State-of-the-Science Workshop Report: Issues and Approaches in Low Dose–response Extrapolation for Environmental Health Risk Assessment

Low-dose extrapolation model selection for evaluating the health effects of environmental pollutants is a key component of the risk assessment process. At a workshop held in Baltimore, MD, on April 23-24, 2007, and sponsored by U.S. Environmental Protection Agency and Johns Hopkins Risk Sciences and Public Policy Institute, a multidisciplinary group of experts reviewed the state of the science regarding low-dose extrapolation modeling and its application in environmental health risk assessments. Discussion topics were identified based on a literature review, which included examples for which human responses to ambient exposures have been extensively characterized for cancer and/or noncancer outcomes.
Topics included:

• the need for formalized approaches and criteria to assess the evidence for mode of action;
• the use of human vs. animal data;
• the use of mode of action information in biologically-based models; and
• the implications of interindividual variability, background disease processes and background exposures in threshold vs. nonthreshold model choice.

Approaches that differ from current practice were recommended for extrapolating high-dose animal data to low-dose human exposures, including categorical approaches for integrating information on mode of action, statistical approaches such as model averaging, and inference-based models that explicitly consider uncertainty and interindividual variability.

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