Double-blind placebo-controlled food challenges in children with alleged cow's milk allergy: prevention of unnecessary elimination diets and determination of eliciting doses.

Contains fulltext : 118318.pdf (publisher's version ) (Open Access)BACKGROUND: Children with cow's milk allergy (CMA) need a cow's milk protein (CMP) free diet to prevent allergic reactions. For this, reliable allergy-information on the label of food products is essential to avoid products containing the allergen. On the other hand, both overzealous labeling and misdiagnosis that result in unnecessary elimination diets, can lead to potentially hazardous health situations. Our objective was to evaluate if excluding CMA by double-blind placebo-controlled food challenge (DBPCFC) prevents unnecessary elimination diets in the long term. Secondly, to determine the minimum eliciting dose (MED) for an acute allergic reaction to CMP in DBPCFC positive children. METHODS: All children with suspected CMA under our care (Oct'05 - Jun'09) were prospectively enrolled in a DBPCFC. Placebo and verum feedings were administered on two randomly assigned separate days. The MED was determined by noting the 'lowest observed adverse effect level' (LOAEL) in DBPCFC-positive children. Based on the outcomes of the DBPCFC a dietary advice was given. Parents were contacted by phone several months later about the diet of their child. RESULTS: 116 children were available for analysis. In 76 children CMA was rejected. In 60 of them CMP was successfully reintroduced, in 2 the parents refused introduction, in another 3 the parents stopped reintroduction. In 9 children CMA symptoms reappeared. In 40 children CMA was confirmed. Infants aged </= 12 months in our study group have a higher cumulative distribution of MED than older children. CONCLUSIONS: Excluding CMA by DBPCFC successfully stopped unnecessary elimination diets in the long term in most children. The MEDs form potential useful information for offering dietary advice to patients and their caretakers

Complex mixtures: Relevance of combined exposure to substances at low dose levels

Upon analysis of chemically complex food matrices a forest of peaks is likely to be found. Identification of these peaks and concurrent determination of the toxicological relevance upon exposure is very time consuming, expensive and often requires animal studies. Recently, a safety assessment framework based on the Threshold of Toxicological Concern (TTC) was published to assess the safety of chemically complex matrices more efficiently. In this safety assessment framework, the toxicological relevance of exposure to unidentified substances in chemically complex food matrices can be related to the Cramer class III TTC threshold, currently set at 90. μg/day. However, possible additive or synergistic effects of combined exposure is not covered.The current evaluation describes the relevance of combined low dose exposure to unidentified substances in chemically complex food matrices. It is concluded that to some extent cumulative effects at exposure levels for each substance at or below the Cramer class III TTC threshold, being present in a complex mixture including food, might occur. However the health relevance of possible cumulative effects at this dose level is considered to be that low that a need for a correction factor to cover possible cumulative effects is very low to absent. © 2013 Elsevier Ltd

Immune-mediated effects upon oral challenge of ovalbuminsensitized brown Norway rats : further characterization of a rat food allergy model

Although several in vivo antigenicity assays using parenteral immunization are operational, no full validated enteral models are available to study food allergy and allergenicity of food proteins. To further validate a developed enteral Brown Norway (BN) rat food allergy model, systemic and local immune-mediated reactions were studied upon oral challenges. The animals were exposed to ovalbumin (OVA) by daily gavage dosing (1 mg OVA/rat/day) for 6 weeks, without the use of an adjuvant, or by intraperitoneal injections with OVA together with AL(OH)3. Subsequently, effects on breathing frequency, blood pressure, and gastrointestinal permeability were investigated upon an oral challenge with 10 to 100 mg OVA in vivo. In both parenterally and orally sensitized rats, an increase in gut permeability (increased passage of β-lactoglobulin as bystander protein) was determined between 0.5 and 1 h after an oral OVA challenge was given. An oral challenge with OVA did not induce a clear effect on the respiratory system or blood pressure in the majority of the animals. However, some animals demonstrated a temporary decrease in breathing frequency or systolic blood pressure. Upon oral challenge with OVA of orally and parenterally sensitized animals, local effects were observed in all animals whereas systemic effects were observed at a low frequency, which reflects the situation in food allergic patients after an oral challenge. These studies show that the BN rat provides a suitable animal model to study oral sensitization to food proteins as well as immune-mediated effects after oral challenge with food proteins

Oral sensitization to food proteins: A Brown Norway rat model

Background: Although several in vivo antigenicity assays using parenteral immunization are operational, no adequate enteral sensitization models are available to study food allergy and allergenicity of food proteins. Objective: This paper describes the development of an enteral model for food allergy research in the Brown Norway (BN) rat. Methods: The animals were exposed to ovalbumin either ad libitum via the drinking water (0.002 to 20mg/mL) continuously for 6 weeks or by garage (1 mg/mL per rat). Garage dosing was performed either daily, twice a week, once a week or once every 2 weeks during a period of 6 weeks. No adjuvants were used during the sensitization studies. Results: After intra-gastric administration of ovalbumin once or twice a week or once every two weeks, no or only a very low frequency of ovalbumin-specific antibody responses were detected. Daily intra-gastric dosing with ovalbumin resulted in antigen-specific IgG as well as IgE responses in almost all animals tested. Upon ad libitum exposure, ovalbumin-specific IgG but no ovalbumin-specific IgE was detected. The cellular response was examined by determination of delayed-type hypersensitivity (DTH) reactions in the animals dosed by daily garage and in the ad libitum exposed rats. Both sensitization protocols sensitized for DTH The response was most pronounced in ad libitum exposed rats at day 28 of exposure. Conclusions: These studies show that the BN rat may provide a suitable animal model for inducing specific IgG and IgE responses as well as specific T-cell mediated hypersensitivity (DTH) to ovalbumin upon exposure via the enteral route without the use of adjuvants