Adverse reactions and allergic reactions to food additives

Food additives
allergy
Topic: 26th April 2024
Tanatchabhorn Soponkanabhorn, MD.
Division of Allergy, Immunology and Rheumatology
Department of Pediatrics, King Chulalongkorn Memorial Hospital

Outline
• Epidermiology of food additives allergy
• Type of common food additives
• Food additives and clinical manifestations
• Antioxidants
• Stabilizers
• Flavor enhancers (flavoring)
• Preservatives (antimicrobial agents)
• Diagnosis
• Management
• Summary

Introduction
• Food additives are substances added to food at any stage
• Production, processing, treatment, packaging, transportation, or storage
• Primarily of ‘natural origin’ then ‘synthetic additives’ were gradually
introduced and became predominant
• Many additives may be used in given food product, the additives are typically
minor ingredients of the composite food
• Coloring, flavoring/sweetening, antimicrobial purposes (preserving foods)
• Because their protein content, natural additives are more likely to induce
immune-mediated adverse reactions
• Ranging from lethargy to severe asthma and anaphylaxis
Middleton’s Allergy. 9th Edition.
Randhawa S, Bahna SL. Curr Opin Allergy Clin Immunol. 2009 Jun;9(3):278-83.

Epidermiology
• The prevalence of additive adverse reactions is difficult to estimate
• Symptoms are prone to subjectivity
• Lack of reliable markers of reactivity
• Despite their widespread use, prevalence of food additive adverse rection was
rare
• In Denmark, the prevalence of additive adverse reactions was 1-2%
• In British survey of more than 15,000 individuals, estimated prevalence of self-
reported symptoms to food additives was 0.01-0.23%
• In Germany, the prevalence estimated of additive adverse reactions was less than
0.18%
Fuglsang G, et al. Pediatr Allergy Immunol. 1993 Aug;4(3):123-9.
Valluzzi RL, et al. Curr Opin Allergy Clin Immunol. 2019 Jun;19(3):256-262.

Epidermiology
• 271 Danish school children was selected
on the basis of the results of a
questionnaire on atopic disease
• The children followed an elimination diet
for two weeks before they were
challenged with a mixture of food
preservatives, colorings and flavors
• The challenge was open and the additives
were prepared as a fizzy lemonade
• If the open challenge was positive, a DBPC
challenge with gelatin capsules was
performed
• Prevalence of food additive allergy in patients with atopic disease

Epidermiology
Results:
• Open challenge was negative in all 98 healthy control
• 173 children reporting present or previous atopic disease
• 17 had a positive open challenge (1 experienced gastrointestinal symptoms, 13
reacted with aggravation of atopic eczema, and 3 with urticaria)
• 12/17 children went through the double-blind challenge
• Positive in 6 cases:
• 5/6 children had positive reactions to synthetic colorings
• 1 child had positive reaction to citric acid
• The prevalence of intolerance to food additives in school children is estimated to
be 1-2%
• Prevalence of food additive allergy in patients with atopic disease

Epidermiology
• 100 patients with CIU (36 male, 64 female),
ages 14-67 years, were challenged
• “Rule of Nines” was used to determine
‘positive challenge’
• 11 common food additives were tested in
opaque capsule
• Tartrazine (FD&C Yellow 5), potassium
metabisulfite, MSG, aspartame, sodium
benzoate, methyl para- ben, butylated hydroxy
anisole, butylated hydroxy toluene, FD&C
Yellow 6, sodium nitrate, and sodium nitrite
• Single-blind challenges were performed as
screening challenges
• Double-blind placebo-controlled challenges
• Prevalence of food additive allergy in patients with CIU
Rajan JP, et al. J Allergy Clin Immunol Pract. 2014 Mar-Apr;2(2):168-71.

Epidermiology
• Prevalence of food additive allergy in patients with CIU
• Results:
• Only 2 patients had a positive urticarial response on single-blind challenge
• Neither of these patients had a positive urticarial response on double-blind
placebo-controlled challenge
• The prevalence of food additive sensitivity in CIU patients is <1%
• If a clinician suspects that a patient with CIU has a food additive sensitivity, then
single-blind challenge with a placebo control should be performed initially
• If there is any objective evidence of reaction, then double-blind placebo-controlled
challenge should be performed with multiple placebos to confirm the sensitivity
• If there is no response to single-blind challenge, then it is unlikely that additives are
the culprit
Rajan JP, et al. J Allergy Clin Immunol Pract. 2014 Mar-Apr;2(2):168-71.

FDA ESFA
• European Safety Food Authority, EU
• E number: idenfied food additive
• Product labeling must specify additive
properties by refereing to its name and E
number
• The Food and Drug Administration, US
• FDA regulatory status
• Provides a list of substances used in
food production
FS: substances permitted as optional ingredient in a
standardized food
GMP: Good Manufacturing Practice
GRAS: Generally Recognized As Safe
GRAS/FS: Generally Recognized As Safe in foods but
limited in standardized food
REG: Food additives for which a regulation has been
issued

