Table 5: Selected resources for evaluating toxicity.

Resource and accessPurpose and scopeCumulative risk remarks

(5.1) Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures (EPA);
Published in 2000, this EPA guidance supplements the EPA’s 1986 guidelines for chemical mixtures and describes risk assessment approaches that depend on the type, nature, and quality of 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. Presents more detailed information on considerations and quantitative methods for assessing risks posed by exposures to environmental mixtures.

(5.2) Relative Potency Factors for Pesticide Mixtures, Biostatistical Analyses of Joint Dose- Response;
In response to requirements of the Food Quality Protection Act of 1996, the EPA prepared a technical report that presents research and methodologies for developing RPFs that can be used to assess 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).Provides information that can be used to assess cumulative risks for sites contaminated with organophosphate pesticides and other organic compounds, such as dioxins and PCBs.

(5.3) CatReg, Categorical Regression (EPA);
This categorical regression model was developed for meta-analyses of toxicology data. The approach could be useful for evaluating different types of data to assess potential cumulative health risks.Can be used to evaluate multiple effects within a chemical grouping (e.g., as grouped by target organ or system) and can also be used as a tool to support the estimate of potential health effect (e.g., hazard index) from multiple-route exposures.

(5.4) Toxicological Profiles (ATSDR);; and Interaction Profiles for Toxic Substances;
Toxicological profiles exist for many chemicals, including some mixtures; they summarize data on sources and uses; physicochemical properties, environmental fate, and environmental levels; toxicity, including environmental and metabolic transformation products on specific target organs; critical effects, secondary organs and systems. ATSDR also prepared guidance for mixtures that outline an assessment approach, as well as interaction profiles for whole mixtures and selected combinations of individual 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. Some profiles address mixtures (e.g., PCBs). These reports can be useful for identifying endpoint-specific effects to support CRAs; the toxicity data organized by organ/system can be 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 guidelines (EPA);
Guidelines exist for carcinogens, chemical mixtures, ecology, neurotoxicity, reproductive toxicity, exposure assessment, developmental toxicity, and mutagenicity; these were developed to support risk evaluations based on recommendations from the National Academy of Sciences.Outlines approaches and data that provide context for assessing mixtures and multiple endpoints. Can be used to guide toxicity groupings for CRAs.

(5.6) BMDS, Benchmark Dose Software (EPA);
Designed to fit mathematical models to dose-response data so results allow the selection of 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 body weight. BMD values used with dose addition could support estimation of a BMD for a mixture. For toxicity endpoints described by RfDs and RfCs, this approach would provide a risk-based dose associated with a particular effect.

(5.7) IRIS, Integrated Risk Information System (EPA);
Key source of chronic toxicity information and standard toxicity 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. Toxicity values address some chemical mixtures (e.g., PCBs, 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 Peer-Reviewed Toxicity Value) database (EPA);
The PPRTV database is similar to IRIS in serving as a source of toxicity values, notably to address chemicals and exposure durations for which an IRIS value is not available, and a need for a provisional value has been identified. Chemical mixtures for which PPRTVs are available include complex mixtures of aliphatic and aromatic hydrocarbons, midrange aliphatic hydrocarbon streams, and xylenes.

(5.9) TOXNET/HSDB, MEDLINE, PubMed, other databases (NIH); via;
for example, TOXNET/HSDB;
NIH sponsors and maintains several databases for toxicology and environmental health applications, including TOXNET and the Hazardous Substances Data Bank (HSDB), 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 of mixtures (such as PCBs, PAHs, coal tar, crude oil, and oil dispersants).Useful source of peer-reviewed information that can be used for toxicity groupings to support CRAs. Although listed with toxicity tools, these databases also contain 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 Initiative;;
Industry-funded scientific program included a cumulative risk focus area. Sponsored by the American Chemistry Council (ACC), research in this area emphasized assessment methods and toxicity studies for mixtures.Research results could offer insights for CRAs at contaminated sites, including regarding joint toxicity.

(5.11) RSLs, Risk-Based Regional Screening Levels (EPA);
RSLs for environmental media (soil, drinking water, and air) are based on specified risk levels, using conservative assumptions and 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). Emphasis is on multiple pathways and chemical concentrations rather than target organs or effects. Although not explicitly for CRAs, 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 RADioactivity (DOE Argonne National Laboratory);
The original RESRAD code was designed to guide radiological cleanup criteria for contaminated 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. Can be used to assess doses and risks associated with radioactively (and chemically) contaminated 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 d’Exposition Moyenne Pondérée (time-weighted average, worker exposure level), database (IRSST);
Database for airborne chemicals commonly found in the workplace and at many contaminated sites. Addresses Canadian occupational standards (many are the same as U.S. standards), toxicokinetics, target organs, effect levels, and mode of action where available. The database 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.Source of useful inhalation toxicity data for a large number of chemicals. This tool could be used to organize chemicals by target organ and effect; exposure levels can be divided by reference levels (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 Safety, Common Mechanism Groups; Cumulative Exposure and Risk Assessment;
Identifies health information to assess pesticide groups that share common mechanisms of toxic action, with links for quantitative approaches (e.g., RPF values) and qualitative approaches (e.g., analysis of mode of action). The pesticide groups evaluated include organophosphates, triazines, n-methyl carbamates, and chloroacetanilides. Can be used to assess index chemical-equivalent doses and risks associated with specific pesticide groups that share a common toxic mode of action.