Analytical methods based-approach, Allergens |
Academia |
Does not agree with the statement that "most test systems do not detect specific allergenic proteins" (See section II.Food Allergy G. Exposure 3 Detecting and measuring proteins). Cites: Nogueira et al. (2004). Can commercial peanut assay kits detect peanut allergens? JAOAC Int.; 87:1480-1484. Many kits detect Ara h 1 and 2 (known peanut allergens), beta-lactoglobulin, soy Kunitz trypsin inhibitor, shrimp tropomyosin, casein, etc.. |
The text of the report was revised to respond to this comment. |
Analytical methods based-approach, Allergens |
Association |
Validated analytical methods for allergens must be available before thresholds are implemented. Acceptable methods must be available to test whether allergens are present above or below the thresholds. Methods must be accepted by FDA or another independent authoritative body (such as AOAC), before the food industry can be held to threshold levels. |
Analytical method issues are discussed in the report. |
Analytical methods-based approach. Gluten. |
Association |
The analytical methods-based approach is not recommended because the detection limit may become lower than the level at which celiac patients have negative reactions as the tests become more sensitive and capable of detecting small levels of gluten. |
This limitation is acknowledged in the report. |
Analytical methods-based approach, Allergens |
Food Association |
If the analytical methods-based approach is used for interim thresholds, it should be replaced as soon as possible with thresholds based on safety or risk assessments. |
We concur. This is noted in the Findings of the report. |
Analytical methods-based approach, Allergens |
Association |
The analytical methods-based approach could be implemented more quickly than the other approaches. This approach should not be used in the long-term. If it is used in the short-term, the levels derived from analytical methods should apply to only the allergen tested by that specific method (e.g., the method for peanut should only be used to establish a threshold for peanut protein and should not be used for hazelnut or cashew). Potential problems with this approach are that: (1) there is currently only one validated method (peanut protein); (2) as sensitivity of the tests improve, eventually, the detection limit could be lower than the levels at which allergic individuals react. |
These limitations of the analytical methods-based approach are acknowledged in the report. |
Analytical methods-based approach, Allergens |
Food Association |
Does not support the use of the analytical methods-based approach because commercially-available methods have not been developed for all major allergens. Also, development of increasingly more sensitive analytical methods could result in a continually changing threshold level. Limits of detection well below 1 ppm could easily be obtained through advances in analytical technology. |
These limitations of the analytical methods-based approach are acknowledged in the report. |
Analytical methods-based approach, Gluten |
Food Association |
It would be appropriate to set a gluten threshold based on the method of analysis approach to define "gluten free" for use on products that contain no detectable levels of gluten. However, when data become available, thresholds should be based on a safety or risk assessment. This approach is consistent with current use of the term "free" - such as "alcohol free" that can be used when a product contains "no detectable alcohol." However, the commenter questions whether any products would qualify as gluten-free with this approach, given the commingling of grains. |
This comment is consistent with the report findings. |
Analytical methods-based approach, Allergens |
Academia |
Assays designed to detect whole allergenic foods are most meaningful to the food-allergenic patient and food industry as supported by the following: 1) Very specific detection of allergenic proteins is not required for an assay to be specific and sensitive for the allergenic food. 2) Not all allergens in the major food allergens have been discovered or characterized. 3) LOAELS and NOAELS are determined with oral challenges using whole foods. |
This comment is consistent with the report findings. |
Celiac disease. |
Health Professional |
Section III, Celiac Disease, B. Pathogenesis: The damage is not "self-perpetuating" in celiac disease and it resolves when gluten is avoided (unlike refractory sprue where the T cell activation is indeed self perpetuating). |
The text of the report was revised to respond to this comment |
Celiac disease |
Health Professional |
Section III, Celiac Disease, C. Adverse Effects: Suggest adding: "The reasons for this spectrum of clinical presentations are unknown but may result the age and immunol...." |