Common food additives
Additive properties Name FDA regulatory status E number
Antioxidants Butylated hydroxyanisole (BHA)
Butylated hydroxytoluene (BHT)
Propyl gallate
GRAS/FS
GRAS
GRAS
E 320
E 321
E 310
Stabilizers Guar gum, xanthan gum GRAS/FS E 412
Miscellaneous Propylene glycol GRAS/FS E 1520
Flavoring Monosodium glutamate
Ethyl vanilla, cinnamic aldehyde
GRAS/FS, GMP E 621
Spices, essential oils Anise
Cinnamon
Coriander
Cumin
Fennel
Ginger
Mustard
Nutmeg
Paprika
Pepper
GRAS
GRAS
GRAS
GRAS
GRAS
GRAS
GRAS
GRAS
GRAS
GRAS
-
-
-
-
-
-
-
-
E 160c (extract)
-
FS: substances permitted as optional ingredient in a standardized food
GRAS/FS: Generally Recognized As Safe in foods but limited in standardized food
REG: Food additives for which a egulation has been issued
ESFA
FDA

Common food additives
Additive properties Name FDA regulatory status E number
Artificial sweeteners Aspartame REG, GMP E 951
Nutrients Vitamin A, ferrous sulfate
Starches and complex
carbohydrates
Corn starch, modified starch
Preservatives Benzoated
Nitrates
Nitrites
Sodium metabisulfite
GRAS/FS
REG
PS
GRAS, GMP
E 211-215, 218, 219
E 251-252
E 249-250
E 223
Dyes
Orange
Red
Yellow
Annatto
Carmine
Saffron
Tartrazine (yellow#5)
GMP
GMP
GMP
GMP
E 160b
E 120
E 164
E 102
FS: substances permitted as optional ingredient in a standardized food
GRAS/FS: Generally Recognized As Safe in foods but limited in standardized food
REG: Food additives for which a egulation has been issued
FDA ESFA

Food additives and
clinical manifestation
• Antioxidants
• Stabilizer, emulsifiers
• Flavoring:
• Monosodium glutamate, spices
• Aspartame
• Preservatives and
antimicrobial
• Food dyes
• Others

Antioxidants
• Antioxidants prevent lipids from oxidative degeneration
• Uses in lipids:
• Magarine
• Salad dressing
• Vegetable oil
• Animal fat, meat, fish
• Bakery and potato products
• Common antioxidants:
• Butylhydroxyanisole (BHA)
• Butylhydroxytoluene (BHT)
Witkowski M, et al. Int J Environ Res Public Health. 2022 Sep 13;19(18):11493.

Butylhydroxyanisole & Butylhydroxytoluene
• Synthetic group of phenolic antioxidants
• Uses: preserved fat and slow spoilage (butter, cereals, chewing gum,baked goods,
snack foods, dehydrated potatoes, and beer)
• Clinical manifestation:
• Chronic urticaria: provoke urticarial flares
• Cutaneous anaphylaxis
• Asthma
• Allergic rhinitis
• Atopic dermatitis (worsening)
Randhawa S, et al. Curr Opin Allergy Clin Immunol. 2009 Jun;9(3):278-83.

Goodman DL, et al. J Allergy Clin Immunol. 1990 Oct;86(4 Pt 1):570-5.
• A 32-year-old white male army pediatrician with a 4-year history of
daily urticaria (worse during the morning)
• He had consulted several physicians for evaluation of his urticaria
and had progressively restricted his diet
• He was eating only fresh beef obtained daily from a butcher,
asparagus, broccoli, one ounce of oatmeal with 2 ounces of milk
each morning, and deionized water
• Investigation:
• Elevated IgE of 1650 IU/ml
• Prick skin tests for 23 foods were negative
• Otherwise normal
• Oral challenges test:
• Patient reacted to all three of the mixed BHA/BHT challenges,
as well as the single BHA challenge
• The oatmeal that patient had been routinely ingesting for
breakfast contained BHA and BHT

Goodman DL, et al. J Allergy Clin Immunol. 1990 Oct;86(4 Pt 1):570-5.

Gums
• Major gums: sugar, tragacanth, xanthan, carrageenan, acacia (gum Arabic), locust bean,
alginate
• Legumes: sugar, tragacanth, acacia, locust bean
• Gums are primarily composed of complex polysaccharides but occassionally contain
residues of proteins
• Uses: thickening agents, increased mixture viscosity without changing the taste of foods
• Guar gum:
• Most common used gum
• Extracted from the guar bean, a vegetable that grows in India (Cyamopsis
tetragonolobus)
• Used as stabilizer and emulsifier, particularly in ice creams, ketchups, salad dressings,
yogurt, and baked goods

Gums
• Occupational asthma, occupational rhinitis from Guar gum
• 16 worker in environmental exposure to guar gum, flour, and psyllium were subjected to
inhalation challenges to those agents after avoidance for an average of 5.7 years
• Bronchospasm to any of those agents occurred in 11 workers
• Anaphylaxis resulting from ingestion of Guar gum contained in meal substitute (case
report)
• Positive basophil activation test, negative sIgE to guar gum
• Severe contact urticaria from Guar gum
• Uses of Guar gum as gelling agent for local anesthetic in dental procedure
• Allergic reactions to gum tragacanth and gum arabic

Monosodium glutamate (MSG)
• Flavor enhancer added to many foods, especially Asian dishes
• Originally obtained from seaweed and later synthezied for wide distribution
• MSG: sodium salt form of a non-essential amino acid in human body
• The average intake in a meal can be 3 – 5 g, with a widely varying daily intake per person
that may reach 12 g in some countries
• Clinical manifestations:
• Asthma
• MSG symptoms complex
• Migraine headache
• Associated with high concentration of MSG
• Urticaria and angioedema
• Rhinitis

Monosodium glutamate complex
(Chinese Restaurant Syndrome)
• First described the clinical reactions to MSG in 1968 by Kwok RH as the term ‘Chinese
restaurant syndrome’
Kwok RH. N Engl J Med. 1968 Apr 4;278(14):796.

