.pdf                includes discussion pertaining to
                            community-based decision making,
                            flexibility in achieving goals,
                            case-specific responses, a focus on all
                            environmental media, and holistic
                            reduction of risk.

                            Published in 2002, this report provides
                            feedback to EPA scientists and managers
(2.2) Lessons Learned on    regarding EPA's experiences with planning
Planning and Scoping for    and scoping as the first step in
Environmental Risk          conducting environmental assessments.
Assessments (EPA);          It is intended to reinforce the
http://www.epa.gov/osa/     importance of formal planning and
spc/pdfs/handbook.pdf       dialogue prior to conducting complex
                            cumulative assessments and to provide
                            case studies and "lessons learned"
                            for planning.

                            Published in 2003, the document provides
(2.3) Framework for         a flexible framework for CRAs.
Cumulative Risk             It identifies the basic elements of the
Assessment (EPA);           process, describes a number of technical
http://www.epa.gov/raf/     and coordination issues, and defines
publications/               terms. This framework has served as a
framework-cra.htm           foundation for the CRAs developed since
                            its publication.

                            Jointly developed by the EPA Office of
                            Environmental Information and Office of
                            Environmental Justice, EJView is a
(2.4) EJView (EPA);         GIS-based module that can be used to
http://epamap14.epa.gov/    guide front-end scoping of CRAs.
ejmap/entry.html            It combines environmental, socioeconomic,
                            and demographic data and health
                            indicators in statistical tables, as well
                            as providing facility-level data.

                            Superfund guidance on suggested community
(2.5) Superfund Community   involvement structure, communications,
Involvement Handbook,       and approach. For contaminated sites,
Appendix A: Superfund       the lead agency informs the public of
Community Involvement       the availability of technical assistance
Requirements (EPA);         grants (TAGs). The TAG is a grant program
http://www.epa.gov/         that provides funds for citizen groups to
superfund/ community/       hire independent technical advisors to
involvement.htm; http://    help them understand and comment on
www.epa.gov/superfund/      technical decisions regarding Superfund
community/cag/pdfs/         cleanup actions. (This is now part of a
ci_handbook.pdf             broader community involvement toolkit.)

                            Explains how to form a partnership,
                            clarify goals, develop a detailed local
(2.6) Community Air         source inventory, and use a risk-based
Screening How-To Manual     process to identify priorities and
(EPA); http://www.epa       develop options for risk reduction.
.gov/oppt/cahp/pubs/        Developed by the EPA's Office of
howto.htm                   Pollution Prevention and Toxics
                            based on the Baltimore (Maryland)
                            approach.

                            HAB was established to provide
                            recommendations and advice to DOE, EPA,
                            and the State of Washington's Department
                            of Ecology on a number of issues related
(2.7) Hanford Site (DOE),   to cleanup of the Hanford site. Among its
Hanford Advisory Board      activities, the HAB created a calendar
(HAB), Public Involvement   for public involvement to list upcoming
Resources and Calendar;     meetings and other events at which input
http://www.hanford.gov/     from affected parties and stakeholders
page.cfm/hab,               was encouraged. A comment response
http://www.hanford.gov/     tracking system was also developed to
public/calendar/            coordinate issues identified
                            by stakeholders during iterative
                            planning and scoping, throughout the
                            assessment process, and to track
                            follow-ups.

                            The Risk Assessment Corporation (RAC)
                            team developed an open process for
                            assessing cumulative risks at LANL and
                            for creating a decision analysis
                            framework for risk reduction, with
                            guidance for participation and an
                            integrated database (with data from
                            multiple collecting organizations) to
                            support risk analyses. Stakeholder
(2.8) Los Alamos National   participation was actively sought in both
Laboratory (LANL) (DOE),    open progress meetings and one-on-one
Risk Assessment             meetings held in various settings; the
Corporation (RAC),          Internet was also used, to announce
Risk Analysis,              activities and availability of draft
Communication,              documents for stakeholder review and to
Evaluation, and Reduction   solicit inputs. Objectives were to
(RACER) project;            develop (1) a process for extensive
http://www.racteam.com/     stakeholder involvement in risk
racer.html                  assessment and decision-making processes
                            for LANL; (2) a method for estimating
                            current human health risks and ecological
                            impacts using available data on chemicals
                            and radionuclides measured in
                            environmental media; (3) a method for
                            implementing a comprehensive
                            risk-informed decision analysis
                            framework, including a prospective risk
                            and ecological impact assessment to guide
                            long-term management of risks and
                            ecological impacts; (4) a consistent
                            approach for compiling, using, and
                            updating data to support the risk
                            assessment and decision-making processes.
                            The RACER project has also involved local
                            schools in science projects, inviting the
                            public to provide input to exposure
                            scenarios.

                            A CAB was created to facilitate public
                            outreach for the DOE Savannah River Site,
                            consisting of 25 individuals who reflect
(2.9) Savannah River Site   the cultural diversity of the local
(DOE), Citizens Advisory    population. The CAB provides advice and
Board (CAB); http://        recommendations to DOE, EPA, and the South
www.srs.gov/general/        Carolina Department of Health and
outreach/srs-cab            Environmental Control on environmental
                            remediation, waste management, and
                            related issues. Regular meetings and
                            public comment sessions were kept open
                            to the public.

(2.10) Weldon Spring Site   A scientific educational partnership
(DOE), Partners in          established more than 20 years ago at the
Education; http://www.lm.   Weldon Spring Site in Missouri promoted
doe.gov/Weldon/             community involvement in evolving
CPAR_WSSRAP_Update_Jun92    evaluations for this DOE legacy waste
.pdf; http://www.lm         site, toward ultimately supporting site
.doe.gov/Weldon/            cleanup plans. An open door policy with
10_23_2002summary.pdf       the community translated to weekly
                            meetings during certain periods.

Resources for guiding
data quality

(2.11) Guidance on          Published in 2006, this guidance outlines
Systematic Planning Using   a systematic planning process for
the Data Quality            collecting environmental data. Designed
Objectives Process          to help analysts ensure that data are
(EPA, QA/G-4);              collected for a specific purpose, it
http://www.epa.gov/         includes the approach for determining
quality/qs-docs/            which chemicals to evaluate or test for,
g4-final.pdf                in which media, and at what locations, as
                            well as detection limits.

(2.12) Software             Computer-based software for determining
(EPA, QA/G-4D);             the feasibility of DQOs using
http://www.epa.gov/         a systematic process. Calculates the
quality/qs-docs/            appropriate number of environmental
g4d-final.pdf               samples required to statistically answer
                            whether soil or water concentrations are
                            above or below a risk-based level; can be
                            used to estimate sampling costs.

(2.13) Guidance on          Guidance on applying standard statistical
Choosing a Sampling         sampling designs (such as simple random
Design for Environmental    sampling) and more advanced sampling
Data Collection             designs (such as ranked set sampling and
(EPA, QA/G5S);              adaptive cluster sampling)
http://www.epa.gov/         to environmental applications.
quality/qs-docs/
g5s-final.pdf

(2.14) Guidance for         General guidance for developing quality
Quality Assurance Project   assurance project plans (QAPPs) for
Plans for Modeling          modeling projects.
(EPA, QA/G-5M);
http://www.epa.gov/
quality/qs-docs/
g5m-final.pdf

                            Guidance to help organizations verify
(2.15) Guidance on          and validate data. Applying this to
Environmental Data          laboratory analytical data allows
Verification and Data       analysts to understand uncertainties
Validation (EPA, QA/G-8);   associated with concentration
http://www.epa.gov/         measurements (which impacts assessment
quality/qs-docs/            results).
g8-final.pdf

                            Describes procedures and methods for
                            ensuring sound data are used in the risk
(2.16) Data Quality         assessment. Identifies tools for
Assessment: A Reviewer's    reviewing DQOs and sampling design,
Guide (EPA, QA/G-9R);       reviewing preliminary data, selecting
http://www.epa.gov/         statistical tests to summarize and
quality/qs-docs/            analyze data, verifying the assumptions
g9r-final.pdf               of the statistical test, and performing
                            calculations.

(2.17) Data Quality         Same as (2.16).
Assessment: Statistical
Methods for Practitioners
(EPA, QA/G-9S);
http://www.epa.gov/
quality/qs-docs/
g9s-final.pdf

Resource and access         Cumulative risk remarks

Resources for planning,
scoping, and problem
formulation

                            Identifies four key steps for planning
                            and scoping: determine overall
(2.1) Guidance on           purpose and risk management
Cumulative Risk             objectives for assessment; determine
Assessment-Part 1,          scope, problem statement, participants
Planning and Scoping        and resources; determine risk
(EPA); http://              dimensions and technical elements
www.epa.gov/OSA/spc/pdfs/   that may be evaluated; formulate a
cumrisk2.pdf                technical approach including a
                            conceptual model and analysis plan for
                            the assessment.

(2 2) Lessons Learned on    Provides information and feedback
Planning and Scoping for    from the Part 1 planning guidance that
Environmental Risk          offer insights for designing and
Assessments (EPA);          conducting CRAs.
http://www.epa.gov/osa/
spc/pdfs/handbook.pdf

(2.3) Framework for         Defines general structure and
Cumulative Risk             components of CRAs; provides the
Assessment (EPA);           groundwork for scoping context
http://www.epa.gov/raf/     considered in this paper.
publications/
framework-cra.htm

                            This tool can help identify problems to
                            be assessed in a CRA. Although
(2.4) EJView (EPA);         presented here within the
http://epamap14.epa.gov/    planning/problem formulation phase,
ejmap/entry.html            this tool is also useful for other
                            phases, including risk characterization.