The text of the report was revised to respond to this comment |
Celiac disease |
Health Professional |
Section III. Celiac Disease. C. Adverse Effects Are the quoted relative risks correct? I thought that the relative risk for lymphomas was greater than for small bowel carcinoma |
The text of the report was revised to respond to this comment |
Celiac disease. |
Health Professional |
Section III, Celiac Disease, C. Adverse Effects "Silent" celiac disease is characterized by the absence of symptoms or nutritional deficiency states, not by the degree of intestinal involvement. |
The text of the report was revised to respond to this comment |
Celiac disease |
Health Professional |
Section III, Celiac Disease, C. Adverse Effects. Silent and latent celiac disease are not characterized by atypical disease manifestations but instead by the absence of symptoms or other disease manifestations (other than the mucosal abnormalities present in silent disease) |
The text of the report was revised to respond to this comment |
Celiac disease |
Health Professional |
Section III, Celiac Disease, D. Prevalence, page 32, line 2. I believe the prevalence reported by Talley in 1994 was ~1:5,000 |
The text of the report was revised to respond to this comment |
Celiac disease |
Health Professional |
Section III, Celiac Disease, D. Prevalence, page 32, line 11. Celiac disease is rarely misdiagnosed as Crohn's disease so I suggest "The disease is often misdiagnosed as another gastrointestinal disorder (e.g., lactose intolerance, irritable bowel syndrome) due to similarities in..." |
The text of the report was revised to respond to this comment |
Celiac disease |
Health Professional |
Section III, Celiac Disease, B. Pathogenesis, page 30 line 2. "and specifically targets" is inaccurate--suggest "and is characterized by damage to" |
The text of the report was revised to respond to this comment |
Challenge studies |
Consumer Group |
There are no studies on the long-term effects of the ingestion of low levels of gluten by a diagnosed celiac patient. Long-term studies that examine the cumulative effect of gluten consumption are needed to set a reasonable threshold. A single, short-term study with a limited number of patients, no peer review, no publication, and no replication should not be the basis for establishing the threshold for a chronic, lifelong, lifestyle changing disease. |
This limitation is noted in the report. |
Data |
Association |
FDA should review the information on allergens from other countries, such as Canada's database on adverse reactions and the European Union's directive on exemptions of certain food ingredients. This information could be helpful to determine what data are needed to set thresholds. |
We did consider the available public information from these sources in the report. |
FALCPA exemption |
Private Industry |
Allergens used in manufacturing of packaging should be excluded from FALCPA labeling requirement. |
This issue is beyond the scope of this report. |
Thresholds, Allergens |
Association |
Dairy processors are prepared to label ingredients that could cause an allergic individual to have a reaction. Reformulation or labeling changes have a significant economic impact on the industry and should be done only if there is a health benefit. |
This issue is beyond the scope of this report. |
Thresholds, Allergens |
Food Association |
FDA should also consider approaches for establishing thresholds for allergens such as that used by the American Academy of Pediatrics in setting a threshold for hypoallergenic infant formulas. That is, an infant formula can be labeled as hypoallergenic if it is documented using double-blind, placebo-controlled conditions, that at a minimum, there is 95% certainty that 90% of the cow's milk allergic population will not react. |
This process is addressed in the report; see Section IV, A. 3. Risk Assessment-Based Approach. |
Thresholds. Allergens |
Association |
The approach used for each allergen should be determined independently based on what works best for that allergen, and reevaluated when new data become available, with the ultimate goal of using safety or risk assessments. For example: initially exempt an ingredient if it contains a non-detectable level of protein from a major food allergen. As more data become available, conduct a safety or risk assessment to set a threshold. |
This comment is consistent with the report findings. |
Thresholds, Gluten |
Association |
Gluten is a concern for cheese-makers. Ingredients used in very small amounts in cheeses (e.g., anti-caking agents) may be derived from wheat. Some cheese cultures are grown on bread or wheat-based media. |
This issue is beyond the scope of this report. |
Thresholds, Gluten |
Association |
