Transcript Smoking in Italy, 2004

Fragrance in our
lives – a choice
worth making?
Allergies in the
population: The
EDEN epidemiology
study
Thomas L. Diepgen
Univ. of Heidelberg
Dept. of Social Medicine,
Occup. & Environmental
Dermatology
Germany
Background:
• The exposure to
cosmetics is
massive and it is
inevitable that
adverse effects
occur.
• Allergic contact
dermatitis from
cosmetics is
quite common.
• Fragrances and
preservatives are
the most culprits.
Fragrance allergies in the population
Outline
• “Sensitive” to
cosmetics
• How to diagnose
• Exposure data
• The EDEN study
• Clinical
consequences
How frequent are adverse effects from fragrances?
• A considerable percentage of the population report
adverse health effects or irritation from fragrance
products
• UK: 23% of women and 13.8% of men experience
some sort of adverse reaction to a personal care
product over the course of a year.1
• U.S. population reports2
– Scented products on others irritating
30.5%
– Adverse health effects from air fresheners 19%
– Irritation by scented laundry products
10.9%
1 Orton
& Wilkinson Am J Clin Dermatol 2004
2 Caress & Steinemann J Environ Health 2009
Adverse effect to cosmetics
does not mean contact sensitisation
• 1998 Glostrup Allergy Study (DK n=482)1
– 51.5% report skin redness, itching or rash after
the use of a cosmetic product
however only
– 2.3% sensitised to Fragrance Mix I
– 1.3% sensitised to balsam of Peru
1
Thyssen et al. BJD 2009
Screening fragrance allergy: Fragrance Mix I
Compound
Formula
Oak moss absolute
Extract
Isoeugenol
C10H22N2
97-54-1
Eugenol
C10H1202
97-53-0
Cinnamic aldehyde
C9H8O
104-55-2
Hydroxycitronellal
C10H18O2
107-75-5
Geraniol
C10H18O
106-24-1
Cinnamic alcohol
C9H10O
104-54-1
α-amyl cinnamic aldehyde
C14H18O
122-40-7
Sorbitan sesquioleate (emulsifier)
CAS number:
8007-43-0
Cross reactions: Balsam of Peru, Cassia oil, Cinnamon. Cloves,
Citronella candles, Ethylene bassylate, Tiger balm
Larsen WG, Arch Dermatol 113: 623-626 (1977)
Patch test data from Europe
Frequencies of positive patch test reactions to
allergens of the European standard series in
10 European centres1
Allergen
Total
M
F
Nickel sulfate (5%)
17.9
4.8
25.5
Fragrance Mix I (8%)
9.7
7.2
11.1
Cobalt chloride (1%)
5.9
3.7
7.2
Potassium dichromate (0.5%)
4.6
5.5
4.1
1Bruynzeel
et al Contact Dermatitis 53:146-9 (2005)
The 10 most frequent sensitisers in the standard series1
Allergen
Frequency
Range
Nickel sulfate 5%
17.9
12.6 – 24,6
Fragrance mix 8%
9.7
5.0 – 12.6
Balsam of Peru 25% *
6.0
2.8 – 10.9
Cobalt chloride 1%
5.9
2.7 – 9.9
Potassium dichromate 0.5%
4.6
1.0 – 11.0
Colophonium 20%
4.0
2.2 – 5.2
p-Phenylenediamine base 1%
3.9
1.3 – 7.4
Thiuram mix 1%
3.2
1.4 – 7.0
Neomycin sulfate 20%
3.0
1.6 – 7.7
Lanolin (wool wax alc.) 30%
2.9
0.6 – 5.7
* Natural extract from the tree Myroxylon pereirae
1Bruynzeel
et al. Contact Dermatitis 53:146-9 (2005)
Fragrance mix I (FM I) and II (FM II)
• A new fragrance mix II (contains 6
fragrance allergens) has been developed
to supplement FM I
• A multicenter study has shown that FM II
detected about 30 % more fragrance
allergic patients1
• The European baseline patch test series
has recently be amended to include FM II2
1Frosch
et al. Contact Dermatitis 52: 207-15 (2005)
2Bruze et al. Contact Dermatitis 58: 129-33 (2008)
Fragrance Mix II
(14% in pet.)
