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Risk Assessment for Food Allergens

Risk Assessment for Food Allergens. Risk Assessment Approaches to Evaluation of Food Allergen Hazards. Hazard Identification Dose/Response Evaluation Exposure Assessment Risk Characterization. Dose/Response Evaluation. Trace amounts can elicit allergic reactions

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Risk Assessment for Food Allergens

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  1. Risk Assessment for Food Allergens

  2. Risk Assessment Approaches to Evaluation of Food Allergen Hazards • Hazard Identification • Dose/Response Evaluation • Exposure Assessment • Risk Characterization Food Allergy Research and Resource Program  2005

  3. Dose/Response Evaluation • Trace amounts can elicit allergic reactions • Severity of response is related directly to dose • Individuals vary in degree of sensitivity • How much is too much? Food Allergy Research and Resource Program  2005

  4. Exposure Assessment • How frequently are food products contaminated with potentially hazardous levels of unlabeled allergens? • How frequently do allergic reactions occur? Food Allergy Research and Resource Program  2005

  5. Food Allergy Research and Resource Program  2005

  6. Sources of CluesRegarding Food Allergen Thresholds • Allergen cross contact episodes • Double-blind, placebo-controlled food challenges • Immunotherapy trials • Clinical threshold experiments Food Allergy Research and Resource Program  2005

  7. INTERPRETATION PROBLEMSALLERGEN CROSS CONTACT EPISODES • Past analytical methods may not have yielded accurate results • Lack of accurate information on amount of allergenic food residues • Uncertainty about amount of food eaten • Questions about other sources of allergen • Individual variability in threshold Food Allergy Research and Resource Program  2005

  8. 1st Threshold Conference September, 1999 Hilton Head, South Carolina, USA

  9. 1st Threshold Conference • Results: Taylor et al. 2002. Factors affecting the determination of threshold doses for allergenic foods: how much is too much? J. Allergy Clin. Immunol. 109: 24-30. Food Allergy Research and Resource Program  2005

  10. 1st Threshold Conference • Results: • Considerable data presented on low dose challenges for peanut, egg and cows’ milk • More limited data available on low dose challenges to other allergenic foods: fish, mustard, soybean and tree nuts Food Allergy Research and Resource Program  2005

  11. 1st Threshold Conference Food Allergy Research and Resource Program  2005

  12. 1st Threshold Conference Major Conclusions • Threshold doses do exist for commonly allergenic foods • Thresholds were finite, measurable, and above zero • Premature to reach consensus on threshold doses for specific foods Food Allergy Research and Resource Program  2005

  13. 1st Threshold Conference Secondary Observations/ Opinions • Reactions occur to hidden/ undeclared allergens in foods • The severity of reactions to undeclared allergens increases with the dose of exposure • Low/ very low dose exposures (LOAELs) result in mild, reversible symptoms Food Allergy Research and Resource Program  2005

  14. 2nd FARRP Threshold ConferenceMay 20-21, 2002Palm Beach, FL

  15. 2nd Threshold Conference • Results: • Taylor et al. 2004. A consensus protocol for the determination of the threshold doses for allergenic foods: how much is too much? Clin. Exp. Allergy 34: 689-695. Food Allergy Research and Resource Program  2005

  16. 3rd FARRP Threshold Conference October 4-5, 2004 Camp De Mar, Mallorca, Spain

  17. Why model dose-response? • It may not be feasible to design studies with sufficient power to give the desired degree of safety assurance (e.g., 268 patients and no reactions are required to say with 95% confidence that the reaction rate is less than 1%). • A conventional approach, applying a safety factor to a no effect level cannot easily be applied: • many challenge studies do not yield a no-effect level • some challenge studies exclude individuals who have suffered a severe response, (are severe reactors the most sensitive?) • No agreement yet on uncertainty factors • Modelling is an accepted way of defining the probability of rare events with potentially severe consequences Food Allergy Research and Resource Program  2005

  18. Figure 4: Diagram showing one possible definition for a allergen threshold using a log-linear model.

  19. Classical Risk Assessment • Typical Uncertainty Factors: 10x – Extrapolation from animals to humans 10x – Inter-individual variation • TDI = NOAEL ÷ 100 (in rats) Food Allergy Research and Resource Program  2005

  20. Risk Assessment for Food Allergens • Determine the NOAEL for specific allergenic food among humans with allergy to that food • Apply uncertainty factor to obtain TDI Food Allergy Research and Resource Program  2005

  21. Determination of NOAEL • Challenge large number of allergic individuals • Identify NOAEL for each patient • Identify LOAEL for each patient • Determine variation between individuals in NOAELs • Standardized protocol leads to consistent interpretation of results Food Allergy Research and Resource Program  2005

  22. Uncertainty Factors • No animal to human extrapolation needed • Have already selected sensitive subset of human population • Did we include the most sensitive individual? • Infants vs. adults Food Allergy Research and Resource Program  2005

  23. 1st Threshold Conference Food Allergy Research and Resource Program  2005

  24. Peanut May (1976) 3 Bock et al. (1978) 14 Atkins et al. (1985) 2 Pastorello et al. (1988) 2 Oppenheimer et al. (1992) 11 Moneret-Vautrin et al. (1995) 2 Hourihane et al. (1997) 14 Moneret-Vautrin et al. (1998) 10 Sicherer et al. (2000) 24 Wensing et al. (2002) 26 Taylor et al. (2002) 306* Morisset et al. (2003) 103 Grimshaw et al. (2003) 4 Leung et al. (2003) 84 Relevant Literature Published LOAELs Food Allergy Research and Resource Program  2005