Monosodium glutamate complex
(Chinese Restaurant Syndrome)
• Characterized by wide variety of subjective
dose-dependent symptoms for up to 2 hour
after food consumption
• Numbness in the neck, which spreads to
the arms and back
• Heat, flushing
• Headache
• Dizziness, diaphoresis
• Palpitation, chest heaviness
• Bronchospasm
Kwok RH. N Engl J Med. 1968 Apr 4;278(14):796.

• 21-year-old woman was diagnosed with allergic
rhinoconjunctivitis at the age of 17
• At age 14 years old, she noticed that her tongue swelled
after eating various snack foods but had no oral itching,
diarrhea, or abdominal pain
• The frequency of swelling of the tongue increased after
she turned 20 years old
• Swelling of the tongue did not occur a7er ea8ng either homemade meals without addi8ves, items
from conveyor-belt sushi restaurants, or at any of the meals in restaurants during a trip to Europe
• In contrast, her tongue swelled a7er she ate at a chain family restaurant and a7er having fast-food
hamburgers, French fries, potato snacks, parmesan cheese, and consommé-ﬂavored (but not light-
salt) potato chips
Osada R, et al. J Asthma Allergy. 2024 Mar 7;17:161-165.

• Investigation:
• Patient’s total serum IgE level was normal
• Antigen-specific serum IgE levels were undetectable for wheat, potato, and pollens
• Skin testing:
• Positive reaction to 100 mg/mL of MSG (Ajinomoto, Ajinomoto Co., Inc, Tokyo,
Japan)
• Negative reactions to 10 mg and 1 mg/mL of MSG, potato, wheat, gluten, and
omega-5-gliadin
• Oral challenge test with potato snacks that contained MSG
• After ingesting 4 sticks (1.5 g each), she experienced only a tingling tongue
• After 23 sticks (about 20 min after starting to eat), she had a sore throat, painful
tongue, itchy palate, and buccal mucosal swelling and bleeding
• Because of severe pain, she could not ingest any more than 31 sticks
• Biopsy of the buccal mucosa: telangiectasia of the buccal mucosa and interstitial
edema in the subepithelial submucosa
Osada R, et al. J Asthma Allergy. 2024 Mar 7;17:161-165.

Spices
• Spices: aromatic additives derived
from vegetables using seeds in food
production
• Eg. Sesame, sunflower, poppy,
pumpkin, flax, and mustard
• Uses: flavoring agent
• Spices are used raw (parsley, lovage),
or processed, for instance pickled
(green pepper), dried (laurel, paprika,
black pepper), toasted (sesame),
roasted (poppy) or cooked (celery)
• Spice allergy is rare (2% in adult
populations)
• Intolerance or allergic reaction? eg.
Capsaicin (hot spices)
Schöll I, et al. Int Arch Allergy Immunol. 2004 Nov;135(3):247-61.

Spices: Reports of allergenicity
• Allergenicity of spice depends on
• Extent and type of processing
• Some of spice allergens may be destroyed and loose their IgE-binding
capacity
• Hot spices as paprika, chilli or pepper are routinely processed by drying and grinding
destroys Bet v 1 as well as profilin
• Poppy seeds (used in the cuisine in roasted condition) and dried Apiaceae spices like
anise, fennel, cumin or coriander
• Still contain intact Bet v 1 and profilin homologues, may even elicit anaphylaxis
• Molecular-weight
• Higher-molecular-weight molecules of spices of the Apiaceae and Solanaceae
families expressing cross-reactive carbohydrate determinants
• More resistant to food processing including grinding, roasting and cooking, and retain
the potential to induce clinical symptoms

Spices: Reports of allergenicity

Spices
• Clinical manifestaDon:
• Persistent Apiaceae (coriander, caraway, fennel, celery) sensi[za[on in children up to
23%
• Cross-reacVvity between birch pollen allergen (Bet v1 proﬁlin), seed storage proteins, or
2S albumin
• ‘Celery-birch-mugwort spice syndrome’
• ‘Mugwort spice syndrome’
• ‘Mugwort mustard allergy’
• HypersensiVvity reacVons mediated by IgE were observed most frequently in the
botanical families: Apiaceae > Solanaceae > Lamiaceae > Asteraceae > Papaveraceae >
Brassicaceae
• Lower extent in Piperaceae, Myrtaceae, Myricaceaea, Orchidaceae, Lauraceaea,
Zingiberaceae, and Alliaceae

Spices
• Diagnosis of spice allergy:
• Skin testing:
• Skin prick tests with native spices and spice extracts rendered comparable results
• Fresh spices can also be used for prick-to-prick tests in cases where extracts are not
commercially available
• Scratch tests may be helpful
• RAST can be negative in more than half of the cases
• A combination of these procedures may be useful
• Double-blind placebo-controlled food challenge
• Powdered spices can be used when entrapped in capsules
• Specific bronchial inhalation challenges
• Less practical value and expensive
• In rare cases, anterior rhinomanometry: for garlic and onion allergy

