Food Toxicology Learning Objectives • Understand the types of adverse food reactions. • Differentiate food and food sensitivity. • Understand the role of IgE () in allergic reaction. • Explore the types of IgE and non-IgE mediated food allergy. Food Toxicology • Summarize the series of Instructor: Gregory Möller, Ph.D. events in allergic reaction. University of Idaho

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Food Toxicology Food Toxicology Learning Objectives Adverse Reactions to Food • Examine symptoms of allergic reaction including • 30% of population report family member with local and systemic . food “allergy” • Summarize the approach to food allergy • Actual % estimates vary <1-7% diagnosis. • Subpopulations/ethnic groups differ markedly • Survey common food .

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Food Toxicology Food Toxicology Most Common Allergic Foods/Groups Adverse Food Reactions •Cows – Sensitivity - Intolerance • Crustacea • General terms that can be applied to any clinically • Eggs abnormal response to food or food additives. •Fish • Many symptoms are similar. • Peanuts • Soybean • Tree nut • Wheat

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•1 Food Toxicology Food Toxicology Types of Adverse Food Reactions Types of Food Sensitivities and • Allergy • Pharmacological (drug interaction) • True food allergy • Non-immune • Toxicity • Food sensitivities anaphylaxis – Anaphylactoid reactions (anaphylactoid) – Metabolic food disorders • Intolerance – Idiosyncratic reactions • Metabolic • Some in several classes • Idiosyncrasy • Food aversions – Mimic sensitivity but no blinded response

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Food Toxicology Food Toxicology Food Allergy: Food Allergies: History • Immune-mediated reaction • Observed since early Greeks and Romans • Can be triggered by very small amounts of food – Hippocrates documents milk sensitivity • Occurs on second exposure or to a cross • Injected normal person with fish extract - no reacting effect (1921) • Anaphylaxis and cutaneous – Injected serum of sensitive person, then fish extract - allergic reaction reactions most common • Researchers discovered IgE (Immunoglobulin E, antibody subclass) in serum was cause (1966)

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Food Toxicology Food Toxicology Food Allergy Epidemiology Epidemiology • Affect ~ 6% of children < 3 years old • Small subpopulation at risk <1% – Milk & soy • 65% of susceptible people have close relative • Cow’s milk: 2.5% with allergy – Over 80% tolerant by 5th birthday • Increased intestinal permeability to • : 1.5% macromolecules predisposes – Over 85% tolerant by 3rd birthday – Viral gastroenteritis, • : 0.5% premature birth, – Leaky gut syndrome (LGS) – Clinical tolerance reached in a minority – Prevalence may be increasing in children

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•2 Food Toxicology Food Toxicology Epidemiology Pathophysiology • Higher in children with other atopic disorders • GI tract forms a barrier to outside environment – 35% of children with moderate to severe atopic • GALT inhibits responses to non-dangerous dermatitis (eczema) while mounting responses to pathogens – 6% of asthmatic children – Gut-Associated Lymphoid Tissue • Adverse reactions to food additives 0.5-1% of • Oral tolerance = unresponsiveness children • Intact food antigens may penetrate the GI tract but not cause clinical symptoms • Develop in genetically predisposed individuals when oral tolerance fails 13 Freiler 14 Freiler

Food Toxicology Food Toxicology Types of Hypersensitivity IgE Mediated • Type I: Immediate hypersensitvity • Type I: Immediate • Type II: Antibody dependent cytotoxicity hypersensitvity • Type III: Antigen-antibody complex mediated – Failure in oral tolerance leads to excessive food-specific IgE • Type IV: Cell-mediated hypersensitivity antibodies – These bind receptors on many cells (esp and mast cells) – Food allergens penetrate mucosal barrier and bind these IgE antibodies – Cellular mediator release

