The Key Events Dose-Response Framework: a cross-disciplinary mode-of-action based approach to examining dose-response and thresholds.
The ILSI Research Foundation convened a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categories of bioactive agents-food allergens, nutrients, pathogenic microorganisms, and environmental chemicals. This effort generated a common analytical framework-the Key Events Dose-Response Framework (KEDRF)-for systematically examining key events that occur between the initial dose of a bioactive agent and the effect of concern. Individual key events are considered with regard to factors that influence the dose-response relationship and factors that underlie variability in that relationship. This approach illuminates the connection between the processes occurring at the level of fundamental biology and the outcomes observed at the individual and population levels. Thus, it promotes an evidence-based approach for using mechanistic data to reduce reliance on default assumptions, to quantify variability, and to better characterize biological thresholds. This paper provides an overview of the KEDRF and introduces a series of four companion papers that illustrate initial application of the approach to a range of bioactive agents.
Julien
Elizabeth
E
ILSI Research Foundation, Washington, DC 20005-1743, USA. solin@ilsi.org
Boobis
Alan R
AR
Olin
Stephen S
SS
D000465:Algorithms; D000485:Allergens / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000009:adverse effects*; D005502:Food; D005512:Food Hypersensitivity; D005516:Food Microbiology; D006801:Humans; D035501:Uncertainty
D000485:Allergens; D004785:Environmental Pollutants
Crit Rev Food Sci Nutr. 2009 Sep;49(8):729-39
19690998
Reprod Toxicol. 2008 Jan;25(1):136-8
18093799
Crit Rev Food Sci Nutr. 2009 Sep;49(8):718-28
19690997
J Cell Biol. 1966 Sep;30(3):465-75
5971002
Food Chem Toxicol. 1995 Sep;33(9):715-30
7557746
Crit Rev Toxicol. 2008;38(2):87-96
18259981
Crit Rev Toxicol. 2003;33(6):581-9
14727732
J Pharmacol Exp Ther. 1949 Jan;95(1):79-91
18111480
Crit Rev Toxicol. 2006 Nov-Dec;36(10):781-92
17118728
Crit Rev Toxicol. 2003;33(6):591-653
14727733
Crit Rev Food Sci Nutr. 2009 Sep;49(8):708-17
19690996
Crit Rev Toxicol. 2005 Oct-Nov;35(8-9):664-72
16417033
Crit Rev Toxicol. 2003;33(6):655-780
14727734
Nature. 1967 Jan 14;213(5072):183-4
4961837
Br J Pharmacol Chemother. 1957 Jun;12(2):159-65
13446367
Crit Rev Food Sci Nutr. 2009 Sep;49(8):690-707
19690995
Regul Toxicol Pharmacol. 2001 Oct;34(2):146-52
11603957