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only be determined using food challenge studies (including open, single-blind, and double-blind, placebo-controlled food challenges). The double-blind, placebo-controlled food challenge (DBPCFC) is the “gold standard” diagnostic measure for determining clinical reactivity to low concentrations of an allergen. In this type of study, neither the subject nor the researcher knows which test foods contain the allergen. Open (where both the subject and the researcher know which test foods contain the allergen) and single-blinded (where only the researcher knows which foods contain the allergen) challenges are used primarily for screening foods of low allergenic importance or for determining tolerance to food allergens. Single-blinded challenges can be placebo- controlled (SBPC). However, in open and SBPC challenges, experimenter bias may play a role in interpreting patient reactions.

The typical diagnostic food challenge protocol is a dose escalation study, usually with 15 to 30 minute dose intervals, which proceeds until a clinical effect is observed or the final dose is achieved. The test substance, starting dose and successive incremental doses vary between protocols. Because reactions are assumed to be less severe at lower doses, the starting dose for most diagnostic studies is generally in the milligram range for whole foods (Bindslev-Jensen et al., 2004). In the few studies designed to determine minimal eliciting doses, the initial doses are in the low microgram range for the whole food or whole food protein (Hourihane et al. 1997; Wensing et al. 2002a; Wensing et al. 2002b). Incremental doses are usually doubled or increased logarithmically, so that a reasonable number of incremental doses (i.e., 6 to 10) separate the starting dose from the end dose. This final dose is usually chosen to be the normal amount in a food serving, usually 8 to 10 gm of dried food or 60 to 100 gm of wet food (Bock et al., 1988; Bindslev-Jensen et al., 2004). The ability to tolerate this amount, followed by a negative open challenge on a different day, is considered to be evidence that the individual is not allergic to that allergen (Taylor et al., 2004).

Most oral challenge studies are designed to establish a diagnosis of food allergy rather than to determine safety (Taylor et al., 2004). Consequently, these studies do not start at doses below a known LOAEL. Thus, individuals who react to the starting dose are not necessarily demonstrating a true LOAEL because it is not possible to know whether these individuals would have reacted to a lower dose without further testing. A NOAEL cannot be established as long as one or more study participants react to the starting dose.

Most elicited reactions occur within 3 to 15 minutes after a challenge (Bindslev-Jensen et al., 2004). Thus, an interval of 15 minutes between challenge doses may be sufficient to confirm a negative response. Most challenge studies report the dose that elicits the first objective sign. Because subjective symptoms may have preceded the first objective sign at lower doses, it is often difficult to ascertain whether the reported LOAEL truly represents the lowest dose to elicit a reaction. The measurement and interpretation of allergic reactions is discussed below.

2. Inclusion/Exclusion of Sensitive Populations Individuals with a history of anaphylaxis to foods, infants and children are often excluded from challenge studies for ethical reasons (Taylor et al., 2002). Moreover, individuals

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