(2.5) Superfund Community
Involvement Handbook,       Developed for the Superfund program;
Appendix A: Superfund       with cross-cutting information about
Community Involvement       community involvement, including
Requirements (EPA);         forming community advisory groups
http://www.epa.gov/         (CAGs), this resource is also useful for
superfund/ community/       CRAs at contaminated sites.
involvement.htm; http://
www.epa.gov/superfund/
community/cag/pdfs/
ci_handbook.pdf

                            Presents a step-by-step process a
                            community can follow to form a
                            partnership to access technical
                            expertise, identify and inventory local
(2.6) Community Air         sources of air pollutants, review these
Screening How-To Manual     sources to identify known hazards that
(EPA); http://www.epa       might pose a health risk to the
.gov/oppt/cahp/pubs/        community, and set priorities and
howto.htm                   develop a plan for making
                            improvements. Covers only the air
                            pathway.

(2.7) Hanford Site (DOE),   The HAB mission language, online tools,
Hanford Advisory Board      and other information can serve as
(HAB), Public Involvement   examples for other CRA projects.
Resources and Calendar;
http://www.hanford.gov/
page.cfm/hab,
http://www.hanford.gov/
public/calendar/

                            Insights for cumulative assessments
(2.8) Los Alamos National   can be found in the RAC guidelines for
Laboratory (LANL) (DOE),    stakeholder involvement, open survey
Risk Assessment             questions, plans for soliciting
Corporation (RAC),          (in various venues) and summarizing
Risk Analysis,              inputs to guide the assessment, and
Communication,              suggestions for pursuing grants for
Evaluation, and Reduction   ongoing stakeholder involvement
(RACER) project;            (aimed to be administered through an
http://www.racteam.com/     independent group), as well as other
racer.html                  plans and products that can be found
                            on the project website.

(2.9) Savannah River Site   Recommendations and information on
(DOE), Citizens Advisory    workshops published on this website
Board (CAB); http://        can offer insights for similar projects.
www.srs.gov/general/
outreach/srs-cab

(2.10) Weldon Spring Site   This early project illustrated the
(DOE), Partners in          essential role of the community in
Education; http://www.lm.   developing and implementing a CRA for
doe.gov/Weldon/             a legacy waste site.
CPAR_WSSRAP_Update_Jun92
.pdf; http://www.lm
.doe.gov/Weldon/
10_23_2002summary.pdf

Resources for guiding
data quality

(2.11) Guidance on          Recommended planning process when
Systematic Planning Using   environmental data are used to select
the Data Quality            between two opposing conditions, useful
Objectives Process          for CRAs. The focus is on the
(EPA, QA/G-4);              (cumulative risk) questions to be
http://www.epa.gov/         answered, while maintaining awareness
quality/qs-docs/            of the appropriate statistical
g4-final.pdf                techniques that should be considered to
                            produce scientifically defensible
                            results.

(2.12) Software             General analytical guidance can be
(EPA, QA/G-4D);             applied to multiple media and multiple
http://www.epa.gov/         contaminants. Could be adapted
quality/qs-docs/            to support chemical grouping.
g4d-final.pdf

(2.13) Guidance on          Can be useful to identify colocated
Choosing a Sampling         contaminants to support grouping for
Design for Environmental    a CRA at a contaminated site or
Data Collection             situation.
(EPA, QA/G5S);
http://www.epa.gov/
quality/qs-docs/
g5s-final.pdf

(2.14) Guidance for         Can be useful for CRAs, particularly
Quality Assurance Project   where air or groundwater models are
Plans for Modeling          needed to extrapolate small data sets
(EPA, QA/G-5M);             to the site or community level.
http://www.epa.gov/
quality/qs-docs/
g5m-final.pdf

                            Useful for determining appropriate
(2.15) Guidance on          data for chemicals to be evaluated in a
Environmental Data          CRA; important with regard to results,
Verification and Data       especially when using conservative
Validation (EPA, QA/G-8);   screening approaches.
http://www.epa.gov/
quality/qs-docs/
g8-final.pdf

                            Can indicate differences in statistical
(2.16) Data Quality         robustness that might affect data
Assessment: A Reviewer's    combinations for chemical grouping
Guide (EPA, QA/G-9R);       and selection of representative
http://www.epa.gov/         concentrations.
quality/qs-docs/
g9r-final.pdf

                            Same as (2.16); for example, if some
                            data were collected according to
(2.17) Data Quality         DQOs established with decision error
Assessment: Statistical     feasibility trials while other data were
Methods for Practitioners   collected under another program that
(EPA, QA/G-9S);             required fewer samples, care would be
http://www.epa.gov/         warranted when combining these data.
quality/qs-docs/
g9s-final.pdf

TABLE 3: Selected resources for evaluating
environmental fate and transport.

Resource and access              Purpose and scope

                                 An online, EPA-linked search engine
                                 that provides access to information
(3.1) ChemBioFinder Database     on the chemical, physical, and
(private, linked via EPA at:     biological properties of a large
http://www.epa.gov/oppt/sf/      number of chemicals. Developed
tools/measured.htm);             by CambridgeSoft, this tool can
http://chemfinder.               search per the chemical's common
cambridgesoft.com/               name, brand name, Chemical
                                 Abstract Service (CAS) number,
                                 chemical formula, or other
                                 designations, including chemical
                                 structure.

                                 This guidance was published
                                 in 1996, with updates continuing
(3 2) Soil Screening Guidance    through the 2002 supplement; it
(EPA), and Supplemental          includes an extensive set of
Guidance for Developing Soil     environmental and physical
Screening Levels for Superfund   constants and parameters that can
Sites (EPA);                     be used to model the fate and
http://www.epa.gov/superfund/    transport of chemicals in soil and
health/ conmedia/soil/           to develop risk-based soil
introtbd.htm; http://            screening levels (SSLs) to protect
www.epa.gov/superfund/health     human health. Tables of
/conmedia/soil/index.htm         chemical-specific constants include
                                 organic carbon partition
                                 coefficient ([K.sub.oc]),
                                 soil-water partition coefficient
                                 ([K.sub.d]), and water and air
                                 diffusivity constants ([D.sub.w]
                                 and [D.sub.i], resp.), as well as
                                 default values for such parameters
                                 as fraction of organic carbon
                                 in soil ([f.sub.oc]), dry soil bulk
                                 density ([[rho].sub.b]), and
                                 water-filled soil porosity
                                 ([[theta].sub.w]), to support the
                                 evaluation of fate and transport.
                                 The primary goal is to provide
                                 simple screening information and a
                                 method for developing site-specific
                                 levels considering soil and
                                 groundwater; although presented in
                                 this section, it is also considered
                                 relevant to Table 4 for
                                 exposure-based screening.

(3.3) Guidance for Comparing     Published in 2002, this guidance
Background and Chemical          outlines statistical methods for
Concentrations in Soil for       characterizing background
CERCLA Sites (EPA);              concentrations of chemicals at
http://www.epa.gov/oswer/        contaminated sites. Developed for
riskassessment/pdf/              both human and ecological risk
background.pdf                   assessors as well as decision
                                 makers.

(3.4) SBAT, Soil                 Tool for estimating
BioAccessibiity Tool (EPA);      bioaccessibility of arsenic and
http://www.epa.gov/              chromium from soil on abandoned
superfund//programs/             mine lands and implications for
aml/tech/news/sbat htm           bioavailability (following
                                 ingestion). Results indicate that
                                 iron and manganese oxides can
                                 oxidize arsenic (III to V), and
                                 that organic matter and ferrous
                                 minerals reduce chromium (from VI
                                 to III), possibly reducing
                                 toxicities from oral exposure.
                                 Sequestration is enhanced by
                                 contact time (indicating less
                                 accessibility of metals from
                                 aged soils).

(3.5) SESOIL, SEasonal SOIL      SESOIL is a one-dimensional (1-D)
compartment model (in the        vertical transport screening-level
public domain although updated   model for the unsaturated (vadose)
versions are available from      zone that can be used to simulate
RockWare, Inc.);                 the fate of contaminants in soil
http://www.rockware.com/;        to support site-specific cleanup
http://www.epa.gov/opptintr/     objectives. Simulates natural
exposure/pubs/gems.htm           attenuation based on diffusion,
                                 adsorption, volatilization,
                                 biodegradation, cation exchange,
                                 and hydrolysis. The model can
                                 evaluate one chemical at a time;
                                 it does not predict interactions in
                                 environmental media.

(3.6) Summers model (as          Screening-level leachate code that
for (3.5));                      estimates groundwater
http://www.seview.com/           concentrations based on mixing.
                                 Simulates dilution of soil in
                                 ground water. Themodel can evaluate
                                 one chemical at a time; it does not
                                 predict interactions
                                 in environmental media.

(3.7) AT123D, Analytical         Generalized three-dimensional (3-D)
Transient 1-, 2- and             groundwater transport and fate
3-Dimensional Simulation of      model; processes simulated include
Waste Transport in the Aquifer   advection, dispersion, adsorption,
System (EPA and private);        and biodegradation as a first-order
http://www. scisoftware.com/;    decay process. Transport can be
http://www.epa.gov/opptintr/     simulated over 10,000 years.
exposure/ pubs/gems.htm          When linked with SESOIL, the model
                                 can simulate up to 1,000 years of
                                 contaminant migration.
                                 It can evaluate one chemical at a
                                 time (including radionuclides),
                                 and it can also evaluate heat
                                 (as a physical stressor); it does
                                 not predict interactions
                                 in environmental media.

(3.8) MODFLOW, with many         This widely used model numerically
iterations/updates (USGS)        solves the 3-D groundwater flow
http://water.usgs.gov/nrp/       equation for a porous medium by
gwsoftware/mo dflow.html         using a finite-difference method.
(Note Visual MODFLOW is          Visual MODFLOW output is graphic,
available for a fee from the     including 2-D and 3-D maps.
developer)                       Designed to model flow, it can
                                 evaluate one chemical at a time
                                 (information is input by the user);
                                 it does not predict interactions in
                                 environmental media.

