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reported to elicit “initial objective signs” are higher than would be expected for the entire allergic population. The observed data may also not be representative of the allergic population in studies that use patient populations that are not known to be allergic to the food being tested (e.g., testing milk allergic patients for sensitivity to soy). In addition, individual sensitivity varies over time and “high sensitivity” may be a transient condition for an individual.

There are a number of case reports in the scientific literature documenting allergic reactions to incidental exposures to allergens. These reports are difficult to interpret because the level of exposure and potential influence of other factors (e.g., medications, exercise) are not known. Nevertheless, if these reports document true allergic reactions, this suggests that these individuals could be considered to be highly sensitive when compared to the general population of food allergic individuals.

Based on currently available data, the Threshold Working Group was unable to identify any scientifically-based studies that indicate that the standard 10-fold uncertainty factor used in safety assessments for inter-individual variability is not adequate to account for variation within the sensitive population. However, because of the limitations in the clinical studies and the case reports discussed above, this assumption should be reexamined as more data on the distribution of sensitivities within the population become available.

b. Biomarkers. Because there are no in vitro markers that can be used to assess the severity of an allergic reaction, and a number of different signs and symptoms are associated with allergic reactions, clinical symptoms elicited during challenge are currently viewed as the best indicators, or biomarkers, of an allergic response. The manifestations of an allergic reaction can be either subjective (reported by the patient but not overtly measurable) or objective (overt reactions that are observed or measured by another person). Objective signs vary on a continuum of severity from mild rashes to fatal anaphylaxis. Although each of these is an “adverse effect,” there is no consensus about where on this continuum they become “serious adverse effects.” This makes it difficult to apply either risk assessment- or safety assessment-based approaches to establish thresholds for food allergens because both approaches require that the adverse end point be well defined.

Most clinical studies expose patients to increasing doses of an allergen until the first objective sign is observed. This is often, but not always, a relatively mild reaction. For ethical and technical reasons, few studies measure dose-response relationships for individual patients beyond the initial objective sign. Therefore, the currently available literature provides data based on the “initial objective sign.” Although the “initial objective sign” is the biomarker measured in most available allergen clinical studies, it is unclear whether these signs are consistently considered across these studies. It is also not clear whether and when subjective reactions should be considered “adverse effects,” or should influence the selection of a NOAEL or LOAEL for safety assessments.

Revised Threshold Report Page 48 of 108

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