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Food Toxicology Food Toxicology IgE Mediated IgE Mediated • Cutaneous • Respiratory – Urticaria () – Upper – (welts) • Ocular pruritus and tearing – Morbilliform rashes • –Flushing –Lower • Bronchospasm/wheezing • Gastrointestinal • Generalized – Lip, tongue, and palatal pruritis and swelling – Anaphylactic shock – Laryngeal edema – Vomiting and diarrhea

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•3 Food Toxicology Food Toxicology Non-IgE Mediated Non-IgE Mediated • Type II: Antibody dependent cytotoxicity • Type III: Antigen-antibody complex mediated – Specific antibody binds to a surface tissue antigen and – Complement activation induces complement activation (system of serum – Has been implicated in food related complaints immunoproteins which interact in a cascade) – Can be found in sera of normal patients – Complement Æ inflammatory mediators Æ tissue damage – IgE-food antigen complexes are more commonly – Milk-induced thrombocytopenia found in patients with food hypersensitivity – Little support for causing disease

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Food Toxicology Food Toxicology Non-IgE Mediated Non-IgE Mediated • Type IV: Cell-mediated hypersensitivity • Cell Mediated Hypersensitivity – Mediated by sensitized CD4+ T lymphocytes which process – Cutaneous antigens and release lymphokines. • Contact dermatitis • Dermatitis herpetiformis – The lymphokines promote a reaction mediated through – Gastrointestinal macrophages beginning in hrs • Food protein-induced enterocolitis but reaching a peak in 2 to 3 days. • Food protein-induced proctocolitis – Implicated in foods with delayed • Food protein-induced enteropathy onset of sx syndromes – Likely to contribute to a number • Celiac disease of GI disorders – Respiratory • Food-induced pulmonary – Ingestion of sensitizing antigen hemosiderosis (Heiner syndrome) may cause mucosal lesions • Intra-alveolar bleeding

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Food Toxicology Food Toxicology Mixed IgE and Cell Mediated Allergic Response Type I Hypersensitivity • Cutaneous 1) The food is eaten. – 2) Reaches the stomach and small intestine where the proteins are not digested correctly • Gastrointestinal 3) Intact proteins cross the small intestine and reach the blood – Allergic and lymph system. – Allergic eosinophilic gastroenteritis 4) The immune system makes • Respiratory antibodies against the proteins – 5) Allergic people make Immuglobulin E (IgE) which non allergic people don’t . 6) IgE binds to the surface of mast cells or basophils which sensitizes them. 23 Freiler 24

•4 Food Toxicology Food Toxicology Allergic Response: Second Exposure IgE Mediated Food Allergy Summary 1) The person eats the food a second time. Epinephrine • Production of IgE antibodies Injector 2) The protein enters the body • IgE bind to surface of mast cells 3) Binds to and cross-links two to IgE antibodies. or basophils 4) Causes the or to degranulate. • Second exposure to 5) Granules contain 40 different substances that cause allergic reactions. • Allergen cross-links IgE on surface ƒ , , • Release of histamine, bradykinin, leukotrienes, TNF • Inflammation and swelling via capillary leakage and wbc • Allergic reaction

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Food Toxicology Food Toxicology Mast Cell Sensitization

Normal Mast Cells

Degranulated Mast Cells 27 28

Food Toxicology Food Toxicology Food Allergy: Symptoms Food Allergy: Symptoms • Respiratory = asthma, wheezing, bronchiospasms, • Other = anaphylaxis dyspnea (shortness of breath) • Mild and annoying to fatal • Cutaneous = urticaria (hives), eczema, rash, pruritis • Depend on amount ingested and length of time • Gastrointestinal = vomiting, diarrhea, abdominal pain from initial exposure • Inflammation, vasoconstriction, • Not all symptoms hypotension, chest pain, in all people nausea

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•5 Food Toxicology Food Toxicology Food Allergens Local Anaphylaxis () • Almost all natural food proteins • About 10% of people have "atopy" (atopic • Papain - only known additive - meat tenderizer syndrome) and are easily sensitized to allergens additive - enzyme that cause a localized reaction when inhaled or • contaminants in meat and dairy products ingested. are potential hazard – This can produce hay fever, hives, asthma, etc.

