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Skin Reactions to Xenobiotics
Ola Bergendorff
Department of Occupational Dermatology
University Hospital
Malmö
Ola Bergendorff May 2017
This lecture has been prepared with help from
Associate Professors Malin Engfeldt and Cecilia Svedman
Department of Occupational Dermatology, University
Hospital, Malmö
Ola Bergendorff May 2017
Overview
1. Skin barrier
2. Chemical burn
3. Phototoxic reactions
4. Urticaria
5. Contact allergy
Ola Bergendorff May 2017
The skin barrier
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The skin
Epidermis
0.1 mm
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Skin blister
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Epidermis
Dermis
Blister
Scarring permanent tattoo
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Stratum
corneum
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Tape strip
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L M Milstone. Epidermal desquamation. Journal of Dermatological Science (2004) 36, 131-140
Psoriasis
4 days
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Skin barrier
0.1 mm
Stratum
corneum
E
p
i
d
e
r
m
i
s
Keratinocyte
Melanocyte
Langerhans’ cell
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Moghimi HR; Williams AC; Barry BW. A lamellar matrix model for stratum corneum intercellular lipids. 2. INTERNATIONAL
JOURNAL OF PHARMACEUTICS. 131 (2) 117-129. 1996
20 µm500 µm
Hadgraft J. Skin deep. Eur J Pharm Biopharm 2004: 58: 291-299
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Lars Norlen, Karolinska Institute
Ola Bergendorff May 2017
Lars Norlen, Karolinska Institute
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How large particles will penetrate skin?
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Rolland A, Wagner N, Chatelus A, Shroot B, Schaefer H. SITE-SPECIFIC DRUG-DELIVERY TO PILOSEBACEOUS
STRUCTURES USING POLYMERIC MICROSPHERES. Pharm Res 1993: 10: 1738-1744.
Nanoparticles < 0,1 µm
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Chemical burns
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Chemical burns due to Kathon CG- an allergenic preservative in paint
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Chemical Treatment
Acids, bases Water
Hydrogen fluoride Calcium salt
Phenols Alcohol, PEG
Bromine, Iodine Thiosulfate
Chemical burn
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Protect your skin!
• Wash your hands thoroughly after contamination
• Use moisturiser
• Use gloves but choose the right material
• Exchange gloves often
TOO MUCH WATER CONTACT WILL
DAMAGE YOUR SKIN BARRIER
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Toxic (non-allergic)
photo reactions
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Fytophotodermatitis
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Photochemical DNA addition
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Psoralen
Crosslinks in DNA
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Fytophototoxic plants
Dictamnus albus
Burning bush /
Mose brinnande buske
Ruta graveolens
Rue / Vinruta
Citrus peel
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Urticaria
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UrticariaStinging nettle(Urtica dioica)
HistamineOla Bergendorff May 2017
Allergy towards rodents
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Urticaria
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Immunologic urticariaAllergy type 1
A fast antibody-mediated reaction to large molecules.
•Proteins from animal saliva, urine, dandruff.
•Pollen.
•House dust mites.
•Natural rubber latex
Occupational allergic asthma from small molecules that form
adducts with proteines in airway mucosa.
•Isocyanates in paints and polyurethane.
•Acid-anhydrides in polymer production.
•Acrylates in polymers. Dental technicians.
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Skin prick test
Blood tests are also available for
most of the allergens.Ola Bergendorff May 2017
Contact allergy
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Nickel Rubber additives
Allergic contact dermatitis
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Contact allergens
• Metal salts: nickel, chromium, cobalt
• Electrophilic organic compounds, MW < 500
• 4000 known allergens
• Preservatives, fragrances, hair/textile-dyes, rubber
vulcanisers, plastic monomers, natural products,
pharmaceuticals
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Contact allergens
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Epicutaneous testings
”Patch test”
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After a few days
”Reading” at day 3 and 7
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Stefan R Ahlfors, Thesis 2008, dept of Dermatology LundOla Bergendorff May 2017
Metalsmetal ions
Nickel: 15-20% sensitive to Ni(II)
Jewellery is the main exposure
Coins, keys
Chromium: 4% sensitive to Chromium (VI)
Leather and cement main exposure
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Legislation28 58.69
NiNickel
24 51.99
CrChromium
Directive 2003/53/EG reduction of Cr (VI) to insolubleCr (III) by addition of reducingagent. No more than 2 ppm Cr(IV) allowed. OCCUPATIONAL
Regulation (EU) 301/2014 content of Cr(IV) in leathermust not exceed 3 ppm.CONSUMER/OCCUPATIONAL
Annex XVII in 1907/2006 (REACH)In products intended to come intodirect and prolonged contact withthe skin the Ni release must not exceed 0.5 µg/cm2 per week after2 yrs of normal use.
