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

Abstract

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.

Multiple cytochromeP-450 genes are concomitantly regulated by vitamin A under steady-state conditions and by retinoic acid during hepatic first-pass metabolism

“…However, there is relatively little information on the patterns of retinoid homeostatic genes that are associated with these nutritional-physiological states. Currently, there is interest in using biochemical and molecular data from dietary studies in risk assessment models to examine dose response and thresholds (19), and vitamin A has been considered an exemplary nutrient for such an analysis (44). Retinoid homeostasis is understood to be complex, consisting of processes that include the reversible removal of excess dietary retinol into storage as retinyl esters, catalyzed by lecithin:retinol acyltransferase (LRAT); the transport of retinol in plasma by retinol-binding protein (RBP)4; the dynamic recycling of retinol between plasma, liver, and extrahepatic organs (7); the production of bioactive retinoids (30); and the irreversible degradation of retinol and RA when they are present in excess (8,24).…”

Adverse Outcome Pathways--Organizing Toxicological Information to Improve Decision Making

“…Implications for chemical-specific dose-response relationships have been formalized in MOA species concordance analysis (Julien et al, 2009). This includes the chemicalspecific ADME components that map external exposure to a target tissue dose for a specific chemical, the interaction with the biologic system in the target tissue, and the progression toward an effect of concern.…”

Key Elements for Judging the Quality of a Risk Assessment

“…EPA 2005, 2010] and international [EFSA 2014a, 2014b; Food and Agriculture Organization of the United Nations/World Health Organization (FAO/WHO) 2012, 2013]. The WHO/IPCS framework has evolved to incorporate the use of quantitative dose–response and temporal relationships for key events within a mode-of-action to reduce uncertainty and to better inform quantitative risk assessment (Julien et al 2009; Simon et al 2014) along with other refinements as experience with its application accrues (Meek et al 2014a, 2014b). In its development of a library of adverse outcome pathways (AOPs), the OECD is coordinating its activities with WHO/IPCS and has incorporated the WoE approach of the WHO/IPCS framework into its guidance and template to assess the evidence in support of an AOP (OECD 2013).…”