(3.9) MULKOM codes, including    Three-dimensional, three-phase flow
TMVOC (and predecessor T2VOC)    of water, air, and volatile organic
(Lawrence Berkeley Laboratory,   compounds (VOCs) in saturated and
DOE); http://www-esd.lbl.gov/    unsaturated (vadose) zones to
TOUGH2                           support remediation evaluations
                                 such as for soil vapor extraction.
                                 TMVOC can address more than one
                                 volatile organic (e.g., to model
                                 a spill of fuel hydrocarbons
                                 or solvents).

(3.10) MT3D (links to            Three-dimensional transport model
MODFLOW); http://www.ess.co      for simulating advection,
.at/ECOSIM/MANUAL/mt3d.html      dispersion, and chemical reactions
                                 in groundwater systems; it assumes
                                 first-order decay and addresses one
                                 chemical at a time.

(3.11) Guidance for Evaluating   Provides a model to estimate
Vapor Intrusion into             convective and diffusive transport
Buildings (EPA);                 of chemical vapors to indoor air.
http://www.epa.gov/oswer/        Could offer insights for situations
vaporintrusion; state example:   where indoor air exposures are a
http://www.envirogroup.com/      concern. More than half the states
links.php;application:           also provide simplified equations
http://www.deq.louisiana.gov/    for screening chemicals via the
portal/ Portals/0/               vapor intrusion pathway. For an
RemediationServices/             indication of states, see the
RPform_5340.pdf                  second web link. Example
                                 application context is provided
                                 from the Louisiana Department of
                                 Environmental Quality (LDEQ)
                                 via the third web link.

                                 In 1998, EPA Region 6 identified a
                                 need for guidance that consolidated
                                 information from earlier EPA
                                 documents and state environmental
                                 agency reports, to provide an
                                 integrated set ofprocedures for
                                 conducting site-specific combustion
                                 risk assessments addressing
(3.12) Risk Assessment           multiple sources and exposure
Protocols for Hazardous Waste    scenarios. Two documents were
Combustion Facilities (EPA);     prepared, the 1999 Screening Level
http://www.epa.gov/osw/          Ecological Risk Assessment Protocol
hazard/tsd/td/combust/risk       for Hazardous Waste Combustion
htm; http://www.epa.gov/         Facilities (SLERAP) and the 2005
osw/hazard/tsd/td/combust/       Human Health Risk Assessment
ecorisk.htm                      Protocol for Hazardous Waste
                                 Combustion Facilities (HHRAP). The
                                 objectives were to (1) apply the
                                 best available methods for
                                 evaluating risks to human health
                                 and the environment from operations
                                 of hazardous waste combustion units
                                 and (2) develop repeatable and
                                 documented methods for consistency
                                 and equity in permitting decisions.
                                 In addition to methods for
                                 evaluating multimedia, multipathway
                                 risks, the second document contains
                                 information on chemical, physical,
                                 and environmental properties of
                                 many chemicals, for use in modeling
                                 environmental fate and transport
                                 and exposure.

Information on the following models is available via compilations on
EPA websites (including http://www.epa.gov/ada/csmos/ and
http://www.epa.gov/esd/databases/datahome.htm); therefore,
individual links are not provided in this section of the table.

                                 Simulates the subsurface flow,
                                 transport, and fate of contaminants
(3.13) 2DFATMIC and 3DFATMIC     that are undergoing chemical and/or
                                 biological transformations.
                                 Applicable to transient conditions
                                 in both saturated and unsaturated
                                 zones. Results can indicate how
                                 far a plume may migrate.

(3.14) BIOCHLOR                  Screening model that simulates
                                 remediation by natural attenuation
                                 of dissolved solvents at sites with
                                 chlorinated solvents. Can be used
                                 to simulate solute transport
                                 without decay and solute transport
                                 with biodegradation modeled as a
                                 sequential first-order process
                                 within one or two different
                                 reaction zones.

(3.15) BIOPLUMEII and            Model 2-D contaminant transport
BIOPLUME III                     under the influence of
                                 oxygen-limited biodegradation
                                 (BIOPLUME II) and under the
                                 influence of oxygen, nitrate,
                                 iron, sulfate, and methanogenic
                                 biodegradation (BIOPLUME III).
                                 Model advection, dispersion,
                                 sorption, biodegradation
                                 (aerobic and anaerobic), and
                                 reaeration (BIOPLUME II) through
                                 instantaneous, first order, zero
                                 order, or Monod kinetics
                                 (BIOPLUME III). BIOPLUME III was
                                 developed primarily for modeling
                                 the natural attenuation oforganic
                                 contaminants in groundwater; it is
                                 particularly useful at
                                 petroleum-contaminated sites.

(3.16) BIOSCREEN                 Screening-level groundwater
                                 transport model that simulates the
                                 natural attenuation of
                                 dissolved-phase hydrocarbons.
                                 It is based on the Domenico
                                 analytical contaminant transport
                                 model and can simulate natural
                                 attenuation based on advection,
                                 dispersion, adsorption, and
                                 biological decay. It estimates
                                 plume migration to evaluate risk at
                                 specific locations and times.
                                 (Selected model comparisons
                                 indicated that concentrations may
                                 be underestimated compared with
                                 AT123D and MODFLOW/MT3D.)

(3.17) CHEMFLO                   Simulates 1-D water and chemical
                                 movement in the vadose zone. Models
                                 advection, dispersion, first-order
                                 decay, and linear sorption. Results
                                 can indicate how far a plume
                                 will migrate.

(3.18) GEOEAS, Geostatistical    Enables geostatistical analysis of
Environmental Assessment         spatially correlated data.
Software                         Can perform basic statistics and
                                 scatter plots/linear and nonlinear
                                 estimation (kriging).

(3.19) GEOPACK                   Comprehensive package for
                                 geostatistical analyses of
                                 spatially correlated data. Can
                                 perform basic statistics,
                                 variography, and linear and
                                 nonlinear estimation (kriging).

(3.20) HSSM, Hydrocarbon Spill   Can simulate light nonaqueous phase
Screening Model                  liquid (LNAPL) flow and transport
                                 from the ground surface to the
                                 water table; radial spreading of
                                 LNAPL phase at the water table;
                                 dissolution the and aquifer
                                 transport of the chemical. It is
                                 1-D in the vadose zone, radial in
                                 the capillary fringe, and provides
                                 a 2-D vertically averaged
                                 analytical solution of the
                                 advection-dispersion equation in
                                 the saturated zone.
                                 (It is available in Spanish.)

(3.21) PESTAN, Pesticide         Vadose zone modeling of the
Analytical Model                 transport of organic pesticides.
                                 Models advection, dispersion,
                                 first-order decay, and linear
                                 sorption. Results can indicate
                                 how far a contaminant plume
                                 will migrate.

(3.22) STF, Soil Transport       Provides data on the behavior of
and Fate Database                organic and a few inorganic
                                 chemicals in soil. (EPA review was
                                 designed to verify data accuracy;
                                 the information is believed to be
                                 accurate, but EPA does not make any
                                 claim regarding data accuracy and
                                 is not responsible for its use.)

(3.23) UTCHEM                    Three-dimensional model that
                                 simulates aqueous phase and
                                 nonaqueous phase liquid (NAPL)
                                 movement in the subsurface.
                                 It can address multiple phases,
                                 dissolution, and/or mobilization by
                                 nondilute remedial fluids, chemical
                                 and microbiological transformations
                                 (including temperature dependence
                                 of geochemical reactions), and
                                 changes in fluid properties as
                                 a site is remediated.

Resource and access              Cumulative risk remarks

                                 Can also be useful to indicate
(3.1) ChemBioFinder Database     common characteristics to support
(private, linked via EPA at:     chemical grouping (e.g.,
http://www.epa.gov/oppt/sf/      by soil-water partition coefficient
tools/measured.htm);             ([K.sub.d]) for exposure analyses,
http://chemfinder.               or considering biological
cambridgesoft.com/               properties to support toxicity
                                 screening).

(3 2) Soil Screening Guidance    Developed for use at contaminated
(EPA), and Supplemental          sites on the National Priorities
Guidance for Developing Soil     List, the concepts can be extended
Screening Levels for Superfund   to other sites and situations.
Sites (EPA);                     It presents both detailed models
http://www.epa.gov/superfund/    and generic SSLs that can be used
health/ conmedia/soil/           to quickly (and conservatively)
introtbd.htm; http://            assess what areas or pathways might
www.epa.gov/superfund/health     warrant more detailed analyses.
/conmedia/soil/index.htm         The guidance includes tables of
                                 chemical-specific constants such
                                 as the [K.sub.oc], [K.sub.d],
                                 [D.sub.w], and [D.sub.i],aswell as
                                 default values for parameters like
                                 [f.sub.oc], [[rho].sub.d], and
                                 [[theta].sub.w], to support
                                 analyses of fate and transport that
                                 can guide fate-based exposure
                                 groupings for CRAs.

(3.3) Guidance for Comparing     This guidance explicitly
Background and Chemical          acknowledges the important role of
Concentrations in Soil for       background concentrations in
CERCLA Sites (EPA);              communicating cumulative risks
http://www.epa.gov/oswer/        associated with contaminated sites
riskassessment/pdf/              and indicates that cumulative risk
background.pdf                   considers all exposure pathways
                                 and the chemicals associated
                                 with them.

(3.4) SBAT, Soil                 Provides context for fate of
BioAccessibiity Tool (EPA);      these combined metals in soil,
http://www.epa.gov/              highlighting specific factors to be
superfund//programs/             measured or otherwise evaluated to
aml/tech/news/sbat htm           produce a more realistic and
                                 practical site-specific assessment;
                                 these include predicted
                                 bioavailability following intake
                                 (notably specific physical and
                                 chemical properties of the soil).

(3.5) SESOIL, SEasonal SOIL      Results can indicate how far a
compartment model (in the        contaminant plume could migrate;
public domain although updated   predicted concentrations can be
versions are available from      compared to media-specific
RockWare, Inc.);                 standards and can be used to
http://www.rockware.com/;        estimate single-chemical risks
http://www.epa.gov/opptintr/     based on standard default exposure
exposure/pubs/gems.htm           parameters, locations, and times.
                                 The location- and time-specific
                                 predictions for single chemicals
                                 can be overlain to support grouping
                                 decisions for a cumulative
                                 assessment.