Adopted in 1994, in force 2000.
CONSUMER
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In contrast, 17% of the concreteworkers suffered from chromatedermatitis during construction of the tunnel between England and France.
vs
Chromate allergyCement
During construction of the bridges over Öresund and Stora Bält no one ofthe builders suffered from chromateinduced dermatitis.
Irvine C et al. Cement dermatitis in underground workers during the construction ofthe Channel Tunnel, Occup Med 44:17-23
Ola Bergendorff May 2017
Fragrances
• 300-400 naturally
occuring substances
• More than 2500
synthetic fragrances
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Limonene (citrus scent)
•Autoxidizes at 10 weeks: 40% limonene, 7% limonene OOH
•Allergenic oxidation products
•Hydroperoxides main allergens, also carvone, limonene oxideformed
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80
Oxidation time (weeks)
Co
ncen
trati
on
Karlberg et al. Contact Dermatitis1997: 36: 201-206
Ola Bergendorff May 2017
Limonene (citrus scent)
•Autoxidizes at 10 weeks: 40% limonene, 7% limonene OOH
•Allergenic oxidation products
•Hydroperoxides main allergens, also carvone, limonene oxideformed
Ola Bergendorff May 2017
12M
Allergenicity from air oxidation
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Poison oak
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Polymers
”Plastics”: Epoxy, acrylates, phenolic etcmonomers are allergens
”Rubber”: Additives are allergens
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Ola Bergendorff May 2017
ACRYLATES
Exposure
Dental fillingsUV-curable paintArtificial nailsEye lash elongation
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UV-curing nail gel
OligomerMethacrylate monomerPhotoinitiatorPigment
ACRYLATES
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Oligomer
Methacrylatemonomer
Photoinitiator
Pigment
MSDS
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+ Pigments
MSDS
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Rubber
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Rubber polymer
Polyisoprene. Isoprene monomers
Trans-isomer i gutta-percha.
Dental material: fillning of root canal.
100% cis-isomer i natural rubber.
95-99% cis-isomer i synthetic
polyisoprene
Palaquium guttaHevea brasiliensis
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Natural rubber
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VULCANIZATION
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Rubber additives
Allergenic accelerators and antioxidants
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Name Abbrev. Structure
Tetramethylthiuram monosulfide TMTM
Tetramethylthiuram disulfide TMTD
Tetraethylthiuram disulfide TETD
Dipentamethylenthiuram disulfide DPTD
N S S
S
N
S
N S S
S
N
S
Thiurams
Accelerators
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Name Abbrev. Structure
2-Mercaptobenzotiazole MBT
2,2’-Dibenzotiazyl disulfide MBTS
2-(4-Morfolinylmercapto)
benzotiazoleMOR
N-Cyclohexyl-2-
benzotiazolsulfenamideCBS
Mercaptobenzothiazoles
S
NSH
S
NS N O
S
NS
S
NS
S
NS
HN
Acceleratorer
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Soga F, Katoh N, Inoue T, Kishimoto S. Contact Dermatitis, 2008;58(2):116-117.
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Preservatives
In water based products
Liquid soaps, shampoos, cosmetics, skin care products
Paint, metal working fluids
Isothiazolinones (MCI/MI)
Formaldehyde (formaldehyde releasers)
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Preservatives
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Preservatives
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Preservatives
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Preservatives
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Bronopol
Quaternium 15
Imidazolidinylurea
Diazolidinylurea
DMDM hydantoin
Formaldehyde releasers
Ola Bergendorff May 2017
Bronopol
Quaternium 15
Imidazolidinylurea
Diazolidinylurea
DMDM hydantoin
Formaldehyde releasers
6 HCHO
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Summary Chemical burn
• Can result in an allergy
• Important to wash thoroughly
• pH-indicator
Phenolics
HF (hydrogen fluoride)
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Summary Phototoxic reaction
• Furocoumarin (psoralen) + UV
• DNA-damage
Wild plants
Cultivated plants
Citrus peel
Ola Bergendorff May 2017
Summary Urticaria
• Immunologic: type 1-allergy to macromolecules
• Antibody-mediated
• Skin Prick Test
• Immediate reaction
• Allergic asthma to small molecules in some cases
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Summary Contact allergy
• Immunologic: type 4-allergy to small molecules
• Epicutaneous test (patch test)
• Delayed reaction
• T-cell-mediated
• Activation / air oxidation mechanisms
Photoallergy to NSAID and Sunscreens
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Black henna tattooing
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p-Phenylenediamine in
henna tattooing
Life-long allergy to:
Hair dyes
Textile dyes
Black rubber
Ola Bergendorff May 2017
Black henna
= Risk!
Brown-orange henna =
Minimal risk
Ola Bergendorff May 2017