The international community may be able to provide resources and models for setting a gluten threshold. Canada, Australia, New Zealand have set thresholds for gluten. There is also work by the Codex Committee on Nutrition and Foods for Special Dietary Uses. |
We considered the public information available from these sources in preparing the report. |
Thresholds, Gluten |
Food Association |
Supports the draft report recommendations on establishing thresholds for gluten for the purposes of establishing definitions for gluten-free |
No response required. |
Gluten, Oats sensitive Population |
Health Professional |
Section IV Discussion and recommendation, D.1.c Foods of Concern: The percentage of individuals with celiac disease that are sensitive to oats has not been determined but is likely to be <> |
The text of the report was revised to respond to this comment |
Labeling, Gluten-free foods |
International Association |
Data needed to establish a definition for the term "gluten-free" are limited at the current time. This was also the conclusion of the National Institute of Health conference on celiac disease (June 2004). However, data from the Italian Microchallenge study and from dietary survey studies in Finland may allow a provisional threshold for labeling gluten-free foods. The maximum level of gluten for wheat starch-based gluten-free foods can be safely set at 200 ppm. A second category of naturally gluten-free products, with guaranteed lower gluten content will fulfill the needs for the most sensitive celiac people. A summary of study results and references were provided: Catassi et al.; 1993, Catassi et al., 2004; Collin et al., 2004; Kaukinen et al., 2004; and Peräaho et al., 2003. |
Discussion of specific thresholds is beyond the scope of this report. The references provided in the comment have been included in the report. |
Analytical Methods, Allergens |
Food Industry |
Provided information for Appendix 1 on LOD, LOQ, etc for ELISA Systems test kits. |
The information provided in the comment has been included in the report. |
General |
Academia |
FDA should be applauded for the effort made to prepare the document and develop methods to establish minimal eliciting doses for major allergenic foods. |
No response required. |
General |
Consumer Group |
The draft report was complete, organized, and readable. |
No response required. |
General |
Federal Government |
The report did an excellent job of reviewing a difficult subject. |
No response required. |
General |
Food Association |
Appreciates FDA's transparency in identifying the various methods that should be explored for establishing allergen thresholds, commends FDA for its efforts in developing the data and information needed to implement FALCPA, for convening the FAC on allergen thresholds, and efforts in preparing the draft threshold report. |
No response required. |
Thresholds, Gluten |
Consumer Group |
Celiac patients that set as their goal no wheat, barley, rye, oats or any of their derivatives, to manage their medically required lifestyle do not know what the "safe" number is and it doesn't matter. |
Discussion of specific thresholds is beyond the scope of this report. |
FALCPA exemption |
Food Industry |
Agency should exclude food packaging and food-contact substances from the scope of FALCPA regulation (labeling) if they contain de minimis levels of allergens. |
This issue is beyond the scope of this report. |
FALCPA implementation |
Food Association |
By establishing thresholds, FDA would prevent the over-labeling of the many food products that currently are being enjoyed and consumed without incident. |
This issue is beyond the scope of this report. |
FALCPA implementation |
Food Association |
FDA should adopt a scientific standard when determining whether there are sufficient data to support the establishment of thresholds under the safety assessment approach that is based on the FALCPA definition for exempting an ingredient - which is a demonstration that the ingredient "does not cause an allergic response that poses a risk to human health." |
The report addresses the strengths and limitations of the safety assessment-based approach. |
FALCPA implementation |
Food Industry |
Requiring declaration of every de minimis amount of an allergen in food could produce consumer confusion and be contrary to the purposes of FALCPA and the Agency's goal of protecting public health |
This issue is beyond the scope of this report. |
Labeling, Gluten |
Individual Consumer |
Food labels should disclose all gluten, including wheat, barley, malt, rye or oats. Some manufacturers no longer indicate whether or not a food is actually "gluten-free". The food labeling law should be changed to appropriately require "gluten" not just "wheat" on labels. |
Labeling issues are beyond the scope of this report. |
FALCPA exemption |
Association |
