1. business and industrial
2. chemicals industry
3. dyes and pigments

Contact Dermatitis • Review Article
COD
Contact Dermatitis
Self-testing for contact sensitization to hair dyes – scientific
considerations and clinical concerns of an industry-led screening
programme
5
´
Jacob P. Thyssen1 , Heidi Søsted2 , Wolfgang Uter3 , Axel Schnuch4 , Ana M. Gimenez-Arnau
, Martine
6
7
8
9
9
Vigan , Thomas Rustemeyer , Berit Granum , John McFadden , Jonathan M. White , Ian R. White9 ,
´ 11 and Jeanne D. Johansen1
Ann Goossens10 , Torkil Menne´ 1 , Carola Liden
1 Department of Dermato-Allergology, National Allergy Research Centre, Copenhagen University Hospital Gentofte, Gentofte DK-2900, Denmark,
2 Department of Dermato-Allergology, Research Centre for Hairdressers and Beauticians, Copenhagen University Hospital Gentofte, Gentofte DK-2900,
¨
D-91054 Erlangen, Germany,
Denmark, 3 Department of Medical Informatics, Biometry and Epidemiology, Friedrich Alexander University, Erlangen-Nurnberg,
4 Information Network of Departments of Dermatology, Institute at the Georg-August Universitat
¨ Gottingen,
¨
¨
D-37075 Gottingen,
Germany, 5 Department of
`
Dermatology, Hospital del Mar, Parc de Salut Mar, Universitat Autonoma
de Barcelona, 08003 Barcelona, Spain, 6 Department of Dermatology,
Dermato-Allergology, CHU Saint Jacques, F-25030 Besanc¸on Cedex, France, 7 Department of Dermatology, Free University Hospital, NL-1081 HV Amsterdam,
The Netherlands, 8 Department of Food, Water and Cosmetics, Norwegian Institute of Public Health, N-0403 Oslo, Norway, 9 Department of Cutaneous
Allergy, St John’s Institute of Dermatology, London SE1 7EH, UK, 10 Department of Dermatology, Contact Allergy Unit, University Hospital KU Leuven, B-3000
Leuven, Belgium, and 11 Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
doi:10.1111/j.1600-0536.2012.02078.x
Summary
The cosmetic industry producing hair dyes has, for many years, recommended that
their consumers perform ‘a hair dye allergy self-test’ or similar prior to hair dyeing, to
identify individuals who are likely to react upon subsequent hair dyeing. This review
offers important information on the requirements for correct validation of screening tests,
and concludes that, in its present form, the hair dye self-test has severe limitations: (i) it
is not a screening test but a diagnostic test; (ii) it has not been validated according to
basic criteria defined by scientists; (iii) it has been evaluated in the wrong population
group; (iv) skin reactions have been read by dermatologists and not by the targeted group
(consumers and hairdressers); (v) hair dyes contain strong and extreme sensitizers that
are left on the skin in high concentrations, potentially resulting in active sensitization;
and (vi) recommendations and instructions on how to perform the hair dye self-test
vary greatly even among products from the same company, again suggesting that the
basis for safe use of the test has not been determined. If the use of a hair dye self-test to
predict contact sensitization becomes widespread, there is severe risk that a tool has been
marketed that may cause morbidity in European consumers.
Key words: allergy alert test; diagnostics; hair dyes; nickel; p-phenylenediamine;
screening; self-test; skin alert test.
Contact allergy, defined as positive patch test reactions to common haptens, is frequent in general populations, affecting up to 20% of people (1–3). It is
Correspondence: Jacob P. Thyssen, Department of Dermatolo-Allergology
Gentofte Hospital, National Allergy Research Centre, University of
Copenhagen, 2900 Hellerup, Denmark. Tel: +45 3977 3977; Fax: +45
3977 7118. E-mail: jacpth01@geh.regionh.dk
Accepted for publication 15 February 2012
300
caused by repeated or prolonged cutaneous exposure
to contact allergens, including metals such as nickel,
cobalt, and chromium; preservatives, such as isothiazolinones, methyldibromo glutaronitrile, formaldehyde,
and formaldehyde-releasers; fragrance substances, such
as Myroxylon pereirae, Evernia prunastri, limonene, and
isoeugenol; and finally, a wide range of very different
chemicals, such as those present in topical drugs, plants,
and hair dyes. Contact allergy is considered to be the latent
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
stage of the disease, whereas allergic contact dermatitis is
the clinical disease. The widespread, and necessary, use
of chemicals and metals in consumer and occupational
products make human allergen exposure unavoidable.
