A Summary of Publications on Methods and Tools for Assessing Cumulative Risk, Project Summary


EPA’s National Center for Environmental Assessment has recently published several papers that provide background information on cumulative risk assessment and approaches to characterize and quantify combined exposures and risks due to multiple agents or stressors, with an emphasis on chemical mixtures exposures, toxicity and risk.


This collection of eight publications on cumulative risk assessment was developed collaboratively among scientists within EPA’s Office of Research and Development and three other organizations. These include scientific collaborations through an Interagency Agreement with Argonne National Laboratory, an ILSI Health and Environmental Science Institute (HESI) Expert Panel on Chemical Mixtures Assessment, and an Expert Workshop on Mixture Toxicity cosponsored by the Society of Environmental Toxicology and Chemistry (SETAC) and the Novel Methods for Integrated Risk Assessment of Cumulative Stressors in Europe (NoMiracle).

Cumulative risk has been defined by the U.S. Environmental Protection Agency (EPA) as the combined risks from aggregate exposures (i.e., multiple route exposures) to multiple agents or stressors, where agents or stressors may include chemical and nonchemical stressors (U.S. EPA, 2003). Cumulative risk assessment (CRA) is an analysis, characterization and possible quantification of the combined risks to health or the environment from exposures to multiple agents or stressors. CRA differs from traditional chemical risk assessments as it has a population focus, and there is an emphasis on stakeholder involvement and population vulnerabilities. Further, CRA focuses on both human health and ecology, although an individual CRA may involve only a subset of these features.

This project summary and its related publications provide information and methods for evaluating combined exposures and cumulative risks in human health risk assessment, with an emphasis on chemical mixtures exposures, toxicity and risk. Lambert et al. (2011) present an overview of current thinking on CRA for chemical and nonchemical stressors (physical, biological, socio-economic) that includes a discussion of CRA initiating factors and population vulnerabilities. Rice et al. (2010) and Rice and MacDonell (2008) discuss an iterative approach for assessing multiple route exposures to environmental chemical mixtures and describe the utility of grouping the chemicals to be analyzed based on both physical-chemical properties and an understanding of environmental fate. Lipscomb et al. (2010) detail the state of the practice for estimating chemical mixtures toxicity and risk and discuss criteria for grouping chemicals by common toxic modes of action. Boobis et al. (2011) explore whether synergistic interactions can occur among chemicals at low, environmentally relevant exposure levels, finding only six studies out of 90 identified in the literature that could be used to quantify the magnitude of low dose synergy; for this small set of data, the magnitude of synergy at low doses did not exceed the levels predicted by additivity models by more than a factor of 4. Ragas et al. (2011) provide a comparison of chemical mixture risk assessment methods from human health and ecological risk assessment and propose approaches for integrating information from the two fields of study. Finally, Hertzberg et al. (2008) and Simmons and Teuschler (2010) discuss the risk assessment of complex mixtures of chemicals in drinking water, with an emphasis on multiple route exposures to drinking water disinfection byproducts.

This set of publications advances the science of analyzing the effects from chemical mixtures and the field of CRA and disseminates information to the scientific community and the general public to promote increased understanding of this area of research.
Chemical mixture risk assessment of environmental pollutants is an important feature of CRA, as the regulation of environmental chemicals is under the purview of EPA. Environmental mixtures can consist of hundreds of chemicals from many chemical classes (e.g., pesticides, pharmaceuticals, metals, organic solvents, polychlorinated aromatic hydrocarbons, and drinking water disinfection by-products); may be present in liquid, vapor, or aerosol forms; and can enter the body via ingestion, respiration, or dermal penetration. Therefore, an accurate CRA of potential human health risk(s) from multiple-route exposures to multiple chemicals in environmental media is needed. EPA has authored risk assessment guidance, including chemical mixtures risk assessment guidelines (U.S. EPA, 1986) and supplementary guidance (U.S. EPA, 2000) and a CRA resource document (U.S. EPA, 2007). Additional CRA research has been conducted to improve on existing methods to assess risk, to incorporate scientific advances into CRA and to address nonchemical stressors.

The research described here was conducted to advance the science of CRA and to be responsive to a number of environmental laws and publications by scientific expert panels. The Comprehensive Environmental Response, Compensation, and Liability Act of 1980 first emphasized the need to address the dangers associated with the accumulation of hazardous chemical substances in the environment. Further, some of the earliest tenets of CRA were captured in the Superfund Amendments and Reauthorization Act of 1986, which included an increased focus on stakeholder (e.g., public, states) involvement. Under the Safe Drinking Water Act Amendments of 1996, EPA was specifically called upon to “develop new approaches to the study of complex mixtures, such as mixtures found in drinking water….” Also in 1996, the Food Quality Protection Act mandated the CRA of multiple-route exposures to pesticides acting by a common mechanism of toxicity. In 2008, the National Research Council’s National Academy of Sciences (NAS) published two expert panel reports related to CRA. One report advised EPA to conduct a CRA for mixtures of phthalates and other anti-androgens and discussed how this might be done (NAS, 2008a). The second described how environmental risk assessments can be improved, specifically recommending that CRA factors such as chemical mixtures and population vulnerabilities be addressed (NAS, 2008b).



Apr 2006SETAC/NoMiracle Mixture Toxicity Workshop. Krakow, Poland.
Aug 2007EPA released the report, Concepts, Methods and Data Sources for Health Risk Assessment of Multiple Chemicals (U.S. EPA, 2007)
Dec 2007HESI expert panel on Chemical Mixtures Assessment meeting to discuss synergy review. Washington, DC.
Dec 2008EPA gave presentations at the Society for Risk Analysis Annual Meeting on Cumulative Risk Assessment Methods, Resources and Applications. Boston, MA.
2008 - 2011Project results are published in peer-reviewed journals and book chapters.
Sep 2012EPA releases this project summary (Web summary).
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Kacee Deener
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