key events dose-response analysis in nutrition

I have always felt that by reading papers from other scientific disciplines it is possible to learn new techniques which are well tried in another context . A series of 3 papers in Critical reviews in Food Science and Nutrition is a case in point.
The papers are applied to thresh hold intakes for toxins, but one paper discusses the metabolism and dosage of Vitamin A, inadequate and toxic intakes.
These papers are to my mind very important and have wide applicability in Nutrition research

Due to limitations that all studies have, it is not possible to prove the existence of a biological threshold by observation alone Therefore an alternative approach is required.
The approach adopted is based on the concept of the mode of action (MOA), that is developing a an analytic framework based on systematic evaluation of key events. A mode of action for a biological effect is a plausible sequence of key events, starting with the interaction of an agent with a cell, through functional and anatomical changes, leading to an observed effect supported by experimental observations and mechanistic data.
A key event is defined as an observable, precursor step that is a necessary component of the mode of action, or is a marker for such change.
The relevance of a key event in a particular mode of action, and of the mode of action overall, are evaluated using a weight of evidence approach.
The individual events may include homeostatic physiological mechanism, immune response and host characteristics age, health, genetic make up, exposure patterns . What events are control pints ie rate limiting steps.
The hypothesis is that by identifying the key events for a specific toxicological effect, these would be more amenable to the experimental demonstration of a threshold than the effect itself. It would be possible to use such information on specific interventions, biological and chemical analogy, and the genetic differences in exploring the evidence for thresholds in a key event. Key events are, in principle, quantifiable by definition. An analysis of dose-response concordance should enable the identification of a rate limiting key event for the mode of action (MOA ) and whether anyone key event is the critical determinant of the response.
The importance of this approach is reflected in the views of a number of regulatory agencies.
“When adequate data on mode of action provide sufficient evidence to support a non linear mode of action for the general population and/or any subpopulations of concern … -a reference dose/reference concentration that assumes that nonlinearityis used.”
“A sufficient basis to support this nonlinear procedure is likely to include data on responses that are key events integral to the biological process.”

Julien et al 2009 The key events dose-response framework : a cross disciplinary mode-of action based approach to examining dose-response and thresholds. Critical reviews in Food Science and Nutrition vol 49 issue 8 pp 682-689

Boobis et al 2009 Application of key events analysis to chemical carcinogens and non carcinogens . Critical reviews in Food Science and Nutrition vol 49 issue 8 pp 690-707

Ross et al 2009 Application of a key events dose-response analysis to nutrients : a case study with vitamin A . Critical reviews in Food Science and Nutrition vol 49 issue 8 pp 708-717

Martin Eastwood
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