Spices blends

Aspartame
• Aspartame (Equal): nonnutritive sweetener, 180 times sweeter than sucrose
• Uses: food, beverage applications
• Clinical manifestation of reported adverse reactions:
• Headache
• Neuropsychiatric symptoms including seizures
• Urticaria and angioedema
• No role of aspartame was found in the provocation of chronic urticaria in DBPC challenge
in patient with or without histories of sensitivities to food additives

Preservatives and antimicrobials

Sulfites
• Sulfiting agents include
• Sulpher dioxide
• Sulfate in the form of sodium salt and potassium salt
• Sodium sulfite
• Sodium and potassium metabisulfite
• Sodium and potassium bisulfite
• Uses:
• Prolonged shelf life, inhibit growth of microorganisms in fermentation industry
• Added to many different type of foods, fermented beverages
• Inhibition of enzymatic browning (fresh fruits, salads)
• Inhibition of nonenzymatic browning (dried fruits, dehydrated potatoes)
• Antimicrobial actions (wines, corn wet milling)
• Dough conditioning (frozen pie crust/pizza crust)
• Antioxidant action
• Bleaching effect (Maaschino cherries)
• Common foods with high
sulfite content (>100 ppm)
• Dried fruits
• Grape juice
• Lemon, lime juice
• Pickles onions
• Wine
Middleton’s Allergy. 9th EdiUon.

• Allergic reactions to sulfites are rare in general population
• More common in women, reactions can range from mild to severe
• Allergic contact dermatitis
• Sodium metabisulfate: most common cause
• Confirmed by patch testing (at a concentration of 1% petrolatum)
• Urticaria
• Anaphylactoid events
• Idiopathic anaphylaxis
• Persistent rhinitis
• Sodium metabisulfate
• Bronchospasm and asthma
• Sulphites are responsible for 5-10% of asthma exacerbation
• Ingestion of sulfite solutions could induce changes in pulmonary function
Sulfites

• Diagnosis:
• Patient history alone: insufficient to establish diagnosis
• Positive sulfate challenge dose not always correlate with patient’s history
• Investigation:
• Skin testing and intradermal testing
• Individuals with severe bronchospasm had negative skin tests
• Sulfiting challenges:
• No standardized procedure for sulfiting agent challenges
• Patients may be challenged with capsules, neutral solution or acid solutions of
metabolites sulfites
• Positive single-blind challenges should always confirmed by double-blind procedure
Sulfites

• Management:
• Avoid sulfite-treated food and drugs triggered the
response
• Multiple challenges might be necessary to determine
which sulfite-containing foods are tolerated
• All sulfite-sensitive asthmatic patients should be avoid
the more highly sulfited food with an excess of 100 ppm
of SO2 equivalent
Sulfites
Labeling required of packaged products
and alcoholic beverages containing
sulfites residue in excess of 10 ppm

Nitrite and nitrate
• Nitrite: Sodium nitrite (E250), potassium nitrite (E249)
• Nitrate: Sodium nitrate (E251), potassium nitrite (E252)
• Uses: preservative agents in meat products (nitrite), dairy industry and fish
processing (nitrate)
• Chronic urticaria/exacerbation of urticaria
• Generalized pruritus (case report)
• Angioedema
• Anaphylaxis

Benzoates
• Food preservative
• Uses: alcoholic beverages, fruit juices, sparkling drinks, and pickles
• Bronchospasm (few patients)
• Nonallergic rhinitis
• 8.8% developed positive objective symptoms after DBPC with monosodium benzoate
• Patients reported symptoms improvement within 1 month on a diet free of benzoates

Food dyes
• Dyes enhance or change the color of food and beverage products
Natural dyes Synthetic dyes
• Type: natural, identical to natural
• Dyeing ability and durability depend on
environmental factors
• Can develop IgE-mediated hypersensitivity
Examples:
• Carmine: red dye
• Annatto: yellow orange pigment
• Saffron: yellow food coloring
• Others: caramel, carotene, tumeric,
paprika, beet extract, grape skin extract
• Type: organic and inorganic, azo and
nonazo dyes
• Allow obtaining a permanent color
• Cheaper
• Standard dyeing strength
• More frequently reported of adverse
reactions
Examples:
• Tartrazine (FD&C Yellow#5)
• Sunset Yellow (FD&C Yellow#6)

Carmine (E 120)
• Red dye extract from dried female
cochineal insects (Dactylopius coccus
Costa), parasite on the prickly pear cactus
• Identifier: INS No. 120, Cochineal extract,
Carmine, Cochineal carmine, CI Natural Red
4, ชาดลิ้นจี่
• Uses:
• Cosmetic
• Beverages and food products (Juices,
ice cream, yogurt, and candy)
• ADI: 0-5 mg/kg body weight
Ganseman E, et al. Clin Exp Allergy. 2022 Oct;52(10):1225-1229.
https://iacmcolor.org/color-profile/carmines/

Carmine
• A ﬁrst carmine allergy case was reported as a pa4ent presented with cheili4s upon the
use of carmine-containing lip salve
• Around 50 cases of food, inhala3on and cutaneous allergy caused by carmine were reported
• Most presented with anaphylac4c reac4ons (over 30 case reports)
• Wu ̈ thrich et al. have reported 5 cases of IgE-mediated anaphylac3c reac3on to carmine,
with posi3ve skin prick tes3ng (SPT) and speciﬁc IgE
• Delayed hypersensi4vity: contact derma44s
• Use of lipsVck
• Beverages and food products
• May exacerbate childhood atopic eczema