It is, however, imperative to reduce allergen exposure
by using chemicals with a low sensitizing capacity and
by reducing use concentrations to protect humans from
developing contact allergy and allergic contact dermatitis, disorders resulting in poor quality of life, sick leave,
and work change (4). Historically, there are a number
of examples of contact allergens that have been used in
too high concentrations or that have been too potent,
resulting in epidemics of contact allergy and allergic contact dermatitis; so far, several have been successfully
addressed by regulation of use concentrations or prohibition, resulting in a decreasing prevalence of contact
allergy (5).
Hair dyeing is very frequent in both women and
men (6), and is thus an exposure of general concern.
Hair dyes are composed of a variety of chemicals, including strong skin sensitizers such as p-phenylenediamine
(PPD) and toluene-2,5-diamine (p-toluenediamine, PTD)
(7–10). Contact allergy to PPD is fairly frequent among
dermatitis patients, and the prevalence seems to be
higher in central and southern Europe than in northern
Europe (11–13). The difference is likely to be attributable
to the use of hair dyes intended for darker shades in these
parts of Europe. In line with this observation, products
intended for darker hair were associated with higher use
concentrations of PPD when more than 2000 products
were reviewed (14). Besides PPD, other potent contact
sensitizers frequently cause contact allergy (15); hence,
patch testing with a broad variety of chemicals is necessary to perform a sufficient diagnostic evaluation of
patients with hair dye reactions. Contact allergy to hair
dyes can be very serious, causing not only allergic contact
dermatitis but also swelling (oedema) of the neck and
face, as well as obstruction of the respiratory tract. The
latter clinical picture is not infrequent, and may result
in high-dose systemic corticosteroid treatment and even
hospitalization. In a study by Krasteva et al., 10 of 34
patients with allergic reactions to hair dyes had facial
oedema, and 33 of 34 presented with dermatitis (14). As
children and teenagers also dye their hair, a similar disease spectrum is encountered in these groups (16). Besides
the severe cutaneous and respiratory complications, the
potential systemic consequences of contact allergy to hair
dyes are currently unknown (17, 18).
The cosmetic industry producing hair dyes has for
many years recommended that their consumers perform
‘a hair dye allergy self-test’ (19) or similar prior to hair
dyeing, to identify individuals who are likely to react
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
upon subsequent hair dyeing. This review evaluates the
scientific basis of the hair dye self-test by examining
published studies, describes current practices with this
test, and discusses its limitations and the clinical and
ethical considerations.
Hair Dyes
Two main categories of hair dye product should be
considered, on the basis of their chemistry: oxidative
and non-oxidative (20). Permanent hair dyeing with
oxidative products requires three main components – an
o-substituted or p-substituted aromatic amine, a coupling
agent, and an oxidant – and are therefore categorized as
oxidative. Self-testing prior to hair dyeing is recommended
by the industry for oxidative hair dyes. In 2006, the European Commission’s Scientific Committee on Consumer
Products (SCCP) produced a memorandum on hair dye
substances and their skin sensitizing properties. The SCCP
assessed 46 hair dye substances, and reported that 27 of
these fulfil the EU criteria for classification as skin sensitizers (R43). A further categorization of their skin sensitizing
potency showed that 10 of the 27 hair dye substances were
extreme sensitizers, 13 were strong sensitizers, and four
were moderate sensitizers (21). Approximately 100 hair
dye substances have now been assessed by the SCCP or the
Scientific Committee on Consumer Safety (SCCS), with a
similar range of skin sensitizers. The present review will
focus only on PPD (INCI; CAS 106-50-3) and PTD (INCI;
CAS 95-70-5). PPD belongs to the family of p-substituted
aromatic amines. Toluene-2,5-diamine is also named 2methyl-p-phenylenediamine, which indicates that it is a
PPD molecule with a methyl group in the ‘2’ position. The
local lymph node assay (LLNA) in mice is used to assess
the potential of substances to cause skin sensitization. The
LLNA EC3 value is the estimated concentration of a chemical that is necessary to give a three-fold increase in lymph
node cell proliferative activity as compared with vehicletreated controls. The EC3 value for PPD is 0.06, indicating
that it is an extremely potent skin sensitizer (http://
ec.europa.eu/health/ph_risk/committees/04_sccp/docs/
sccp_o_069.pdf), whereas the EC3 value for PTD is 0.31,
indicating that it is at least a strong sensitizer (http://
ec.europa.eu/health/scientific_committees/consumer_
safety/docs/sccs_o_052.pdf). PTD is also used as a salt,
with PTD as the cation and sulfate as the anion, that is,
toluene-2,5-diamine sulfate (INCI; CAS 615-50-9), and
in this case the molecule is named PTDS. In a recent study,
PTD, PTDS or PPD were identified in 96% (n = 117) of
122 hair dye products on the Swedish market (9); 98%
(n = 120) were found to contain hair dye substances categorized as potent skin sensitizers (Table 1). Of 25 light
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SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
Table 1. Hair dye substances categorized as potent skin sensitizers, identified on more than 20% of the labels of oxidative hair dye products
on the market in Spain (n = 105) or in Sweden (n = 122)
Proportion of products containing substance
INCI name
4-Amino-2-hydroxytoluene
m-Aminophenol
p-Aminophenol
2,4-Diaminophenoxyethanol-HCl
2-Methylresorcinol
p-Phenylenediamine
Resorcinol
Toluene-2,5-diamine or toluene-2,5-diamine sulfate
CAS no.
