# Presentation: 227594

## 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
- Severity of response is related directly to dose
- Individuals vary in degree of sensitivity
- How much is too much?

## Exposure Assessment

- How frequently are food products contaminated with potentially hazardous levels of unlabeled allergens?
- How frequently do allergic reactions occur?

## Slide 5

## Sources of CluesRegarding Food Allergen Thresholds

- Allergen cross contact episodes
- Double-blind, placebo-controlled food challenges
- Immunotherapy trials
- Clinical threshold experiments

## INTERPRETATION PROBLEMSALLERGEN 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

## 1st Threshold Conference

- September, 1999
- Hilton Head, South Carolina, USA

## 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.

## 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

## 1st 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 |

## 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

## 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

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

## 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.

## 3rd FARRP Threshold Conference

- October 4-5, 2004
- Camp De Mar, Mallorca, Spain

## 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

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

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

## Classical Risk Assessment

- Typical Uncertainty Factors:
- 	  10x – Extrapolation from animals to humans
-      10x – Inter-individual variation
- TDI = NOAEL ÷ 100 (in rats)

## 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

## 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

## 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

## 1st 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 |

## 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**

## 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**
**	****	**

## 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**
**	****	**

## Uncertainties Regarding Establishment of Threshold Doses 

- Adults vs. children (mg vs. mg/kg)
- Nature of challenge material
- Allergen content of challenge material

## Nature of Challenge Material

| Peanut | Egg | Milk |
| --- | --- | --- |
| 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 |  |

## 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)

## Uncertainties Regarding Establishment of Threshold Doses

- Blinding of challenges (single-blind vs. double-blind)
- Oral vs. labial challenges
- Choice of dosages for challenges

## 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

## NOAELs vs. LOAELs

**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?

## NOAELs vs. LOAELsSize 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

## 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

## 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

## 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?

## 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)

- Morisset et al. CEA 2003;33:1046-51.

## 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?

## Slide 39

## 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 (**μ**g)      **ED obj **(cum) **(**μ**g) *
- 	25 	         10 - 30             14.43 – 44

- Wensing  et al. JACI 2002;110:915-20.

## Slide 41

## 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