Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures

This document is a supplement to the EPA Guidelines for the Health Risk Assessment of Chemical Mixtures of 1986. The 1986 Guidelines represent the Agency's science policy and are a procedural guide for evaluating data on the health risks from exposures to chemical mixtures. The emphasis is on dose response and risk characterization. The principles and concepts put forth in the Guidelines remain in effect. However, where the Guidelines describe broad principles and include few specific procedures, the present guidance is a supplement that is intended to provide more detail on these principles and their applications.

After an overview of the background and scope, this supplementary guidance puts forth the risk assessment paradigm for mixtures. This paradigm begins with problem formulation, then briefly discusses hazard identification, dose-response assessment, exposure, and risk characterization. The document is organized according to the type of data available. Procedures are described for assessment using data on the mixture of concern, data on a toxicologically similar mixture, and data on the mixture component chemicals. The state of the science varies dramatically for these three approaches. The whole-mixture procedures are most advanced for assessing carcinogenic risk, mainly because of the long use of in vitro mutagenicity tests to indicate carcinogenic potency. In vitro test procedures for noncancer endpoints are still in the pioneering stage. In contrast, the component-based procedures, particularly those that incorporate information on toxicologic interactions, are most advanced for noncarcinogenic toxicity. No single approach is recommended. Instead, guidance is given for the use of several approaches depending on the nature and quality of the data. The appendices contain definitions, a discussion on toxicologic interactions and pharmacokinetic models, and a reprint of the 1986 Guidelines.

This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

For more information, please contact Richard Hertzberg via e-mail (, or the Technical Information Staff by telephone (202-564-3261) or facsimile (202-565-0050).