(3.6) Summers model (as
for (3.5));                      Same as (3.5) for SESOIL (and (3.7)
http://www.seview.com/           for AT123D).

(3.7) AT123D, Analytical
Transient 1-, 2- and             Same as (3.5) and (3.6). This model
3-Dimensional Simulation of      can evaluate single chemicals,
Waste Transport in the Aquifer   including radionuclides, and
System (EPA and private);        it can also evaluate heat
http://www. scisoftware.com/;    (a physical stressor).
http://www.epa.gov/opptintr/
exposure/ pubs/gems.htm

(3.8) MODFLOW, with many         Results can indicate how far a
iterations/updates (USGS)        contaminant plume could migrate;
http://water.usgs.gov/nrp/       predicted concentrations can be
gwsoftware/mo dflow.html         compared to media-specific
(Note Visual MODFLOW is          standards and can be used to
available for a fee from the     estimate single-chemical risks
developer)                       based on standard default exposure
                                 parameters, locations, and times.
                                 Location- and time-specific
                                 predictions for single chemicals
                                 can be overlain to support grouping
                                 decisions for a cumulative
                                 assessment.

(3.9) MULKOM codes, including    Similar to MODFLOW (see (3.8)), but
TMVOC (and predecessor T2VOC)    it can address a mixture of VOCs.
(Lawrence Berkeley Laboratory,   Like the other models, this set
DOE); http://www-esd.lbl.gov/    depends heavily on extensive site
TOUGH2                           setting characterization for
                                 results to be meaningful; it can be
                                 difficult to get the data needed
                                 for all parameters.

(3.10) MT3D (links to            Chemical reactions can be addressed
MODFLOW); http://www.ess.co      with a loss term (chemical data
.at/ECOSIM/MANUAL/mt3d.html      must be input by the user), but the
                                 degradation product is not tracked.
                                 Depends heavily on extensive site
                                 characterization; it can be
                                 difficult to get the data needed
                                 for all parameters.

(3.11) Guidance for Evaluating
Vapor Intrusion into
Buildings (EPA);
http://www.epa.gov/oswer/        Model output can be used to support
vaporintrusion; state example:   CRAs, as concentrations of multiple
http://www.envirogroup.com/      chemicals can be evaluated
links.php;application:           simultaneously.
http://www.deq.louisiana.gov/
portal/ Portals/0/
RemediationServices/
RPform_5340.pdf

                                 Provides methods for evaluating
                                 multimedia, multipathway risks.
                                 Volume II contains information and
(3.12) Risk Assessment           data on the physicochemical and
Protocols for Hazardous Waste    environmental properties ofmany
Combustion Facilities (EPA);     chemicals, which can be used to
http://www.epa.gov/osw/          model environmental fate and
hazard/tsd/td/combust/risk       transport and exposure.
htm; http://www.epa.gov/         This information could be used to
osw/hazard/tsd/td/combust/       predict which chemicals are likely
ecorisk.htm                      to share a similar fate in the
                                 environment, to support exposure
                                 groupings for CRAs.

Information on the following models is available via compilations on
EPA websites (including http://www.epa.gov/ada/csmos/ and
http://www.epa.gov/esd/databases/datahome.htm); therefore,
individual links are not provided in this section of the table.

                                 Predicted concentrations can be
                                 compared to media-specific standards
                                 to assess single-chemical risks using
                                 exposure parameters, locations, and
                                 times. The model can evaluate one
(3.13) 2DFATMIC and 3DFATMIC     chemical at a time; it does not predict
                                 interactions in environmental media.
                                 Location- and time-specific
                                 predictions for single chemicals can be
                                 overlain to support grouping decisions
                                 for a cumulative assessment.

(3.14) BIOCHLOR                  Same as (3.13) and (3.15).

(3.15) BIOPLUMEII and            Same as (3.13) and (3.15).
BIOPLUME III
(3.16) BIOSCREEN                 Predicted concentrations can be
                                 compared to media-specific
                                 standards and can be used to
                                 estimate single-chemical risks
                                 based on standard default exposure
                                 parameters, locations, and times.
                                 The model can evaluate one chemical
                                 at a time; it does not predict
                                 interactions in environmental
                                 media. Location- and time-specific
                                 predictions for single chemicals
                                 can be overlain to support grouping
                                 decisions for a cumulative
                                 assessment.

(3.17) CHEMFLO                   Same as (3.16).

(3.18) GEOEAS, Geostatistical
Environmental Assessment         Same as (3.16).
Software

(3.19) GEOPACK                   Same as (3.16).

(3.20) HSSM, Hydrocarbon Spill   Predicted concentrations can be
Screening Model                  compared to media-specific
                                 standards and used to estimate
                                 single-chemical risks based on
                                 exposure parameters, locations,
                                 and times. The model can evaluate
                                 one chemical at a time; it does
                                 not predict interactions in
                                 environmental media. Location- and
                                 time-specific predictions for
                                 single chemicals can be overlain
                                 for CRA groupings.

(3.21) PESTAN, Pesticide         Same as (3.20).
Analytical Model

(3.22) STF, Soil Transport       This general-use tool can be used
and Fate Database                to evaluate the physicochemical
                                 properties of environmental
                                 contaminants for CRAs. The focus
                                 is one chemical at a time;
                                 interactions are not addressed.

(3.23) UTCHEM                    This general-use tool can be
                                 applied to evaluate environmental
                                 contaminants for CRAs.
                                 It can be interesting when used
                                 to assess cumulative risk because
                                 NAPL is commonly a complex mixture
                                 itself and can be present
                                 in multiple phases, which are
                                 assessed by the model.

TABLE 4: Additional resources for evaluating exposure.

Resource and access              Purpose and scope

(4.1) Exposure Factors           Provides extensive values and
Handbook (EPA); http://cfpub.    underlying bases for many factors
epa.gov/ncea/risk/               that affect exposures. Examples
recordisplay.cfm?deid=236252     include exposure duration,
(this 2011 handbook updated      frequency, surface area, inhalation
the 1997 document; highlights    rate per activity level, and
are also available, at           age/gender, as well as ingestion
http://cfpub.epa.gov/ncea/       rates (including for incidental
risk/recordisplay                soil ingestion and by food type)
.cfm?deid=221023);               based on age and gender. Because
child-specific handbook:         children can exhibit different
(published in 2008):             exposure patterns to environmental
http://cfpub.epa.gov/ncea/       toxicants than adults, the
risk/recordisplay                EPA published the Child-Specific
.cfm?deid=199243                 Exposure Factors Handbook in 2008
                                 to provide a summary of available
                                 statistical data on various factors
                                 assessing children's exposures.

(4.2) Sociodemographic Data      Setting-specific social and
Used for Identifying             demographic characteristics can
Potentially Highly Exposed       cause various subgroups to incur
Populations (EPA);               higher exposures than the general
http://cfpub.epa.gov/ncea/       population. Published in 1999, this
cfm/recordisplay                 report provides information to help
.cfm?deid=22562                  identify those population
                                 subgroups; it includes information
                                 related to activity patterns
                                 (how time is spent),
                                 microenvironments (where time is
                                 spent), and other data such as
                                 gender, race, age, and economic
                                 status. Fact Finder searches and
                                 returns data from this document.

(4.3) NHEXAS, National Human     The EPA Office of Research and
Exposure Assessment              Development conducted the NHEXAS
Survey (EPA);                    survey in the 1990s to assess U.S.
http://www.epa.gov/heasd/        exposures to chemicals in concert
edrb/nhexas.html; HEDS, Human    with their activities.
Exposure Database System;
http://www.epa.gov/heds/

(4.4) 3MRA (Center for           Developed for screening-level
Exposure Assessment Modeling,    exposure and risk assessments for
CEAM) (EPA); http://www.epa      multiple media, multiple pathways,
.gov/ceampubl/mmedia/            and multiple receptors, for
3mra/index.htm                   potential human and ecological
                                 health risks from chronic exposures
                                 to chemicals released from
                                 land-based waste management units
                                 containing listed waste streams.
                                 Site based, it was intended for
                                 national-scale application to
                                 generate risk-based standards
                                 (e.g., levels to exit from
                                 hazardous waste regulation);
                                 it evaluates human and ecological
                                 receptors and captures uncertainty
                                 and variability in risk estimates.
                                 (Ecological exposure and risk focus
                                 on population effects related to
                                 key species within habitats found
                                 in the proximity of sites.)

(4.5) E-FAST, Exposure and       Provides screening-level estimates
Fate Assessment Screening Tool   for general population, consumer,
(EPA); http://www.epa.gov/       and environmental exposures to
oppt/exposure/pubs/efastdl.htm   concentrations of chemicals
                                 released to air, surface water,
                                 and landfills and released from
                                 consumer products. It estimates
                                 potential inhalation, dermal and
                                 ingestion doses, and the modeled
                                 concentrations and doses are
                                 designed to reasonably overestimate
                                 exposures for use
                                 in screening-level assessments.

(4.6) FRAMES, Framework for      Integrated software system to
Risk Analysis in Multimedia      conduct screening-level
Environmental Systems            assessments of health and
(DOE Pacific Northwest           ecological risks for hazardous
National Laboratory,             waste identification rule (HWIR)
in support of EPA);              chemicals from land-based waste
http://www.epa.gov/athens/       management units.
research/modeling/3mra.html

(4.7) TRACI, Tool for the        TRACI is an impact assessment tool
Reduction and Assessment of      for evaluating multiple
Chemical and Other               chemical-impact and resource-use
Environmental Impacts (EPA);     categories to analyze various study
http://www.epa.gov/nrmrl/std/    designs. Impacts that can be
traci/traci.html                 modeled include ozone depletion,
                                 global warming, acidification,
                                 eutrophication, photochemical smog,
                                 cancer risk and noncancer health
                                 effects, human health criteria,
                                 ecotoxicity, fossil fuel use, land
                                 use, and water use. The program
                                 includes quantitative data on human
                                 carcinogenicity and
                                 noncarcinogenicity (based on human
                                 toxicity potentials),
                                 acidification, smog formation, and
                                 eutrophication. The model uses
                                 a probabilistic approach to
                                 determine spatial scale(s) for
                                 other impact categories such as
                                 acidification, smog formation,
                                 eutrophication, and land use.