• Hydroxylisohexyl 3cyclohexene
carboxaldehyde (Lyral)
(2.5%)
• Citral (1.0%)
• Farnesol (2.5%)
• Coumarin (2.5%)
• Citronellol (0.5%)
• α-hexyl
cinnamaldehyde (5%)
plus Lyral 5%
in the standard series
No. 7, PI:
5% Lyral
+
Neg.
IR
?
+
++
5
5
+++
Germany: IVDK – DKG 2009
Allergens 2007 (n=11.099) und 2008 (n=10.745)
Allergen
2007
2008
Nickel sulfate
17,3
17,3
Cobalt chloride
7,4
7,1
Balsam of Peru
6,7
6,6
Fragrance Mix
6,5
6,5
Dichromate
6,1
4,9
Fragrance Mix II
4,6
4,7
Colophony
3,9
3,8
percentages
Germany: IVDK – DKG 2009
Allergens 2007 (n=11.099) und 2008 (n=10.745)
Allergen
2007
2008
Propolis
2,2
2,5
Lyral
2,2
2,3
Thiuram-Mix
2,0
2,3
Wollwachsalkohole
2,0
2,3
Methyldibromoglutaronitrile
MDBGN
MCI / MI (Kathon CG)
3.9
2.1
2,1
2,1
Epoxy resin
1,4
1,7
percentages
Epidemiology of fragrance allergy
• Most knowledge about contact dermatitis is
derived from
– clinical case reports,
– clinical studies of in- and out-patient groups,
– statistical compilations of patch test reports, and
– from studies of small outbreaks of skin diseases at
the work place.
• All these data sources have their limitations
and the data must be interpreted carefully.
Contact sensitisation to fragrances in the
general population
•
•
•
•
•
•
Systematic review (19 studies)
Sample size 82 – 2545
Participation rate 21.3 – 83.1 %
True test, Epiquick (8); standard patch test (11)
Reading day 3 but in 6 studies only day 2
Average weighted prevalence in adults (13 studies):
– Fragrance Mix I 3.7%
– Balsam of Peru 1.6%
• No study on Fragrance Mix II
1
Thyssen et al. BJD 2009
Contact sensitisation to fragrances in the general population
Author
Year N
Dotterud
2007 1236 GP (N)
Svedmann 2007
Sample
484 Stent pat (S)
F*
M*
1.7
1.8
4.9
5.0
White
2007 2545 GP (Thai)
2.7
2.1
Bryld
2003
627 Twins (DK)
1.3
1.3
Nielsen
2001
469 GP (DK)
3.2
1.0
Greig
2000
219 Volunteers (Aus) 4.5
3.5
Nielsen
1992
567 GP (DK)
1.0
1.1
Seidenari
1990
593 Male cadets
-
0.5
* Percentage of positive reaction to FM I
1
Thyssen et al. BJD 2009
Contact sensitisation to fragrances in adolescents
• 1146 schoolchildren in DK
• 12-16 yrs of age
• Positive reactions to FM I
– Girls 1.6 %
– Boys 2.1 %
Mortz et al. Acta Derm Venereol 2002
Fragrance allergy – a challenge to
interpretation
Problems:
1. Irritant versus allergic patch test
reaction.
2. Contact allergy versus allergic contact
dermatitis
3. Did we patch tested the responsible
allergen?
Do we test with the right FM I ?
• Patch test of FM I (True Test and Trolab) in 5006
eczema patients*
• The clinical relevance was recorded as present or
past
• 495 (9,9%) positive reactions
– 187 positive according to both patch test systems
– 277 positive only to Trolab
– 31 positive only to True Test
• Significant difference between the 2 tests in
frequency of positive reactions (p<0.0001).
*personal communication Andersen 2010
Do we test with the right FM I ?