Carmine
• Diagnosis of carmine allergy
• Can be difficult because of the nature of
protein residues and interactions with
carminic acid
• Carminicacidin basophil activation tests
may improve carmine allergy diagnosis
• Oral challenge may need to confirm
carmine allergy

Annatto (E 160b)
• Yellowish orange pigment extracted from the
seeds of Bixa orellana (Bixin is carotenoid)
• Used to impart an orange or deep yellow color
to ﬁnished food
• Uses: common ingredients in dairy, bakery
products, vegetable oils, and drinks
• ADI of 6 mg/kg body weight per day (bixin) and
0.3 mg/kg body weight per day (norbixin)
https://iacmcolor.org/color-profile/annatto-extract/
Identifier:
- Annatto extract, เมล็ดคำแสด
- INS No. 160b(i); Annatto extracts, bixin-based, INS
No. 160b(ii); Annatto extracts; norbixin-based
- E160b(i); Annatto bixin, E160b(ii); Annatto norbixin

Annatto (E 160b)
• Prevalence of annatto sensitivity
0.01-0.07%
• Urticarial and anaphylactic reaction
after annatto food consumption
(case reports)
• Annatto-containing cheese,
crackers, and breakfast cereals
• Positive skin tests, IgE
immunoblot, and BAT

Saffron
• Yellow food coloring, extract from dried
s[gma of the flower of saffron crocus
(Crocus sa[vus)
• Iden[fier: CI Natural Yellow 6, Crocus
• ESFA: Saffron is generally considered a
coloring food in the EU, rather than an
addi[ve food color
• LTP (Cro 3) in the saffron extract lead to
systemic reac[ons or cross-reac[vity to
other LTP allergens
• Case report: saffron profilin allergen
(Cro 2) may induce respiratory reac[ons
https://bafanghealth.en.made-in-china.com/product/ZmfrayDEgMkv/China-Food-Additive-
Pharmaceutical-Zanghonghua-Traditional-Chinese-Herb-Medicine-Saffron-for-Skin-Care.html

Tartrazine (FD&C Yellow #5)
• Synthetic azo dye, also known as E102
• Lemon yellow in color and water soluble
• Uses: dairy products (ice cream, ice pops), beverages
(Mountain dew), dressings, sauces, jellies, cosmetics
• Acceptable daily intake (ADI) of 7.5 mg/kg of body weight daily
• Young et al. estimated prevalence of tartrazine sensitivity
appears to be very low (0-0.12% in population)
• Possible causative role in urticaria and angioedema
• The La Jolla group (1st DBPC trial of tartrazine in
chronic urticaria): lacking evidence
• Possible role in tartrazine induced asthma
• The La Jolla/Scripps group: suggesting that tartazine
dose not provoke asthma
https://iacmcolor.org/color-profile/tartrazine-fdc-yellow-no-5/

Sunset Yellow (FD&C Yellow #6)
• Synthe8c yellow azo dye
• Also known as Orange Yellow S, E110
• Uses: fermented foods, orange sodas, apricot jams, lemon curd,
packaged lemon gelaVn desserts, Swiss rolls, cake decoraVons
with icing, cheese sauce mixes
• Oien used in conjuncVon with amaranth (E123) to produce
brown coloring in both chocolate and caramel
• Acceptable daily intake (ADI) of 0-4 mg/kg of body weight daily
• Clinical manifestaGon:
• Less oien linked to food sensiVviVes than tartrazine
• Prevalence of sunset yellow hypersensiVvity appears to be
very low
• Possible role in urVcaria and angioedema, asthma
• Provoking atopic dermaVVs
https://iacmcolor.org/color-profile/tartrazine-fdc-yellow-no-5/

Other synthetic colors
• There is no compelling evidence for the
involvement of these colors in urticaria,
angioedema, asthma, and atopic dermatitis
Synthetic colors
Red Amaranth (FD&C Red #2), Erythrosine (FD&C Red #3), azorubin,
Ponceau 4R (E124), Carmosine (E122)
Blue Brilliant blue (FD&C Blue #1), Indigo carmine (FD&C Blue #2),
Patent blue
Yellow Quinoline yellow (E104)
Green Fast green (FD&C Green #3)
Black Brilliant black BN

• Edible oils are derived from commonly allergenic
foods such as peanut, soybean, fish and sunflower seed
• Highly refined oils:
• Safely ingested by individual allergic to the
source product from which the oil is derived
• Contain extremely low levels of detectable
allergen
• Eg. Peanut oil, soybean oil, fish oil, and
sunflower seed oil
• Less well refined oils, cold-pressed oils or gourmet
oils made:
• Can contain protein residuals, may be hazardous
for consumption by allergic individual
• Eg. Sesame seeds, treenuts
Edible oils
https://www.patcharapa.com/ingredient/soy-oil/

• Gelatin
• Typically derived from beef or pork
(major source of gelatin)
• Kosher gelatin is made from skin of
several fish including cod
• Considered as protein with rather low
allergenic potential
Gelatin

