How much is too much? Food-allergic consumers attempt to entirely avoid the allergenic foods that provoke their symptoms (a zero threshold approach). The food industry attempts to clean shared equipment until no allergens remain (also a zero threshold approach). Because of the uncertainties associated with cleaning to that level, advisory labeling (e.g. may contain x) flourishes. Yet, in clinical challenge settings, doses can be administered to food-allergic individuals without provoking allergic reactions. Thus, safe doses do exist. But, how much is too much? That question remains. (Provide link to FARRP Resource section on thresholds)
The major research priority for FARRP is to establish the necessary scientific and clinical evidence and approaches needed to establish threshold levels that are safe for the vast majority of food-allergic consumers. FARRP initiated this research effort by sponsoring a series of Threshold Roundtable Conferences.
FARRP Threshold Roundtable Conference #1 - Hilton Head Island, South Carolina USA, September 23-24, 1999: The purpose of the initial roundtable conference was to determine the amount of clinical data that might be available relating to low and very low dose oral challenges of food-allergic patients. Before that time, the typical diagnostic food challenge started at a dose of 400 - 500 mg (Bock et al., J. Allergy Clin. Immunol. 82:986-997, 1988; Bindslev-Jensen et al., Allergy 59:590-597, 2004), a comparatively high dose where as many as 20% of the patients would react (Sicherer et al., J. Allergy Clin. Immunol. 105:582-586, 2000). Clearly, to establish threshold levels, clinical data on lower-dose challenges were needed. Clinicians who might have such data were invited to this roundtable conference.
Outcome: Low-dose challenge data were available. However, many different clinical challenge protocols were used in the various clinics making comparison of the data difficult. The consensus was that insufficient data existed to recommend specific threshold levels.
Publication: Taylor, S. L., S. L. Hefle, C. Bindslev-Jensen, S. A. Bock, A. W. Burks, L. Christie, D. J. Hill, A. Host, J. O'B. Hourihane, G. Lack, D. D. Metcalfe, D. A. Moneret-Vautrin, P. A. Vadas, F. Rance, D. J. Skrypec, T. A. Trautman, I. Malmeheden Yman, and R. S. Zeiger. 2002. Factors affecting the determination of threshold doses for allergenic foods: how much is too much? J. Allergy Clin. Immunol. 109:24-30..
FARRP Threshold Roundtable Conference #2 - West Palm Beach, Florida USA, May 20-21, 2002: The purpose of the second roundtable conference was to develop a consensus protocol for double-blind, placebo-controlled oral food challenges that would yield clinical information that would be more useful to assessment of safe threshold levels for food-allergic individuals. Clinicians (many had also participated in the first roundtable) with experience in DBPCFCs were invited to participate in the discussions.
Outcome: A consensus protocol was developed.
Publication: Taylor S. L., S. L. Hefle, C. Bindslev-Jensen, F. M. Atkins, C. Andre, C. Bruijnzeel-Koomen, A. W. Burks, R. K. Bush, M. Ebisawa, P. A. Eigenmann, A. Host, J. O'B. Hourihane, E. Isolauri, D. J. Hill, A,. C. Knulst, G. Lack, H. A. Sampson, D. A. Moneret-Vautrin, F. Rance, P. A. Vadas, J. W. Yunginger, R. S. Zeiger, J. W. Salminen, C. Madsen, and P. Abbott. 2004. A consensus protocol for the determination of the threshold doses for allergenic foods: how much is too much? Clin. Exp. Allergy 34:689-695.
FARRP Threshold Roundtable Conference #3 - Camp de Mar, Mallorca, Spain, October 4-5, 2004. The purpose of the third roundtable conference was to discuss how emerging clinical threshold data might be handled from a risk assessment perspective. Clinicians and risk assessors from various worldwide governmental agencies were invited to participate.
Outcome: A rich discussion occurred but no consensus was reached. However, the discussion at this roundtable seemed to initiate later dialogue that has led to emerging consensus regarding the optimal risk assessment approaches to use in the development of thresholds for allergenic foods.
Subsequent Important Food Allergen Threshold Meetings
The U.S. Food & Drug Administration established a Threshold Working Group in 2005 and held a public meeting in the summer of 2005 to get input from various stakeholders on the establishment of thresholds. The FDA Threshold Working Group evaluated several possible approaches that might be used to establish thresholds for allergenic foods and concluded that "the quantitative risk assessment-based approach provides the strongest, most transparent scientific analyses to establish thresholds for the major food allergens. However, . . . the currently available data are not sufficient to meet the requirements of this approach. A research program should be initiated to develop applicable risk assessment tools and to acquire and evaluate the clinical and epidemiological data needed to support the .... approach." The report of the FDA Threshold Working Group was published on the web in 2006 (provide the link; Jamie can get) and in a journal in 2008 (Threshold Working Group, J. Food Prot. 71:1043-1088, 2008).