• If a patient had a positive reaction to one of
the FM I tests, the individual constituents of
FM I (Trolab®) were tested:
– + reactions show only few reactions to the
individual constituents of the FM I (True Test
54%, Trolab 29%)
– Only ++ or +++ reactions show also in a high
percentage positive reactions to the individual
constituents of the FM I (True Test: 83.3 %;
100%; Trolab: 74.6%; 96.7%)
*personal communication Andersen 2010
No. 3, PI:
8% Fragr. Mix
+
Neg.
IR
?
+
1
9
++
+++
Individuals (%) reported
a rash from scented products
• Dermatitis patients
– with positive patch test to FM I
– with negative patch test to FM I
62.8%
40,8%
• General population
31.8%
1
Johansen et al. Am J Contact Derm 1998
7th amendment of the
European Union (EU) Cosmetics Directive &
the Detergents Regulations of the EU (2005)
• cosmetic products and detergents must be
labelled for 26 individual named fragrances,
if their concentrations in the product exceed
– leave-on products 0.001% (> 10 ppm)
– rinse-off products 0.01% (> 100 ppm)
– household products 0.01% (> 100 ppm)
• Screening by using FM I and II
Exposure data
• Exposure pattern to fragrance of the U.K. consumer
was assessed (300 products)
• 6 most frequently labelled fragrances:
–
–
–
–
–
–
linalool (63%),
limonene (63%),
citronellol (48%), FM II
geraniol (42%), (FM I)
butyl phenyl methyl propional (Lilial) (42%)
hexyl cinnamal (42%) FM II
• oxidized limonene and oxidized linalool should be
added to the test series
• 11% contained none of the listed fragrances but
were labelled as containing 'parfum' or 'aroma'
1
Buckley BJD 2007
Exposure pattern to fragrance of the U.K.
consumer was assessed (300 products)
• FM I:
–
–
–
–
–
–
–
–
geraniol 42%
eugenol 27%
hydroxycitronellal 17%
isoeugenol 9%
cinnamic alcohol 8%
amyl cinnamal 7%
cinnamal 6%
oak moss absolute 4%
• FM II:
–
–
–
–
–
–
geraniol 42%
hexyl cinnamal 42%
coumarin 30%
Lyral 29%
citral 25%
farnesol 8%
1
Buckley BJD 2007
Frequencies of reactions to 26 fragrances in a
German multicentre study1
•
•
•
•
•
•
•
•
•
•
•
•
•
tree moss
Lyral
oak moss
hydroxycitronellal
isoeugenol
cinnamic aldehyde
farnesol
cinnamic alcohol
citral
citronellol
geraniol
eugenol
coumarin
2.4%
2.3 %
2.0 %
1.3 %
1.1 %
1.0 %
0.9 %
0.6 %
0.6 %
0.5 %
0.4 %
0.4 %
0.4 %
•
•
•
•
•
•
•
•
•
•
•
•
•
lilial
amyl-cinnamic alcohol
benzyl cinnamate
benzyl alcohol
linalool
methylheptin carbonate
amyl-cinnamic aldehyde
hexyl-cinnamic aldehyde
limonene
benzyl salicylate
gamma-methylionon
benzyl benzoate
anisyl alcohol
1Schnuch
0.3 %
0.3 %
0.3 %
0.3 %
0.2 %
0.2 %
0.1 %
0.1 %
0.1 %
0.1 %
0.1 %
0.0 %
0.0 %
et al. Contact Dermatitis 57: 1-10 2007
Fragrance allergy – oxidation forms sensitizers
• R-Limonene is a common fragrance terpene,
widely used in cosmetics and in domestic and
industrial products
• R-limonene is a very weak sensitizer but forms
allergenic oxidation products upon contact with air
(= prehapten).
