factors. It is unclear whether the standard 10-fold uncertainty factor for variability within a species is sufficient to account for potential highly sensitive subpopulations. Because of the potential severity of reaction for this subpopulation it seems prudent to include an additional margin of safety (e.g., a 10-fold uncertainty factor) for this uncertainty. It is not unusual for safety assessments to provide additional protection for susceptible populations. For example, EPA uses an additional safety factor in reevaluating pesticides as per the Food Quality Protection Act (FQPA, 1996) to account for the greater susceptibility of children to certain pesticides.
Adequacy of clinical trial data. Most of the available data from clinical trials report LOAELs. There is uncertainty associated with using LOAELs rather than NOAELs to establish a threshold. For peanuts, one of the few food allergens for which NOAEL values are available, the LOAELs for objective signs are approximately 2 to 3 fold greater than the NOAELs.
Other. Additional data gaps have been identified by the Threshold Working Group; however, concluded that uncertainties associated with these factors were not sufficient to warrant additional uncertainty factors. These data gaps include the following: (1) the use of total protein from a food as a surrogate for measuring the level of specific allergenic proteins in clinical trials; (2) variability in serving sizes and related exposure factors; and (3) the incompletely defined effects of food processing on the levels and reactivity of allergenic proteins.
The Threshold Working Group acknowledges that it is difficult to estimate uncertainty factors that apply in all situations for all allergen threshold determinations when using a safety assessment-based approach. We can, however, assume that a standard uncertainty factor of 10-fold should be applied for intraspecies differences in humans. Additional uncertainty factors could be added if justified from data gaps. In Table IV-6, we use peanuts, widely considered to be among the most potent food allergens, to illustrate how specific uncertainty factors may be developed for use in a safety assessment-based approach to set a threshold if that approach is adopted.
Table IV-6. Example of Uncertainty Factors for the Safety Assessment-Based Approach Using Peanuts.
Uncertainty Factor 10
Estimation of NOAEL2
Overall Uncertainty Factor for Peanuts = 100
Standard factor for intraspecies variability Two studies were identified that report NOAELs Used to account for additional
margin of protection for more susceptible populations not included in clinical trials
This includes both between- and within-individual variability.
Revised Threshold Report Page 55 of 108