State-of-the-Science Workshop Report:
Issues and Approaches in Low Dose-Response Extrapolation for Environmental Health Risk Assessment
Ronald H. White, Ila Cote, Lauren Zeise, Mary Fox, Francesca Dominici, Thomas A. Burke, Paul D. White, Dale B. Hattis and Jonathan M. Samet
ABSTRACT
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.
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.
doi: 10.1289/ehp.11502 (available at http://dx.doi.org/)
Online 19 September 2008
Full Text at : http://www.ehponline.org/members/2008/11502/11502.pdf