(4.8) SCRAM, Support Center      Provides descriptions and
for Regulatory Atmospheric       documentation for different types
Modeling (EPA), includes links   of air quality models, information
for air quality models,          on modeling tools, and support for
applications, and tools;         existing models. Also provides
http://www.epa.gov/ttn/scram/    links to relevant workshops,
                                 conferences, reports, journal
                                 articles, and websites with further
                                 information about atmospheric and

                                 air quality models and monitors.

(4.9) Technology Transfer        EPA resource of tools to support
Network (TTN), CHIEF,            air pathway analyses. The TTN
Clearinghouse for Inventories    maintains a Clearinghouse for
and Emissions Factors (EPA);     Inventories and Emission
http://www.epa.gov/ttn/chief/    Factors(CHIEF) that links to a number
                                 of helpful technical documents on
                                 methods and data for constructing
                                 emissions inventories, including
                                 the Handbook for Criteria Pollutant
                                 Inventory Development:
                                 A Beginner's Guide for Point and
                                 Area Sources, Handbook for Air
                                 Toxics Emission Inventory
                                 Development, Volume I: Stationary
                                 Sources, and Compilation of
                                 Air Pollutant Emission Factors.

(4.10) HARP, Hotspots Analysis   Software package for facility
and Reporting Program Tool       emissions inventory databases;
(California Air Resources        prioritize facilities for
Board, CARB);                    management; model atmospheric
http://www.arb.ca.gov/toxics/    dispersion of chemicals from one or
harp/downloads.htm#2             multiple facilities using EPA
                                 models; calculate cancer and
                                 noncancer (acute and chronic)
                                 health impacts using Cal/EPA
                                 guidance; use point estimates or
                                 data distributions of exposures to
                                 calculate inhalation and
                                 multipathway risks; perform
                                 stochastic health risk analyses;
                                 calculate potential health effects
                                 for individual receptors,
                                 population exposures, cumulative
                                 impacts for one or multiple
                                 facilities and one or multiple
                                 pollutants, and potential health
                                 effects using ground-level
                                 concentrations; present results as
                                 tables and isopleth maps.

(4.11) CalTOX Model;             Spreadsheet-based model that
http://www.dtsc.ca.gov/          relates the concentration of a

AssessingRisk/caltox.cfm         chemical in soil to the risk of an
                                 adverse health effect for a person
                                 living or working on or near
                                 a site. Defaults are available, but
                                 site-specific values are
                                 recommended. It estimates the
                                 chemical concentration in the
                                 exposure media of breathing zone
                                 air, drinking water, food, and soil
                                 that people inhale, ingest, and
                                 dermally contact, and uses the
                                 standard equations found in RAGS
                                 (EPA 1989) to estimate exposure
                                 and risk.

(4.12) DEPM, Dietary Exposure    Estimates dietary exposures to
Potential Model (EPA);           multiple chemicals based on data
http://www.epa.gov/              from several national,
nerlcwww/depm.html               government-sponsored food intake
                                 surveys and chemical residue
                                 monitoring programs. Includes
                                 recipes developed specifically for
                                 exposure analyses that link
                                 consumption survey data for
                                 prepared foods to chemical residue
                                 information, which is normally
                                 reported for raw food ingredients,
                                 to estimate daily dietary exposure.
                                 The summary databases are
                                 aggregated in a way that allows the
                                 analyst to select appropriate
                                 demographic factors, such as
                                 age/gender groups, geographical
                                 regions, ethnic groups, and
                                 economic status. Includes modules
                                 for evaluating exposures from
                                 residues, soil, and tap water.

(4.13) All-Ages Lead Model       EPA model used to predict lead
(EPA); http://cfpub.epa.gov/     concentrations in body tissues and
ncea/cfm/ recordisplay           organs for a hypothetical
.cfm?deid=139314; supporting     individual based on a simulated
technical data and related       lifetime of lead exposure,
methods and models are at        extrapolated to a population of
http://www.epa.gov/superfund/    similarly exposed individuals.
health/contaminants/lead/        Rather than external dose, most
products.htm; related            health effects data for lead are
documents including interim      based on blood lead concentration
soil lead guidance for CERCLA    which is an integrated measure of
sites and RCRA corrective        internal dose, reflecting total
action facilities are also       exposure from all sources (e.g.,
available: http://www.epa.gov/   both site-related and background
superfund/lead/products/         sources for Superfund sites).
oswerdir.pdf                     Both the EPA and Cal/EPA Department
                                 of Toxic Substances Control (DTSC)
                                 have developed models to estimate
                                 blood lead concentrations from
                                 exposures to lead from various
                                 media, including soil, water, air,
                                 and food. In addition to its tool
                                 for assessing exposures to children
                                 (IEUBK, integrated exposure uptake
                                 and biokinetic model), the EPA also
                                 developed a further set of models
                                 for evaluating lead exposures and
                                 risks for nonresidential adults
                                 (the all-ages model).

(4.14) NIOSH NORA Mixed          Provides technical and support
Exposures program;               information on projects involving
http://www.cdc.gov/niosh/nora/   mixed exposures in the workplace.
                                 National Occupational Research
                                 Agenda (NORA) program identified a
                                 number of research areas for NIOSH
                                 that addressed mixed occupational
                                 exposures, with an aim of
                                 protecting individuals in the
                                 workplace from exposures to
                                 multiple chemicals. The website
                                 for the mixed exposures team
                                 provides links to related studies,
                                 as well as information on how to
                                 join a listserv group to discuss
                                 topics related to mixed exposures.

(4.15) National Cancer           A number of health registry
Registry (CDC);                  databases contain information on
http://www.cdc.gov/cancer/       various diseases, conditions, and
dcpc/data/ (this website         other health-related data,
includes links to various        including cancer, asthma, birth
state registries);               defects, and blood lead levels.
U.S. census data;                Organizations such as the CDC and
http://www.census.gov            others maintain these databases to
                                 allow these data to be evaluated in
                                 concert with modeled or measured
                                 chemical exposure data to correlate
                                 potential influences of multiple
                                 exposures and to calibrate risk
                                 models. For example, the CDC
                                 national registry of cancer cases
                                 includes cancer type and target
                                 tissue, as well as demographic and
                                 location information. Many state
                                 and local government health
                                 departments and other health
                                 organizations also maintain disease
                                 and condition registries to monitor
                                 trends over time; determine
                                 patterns in various populations;
                                 guide planning and evaluation of
                                 control programs; help set
                                 priorities for allocating health
                                 resources; advance clinical,
                                 epidemiologic, and health services
                                 research; provide information for
                                 a national database of cancer
                                 incidence. Other government
                                 resources can also be used to
                                 indicate vulnerable population
                                 groups who might be at increased
                                 risk, such as data from the U.S.
                                 Census Bureau.

Resource and access              Cumulative risk remarks

(4.1) Exposure Factors
Handbook (EPA); http://cfpub.
epa.gov/ncea/risk/
recordisplay.cfm?deid=236252     Compendia of values for exposure
(this 2011 handbook updated      parameters that can be reviewed to
the 1997 document; highlights    determine those most appropriate
are also available, at           for a given site/setting, for
http://cfpub.epa.gov/ncea/       adults and children. Can be used
risk/recordisplay                to assess multiple pathways and
.cfm?deid=221023);               activities/intake rates for
child-specific handbook:         exposures to multiple chemicals.
(published in 2008):
http://cfpub.epa.gov/ncea/
risk/recordisplay
.cfm?deid=199243

(4.2) Sociodemographic Data      Can be used to guide the
Used for Identifying             identification and characterization
Potentially Highly Exposed       of subgroups within the general
Populations (EPA);               population who could be at risk for
http://cfpub.epa.gov/ncea/       higher contaminant exposures and
cfm/recordisplay                 related effects, to be addressed
.cfm?deid=22562                  in a CRA.

(4.3) NHEXAS, National Human     This extensive set of exposure data
Exposure Assessment              linked to activity patterns can be
Survey (EPA);                    used to support CRAs, including
http://www.epa.gov/heasd/        providing insights into potentially
edrb/nhexas.html; HEDS, Human    vulnerable subpopulations.
Exposure Database System;
http://www.epa.gov/heds/

(4.4) 3MRA (Center for           Can quantify exposure via multiple
Exposure Assessment Modeling,    pathways after a simulated release.
CEAM) (EPA); http://www.epa      Human receptors include adult/child
.gov/ceampubl/mmedia/            residents, home gardeners, beef and
3mra/index.htm                   dairy farmers, and recreational
                                 fishers. Pathways include
                                 inhalation of outdoor air and
                                 indoor air while showering,
                                 ingestion of drinking water, and
                                 ingestion of farming products
                                 and fish.

(4.5) E-FAST, Exposure and       Default exposure parameters are
Fate Assessment Screening Tool   available, but the use of
(EPA); http://www.epa.gov/       site-specific values is
oppt/exposure/pubs/efastdl.htm   recommended. Can predict exposure
                                 concentrations for comparison to
                                 media-specific standards.

(4.6) FRAMES, Framework for      Can be applied to conduct health
Risk Analysis in Multimedia      and ecological screening of
Environmental Systems            multiple chemicals for disposal
(DOE Pacific Northwest           facilities.
National Laboratory,
in support of EPA);
http://www.epa.gov/athens/
research/modeling/3mra.html

(4.7) TRACI, Tool for the        Can be used to model and compare
Reduction and Assessment of      exposures to multiple chemicals
Chemical and Other               and health risks associated with
Environmental Impacts (EPA);     different projects. For example,
http://www.epa.gov/nrmrl/std/    it can graphically analyze the
traci/traci.html                 reduction in risk projected from
                                 one implementation design versus
                                 another. This tool is also relevant
                                 to risk characterization (Table 6).