Low levels of food allergen-derived materials are used in paperboard food packaging. These substances should be excluded from FALCPA's labeling requirements. No allergic reactions attributable to food allergens in packaging or food contact substances have ever been reported. FDA has the authority to exempt food packaging and food contact substances from FALCPA. |
This issue is beyond the scope of this report. |
FALCPA exemption |
Association |
Requiring declaration of every de minimis amount of an allergen would be contrary to the purposes of FALCPA and public health goals. Low levels of food allergen-derived materials are used in the vast majority of paperboard food packaging. No incidents of allergic reactions attributable to food packaging or food contact substances have ever been reported. FDA should categorically exclude food packaging and food contact substances from the scope of FALCPA. The FALCPA petition and notification processes are not viable for the paperboard food packaging and food contact substance industry because there are a broad range of allergen-derived substances and a variety of types of packaging; use of recycled materials also adds complications - which means that a large number of individual petitions or notifications would need to be submitted, imposing an immense burden upon manufacturers of paperboard food packaging and food contact substances. |
This issue is beyond the scope of this report. |
FALCPA exemption |
Food Industry |
Not aware of any reported incidence of single-use packaging or single-use food-contact substances being cited as causing an allergenic reaction. |
No response needed. |
FALCPA exemption |
Food Industry |
The FDA should exclude food packaging and food contact substances from the scope of FALCPA. Some of the major food allergens are ubiquitous presences in the primary materials used for conversion into corrugated products and in the substances used in the converting process. |
This issue is beyond the scope of this report |
FALCPA implementation |
Individual Consumer |
FALCPA does not require FDA to establish threshold levels for ingredient labeling. FDA has no obligation to set levels or otherwise grant exemptions from labeling requirements and the burden is on the petitioner to provide adequate scientific evidence. |
The requirements of FALCPA are discussed in the report. |
FALCPA exemption |
Industry, Private Food |
Any fermentation ingredient that is a minor component of the fermentation media (<10%) is="" requested="" to="" be="" exempt="" from="" labeling="" in="" the="" finished="" ingredient.="" commenter="" claims="" that="" these="" are="" not="" the="" major="" food="" allergens="" that="" the="" law="" was="" intended="" to=""> |
This issue is beyond the scope of this report.. |
Risk assessment-based approach, Allergens |
Association |
Strongly encourages FDA to carry out an allergen risk assessment to determine (1) the levels of allergenic protein that cause reactions in allergic individuals and (2) whether there are some ingredients that may contain trace levels of protein from allergenic sources but do not cause reactions (e.g., soy lecithin, fish gelatin). |
We agree that the risk assessment-based approach provides the strongest, most transparent scientific analysis to establish thresholds for the major food allergens. The report discusses limitations to implementing this approach. |
Risk assessment-based approach, Allergens |
Food Association |
Agrees with FDA that there are insufficient data and information at this time to set thresholds using the risk assessment-based approach. As more data become available either the safety or risk assessment approaches should be used. |
This is discussed in the report. |
Risk assessment-based approach, Gluten |
Food Association |
Additional research should be conducted before the risk assessment-based approach is used. |
The need for additional research is addressed in the report,. |
Safety assessment-based approach, Allergens |
Individual Consumer |
The report does not consider sensitization as a health endpoint of concern. Sensitization as a health endpoint is good public policy--if labeling helps children avoid or outgrow allergies, there would be significant economic and health benefits. |
This is discussed in the report and Committee's comments. This is currently not a viable endpoint of concern because there are no methods available to assess sensitization. |
Safety assessment-based approach, Allergens |
Individual Consumer |
Commenter does not support the recommendation of the report to only include data on objective reactions. Data on subjective reactions that could be significant indicators of risk to human health should not be excluded. |
This is discussed in the report and the Committee's comments. Objective reactions are the only widely used biomarkers reported in the literature. |
