The Key Events Dose-Response Framework: A Cross-Disciplinary Mode-of-Action Based Approach to Examining Dose-Response and Thresholds

Figures & data

Table 1 ILSI RF Threshold Working Group

Alan R. Boobis—Imperial College London, London, UK

Robert L. Buchanan—University of Maryland, College Park, MD, USA*

George P. Daston—The Procter & Gamble Company, Cincinnati, OH, USA*

Steven M. Gendel—FDA/Center for Food Safety and Applied Nutrition, College Park, MD, USA

Arie H. Havelaar—National Institute of Public Health and the Environment (RIVM), Bilthoven, THE NETHERLANDS*

Geert F. Houben—TNO Quality of Life, Zeist, THE NETHERLANDS

Elizabeth Julien—ILSI Research Foundation, Washington, DC, USA* ^†

Sanford A. Miller—University of Maryland, College Park, MD, USA*

Ian C. Munro—CANTOX Health Sciences International, Mississauga, Ontario, CANADA*

Stephen S. Olin—ILSI Research Foundation, Washington, DC, USA*

R. Julian Preston—U.S. EPA/National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, USA*

Joseph V. Rodricks—ENVIRON, Arlington, VA, USA

A. Catharine Ross—The Pennsylvania State University, University Park, PA, USA

Robert M. Russell—Tufts University (emeritus), Boston, MA, USA

Mary Alice Smith—University of Georgia, Athens, GA, USA

Steve L. Taylor—University of Nebraska, Lincoln, NE, USA*

Peter van Bladeren—Nestlé Research Center, Lausanne, SWITZERLAND*

Richard C. Whiting—Exponent, Bowie, MD, USA

Elizabeth A. Yetley—NIH Office of Dietary Supplements (retired), Bethesda, MD, USA

Figure 1 Factors operating at the level of Key Events. In addition to dose, other factors may influence the outcome of an individual event. In combination, they may affect the likelihood of progression to the next event, or they may affect the magnitude of the ultimate response of concern.

Figure 2 The Key Events Dose-Response Framework organizes available information on the multiple kinetic and dynamic events that occur between an initial dose and the effect of concern. Events are indicated generically here; but, for a given pathway, many specific kinetic and dynamic events may occur.

Table A-1 Some authoritative definitions of “threshold”

Authoritative Source	Definition of “Threshold”
International Programme on Chemical Safety (IPCS) Risk Assessment Terminology. http://www.who.int/ipcs/methods/harmonization/areas/ipcsterminol-ogyparts1and2.pdf	Threshold: Dose or exposure concentration of an agent below which a stated effect is not observed or expected to occur.
USEPA IRIS Glossary. http://www.epa.gov/ncea/iris/help_gloss.htm	Threshold: The dose or exposure below which no deleterious effect is expected to occur.
USEPA Terms of Environment: Glossary, Abbreviations and Acronyms. http://www.epa.gov/OCEPATERMS/	Two definitions are provided: Threshold: The dose or exposure level below which a significant adverse effect is not expected. Threshold: The lowest dose of a chemical at which a specified measurable effect is observed and below which it is not observed.

Figure A1 Theoretical population distribution curve of individual biological thresholds for a specified effect. The ordinate shows the cumulative percentage (“y”) of individuals with a biological threshold ≤ the corresponding value of “x”, on the abscissa.