EuroPrevall, ILSI-Europe, and the U.K. Food Standards Agency sponsored a workshop in 2007 in Madrid, Spain to discuss approaches for the establishment of thresholds for allergenic foods. While consensus was not reached on one particular approach, quantitative risk assessment-based approaches were highlighted as scientifically sound and desirable and the probabilistic modeling approach was considered as the most promising (Madsen et al., Food Chem. Toxicol. 47:480-489, 2009).
FARRP Threshold Research
Using the Probabilistic Risk Assessment Model
FARRP, together with collaborators from Unilever, published a key paper on probabilistic risk assessment modeling. While this manuscript does not contain clinical threshold data, it does delineate the approach (Crevel et al., Food Chem. Toxicol. 45:691-701, 2007).
FARRP initiated a major effort to determine if sufficient clinical data might exist to establish threshold doses for allergenic foods using the probabilistic modeling approach. The initial effort was conducted in collaboration with Unilever scientists (Rene Crevel and David Sheffield). This first effort was focused on peanut thresholds. The initial effort was to mine clinical publications for information on individual threshold doses for peanut-allergic subjects. Ultimately the published literature yielded information on 185 peanut-allergic individuals evaluated among 12 publications. Clearly the literature yielded sufficient information to consider establishment of a threshold but inspection of these data revealed a publication bias that made us suspect that the data were perhaps weighted toward more highly sensitive subjects. The results of this initial effort have been published (Taylor et al., Food Chem. Toxicol. 47:1198-1204, 2009 with corrigendum, Taylor et al., Food Chem. Toxicol. 48:1002, 2010).
As a result of this initial effort, FARRP determined that some allergy clinics might possess a large quantity of challenge information that would be useful for probabilistic modeling for development of a peanut allergy threshold. Subsequently, an effort jointly funded by ILSI-North America was conducted to mine existing clinical data from a large allergy clinic in Nancy, France. Ultimately, data on individual threshold doses for peanut were found for 286 peanut-allergic individuals examined over a period of more than 10 years. Since all potential peanut-allergic patients were subjected to challenges, the amount of patient selection bias in this dataset is drastically reduced. Because the datasets from the published papers (164 subjects after removing 21 subjects from Nancy to avoid the possibility of counting them twice) and the Nancy group yielded similar ED10 estimates, an analysis of the combined dataset of 450 peanut-allergic subjects was conducted. The ED10 was 12.3 mg of whole peanut (95% CI of 9.0 and 16.8 mg) while the ED05 was 5.2 mg of whole peanut (95% CI of 3.6 and 7.4 mg). Clearly, sufficient data now exist to establish a threshold level for peanut. The results of this effort have also been published (Taylor et al., Food Chem. Toxicol. 48:814-819, 2010).
FARRP is currently exploring the acquisition of clinical challenge data for milk, wheat, egg, and possibly other commonly allergenic foods. FARRP is also screening the published clinical literature for data on individual threshold doses for other allergenic foods, beyond peanut, that may be useful in probabilistic risk assessment modeling. And, FARRP is attempting to gather information on other groups of peanut-allergic subjects to determine whether the ED10 from the Nancy group is representative of data from other worldwide allergy clinics.
Current Clinical Threshold Studies
Clearly, the development of additional data is needed for other allergenic foods beyond peanut because it is unlikely that sufficient data will be found in the published literature. Current clinical projects are being conducted on soybean flour and almond.
FARRP Threshold Publications
- Hourihane, J. O'B., S. A. Kilburn, J. A. Nordlee, S. L. Hefle, S. L. Taylor, and J. O Warner. 1997. An evaluation of the sensitivity of subjects with peanut allergy to very low doses of peanut: a randomized, double-blind, placebo-controlled study. J. Allergy Clin. Immunol, 100:596-600.
- Wensing, M., A. H. Penninks, S. L. Hefle, S.J. Koppelman, C. A. Bruijnzeel-Kooman, and A. C. Knulst. 2002. The distribution of individual threshold doses eliciting allergic reactions in a population with peanut allergy. J. Allergy Clin. Immunol. 110:915-920.