(4.8) SCRAM, Support Center      Good source of models, guidance,
for Regulatory Atmospheric       and other information useful for
Modeling (EPA), includes links   CRAs that involve air quality
for air quality models,          monitoring.
applications, and tools;
http://www.epa.gov/ttn/scram/

(4.9) Technology Transfer        Source for many tools used to
Network (TTN), CHIEF,            assess emissions and dispersion of
Clearinghouse for Inventories    contaminants released to air. For
and Emissions Factors (EPA);     some cases (notably for metals,
http://www.epa.gov/ttn/chief/    including radionuclides), unit
                                 particulate emissions can be used
                                 to scale to source concentrations
                                 in order to estimate airborne and
                                 deposited contaminant
                                 concentrations.

(4.10) HARP, Hotspots Analysis   Designed to address multiple
and Reporting Program Tool       sources, pollutants,
(California Air Resources        concentrations, and exposure
Board, CARB);                    pathways to estimate cumulative
http://www.arb.ca.gov/toxics/    health effects. Also relevant to
harp/downloads.htm#2             risk characterization (Table 6),
                                 results can be printed, added to
                                 reports, or input to a GIS.

(4.11) CalTOX Model;             Can be used to assess multiple
http://www.dtsc.ca.gov/          exposures; it has tended to be more
AssessingRisk/caltox.cfm         for research than practical
                                 applications. It can predict
                                 exposure concentrations that can
                                 be compared to media-specific
                                 standards and used to estimate
                                 single-chemical risks, which could
                                 then be overlain for CRAs.

(4.12) DEPM, Dietary Exposure    Can be used to assess exposures to
Potential Model (EPA);           multiple chemicals from ingesting
http://www.epa.gov/              food andtap water; it could
nerlcwww/depm.html               potentially provide context for
                                 ambient exposures in the area
                                 of a site.

(4.13) All-Ages Lead Model       Useful for evaluating the impact of
(EPA); http://cfpub.epa.gov/     multiple sources of lead by
ncea/cfm/ recordisplay           multiple routes. Results could
.cfm?deid=139314; supporting     potentiallybe combined with risks
technical data and related       estimated for certain other
methods and models are at        contaminants if interactions with
http://www.epa.gov/superfund/    lead are known to occur (e.g., see
health/contaminants/lead/        ATSDR interaction profiles, (5.4)
products.htm; related            in Table 5).
documents including interim
soil lead guidance for CERCLA
sites and RCRA corrective
action facilities are also
available: http://www.epa.gov/
superfund/lead/products/
oswerdir.pdf

(4.14) NIOSH NORA Mixed          Information resource for mixtures
Exposures program;               in the workplace; scientific
http://www.cdc.gov/niosh/nora/   knowledge developed through this
                                 effort can offer insights for
                                 assessing the combined effects of
                                 chemicals at contaminated sites,
                                 occupational settings, and other
                                 scenarios involving multiple
                                 chemicals.

(4.15) National Cancer           Data could be used to indicate key
Registry (CDC);                  community health concerns or for an
http://www.cdc.gov/cancer/       exploratory investigation of a
dcpc/data/ (this website         certain disease or condition that
includes links to various        might increase the vulnerability of
state registries);               certain people who could be exposed
U.S. census data;                to a given chemical. However, the
http://www.census.gov            links to diseases from
                                 environmental exposures or directly
                                 to environmental pollutants as
                                 causal or contributing factors are
                                 not usually clear. This tool is
                                 also directly relevant to risk
                                 characterization (Table 6).

TABLE 5: Selected resources for toxicity

Resource and access              Purpose and scope

(5.1) Supplementary Guidance     Published in 2000, this EPA
for Conducting Health Risk       guidance supplements the EPA's
Assessment of Chemical           1986 guidelines for chemical
Mixtures (EPA);                  mixtures and describes risk
http://cfpub.epa.gov/ncea/       assessment approaches that depend
cfm/recordisplay                 on the type, nature, and quality of
.cfm?deid=20533                  available data. The report presents
                                 approaches for assessing whole
                                 mixtures, surrogate mixtures and
                                 individual mixture components,
                                 including equations, definitions,
                                 and the theory behind dose
                                 addition, response addition,
                                 toxicological interactions, and the
                                 concept of sufficient similarity
                                 among whole mixtures. Guidance is
                                 given on how to practically use
                                 whole-mixture methods to develop a
                                 whole-mixture reference dose (RfD),
                                 reference concentration (RfC), and
                                 slope factor, and to assess
                                 comparative potency and
                                 environmental transformations.
                                 Guidance is also provided for using
                                 component-based methods, including
                                 the hazard index (HI);
                                 interaction-based HI; relative
                                 potency factors (RPFs); response
                                 addition.

(5.2) Relative Potency Factors   In response to requirements of the
for Pesticide Mixtures,          Food Quality Protection Act of
Biostatistical Analyses of       1996, the EPA prepared a technical
Joint Dose- Response;            report that presents research and
http://cfpub.epa.gov/ncea/       methodologies for developing RPFs
cfm/recordisplay                 that can be used to assess
.cfm?deid=66273                  cumulative risks from exposures to
                                 mixtures such as organophosphate
                                 pesticides, dioxins, and
                                 polychlorinated biphenyls (PCBs).
                                 The document presents three
                                 scenarios for which biostatistical
                                 methods for toxicity assessment can
                                 be used, including dose addition
                                 (for simple cases where common
                                 modes of toxicity are present),
                                 integration of dose and response
                                 addition (for cases where
                                 toxicities are independent),
                                 and joint dose-response modeling
                                 (for cases where the mode of
                                 action is uncertain).

(5.3) CatReg, Categorical        This categorical regression model
Regression (EPA);                was developed for meta-analyses of
http://cfpub.epa.gov/ncea/       toxicology data. The approach could
cfm/recordisplay                 be useful for evaluating different
.cfm?deid=18162                  types of data to assess potential
                                 cumulative health risks.

(5.4) Toxicological Profiles     Toxicological profiles exist for
(ATSDR); http://www.atsdr.cdc    many chemicals, including some
.gov/toxprofiles/index.asp;      mixtures; they summarize data on
and Interaction Profiles for     sources and uses; physicochemical
Toxic Substances;                properties, environmental fate,
http://www.atsdr.cdc.gov/        and environmental levels; toxicity,
interactionprofiles/index.asp    including environmental and
                                 metabolic transformation products
                                 on specific target organs; critical

                                 effects, secondary organs and
                                 selected combinations of individual
                                 systems. ATSDR also prepared
                                 guidance for mixtures that outline
                                 an assessment approach, as well as
                                 interaction profiles for whole
                                 mixtures and chemicals with toxic
                                 interactions (often evaluated
                                 in pairs). These profiles include
                                 directions of interactions with
                                 confidence indicators by
                                 organ/system. Initial combinations
                                 are (1) arsenic, cadmium, chromium,
                                 and lead; (2) benzene, toluene,
                                 ethylbenzene, and xylene; (3)

                                 lead, manganese, zinc, and copper;
                                 (4) cyanide, fluoride, nitrate, and
                                 uranium; (5) cesium, cobalt, PCBs,
                                 strontium, and trichloroethylene;
                                 (6) 1,1,1-trichloroethane, 1,1-
                                 dichloroethane, trichloroethylene,
                                 and tetrachloroethylene;
                                 (7) arsenic, hydrazines, jet fuels,
                                 strontium-90, and
                                 trichloroethylene.

(5.5) Risk assessment            Guidelines exist for carcinogens,
guidelines (EPA);                chemical mixtures, ecology,
http://cfpub.epa.gov/ncea/cfm/   neurotoxicity, reproductive
recordisplay.cfm?deid=55907      toxicity, exposure assessment,
                                 developmental toxicity, and
                                 mutagenicity; these were developed
                                 to support risk evaluations based
                                 on recommendations from the
                                 National Academy of Sciences.

(5.6) BMDS, Benchmark Dose       Designed to fit mathematical models
Software (EPA);                  to dose-response data so results
http://www.epa.gov/ncea/         allow the selection of a benchmark
bmds/index.html                  dose (BMD) associated with a
                                 predetermined benchmark response
                                 (BMR), such as a 10% increase in
                                 the incidence of a particular
                                 lesion or a 10% decrease
                                 in body weight.

(5.7) IRIS, Integrated Risk      Key source of chronic toxicity
Information System (EPA);        information and standard toxicity
http://www.epa.gov/iris          values including RfDs and RfCs,
                                 cancer slope factors unit risks and
                                 corresponding risk-based
                                 concentrations; it includes
                                 information for more than
                                 500 chemicals. Combined with
                                 exposure information, these data
                                 can be used to characterize health
                                 risks from exposure to individual
                                 chemicals across multiple routes
                                 (where reference values are
                                 available). The toxicity values
                                 and information on target tissues
                                 included in IRIS summaries and
                                 technical support documents (TSDs)
                                 can be used in CRAs to identify
                                 chemicals that can exert primary
                                 as well as secondary effects on
                                 similar target tissues or systems.
                                 That is, although chemical
                                 interactions other than addition
                                 are not quantifiable using toxicity
                                 criteria from IRIS, the information
                                 in the accompanying technical
                                 evaluations can be used to
                                 qualitatively assess the nature and
                                 magnitude of certain interactions,
                                 and the ATSDR interaction profiles
                                 and the primary literature can be
                                 pursued for additional information.

(5.8) PPRTV (Provisional         The PPRTV database is similar to
Peer-Reviewed Toxicity Value)    IRIS in serving as a source of
database (EPA);                  toxicity values, notably to address
http://hhpprtv.ornl.gov          chemicals and exposure durations
                                 for which an IRIS value is not
                                 available, and a need for a
                                 provisional value has been
                                 identified.