  25. Egg May (1976) 4 Bock et al. (1978) 10 Atkins et al. (1985) 1 Pastorello et al. (1989) 1 Norgaard & Bindslev-Jensen (1992) 7 Moneret-Vautrin et al. (1995) 8 Caffarelli et al. (1995) 13 Sicherer et al. (2000) 267 Eggesbo et al. (2001) 9 Taylor et al. (2002) 281* Osterballe & Bindslev-Jensen (2003) 56 Morisset et al. (2003) 125 Relevant Literature Published LOAELs Food Allergy Research and Resource Program  2005

  26. Milk May (1976) 1 Bock et al. (1978) 10 Bernstein et al. (1982) 5 Hill et al. (1988) 68 Pastorello et al. (1989) 7 Baehler et al. (1995) 10 Norgaard & Bindslev-Jensen (1992) 4 Moneret-Vautrin et al. (1995) 5 Sicherer et al. (2000) 117 Taylor et al. (2002) 299* Morisset et al. (2003) 59 Meglio et al. (2004) 13 Relevant Literature Published LOAELs Food Allergy Research and Resource Program  2005

  27. Uncertainties Regarding Establishment of Threshold Doses • Adults vs. children (mg vs. mg/kg) • Nature of challenge material • Allergen content of challenge material Food Allergy Research and Resource Program  2005

  28. Nature of Challenge Material Food Allergy Research and Resource Program  2005

  29. Uncertainties About Challenge Materials • Studies should be compared by using protein content • If the protein content of the challenge material was not determined experimentally or cannot be determined with reliable factors, then the study should be rejected from consideration in establishment of thresholds • Well-characterized challenge material: NFDM, dried egg white, soy flour • Thresholds should be established in terms that can be related to analytical methods (mg food) Food Allergy Research and Resource Program  2005

  30. Uncertainties Regarding Establishment of Threshold Doses • Blinding of challenges (single-blind vs. double-blind) • Oral vs. labial challenges • Choice of dosages for challenges Food Allergy Research and Resource Program  2005

  31. Uncertainties Regarding Establishment of Threshold Doses • LOAELs vs. NOAELs • Uncertainty in using LOAEL to establish threshold dose • Patient selection and exclusion of severely affected patients • Variability in individual threshold doses Food Allergy Research and Resource Program  2005

  32. NOAELs vs. LOAELs • Diagnostic challenges report only LOAELs • NOAELs may not be recorded • In many cases (how many?), the patient has responded to the lowest dose administered • How far above the NOAEL is the LOAEL? • If using LOAEL, how big should the UF be? Food Allergy Research and Resource Program  2005

  33. NOAELs vs. LOAELsSize of UF • UF = 1 if LOAEL based upon subjective symptoms • UF = 2 if LOAEL based on mild, objective symptoms at first dose and very low doses (0.1 – 20 mg) were given • UF = ? If LOAEL based on objective symptoms, at first dose and higher doses (400+ mg) were given • Use NOAEL in cases where objective symptoms occurred at doses above the initial dose Food Allergy Research and Resource Program  2005

  34. Uncertainties Regarding Establishment of Threshold Doses • LOAELs vs. NOAELs • Uncertainty in using LOAEL to establish threshold dose • Patient selection and exclusion of severely affected patients • Variability in individual threshold doses Food Allergy Research and Resource Program  2005

  35. Selection of Subjects • Diagnostic evaluations (DBPCFC) may be representative of the whole population of allergic individuals • Referral clinics? • Clinical threshold studies may be skewed toward the more highly sensitive Food Allergy Research and Resource Program  2005

  36. Selection of Subjects • Sicherer et al. 2000. Dose-response in double-blind, placebo-controlled oral food challenge in children with atopic dermatitis. J. Allergy Clin. Immunol. 105: 582-586. • DBPCFC of 53 soy-allergic children • 28% reacted at first dose (400 or 500 mg) • 53% reacted at intermediate doses • 19% reacted at final dose (2.0 or 2.5 g) or on open challenge • Soy protein or soy flour? Food Allergy Research and Resource Program  2005

  37. Minimal Eliciting Dose Peanut (n=103) • Patients with suggestive symptoms (OAS – shock) • SBPCFC or DBPCFC, 5 active doses • 20 min interval • Dose range: 5 – 700mg/10 – 5000mg • Roasted crushed peanuts in mashed potatoes • Severe symptoms: abdominal pain (3.3%), asthma (20%), drop in BP (3%) Age ED (cum) Children < 15 mg - > 7110 mg Adults < 15 mg - > 7110 mg (one patient 5 mg) Food Allergy Research and Resource Program  2005 Morisset et al. CEA 2003;33:1046-51.

  38. Severely Affected Individuals • Have they been excluded from challenge trials? • Do they have lower minimal eliciting doses? • Do they experience severe reactions at very low doses? • Have they simply made big mistakes in their avoidance diets? Food Allergy Research and Resource Program  2005

  39. Food Allergy Research and Resource Program  2005

  40. Minimal Eliciting Dose Peanut (n=26) • Adult patients with suggestive history (OAS – shock) • Double blind challenge, 7 active doses, 7 placebo • Randomly interspersed, 15 – 30 min interval • 85% defatted roasted peanut flour in mashed potatoes • 26/26 had symptoms, 5/26 objective • Symptoms: OAS (26), lipswelling (3), nausea (2), vomiting (2) • Clinical score: mild, moderate, severe Age (mean) ED obj (μg) ED obj (cum) (μg) 25 10 - 30 14.43 – 44 Food Allergy Research and Resource Program  2005 Wensing et al. JACI 2002;110:915-20.

  41. Food Allergy Research and Resource Program  2005

  42. Uncertainties Regarding Establishment of Threshold Doses • LOAELs vs. NOAELs • Uncertainty in using LOAEL to establish threshold dose • Patient selection and exclusion of severely affected patients • Variability in individual threshold doses Food Allergy Research and Resource Program  2005

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