- Wensing, M., A. H. Penninks, S. L. Hefle, J. H. Akkerdaas, R. van Ree, S. J. Koppelman, C. A. F. M. Bruijnzeel-Koomen, and A. C. Knulst. 2002. The range of minimum provoking doses in hazelnut-allergic patients as determined by double-blind placebo-controlled food challenges (DBPCFCs). Clin. Exp. Allergy 32:1757-1762.
- Hefle, S. L, and S. L. Taylor. 2002. How much food is too much? Threshold doses for allergenic foods. Current Allergy and Asthma Reports 2:63-66.
- Taylor, S. L., S. L. Hefle, C. Bindslev-Jensen, S. A. Bock, A. W. Burks, L. Christie, D. J. Hill, A. Host, J. O'B. Hourihane, G. Lack, D. D. Metcalfe, D. A. Moneret-Vautrin, P. A. Vadas, F. Rance, D. J. Skrypec, T. A. Trautman, I. Malmeheden Yman, and R. S. Zeiger. 2002. Factors affecting the determination of threshold doses for allergenic foods: how much is too much? J. Allergy Clin. Immunol. 109:24-30.
- Taylor S. L., S. L. Hefle, C. Bindslev-Jensen, F. M. Atkins, C. Andre, C. Bruijnzeel-Koomen, A. W. Burks, R. K. Bush, M. Ebisawa, P. A. Eigenmann, A. Host, J. O'B. Hourihane, E. Isolauri, D. J. Hill, A. Knulst, G. Lack, H. A. Sampson, D. A. Moneret-Vautrin, F. Rance, P. A. Vadas, J. W. Yunginger, R. S. Zeiger, J. W. Salminen, C. Madsen, and P. Abbott. 2004. A consensus protocol for the determination of the threshold doses for allergenic foods: how much is too much? Clin. Exp. Allergy 34:689-695.
- Crevel, R. W. R., D. Briggs, S. L. Hefle, A. C. Knulst, and S. L. Taylor. 2007. Hazard characterisation in food allergen risk assessment: the application of statistical approaches and the use of clinical data. Food Chemical Toxicol. 45:691-701.
- Taylor, S. L. and J. O'B. Hourihane. 2008. Food allergen thresholds of reactivity. In: Food Allergy - Adverse Reactions to Foods and Food Additives, 4th ed., ed. D. D. Metcalfe, H. A. Sampson, and R. A. Simon, Blackwell Publishing, Malden, MA, pp. 82-89.
- Crevel, R. W. R., B. K. Ballmer-Weber, T. Holzhauser, J. O'B. Hourihane, A. C. Knulst, A. R. Mackie, F. Timmermans, and S. L. Taylor. 2008. Thresholds for food allergens and their value to different stakeholders. Allergy 63:597-609.
- Madsen, C. B., S. Hattersley, J. Buck, S. M. Gendel, G. F. Houben, J. O'B. Hourihane, A. Mackie, E. N. C. Mills, P. Norhede, S. L. Taylor, and R. W. R. Crevel. 2009. Approaches to risk assessment in food allergy: report from a workshop "Developing a framework for assessing the risk from allergenic foods". Food Chem. Toxicol. 47:480-489.
- Taylor, S. L., R. W. R. Crevel, D. Sheffield, J. Kabourek, and J. Baumert. 2009. Threshold dose for peanut: a risk assessment based upon published results from challenges of peanut-allergic individuals. Food Chem. Toxicol. 47:1198-1204.
- Taylor, S. L., R. W. R. Crevel, D. Sheffield, J. Kabourek, and J. Baumert. 2010. Corrigendum to "Threshold dose for peanut: risk characterization based upon published results from challenges of peanut-allergic individuals" [Food and Chemical Toxicology 47 (2009) 1198-1204]. Food Chem. Toxicol. 48:1002.
- Taylor, S. L., S. M. Gendel, G. F. Houben, and E. Julian. 2009. The key events dose-response framework: a foundation for examining variability in elicitation thresholds for food allergens. CRC Crit. Rev. Food Sci. Nutr. 49:729-739.
- Taylor, S. L., D. A. Moneret-Vautrin, R. W. R. Crevel, D. Sheffield, M. Morisset, P. Dumont, B. C. Remington, and J. L. Baumert. 2010. Threshold dose for peanut: risk characterization based upon diagnostic oral challenges of a series of 286 peanut-allergic individuals. Food Chem. Toxicol. 48:814-819.