The Key Events Dose-Response Framework: A Foundation for Examining Variability in Elicitation Thresholds for Food Allergens

Abstract

Food allergies are caused by immunological reactions in individuals sensitized to normal protein components of foods. For any given sensitized individual, the severity of a reaction is generally assumed to be proportional to the dose of allergenic protein. There is substantial clinical evidence that “threshold” doses exist for the elicitation of an allergic reaction; however, the threshold (i.e., lowest dose that elicits a reaction) varies substantially across the sensitized population. Current approaches to protecting sensitized individuals from exposure to food allergens are highly qualitative (i.e., they rely on food avoidance). The Key Events Dose-Response Framework is an analytical approach for refining understanding of the biological basis of the dose-response. Application of this approach to food allergy provides a foundation for a more rigorous quantitative understanding of variability in allergic response. This study reviews the allergic disease process and the current approaches to identifying thresholds for food allergens. The pathway of key biological events occurring between food intake and allergic response is considered, along with factors that may determine the nature and severity of response to food allergens. Data needs, as well as implications for identifying thresholds, and for characterizing variability in thresholds, are also discussed.

Scientific Opinion on the evaluation of allergenic foods and food ingredients for labelling purposes

“…However, many DBPCFCs do not allow establishment of either the MED or the NOAEL for some individuals (see section 12.2). A statistical methodology, the interval censoring survival analysis (ICSA), has been applied to determine individual thresholds, taking into account these uncertainties (Taylor et al, 2009a). If the highest challenge dose is the NOAEL, the LOAEL is set to infinity and subjects are right censored; if the lowest challenge dose (first dose tested) is the LOAEL, the NOAEL is set to zero and subjects are left censored.…”

“…Subjective allergic symptoms, such as abdominal pain, headaches, tingling sensation in the throat and similar could occur at lower dose levels (FDA, 2006;Taylor et al, 2009a). MED is the lowest tested dose of an allergen triggering an allergic reaction in an individual, whether objective or subjective.…”

Outcome of the public consultation on the draft guidance on allergenicity assessment of genetically modified plants

“…More generally, there is no quantitative association between the exposure to an individual amount of a protein allergen(s) and the risk for sensitization and/or clinically relevant reaction, which prevents the interpretation of any differences between the GM and non-GM crop (Chassy 2010;Taylor et al, 2009;Taylor et al, 2002) (lines 662-664). In fact for the small percentage of the population that is more susceptible to food-related allergies, the onset of those allergies appears to be as much influenced by the timing of exposure as the amount of exposure (allergen levels) (Du Toit et al, 2008).…”

Multi‐allergen quantification of fining‐related egg and milk proteins in white wines by high‐resolution mass spectrometry

“…A great deal of data regarding the human allergic response to food, usually based on oral challenge trials, has been gathered in the last years, showing that a high variability exists between the individual thresholds. [26][27][28] Recently, the VITAL Scientific Expert Panel, born from a collaboration between the Allergen Bureau (Australia & New Zealand), the Food Allergy Research & Resource Program (FARRP) of the University of Nebraska (USA) & the Netherlands Organization for Applied Scientific Research (TNO), has actively worked at the establishment of "allergens action levels" in the VITAL grid. The panel recognized that sufficient threshold data, arising from clinical oral challenges, have been collected for the major food allergens to allow the development of dosedistribution relationships using statistical modeling, as described by Crevel et al [29] The dose-response curves enable the identification of an allergen dose at which a proportion of the allergic population would likely react, although they cannot identify a dose below which no allergic individual would react.…”