(5.9) TOXNET/HSDB, MEDLINE,      NIH sponsors and maintains several
PubMed, other databases          databases for toxicology and
(NIH); via http://www.nih.gov;   environmental health applications,
for example, TOXNET/HSDB;        including TOXNET and the Hazardous
http://toxnet.nlm.nih.gov/       Substances Data Bank (HSDB),
hsdb.htm                         Haz-Map (occupational health
                                 database), PubMed, and MEDLINE,
                                 with links to biomedical journals.
                                 These contain thousands of entries
                                 for single chemicals and also
                                 include data for a substantial
                                 number ofmixtures (such as PCBs,
                                 PAHs, coal tar, crude oil, and oil
                                 dispersants).

(5.10) LRI, Long-Range           Industry-funded
Research Initiative;             scientific program included a
http://www.uslri.org/;           cumulative risk focus area.
http://lri                       Sponsored by the American Chemistry
.americanchemistry.com/          Council (ACC), research in this
                                 area emphasized assessment methods
                                 and toxicity studies for mixtures.

(5.11) RSLs, Risk-Based          RSLs for environmental media (soil,
Regional Screening Levels        drinking water, and air) are based
(EPA); http://www.epa.gov/       on specified risk levels, using
reg3hwmd/risk/human/rb-          conservative assumptions and
concentrationJtable/index.htm    established toxicity values
                                 primarily developed by EPA, as
                                 supplemented by other organizations
                                 (e.g., Cal/EPA). The RSLs were
                                 harmonized in 2008, combining the
                                 Region 3 risk-based concentrations
                                 (RBCs), Region 6 medium-specific
                                 screening levels (MSSLs), and
                                 Region 9 preliminary remediation
                                 goals (PRGs).

(5.12) RESRAD, RESidual          The original RESRAD code was
RADioactivity (DOE Argonne       designed to guide radiological
National Laboratory);            cleanup criteria for contaminated
http://www.ead.anl.gov/resrad    sites and assess doses and risks
                                 from residual radionuclides. Sister
                                 codes cover chemical contaminants
                                 to support a combined evaluation of
                                 risks and hazard indices at sites
                                 with radionuclides and chemicals.
                                 The code includes a screening
                                 groundwater model and links to an
                                 air dispersion model; it also
                                 includes a probabilistic module.
                                 The toxicity values provided
                                 include radiological risk
                                 coefficients. Results can be
                                 presented in graphs and tables.

(5.13) VEMPire, Valeur           Database for airborne chemicals
d'Exposition Moyenne Ponderee    commonly found in the workplace and
(time-weighted average,          at many contaminated sites.
worker exposure level),          Addresses Canadian occupational
database (IRSST);                standards (many are the same as
http://www.irsst.qc.ca/en/-      U.S. standards), toxicokinetics,
tool-vempire-5-5-version.html    target organs, effect levels, and
                                 mode of action whereavailable.
                                 The data base also includes
                                 a calculation tool that allows up
                                 to 10 chemicals to be assessed at
                                 a time, comparing the concentration
                                 of interest to the occupational
                                 standard to produce a sum of
                                 ratios, assuming additivity as the
                                 default approach.

(5.14) Pesticides: Health and    Identifies health information to
Safety, Common Mechanism         assess pesticide groups that share
Groups; Cumulative Exposure      common mechanisms of toxic action,
and Risk Assessment;             with links for quantitative
http://www.epa.gov/oppsrrd1/     approaches (e.g., RPF values) and
cumulative/                      qualitative approaches (e.g.,
commo_mec_groups.htm             analysis of mode of action).
                                 The pesticide groups evaluated

                                 include organophosphates,
                                 triazines, n-methyl carbamates,
                                 and chloroacetanilides.

Resource and access              Cumulative risk remarks

(5.1) Supplementary Guidance     Presents more detailed information
for Conducting Health Risk       on considerations and quantitative
Assessment of Chemical           methods for assessing risks posed
Mixtures (EPA);                  by exposures to environmental
http://cfpub.epa.gov/ncea/       mixtures.
cfm/recordisplay
.cfm?deid=20533

(5.2) Relative Potency Factors   Provides information that can be
for Pesticide Mixtures,          used to assess cumulative risks for
Biostatistical Analyses of       sites contaminated with
Joint Dose- Response;            organophosphate pesticides and
http://cfpub.epa.gov/ncea/       other organic compounds, such as
cfm/recordisplay                 dioxins and PCBs.
.cfm?deid=66273

(5.3) CatReg, Categorical        Can be used to evaluate multiple
Regression (EPA);                effects within a chemical grouping
http://cfpub.epa.gov/ncea/       (e.g., as grouped by target organ
cfm/recordisplay                 or system) and can also be used as
.cfm?deid=18162                  a tool to support the estimate of
                                 potential health effect (e.g.,
                                 hazard index) from multiple-route
                                 exposures.

(5.4) Toxicological Profiles     Some profiles address mixtures
(ATSDR); http://www.atsdr.cdc    (e.g., PCBs). These reports can be
.gov/toxprofiles/index.asp;      useful for identifying
and Interaction Profiles for     endpoint-specific effects to
Toxic Substances;                support CRAs; the toxicity data
http://www.atsdr.cdc.gov/        organized by organ/system can be
interactionprofiles/index.asp    used to determine at what levels
                                 joint toxicity could be a factor,
                                 as an initial step to guide pursuit
                                 of the primary literature.
                                 Information is included for
                                 secondary effects (those occurring
                                 at doses higher than that
                                 corresponding to the most
                                 sensitive, or critical, effect),
                                 which can also support toxicity
                                 groupings for CRAs.

(5.5) Risk assessment            Outlines approaches and data that
guidelines (EPA);                provide context for assessing
http://cfpub.epa.gov/ncea/cfm/   mixtures and multiple endpoints.
recordisplay.cfm?deid=55907      Can be used to guide toxicity
                                 groupings for CRAs.

(5.6) BMDS, Benchmark Dose       BMD values used with dose addition
Software (EPA);                  could support estimation of a BMD
http://www.epa.gov/ncea/         for a mixture. For toxicity
bmds/index.html                  endpoints described by RfDs and
                                 RfCs, this approach would provide
                                 a risk-based dose associated with
                                 a particular effect.

(5.7) IRIS, Integrated Risk      Toxicity values address some
Information System (EPA);        chemical mixtures (e.g., PCBs,
http://www.epa.gov/iris          toxaphene, and others); target
                                 organ information can be used to
                                 group chemicals for CRAs, for
                                 example, to identify those exerting
                                 primary and secondary effects on
                                 common tissues or systems.
                                 Interactions other than addition
                                 are not quantifiable using these
                                 toxicity criteria; however, the
                                 nature and magnitude of some
                                 interactions could be predicted
                                 using the information provided,
                                 notably in the TSDs. The toxicity
                                 values can be used to estimate
                                 collective noncancer effects and
                                 cancer risks by summing, assuming
                                 additivity. Age-dependent
                                 adjustment factors can be applied
                                 as indicated in TSDs when
                                 estimating risks for sensitive
                                 subpopulations, assumed to incur
                                 childhood exposures (to age 16).

(5.8) PPRTV (Provisional         Chemical mixtures for which PPRTVs
Peer-Reviewed Toxicity Value)    are available include complex
database (EPA);                  mixtures of aliphatic and aromatic
http://hhpprtv.ornl.gov          hydrocarbons, midrange aliphatic
                                 hydrocarbon streams, and xylenes.

(5.9) TOXNET/HSDB, MEDLINE,      Useful source of peer-reviewed
PubMed, other databases          information that can be used for
(NIH); via http://www.nih.gov;   toxicity groupings to support CRAs.
for example, TOXNET/HSDB;        Although listed with toxicity
http://toxnet.nlm.nih.gov/       tools, these databases also contain
hsdb.htm                         information to support
                                 exposure/fate groupings.
                                 The databases
                                 are expected to reflect further
                                 content relevant to cumulative risk
                                 as those data become available from
                                 ongoing research.

(5.10) LRI, Long-Range           Research results could offer
Research Initiative;             insights for CRAs at contaminated
http://www.uslri.org/;           sites, including regarding joint
http://lri                       toxicity.
.americanchemistry.com/

(5.11) RSLs, Risk-Based          Emphasis is on multiple pathways
Regional Screening Levels        and chemical concentrations rather
(EPA); http://www.epa.gov/       than target organs or effects.
reg3hwmd/risk/human/rb-          Although not explicitly for CRAs,
concentrationJtable/index.htm    this tool includes a suite of
                                 equations that can be used to
                                 assess multiple pathways then
                                 combine results, and the screening
                                 basis can help focus a CRA on those
                                 chemicals likely to contribute
                                 substantially to overall risks.

(5.12) RESRAD, RESidual          Can be used to assess doses and
RADioactivity (DOE Argonne       risks associated with radioactively
National Laboratory);            (and chemically) contaminated
http://www.ead.anl.gov/resrad    facilities. Accounts for
                                 radioactive decay but not
                                 environmental transformation to
                                 address changes over time; produces
                                 risks and HIs summed across
                                 contaminants and pathways; does not
                                 address toxic interactions. Can
                                 conduct a probabilistic analysis
                                 and assess sensitivity, so this is
                                 also relevant for risk
                                 characterization (Table 6).

(5.13) VEMPire, Valeur           Source of useful inhalation
d'Exposition Moyenne Ponderee    toxicity data for a large number of
(time-weighted average,          chemicals. This tool could be used
worker exposure level),          to organize chemicals by target
database (IRSST);                organ and effect; exposure levels
http://www.irsst.qc.ca/en/-      can be divided by reference levels
tool-vempire-5-5-version.html    (occupational standards), with an
                                 option for calculating a sum of
                                 ratios for 10 chemicals, assuming
                                 additivity. This approach could
                                 presumably be supplemented to
                                 account for interactions
                                 if/where known.