Safety assessment-based approach, Allergens |
Individual Consumer |
The report includes studies where subjects reacted to the lowest administered dose and incorrectly characterizes those doses as LOAELs. If a study shows a reaction at the first dose, it is not usable for the purpose of setting threshold levels. |
The report acknowledges and discusses the difficulties associated with LOAELs from publications that do not establish NOAELs. |
Safety assessment-based approach, Gluten |
Association |
There appears to be enough scientific data for the LOAEL to set a threshold for gluten. It should be updated as additional data become available. |
The comment is consistent with the report findings. |
Safety assessment-based approach, Gluten, Uncertainty factor |
Association |
A 100-fold uncertainty factor that allows for intraspecies differences and extrapolation from the LOAEL should protect individuals while also allowing the food industry to actually produce foods that can be labeled "gluten free" |
These issues are discussed in the report. If the safety assessment-based approach is implemented, decisions on uncertainty factors will be based on the available data. |
Safety assessment-based approach, Allergens |
Individual Consumer |
Some findings do not separate science and policy. Example, in Finding 3, the term "viable" is based on policy interpretation that is contrary to the intent of FALCPA. "Finding 3. The safety assessment-based approach, based on currently available clinical data, is a viable way to establish thresholds for the major food allergens." |
The term "viable way" refers only to the scientific viability and not policy decisions. |
Safety assessment-based approach, Allergens |
Association |
Data are sufficient to set thresholds for peanuts, egg and milk but not for the other allergenic foods, using this approach. LOAELs : peanut (0.25-66 mg), egg (0.13-200mg), and milk (0.6-180 mg). Data collection on the other allergens should continue in order to develop NOAEL/LOAELS and threshold levels. |
Specific threshold levels are beyond the scope of this report. |
Safety assessment-based approach, Allergens, Uncertainty factor |
Association |
An uncertainty factor of 100 should allow for intraspecies differences with extra allowance for particularly sensitive individuals |
This issue is discussed in the report. If the safety assessment-based approach is implemented, decisions on uncertainty factors will be based on the available data. |
Safety assessment-based approach, Allergens |
Association |
It is not appropriate to set threshold levels for all allergens using the LOAEL of the most potent allergen. This would set the threshold level lower than required for the majority of food allergens and unnecessarily limit foods available to allergic consumers. |
The strengths and limitations of this approach are discussed in the report and in the Committee's comments. |
Safety assessment-based approach, Allergens |
Food Association |
This approach is appropriate for establishing thresholds. |
This is noted in the Findings of the report. |
Safety assessment-based approach, Allergens, Uncertainty factor |
Food Association |
It is not possible to set one uncertainty factor that can be applied across all studies. Therefore, the commenter does not agree that the factor of 100 (10-fold for intraspecies and 10-fold for severity of response and sensitivity of the population). Some studies may not require an uncertainty factor to be applied. |
This issue is discussed in the report and the Committee's comments. If the safety assessment-based approach is implemented, decisions on uncertainty factors will be based on the available data. |
Safety assessment-based approach, Allergens |
Food Association |
Use the first objective symptom when determining the LOAEL or NOAEL. Subjective responses do not "pose a risk to human health" |
This issue is discussed in the report and the Committee's comments. |
Safety assessment-based approach, Allergens, Uncertainty factor |
Food Association |
Does not agree with the FAC deliberations. The uncertainty factor should not be increased to accommodate the first subjective symptom. Each study must be evaluated to decide whether the first subjective symptom is indicative of a true allergic response or a psychologically-induced response. It would be inappropriate to use the first subjective response as the basis for the uncertainty factor if there is no evidence of an objective response until a significantly higher level than reported for the first subjective response. |
This issue is discussed in the report and the Committee's comments. If the safety assessment-based approach is implemented, decisions on uncertainty factors will be based on the available data. |
Safety assessment-based approach, Gluten, Uncertainty factor |