• Oxidized (ox.) limonene is a frequent cause of
contact allergy in clinical testing1
• Oxygen-centred radicals are important in haptenprotein complex formation of hydroperoxides
1Christensen
et al. Contact Dermatitis 59: 344-52 (2008)
Fragrance allergy – ROAT
• Whenever a certain cosmetic product is
suspected of causing an allergic reaction a
repeated open application test (ROAT) should be
performed (twice daily for 7 days)
• A ROAT is used to mimic the normal exposure
• Fragrance ingredients are special as significant
amounts of allergen may evaporate from the skin
-> Lyral: the ROAT threshold in dose per area per
application is lower than the patch test threshold1
1Fischer
et al. Br J Dermatol 2009
Safety assessment FRAGRANCE ALLERGY
Other
Clinical Diagnostic
Tests
Other Clinical
Diagnostic
Tests
Elicitation
Threshold
Other Clinical
Diagnostic Tests
Epidemiology Study
Quantitative
Risk
Assessment
Oxidation
Research
Supplying
Patch Test
Materials
An international study assessing the prevalence
of contact allergy to fragrances in the general
population: The European Dermatoepidemiology Network (EDEN) Fragrance Study
in collaboration with ESCD supported by RIFM
STUDY PROTOCOL
• Study has two major parts:
– Assess the prevalence & severity of contact
dermatitis, avoidance of products in the general
population through a standardized interview.
– Assess the rate of sensitization to fragrances through
standard patch test procedures
• Patch testing (47 substances)
– 2 Fragrance mixes + 14 materials that comprise it
– True Test panel 1, 2, 3 (29 substances)
• Geographical Regions
– Italy, Sweden, The Netherlands, Germany (East &
West), Portugal
Pilot Study (n= 589): Fragrance substances
++ / +++
+
Ir
?
-
Fragrance Mix I
6
7
1
2
347
Fragrance Mix II
5
2
1
1
355
Fragrance Mix I
with sorbitan sesq.
5
5
0
2
352
Single fragrances*
14
19
9
13
5041
* positive reactions in 0.65 %
36
Fragrance sensitisation, avoidance and skin problems
++ / +++
Total sensitisation rate
Avoidance of products
N
(%)
Skin rash
(1 yr. Prevalence)
13
+
Ir
?
-
15
9
8
319
Yes
11
6
(84.6) (40.0)
3
(33.3)
4
(50.0)
125
(39.2)
No
2
9
(15.4) (60.0)
6
(66.7)
4
(50.0)
194
(60.8)
Yes
No
5
8
2
6
129
8
7
7
2
190
37
Patch test reactions and fragrance allergy
589 subjects
28 (4.7%) (17 f; 11 m)
no clear reaction: 7 f; 3 m
18 (3.0%)
no avoidance: 3 f; 3 m
12 (2.0%)
no skin rash: 3 f; 3 m
7 (1.2%)
Fragrance allergy – a challenge to
interpretation
• Most people in modern society are exposed
daily to fragrance ingredients from one or
more sources.
• Fragrance ingredients are also one of the
most frequent causes of contact allergic
reactions.
• Patch testing is mandatory – however do
we patch test the right substances?
The most frequent sensitizers in cosmetics
• Fragrances
• Methylchlorisothiazolinone
and Methylisothiazolinone
• Methlydibromoglutaronitrile
• Formaldehyde
• Formaldehyde donors
• Quartenium 15
• Imidazolidinylurea
• Diazolidinylurea
• Bronopol
• DMDM hydantoin
• Parabens
• Iodopropynyl
butlycarbamate
• Formaldehyde resin
• P-Phenylendiamine and
related hair dyes
• Cocamidopropyl betain
• UV filters
• Lanolin and derivates
• Glycerylthioglycolate
• Propylene glycol
• Antioxidants
Fragrance allergy – Clinical consequencies
• The diagnosis is made by patch testing with a
mixture of fragrance ingredients: FM I and FM II
• With investigator-loaded Finn Chamber the major
problem is false-positive reactions
• Weak positive reactions to FM should be
evaluated carefully for clinical relevance.
• Whenever there is a positive reaction to FM,
additional patch testing with the ingredients is
recommended.
• In addition, testing of 'whole' products and ROAT
can be used to confirm the relevance of reactions
in cases of doubt.
Thank you
Thank you
No. 2, PI:
After shave
++
Neg.
IR
?
+
++
3
7
+++
No. 8:
1% Shampoo
(soap effect)
IR
Neg.
IR
10
?
+
++
+++