• Beef and pork gelatin
• Uses: plasma volume expander and a stabilizer in vaccines (Zostavax, MMR)
• Allergic reactions have occurred to injected pharmaceutical preparations
containing gelatin
• Both IgE-mediated and cell-mediated allergic reactions have been
reported
• Other gelatin containing pharmaceutical uses such as capsules, rectal
suppositories, and hemostatic sponge have also been less frequently
associated with allergic reactions
• Allergic reactions to gelatin used as food ingredient are are rarely reported
Gelatin

• Beef and pork gelatin
• Alpha-gal allergy:
• Gelatin protein can carry α-Gal epitopes
• The quantity of the oligosaccharide varies
according to the methods of extraction
• Cross-reactions occurring between beef
and pork gelatin and gelatin derived from
other mammalian species were related to
IgE to alpha-gal (galactose-⍺-1,3-galactose)
• Gelatin containing vaccines can be safely
administered to patients with known alpha-
gal allergy
• Reactions to vaccines have also occurred in
patients who had IgE to gelatin, but not to α-Gal
Gelatin
Platts-Mills TAE, et al. J Allergy Clin Immunol Pract. 2020 Jan;8(1):15-23.e1
Gelatin is a main ingredient of jelly babies,
marshmallows, and jello

• Kosher gelatin
• Obtain from fish skin (frequently allergenic
source)
• The allergens in fish are localized in the edible muscle
tissue
• Remnants of muscle tissue are likely to adhere to skin
• Parvalbumin (major fish allergen) essentially not
present in fish gelatin made with extensive
washing of fish skin
• Gelatin-making process involves rather
significant modifications of protein structure
• IgE to fish gelatin is rarely observed in individuals
with known gelatin allergies
Gelatin
hFps://www.woolworths.com.au/shop/productdetails/670557/hanamal-pure-kosher-ﬁsh-gelaLn

• PEGs commonly used as pharmaceutical excipients acting
as a solvent, plasticizer, surfactant or capsule or
suppository lubricant
• PEGs are known to elicit immediate hypersensitivity
reactions associated with administration by multiple
routes
• Greater risk with injectable drugs (PEGs are poorly
absorbed)
• Reactions have occurred to orally administered drugs
• Contact urticaria has been reported to PEGs
Polyethylene Glycol (PEG)
https://punchout.medline.com/product/Polyethylene-
Glycol/Lab-Chemicals/Z05-PF85803

When to suspect food additives allergy
• Key features:
• Food additives should be suspected as the culprit if patient
• Report a history of reactions to a number of unrelated foods or
• Report a history to a certain food when commercially prepared but not when
prepared at home
• A proposed diagnostic approach:
1. Detailed medical history
2. Physical examination
3. Rule out allergy to common foods
4. Look for hidden foods the patient is allergic to (Label reading)
5. Possible skin prick testing or specific IgE to selected natural additives
6. A trial of additive-free diet for a few weeks: avoid all commercial and preprepared foods
7. Double-blind challenges with the suspected food

Diagnosis
• Detailed medical history
• Amount of consumed food
• Time interval between food intake and symptoms onset
• Clinical manifestation
• Consideration hidden or unidenitified ingredients using ‘food labels’
• Food diary
• Write down recipe of the consumed dish, labels the ingredients of purchased
products
• Co-factor
• Alcohol, drug consumption, exercise
• Physical examination

Diagnosis
• Investigation
• In-vivo skin tests
• Prick test with food extract
• Prick-prick test with culprit additive
• Very limited value except in reactions to natural additives such as annatto,
saffron, carmine, mannitol and vegetable gums
• In-vitro tests
• Immediate reaction: sIgE, basophil activarion test, CRD
• Cell-mediated reaction: Patch tests
• Natural additives (spices and dyes extracted from vegetables):
• Molecular sensitization profile

BAT in CIU patients
• 15 paènts who had a history of recurrent ur`carial
aggravaòn following intake of various foods without a
definite food-specific IgE
• Using BAT with a commercially available Flow-CAST® kit
(Bühlmann, Schönenbuch, Switzerland) to 15 common
food addi`ves
• MSG, sodium nitrite, tartrazine, sodium salicylate,
potassium metabisulfite, sodium benzoate, and food
colorant mix
• 2/15 paZents studied(13.3%) showed posiZve BAT
results for one of the tested food addiZves
• 1 paènt responded to monosodium glutamate,
showing 18.7% of CD203c-posi`ve basophils
• Another paènt showed a posi`ve BAT result to
sodium benzoate
• Both paènts had clinical correlaòns with the agents,
which were partly determined by eliminaòn diets Kang MG, et al. Clin Nutr Res. 2014 Jan;3(1):9-16.

Diagnosis
• Oral challenge test with a DBPC trial
• Diagnostic gold standard
• Should be performed in a hospital ward
• Additive challenge studies to confirm
diagnosis:
• Patients with urticaria
• Patients with asthma

Patient with urticaria
• Patient:
• Patients with histories suggestive of food additive-induced urticaria
• Patients whose urticaria improves on an additive-free diet
• Procedure:
• Patient preparation:
• Antihistamine discontinuation or continue at lowest effective dose
• Withheld the questionable additive agents at least 48 hours before the challenge
• NPO
• Emergency drug preparation
• Blinded challenges with active agent and placebo controls
• Start with single blind challenge using placebo control
• If positive response is observed, then double-blinded may be necessary for confirmation

Patient with urticaria
• Control:
• Using multiple placebos randomly interspresd during the challenges
• Blind both subjectes and observer
• Criteria for positive reactions:
• Scoring system based on ‘rule of nines’
• Divided body area into 9 areas
• Scored a scale from 0 to 4
• Zero: no urticaria
• 1: 25% of areas involved
• A score of ‘9’ or a 30% increase from baseline urticaria is considered ‘positive’
challenge
• If blinded challenge procedures are negative >> final open feeding without reaction after negative
challenge is considered to ensure the correctness of diagnosis Middleton’s Allergy. 9th Edition.

