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We have identified several data gaps for gluten that contribute to current uncertainty


setting gluten thresholds. The critical areas of uncertainty and variability are: Intraspecies differences. Safety assessments typically apply a 10-fold uncertainty factor to account for the variability both between individuals and variability in responses for a particular individual. Chronic low-level exposure to gluten in "gluten-free" diets. Data, from either prospective studies or long-term clinical trials, are severely limited on the effect of a long-term gluten-free diet on the manifestations of celiac disease. Adequacy of clinical trial data. There is uncertainty as to whether 4-week studies, or even 4-month studies, are of sufficient duration to predict the consequences of long-term ingestion of low levels of gluten. There is additional uncertainty as to whether currently available clinical trials include the most sensitive individuals. Accordingly, there is uncertainty as to whether the standard 10-fold uncertainty factor for variability within a species is sufficient to account for potential highly sensitive individuals. Additional uncertainty arises from the fact that the published clinical trials were designed to identify LOAELs rather than NOAELs. Other. Additional data gaps have been identified by the Threshold Working Group; however, the working group concluded that uncertainties associated with these factors were not sufficient to warrant additional uncertainty factors. These other data gaps include the following: (1) it is uncertain what percentage of individuals with celiac disease are sensitive to oat gluten and whether the levels to which they are sensitive are equivalent to those observed for wheat; (2) variability in serving sizes and related exposure factors; and (3) the incompletely defined effect of food processing on the levels of gluten tolerated by individuals with celiac disease.

The uncertainty associated with gluten thresholds arises primarily from the limited amount of clinical data. The critical knowledge gap about individuals with celiac disease is whether chronic, low-level exposure to gluten in a gluten-free diet will cause any harm over a lifetime. We are not aware of any prospective clinical trials that have examined the health of individuals with celiac disease on a gluten-free diet for more than a few months. There is uncertainty as to whether data from these short-term clinical trials will accurately predict reactions following chronic, low-level gluten exposure. Conversely, there appears to be only a small degree of uncertainty as to whether the most sensitive celiac disease populations were included in the available clinical trials since most of the participants had evidence of disease.

As discussed in Section III, there may be an oat-sensitive subpopulation. The possible existence of this oat-sensitive subpopulation raises questions related to the definition of "gluten." Because there are limited clinical data on the sensitivity of this subpopulation of individuals with celiac disease, the uncertainty related to the LOAELs or NOAELs for these individuals is high. Nevertheless, it is unlikely that theses individuals are substantially more sensitive to oat gluten than they are to wheat gluten.

Table IV-10 presents an example of how an overall uncertainty factor could be derived when estimating a threshold for gluten using the safety assessment-based approach. A

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