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Food Toxicology Food Toxicology Generalized Systemic Anaphylaxis Fatal Food-Induced Anaphylaxis (32 cases) • Accounts for 1/3 of all • Most were adolescents or young adults anaphylaxis seen in emergency • History of prior reaction to implicated food rooms • Symptoms • Only 10% had epinephrine available – Skin – urticaria / angioedema • Peanuts and tree nuts for majority (94%) – Respiratory – , bronchial hyperreactivity – Cardiac – hypotension, arrhythmias, vascular collapse – GI – nausea, vomiting, abdominal cramping, diarrhea • Dx by history and demonstration of food specific IgE 33 Freiler 34 Freiler

Food Toxicology Food Toxicology Exercise-Induced Anaphylaxis (EIA) Diagnosis of Food Allergy • Rare form occurring when patient • Self/parental often erroneous exercises 2-4 hrs after ingestion of • Food diary-when/what/how much specific food • Double-blind food challenge(DBFC) • Without exercise, food no problem – Neither patient nor doctor know if placebo or allergen • Most common in women 15-35 y.o. (crossover) – Sx more pronounced just • Skin prick test prior to menstruation • RAST – Dx based on history and evidence of specific IgE • Common offenders: wheat, celery, shellfish, fish, fruits, milk 35 36

•6 Food Toxicology Food Toxicology Skin Prick Test Radio-Allergosorbent Test (RAST) • To determine if IgE involved • Also test for IgE • Usually preliminary test • Apply crude extract of allergen to solid phase • Apply allergen extract to skin (tissue culture plate) • Scratch to increase access • Add patient serum to blood • IgE (if present) binds allergen • Inflammation results from • Add anti-IgE radiolabeled release of histamine, edema antibody and swelling • Measure binding • Positive control = histamine • Result in ~ 20 min

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Food Toxicology Food Toxicology Common Allergenic Foods: Infants/Children Common Allergenic Food: Adults • Cow’s milk - most common • Legumes - peanuts, soybean • Eggs • Crustacea - shrimp, crab, lobster • Legumes • Molluscs - clams, oyster, scallop – peanuts • Fish – soybean • Tree nuts • Wheat • Eggs • Wheat

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Food Toxicology Food Toxicology Food Allergens Protein Allergens • Most food allergens contain multiple proteins • Milk - casein, lactoglobulins, lactoalbumins which are allergenic – No reduction by pasteurization, condensation, evaporation, and drying • Eggs - ovalbumin, conalbumin, lipoprotein – Egg white more allergenic – No reduction by cooking • Peanuts - arachin, lectin- reactive glycoprotein, Peanut I – Very heat stable, trace sensitivity

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•7 Food Toxicology Food Toxicology Allergen M Allergenic Proteins • Common protein allergen in fish • Not many specific allergens have been identified • Muscle protein - parvalbumin • Peanuts - 30% protein • These proteins are conserved in fish species • Soybeans - 42% protein • Very cross-reactive • Difficult to isolate specific moieties • Very stable in processing • Groups - albumins, lipoproteins, globulins, glycoproteins, S-fractions

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Food Toxicology Food Toxicology Food Allergen Proteins Food Allergens • Cow milk ¾ β-lactoglobulin • Allergens such as chocolate, strawberries and •Egg yolk ¾ Lipoprotein citrus often do not show positive on double blind • Peanuts ¾ Peanut I + others studies • Soybeans ¾ Glycinin + others •Codfish ¾ Allergen M • Green peas ¾ Albumin •Rice ¾ Glutelin/globulins • Tomatoes ¾ Glycoproteins

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Food Toxicology Treatment of Food Allergy • Total avoidance of specific allergen • No level is safe • Very small doses can elicit – Distinguishes from other food sensitivities • Cross reactivity is constant worry

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