Patient with asthma
• Patient:
• Asthma must be stable at the time of challenge
• Pulmonary function test
• Skin test or/and serum IgE tests
• On the day of challenge: withhold inhaled/oral β2
agonists (theophylline does not interfere the challenge)
• Procedure:
• Single-blind challenge
• Using opaque capsule
• Recommended the starting dose be one log
lower than the lowest dose known to cause a
reaction

Patient with asthma
• Control:
• If single-blind challenge is positive >> should be repeated in a double-blind, placebo-
controlled manner
• Initial dose in the the double-blind protocol can be based on patient’s previously
established provoking dose or onefold to twofold lower dose
• Should accompanied by at least two placebo challenges
• Criteria for positive reactions
• Pulmonary function is measured before the challenge and before next scheduled
dose or sooner if symptoms develops
• A 20% or greater decrease in FEV1 from baseline considered ‘positive response’
• If blinded challenge procedures are negative >> final open feeding without reaction
after negative challenge is considered to ensure the correctness of diagnosis

Patient with asthma

• Oral challenges for food additives
Additive Challenge
substance
Placebo
suggestions
Vehicle Doses Time interval
Sulfites Potassium
metabisulfite
Powdered sucrose Capsules 1,5,25,50,100, and
200 mg
20-30 min
Monosodium
glutamate
Monosodium
glutamate powder
Lactose,
microcystalline
cellulose, citrus
drink
Capsules or citrus
drink
200,400,800,1600
mg as much as 5 gm
20-30 min
Tartrazine Tartrazine powder Lactose Opaque capsules Placebo, tartazine
25 and 50 mg
3 hr
Aspartame Aspartame Lactose,
microcystalline
cellulose
Capsules 100,200,400,800
mg
3 hr
Others Sodium benzoate,
butylated
hydroxyanisole,
butylated
hydroxytoluene,
parabens, nitrates
and nitrites
Lactose, one
preservative might
be used as a
placebo for
another
Opaque and dye-free
capsules
1,5,25,50,100, and
200 mg
20-30 min

Whether Oral Food Challenge (OFC)
outcomes supported a suspected diagnosis of
an allergic reaction to food additives?
Lemoine A, et al. Arch Pediatr. 2020 Oct;27(7):368-371.

• 23 patients (median age 5 years old) underwent to an open OFC to food dyes, and/or sodium
benzoate
• 45 OFCs were performed, included 20 OFCs with a mixture of several food dyes
• The most frequently tested allergens were carmine red (n = 20), synthetic cochineal red (n = 19),
sodium benzoate (n = 13), sunset yellow (n = 11), erythrosine (n = 10), and patent blue V (n = 9)
• Native foods or drugs were also tested depending on the patient’s history: sweets in various
forms in five patients, amoxicillin in the form of syrup in two patients, ibuprofen syrup in one
patient
• The median age at time of the OFC was 6.2 years (IQ25–75: 3.9– 8.4 years)
Results:
• 3 patients developed adverse reactions (63%)
• The diagnosis of IgE-mediated allergy was only formally confirmed in 1 OFC out of 45 (2.2%)
• Patient A developed localized urticaria 60 min after ingestion of carmine and cochineal red
(E120, E124), which resolved after treatment with oral antihistamine
Lemoine A, et al. Arch Pediatr. 2020 Oct;27(7):368-371.

Food dyes
• Common uses for Red No. 40 include as a color additive in
• Baked goods (eg, cakes, pastries, candy)
• Flavored dairy products such as yogurt, sports-themed drinks
(eg, Gatorade® Fruit Punch)
• Red-dyed Slurpee® beverages
• Gatorade® and Pedialyte® beverage products are often used by
athletes to replace fluids
• 24-year-old female teacher
• History of experiencing throat closure within
minutes after each of several attempts to ingest
the Fanta Wild Cherry flavor of Slurpee®
• History of developing a mild facial rash when
attempting to consume cupcakes that were dyed
red with Wilton® gel- based red food coloring,
which contains Red No. 3 and Red No. 40
Weisbrod DB, et al. Yale J Biol Med. 2023 Mar 31;96(1):79-82.

Food dyes
• Skin testing:
• Percutaneous skin testing using Duotip-Test® II (Lincoln Diagnostics, Inc., Decatur, IL)
• Using two red color additives:
• Wilton® gel-based red food coloring
• McCormick® liquid red food coloring
• Skin prick tests:
• Negative skin test control (sodium chloride 0.5)
• Positive skin test control (histamine based): 8 mm wheal
• 1 drop of undiluted Wilton® gel-based food coloring: negative
• 1 drop of undiluted McCormick® liquid red food coloring: negative
• Oral challenge test:
• Two hours after ingesting 50 grams of red-colored icing
• Patient did not exhibit any symptoms with the red dye utilized
• The specific color additive precipitating her symptoms was not conclusively identified
Weisbrod DB, et al. Yale J Biol Med. 2023 Mar 31;96(1):79-82.

