1. Risk Assessment for Food Allergens

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

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

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

5. Food Allergy Research and Resource Program  2005

6. Sources of Clues Regarding Food Allergen Thresholds l Allergen cross contact episodes l Double-blind, placebo-controlled food challenges l Immunotherapy trials l Clinical threshold experiments

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

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

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

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

11. Food Allergy Research and Resource Program  2005 1 st Threshold Conference Food Protocol Lowest Provoking Doses (mg protein) No. Patients Peanut 0.25 mg (0.25 – 66 mg) 306 Egg 0.13 mg (0.13 – 200 mg) 281 Cows’ Milk 0.6 mg (0.6 – 180 mg) 299

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

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

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

15. Food Allergy Research and Resource Program  2005 2 nd Threshold Conference l 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.

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

17. Food Allergy Research and Resource Program  2005 Why model dose-response? l 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%). l 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 l Modelling is an accepted way of defining the probability of rare events with potentially severe consequences

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

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

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

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

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

23. Food Allergy Research and Resource Program  2005 1 st Threshold Conference Food Protocol Lowest Provoking Doses (mg protein) No. Patients Peanut 0.25 mg (0.25 – 66 mg) 306 Egg 0.13 mg (0.13 – 200 mg) 281 Cows’ Milk 0.6 mg (0.6 – 180 mg) 299

24. Food Allergy Research and Resource Program  2005 Relevant Literature Published LOAELs 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

25. Food Allergy Research and Resource Program  2005 Relevant Literature Published LOAELs 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

26. Food Allergy Research and Resource Program  2005 Relevant Literature Published LOAELs 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

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

28. Food Allergy Research and Resource Program  2005 Nature of Challenge Material PeanutEggMilk Ground peanut Egg white Whole milk Peanut flour Dried egg white Non-fat dry milk Peanut butter Whole egg Infant formula Dried whole egg Raw vs. cooked

29. Food Allergy Research and Resource Program  2005 Uncertainties About Challenge Materials l Studies should be compared by using protein content l 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 l Well-characterized challenge material: NFDM, dried egg white, soy flour l Thresholds should be established in terms that can be related to analytical methods (mg food)

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

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

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

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

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

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

36. Food Allergy Research and Resource Program  2005 Selection of Subjects l 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. l 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 l Soy protein or soy flour?

37. Food Allergy Research and Resource Program  2005 Minimal Eliciting Dose Peanut (n=103) l Patients with suggestive symptoms (OAS – shock) l SBPCFC or DBPCFC, 5 active doses l 20 min interval l Dose range: 5 – 700mg/10 – 5000mg l Roasted crushed peanuts in mashed potatoes l Severe symptoms: abdominal pain (3.3%), asthma (20%), drop in BP (3%) AgeED (cum) Children 7110 mg Adults 7110 mg (one patient5 mg) (one patient5 mg) Morisset et al. CEA 2003;33:1046-51.

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

39. Food Allergy Research and Resource Program  2005

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

41. Food Allergy Research and Resource Program  2005

42. Uncertainties Regarding Establishment of Threshold Doses l LOAELs vs. NOAELs l Uncertainty in using LOAEL to establish threshold dose l Patient selection and exclusion of severely affected patients l Variability in individual threshold doses