(5.14) Pesticides: Health and    Can be used to assess index
Safety, Common Mechanism         chemical-equivalent doses and risks
Groups; Cumulative Exposure      associated with specific pesticide
and Risk Assessment;             groups that share a common toxic
http://www.epa.gov/oppsrrd1/     mode of action.
cumulative/
commo_mec_groups.htm

TABLE 6: Selected resources for characterizing risk and uncertainty
and presenting results.

Resource and access              Purpose and scope

(6.1) SADA (Spatial Analysis     Integrated software with flexible
and Decision Assistance);        land use scenarios and exposure
http://www.tiem.utk.edu/~sada/   pathways. Emphasizes spatial
                                 distribution of contaminant data;
                                 modules cover visualization,
                                 geospatial analysis, statistical
                                 analysis, sampling design, and
                                 decision analysis. Outputs can be
                                 tabular or graphical. Can address
                                 both health and ecological risk to
                                 support integrated decisions.

(6.2) RAIMI, Regional Air        Risk-based prioritization tool
Impact Modeling Initiative       developed by Region 6 to support
(EPA); http://www.epa.gov/       regional risk-based prioritization
region6/6en/raimi/index.htm      at the community level from
                                 exposures to multiple airborne
                                 contaminants from multiple sources
                                 via multiple exposure pathways.
                                 Designed to support cross-program
                                 analyses. Includes Risk-MAP, to
                                 estimate health risks from
                                 exposures to chemical emissions
                                 over large areas.

(6.3) Environmental Load         Compares indicators ofwell-being
Profile (EPA);                   with derived benchmarks.
http://www.epa.gov/region2/      This screening-level tool was
ej/guidelines.htm                developed by EPA Region 2 to
                                 represent the environmental burden
                                 in a community in support of EJ
                                 evaluations, with links to census
                                 data via a GIS layer to support the
                                 demographic component of such
                                 assessments.

(6.4) Cumulative Adjustment of   PCLs are a set of toxicity-based
Protective Concentration         screening criteria developed

Levels (PCLs), TCEQ (Texas       for use in risk assessments.
Commission on Environmental      Individual PCLs were derived
Quality); http://www.tceq        to evaluate risks from individual
.state.tx.us/commexec/           chemicals, and TCEQ developed an
forms_pubs/pubs/rg/rg-           equation to adjust these downward
366_trrp _18.html/view           when evaluating multiple chemicals,
                                 when at least 10 carcinogenic or
                                 noncarcinogenic chemicals of concern
                                 (COCs) are identified for a given
                                 pathway. These adjustments reduce
                                 PCLs for individual chemicals based
                                 on the ratio of the measured
                                 concentration of each to its PCL.
                                 If the sum of these ratios exceeds
                                 a predetermined target, adjusted
                                 PCL values may be necessary for
                                 some COCs to ensure that state risk
                                 reduction rule mandates are met
                                 (e.g., to not exceed a risk of 10-4 or
                                 an HI of 10). COCs to be adjusted
                                 are determined from a decision
                                 process outlined in the guidance.

(6.5) HEM-3, Human Exposure      Designed to predict risks
Model-3 (EPA);                   associated with chemicals released
http://www.epa.gov/ttn/fera/     to ambient air, used primarily to
hemdownload.html                 assess risk for major point sources
                                 of air toxics. Generates results
                                 for one facility at a time focusing
                                 on the inhalation pathway. Contains
                                 an atmospheric dispersion model and
                                 U.S. census information at the
                                 census block level. Each source
                                 must be located by latitude and
                                 longitude, and its release
                                 parameters must be described.
                                 This tool is generally used to
                                 estimate concentrations within

                                 50 km of a source. It provides
                                 ambient air concentrations as
                                 surrogates for lifetime exposure,
                                 for use with unit risk estimates
                                 and inhalation RfCs to produce
                                 estimates of cancer risk and
                                 noncancer HI, respectively.

(6.6) Probabilistic tools        Statistical methods for addressing
(Monte Carlo analysis            uncertainty and variability in
resources), such as those        estimating health risks by
described at: http://www.epa     developing multiple descriptors to
.gov/raf/prawhitepaper/index.    calculate a quantity repeatedly
htm; http://www.epa.gov/raf/     with randomly selected scenarios
prawhitepaper/index.htm;         for each calculation. These are
                                 most useful for single-point risk
                                 estimates, and they can be used as
                                 a presentation tool because
                                 graphics show the range of
                                 scenarios and outputs.

(6.7) Software and User's        The IEUBK model consists of four
Manual for the Integrated        modules (exposure, uptake,
Exposure Uptake Biokinetic       biokinetic, and probability
Model for Lead in Children       distribution) to estimate blood
(IEUBK) (also Adult Lead         lead levels in children exposed to
Model, other data) (EPA);        lead by various routes.
http://www.epa.gov/superfund/    A distribution of lead
lead/index.htm;                  concentrations from the geometric
http://www.epa.gov/superfund/    mean can be used to estimate the
lead/products.htm                risk that lead level sin blood for
                                 a child or group of children will
                                 exceed a target level. The tool is
                                 included here (in addition to the
                                 related entry in Table 4) because
                                 it can also be used to assess the
                                 uncertainty in the risk estimate.

(6.8) Policy for Risk            Emphasizes transparency in decision
Characterization (EPA);          making, clarity in communication,
http://www.epa.gov/OSA/spc/      and consistency in assumptions and
pdfs/rccover.pdf                 policies. Encourages plans that
                                 reflect these values and
                                 consistency and calls for programs
                                 to fall within a "zone of
                                 reasonableness."

(6.9) Elements to Consider       Outlines the basic principles of
When Drafting EPA Risk           risk characterization and presents
Characterizations;               an outline for developing chemical
http://www.epa.gov/osa/spc/      risk assessments that includes
pdfs/rcelemen.pdf                hazard identification, dose
                                 response, exposure, conclusions,
                                 and context.

(6.10) Handbook on Risk          Describes the importance of
Characterization (EPA);          risk characterization process in
http://www.epa.gov/spc/pdfs/     a transparent manner, with products
rchandbk.pdf                     that are clear, conducting the
                                 consistent,andreasonable (TCCR).
                                 Appendices of this handbook include
                                 the EPA 1995 risk characterization
                                 policy and illustrative
                                 case studies.

Resource and access              Cumulative risk remarks

(6.1) SADA (Spatial Analysis     Useful for cumulative risk
and Decision Assistance);        assessments; can combine pathways
http://www.tiem.utk.edu/~sada/   to assess overall exposures and
                                 summed risks and His for receptors
                                 of interest. Input data can reflect
                                 site-specific conditions;
                                 interactions are not considered.

(6.2) RAIMI, Regional Air        Assesses multiple contaminants and
Impact Modeling Initiative       multiple sources for EPA programs,
(EPA); http://www.epa.gov/       for air contaminants. Designed to
region6/6en/raimi/index.htm      consider source-specific and
                                 contaminant-specific contributions
                                 to cumulative exposures associated
                                 with the air pathway.

(6.3) Environmental Load         Similar to RAIMI but as a screening
Profile (EPA);                   tool, focuses on inputs for Toxics
http://www.epa.gov/region2/      Release Inventory (TRI) emissions,
ej/guidelines.htm                air toxics, and facility density.
                                 More detailed analyses of a
                                 community burden would be conducted
                                 at the local level.

(6.4) Cumulative Adjustment of   Can be used for screening
Protective Concentration         calculations based on the sum of
Levels (PCLs), TCEQ (Texas       ratios approach (similar to NIOSH,
Commission on Environmental      IRSST, and others, including the
Quality); http://www.tceq        approach used to assess
.state.tx.us/commexec/           radionuclides), under the default
forms_pubs/pubs/rg/rg-           assumption of additivity.
366_trrp _18.html/view

(6.5) HEM-3, Human Exposure      Presents risk and non cancer
Model-3 (EPA);                   estimates. To support a CRA,
http://www.epa.gov/ttn/fera/     estimates for individual sources
hemdownload.html                 could be overlain to suggest
                                 insights for multiple sources.

(6.6) Probabilistic tools        Combining approximations for
(Monte Carlo analysis            multiple sources of potential risk
resources), such as those        (e.g., from environment and
described at: http://www.epa     lifestyle) is complicated.
.gov/raf/prawhitepaper/index.    These tools could be used to
htm; http://www.epa.gov/raf/     combine results for individual
prawhitepaper/index.htm;         exposures that consider variability
                                 and uncertainty.

(6.7) Software and User's        Can estimate blood lead levels
Manual for the Integrated        based on exposures to multiple
Exposure Uptake Biokinetic       sources via multiple routes using
Model for Lead in Children       a complex set of variables that
(IEUBK) (also Adult Lead         include adjustable exposure,
Model, other data) (EPA);        uptake, and biokinetic parameters.
http://www.epa.gov/superfund/    (See related entry in Table 4.)
lead/index.htm;
http://www.epa.gov/superfund/
lead/products.htm

(6.8) Policy for Risk            Encourages an open process as well
Characterization (EPA);          as program- and region-specific
http://www.epa.gov/OSA/spc/      policies, procedures, and
pdfs/rccover.pdf                 implementation for CRAs.

(6.9) Elements to Consider       Provides insights for applying risk
When Drafting EPA Risk           characterization principles for
Characterizations;               CRAs, with suggestions for topics
http://www.epa.gov/osa/spc/      to consider when conducting
pdfs/rcelemen.pdf                an assessment.

(6.10) Handbook on Risk          The basic principles outlined in
Characterization (EPA);          this report are useful for CRAs and
http://www.epa.gov/spc/pdfs/     can be helpful to risk assessment
rchandbk.pdf                     practitioners, managers, and the
                                 general public.
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Author:MacDonell, Margaret M.; Haroun, Lynne A.; Teuschler, Linda K.; Rice, Glenn E.; Hertzberg, Richard C.
Publication:Journal of Toxicology
Article Type:Report
Geographic Code:1U9CA
Date:Jan 1, 2013
Words:20386
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