Management
• If the patient’s
hypersensitivity is confirmed
• Eliminates additives that
contribute to the occurrence
of certain symptoms
• Providing the patient with a
list of foods that are unlikely
to contain additives would be
helpful (diet-free food
additives)

Management
• If the patient’s hypersensitivity is confirmed
• Self-injectable epinephrine should be available for all patients with a history
of severe systemic reactions to food additives products
• Despite sodium metabisulphite in epinephrine formulations, in an emergency such as
anaphylaxis, potential adverse effects would not justify restricting its administration
• The use of a long-acting antihistamine before an anticipated exposure might reduce
the severity of a reaction
• Leukotriene modifiers may be useful, particularly in patients sensitive to acetylsalicylic
acid
• Patient education on self-care management techniques and treatment of
anaphylaxis

Summary
• Hypersensievity to food addieves should be suspected as the culprit
• If paVents report a history of reacVons to a number of unrelated foods or to a certain food
when commercially prepared but not when prepared at home
• Hypersensievity to food addieves appears to be rare phenomenon but the results
on its appearance might be a nuisance and even dangerous for the paeent
• Hypersensievity to food addieves may have many types of manifestaions, and the
disease itself might have an early, delayed or late reaceon
• Allergic paeents will have to avoid all the possible oﬀending foods by paying
ageneon to the labels of food products
• To date, there are no published reports on successful desensiezaeon procedures

References
• Middleton’s Allergy. 9th Edition.
• Fuglsang G, Madsen C, Saval P, Osterballe O. Prevalence of intolerance to food additives among Danish school children. Pediatr Allergy Immunol. 1993 Aug;4(3):123-9.
• Ganseman E, Ieven T, Frans G, Denorme P, Coorevits L, Van Hoeyveld E, Martens E, Bullens D, Schrijvers R, Breynaert C, Proost P. Diagnosis of carmine allergy using carminic acid solves
interference of house dust mite and crustacean cross-reactivity. Clin Exp Allergy. 2022 Oct;52(10):1225-1229.
• Goodman DL, McDonnell JT, Nelson HS, Vaughan TR, Weber RW. Chronic urticaria exacerbated by the antioxidant food preservatives, butylated hydroxyanisole (BHA) and butylated
hydroxytoluene (BHT). J Allergy Clin Immunol. 1990 Oct;86(4 Pt 1):570-5.
• Kang MG, Song WJ, Park HK, Lim KH, Kim SJ, Lee SY, Kim SH, Cho SH, Min KU, Chang YS. Basophil activation test with food additives in chronic urticaria patients. Clin Nutr Res. 2014
Jan;3(1):9-16.
• Kwok RH. Chinese-restaurant syndrome. N Engl J Med. 1968 Apr 4;278(14):796.
• Lemoine A, Pauliat-Desbordes S, Challier P, Tounian P. Adverse reactions to food additives in children: A retrospective study and a prospective survey. Arch Pediatr. 2020 Oct;27(7):368-
371.
• Osada R, Oshikata C, Kurihara Y, Terada K, Kodama Y, Yamashita Y, Nakadegawa R, Masumitsu H, Motobayashi Y, Takayasu H, Masumoto N, Manabe S, Zhu Y, Tanaka R, Kaneko T, Sasaki
A, Tsurikisawa N. A Case of Type I Food Allergy Induced by Monosodium Glutamate. J Asthma Allergy. 2024 Mar 7;17:161-165.
• Rajan JP, Simon RA, Bosso JV. Prevalence of sensitivity to food and drug additives in patients with chronic idiopathic urticaria. J Allergy Clin Immunol Pract. 2014 Mar-Apr;2(2):168-71.
• Randhawa S, Bahna SL. Hypersensitivity reactions to food additives. Curr Opin Allergy Clin Immunol. 2009 Jun;9(3):278-83.
• Schöll I, Jensen-Jarolim E. Allergenic potency of spices: hot, medium hot, or very hot. Int Arch Allergy Immunol. 2004 Nov;135(3):247-61.
• Platts-Mills TAE, Li RC, Keshavarz B, Smith AR, Wilson JM. Diagnosis and Management of Patients with the α-Gal Syndrome. J Allergy Clin Immunol Pract. 2020 Jan;8(1):15-23.e1.
• Valluzzi RL, Fierro V, Arasi S, Mennini M, Pecora V, Fiocchi A. Allergy to food additives. Curr Opin Allergy Clin Immunol. 2019 Jun;19(3):256-262.
• Weisbrod DB, Caruana DL, Li D, Wan L, Szema AM. A Case Report of Allergic Hypersensitivity to Color Additives in Slurpee® Beverages. Yale J Biol Med. 2023 Mar 31;96(1):79-82.
• Witkowski M, Grajeta H, Gomułka K. Hypersensitivity Reactions to Food Additives-Preservatives, Antioxidants, Flavor Enhancers. Int J Environ Res Public Health. 2022 Sep
13;19(18):11493.
• https://www.foodqualityandsafety.com/article/how-to-ensure-the-safety-of-food-additives/

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