Food Association |
Objective rather than subjective response should be used when setting LOAELs and NOAELs. It is inappropriate to set a single uncertainty factor for all studies; the quality of the underlying study must be the basis for the uncertainty factor. |
This issue is discussed in the report and the Committee's comments. |
Safety assessment-based approach, Allergens, Uncertainty factor |
Individual Consumer |
The currently available clinical data deliberately exclude the populations that are most likely to be of concern. There is no scientific evidence that a 10-fold uncertainty factor would be protective. |
This issue is discussed in the report and the Committee's comments. If the safety assessment-based approach is implemented, decisions on uncertainty factors will be based on the available data. |
Statutorily derived approach, Allergens |
Association |
There appear to be significant problems with accurately determining the level of protein found in highly refined oils. There will not be a strong basis for using the statutorily derived approach without an accurate quantification of the allergenic protein in ingredients that are already exempted from labeling. This approach should not be used unless there is a way to accurately assess the level of protein in highly refined oils. |
The comment is consistent with the report findings. |
Statutorily-derived approach, Allergens |
Food Association |
It would be appropriate to develop interim thresholds using the statutorily derived approach, until sufficient data are available to conduct a safety or risk assessment. At the time Congress passed FALCPA, the literature contained numerous references to the presence of detectable levels of protein in highly refined oils (e.g., Crevel et al. (2000) reported levels up to 48 ppm in refined peanut oil.) |
The comment is consistent with the report findings. |
Statutorily-derived approach., Allergens |
Individual Consumer |
The report does not explain how the statutorily derived approach would ensure that an ingredient would not cause an allergic response that poses a risk to human health. To meet information quality requirements for clarity, the report should provide information on the protein in oils on the same matrices as on health-based thresholds so that the reader can compare the two. |
The limitations of this approach are discussed in the report. |
Statutorily-derived approach, Allergens |
Individual Consumer |
Excluding studies (without explanation) with data on oils with no detectable amounts of protein, fails the information quality requirements of objectivity and clarity. Oils with no detectable protein are likely the only ones that would meet Congress's intent in exempting highly refined oils. Instead of using protein levels in different oils to define a threshold, FDA should use the lack of protein to define whether an oil was "highly refined." The range of protein concentrations (see section IV.C.2.d) should not exclude studies that reported levels "not detected". |
This is discussed in the report and the Committee's comments. Data from studies reporting no detectable protein were not reported in the appendix because these studies did not provide sufficient information to determine the accuracy and sensitivity of the assays used. |
Thresholds, Allergens |
Food Association |
A threshold level should not be based on the average levels of protein (as per FDA's statutorily-derived approach). The published literature contains reports up to 48 ppm. However, an interim level of 10 ppm is more reasonable. As evidence, information was provided on the level of consumer complaints in control products and in products with undeclared soy lecithin and fish gelatin. |
Specific threshold values and methods to calculate them are beyond the scope of this report. |
Use of non-peer reviewed data |
Consumer Group |
Non-peer reviewed, non-published studies should not be used in consideration for establishing a threshold for celiac disease in the US. |
This issue is discussed in the Committee's comments. |
Wheat allergies |
Federal Government |
Not much information was included in the report on allergies to wheat |
Some additional information was added. The revised report reflects the current state of knowledge about wheat allergies. |
Wheat allergies |
Federal Government |
Statement in Section 2- Food Allergens "whereas the principal wheat allergenic proteins are albumins" is not necessarily true. Many wheat flour proteins have been implicated in allergic responses to wheat. |
The text of the report was revised to respond to this comment |
Wheat allergies |
Federal Government |
Research is needed to determine if proteins in barley and rye can induce the same responses in subjects who are allergic to wheat. |
This is discussed in the report. |