In Spain (%)
In Sweden (%)
2835-95-2
591-27-5
123-30-8
66422-95-5
608-25-3
106-50-3
108-46-3
95-70-5 or 615-50-9
35
76
32
30
33
50
81
49
35
68
25
25
39
16
82
80
Based on (9, 10).
blond shade products, only two did not contain potent skin
sensitizers, whereas the remainder contained up to eight
potent hair dye skin sensitizers. All 105 oxidative hair dye
products examined in a similar study conducted in Spain
contained potent skin sensitizers (Table 1); 50% contained
PPD and another 49% contained PTD or PTDS (10). In
comparison, 16% of hair dyes sold in Sweden contained
PPD and 80% contained PTD or PTDS (9). Hair dye products sold in Spain and Sweden typically contained five
potent hair dye sensitizers each (9, 10). It is important to
realize that PPD and PTD are only two of many frequently
used sensitizing hair dye substances, and that the use
concentrations of skin sensitizers in hair dye products are
not labelled, and are therefore unknown to the consumer.
Moreover, hair dyes often contain fragrances and other
chemicals that are known to induce contact sensitization.
Given all of the above, if a hair dye self-test is applied
to the skin, the test person will come into contact with
several potent skin sensitizers, as it is currently (almost)
impossible to buy an oxidative hair dye product without
them.
Self-Testing for Hair Dye Allergy
The European Cosmetics Toiletry and Perfumery Association (COLIPA) advises hair dye manufacturers to instruct
their consumers to perform a hair dye allergy self-test (also
referred to as the ‘allergy alert test’, ‘skin alert test’, or ‘skin
allergy test’) prior to hair dyeing with oxidative hair dyes.
In line with this, manufacturers provide test guidelines
in their products, in an attempt to have their consumers
perform a test prior to each hair dyeing, to predict whether
the colouring will result in an allergic reaction. It is of note
that a multitude of different tests are currently advised in
different hair dye products, but only one commercial test
has so far been validated (the Colourstart®). However,
the Colourstart® is not used or recommended in any of
302
the tested products from this study, and the validation
has many severe flaws, as we will show in this review
article. During October 2011, a total of 20 permanent
hair dye products were purchased from stores in seven
different countries (Denmark, Sweden; Norway, France,
Spain, Germany, and the United Kingdom) (Table 2). We
intended to include a large range of brands to evaluate
whether the manufacturer recommended self-testing for
hair dye allergy, and, if they did, how to do so (Table 2).
We investigated the preparation procedure, anatomical
site of application, duration of exposure, reading recommendations and the advised actions in case of a positive
test reaction. Overall, products from 16 different manufacturers were obtained (Keranove, l’Oreal, Garnier,
Cosvalitaly, Wella, Tints of Nature, Syoss, Schwarzkopf,
Procter & Gamble, Franck Provost, Boots, Superdrug,
Naturtint, Colomer Beauty, Eugene, and Laboratorios
Belloch). According to the ingredient labels, 19 (95%) of
the products contained PPD, PTD, or PTDS. We found
that eight different names were used to describe the hair
dye self-test. The most frequently used term was the ‘skin
allergy test’, used in seven products, followed by the ‘skin
sensitivity test’, used in four products. Other terms were
‘warning test for allergy’, etc. Use instructions showed
that the self-test should be applied in the elbow flexure
for eight of the products, and behind the ear for 11 of the
products; for one product, both locations could be used.
For 11 products, the test should be performed with only
the hair dye cream, whereas for six products, a mixture
of the colour cream and the developer should be used. For
three products, no instructions were given on whether to
use the cream only or a mixture of the two. For seven products, the suggested amount of hair dye to be applied was
largely unspecified, as terms like ‘a small quantity’ or ‘a
few drops’ were used. For 13 products, the size of the application area should be equivalent to 1 cm2 or a ¤1 coin,
and the applied amount was specified as ‘enough to cover
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
Table 2. Overview of allergy self-test instructions provided by 16 different companies, found during an investigation of 20 different permanent
hair dye products purchased in seven different countries
Amount of hair dye
and suggested area
size
Apply a small quantity
No area size suggested
Cover with plaster
n=1
Apply enough to cover an area
corresponding to a ¤1 coin
n=4
Apply a small amount with a
cotton bud on 1 × 1 cm
Do not cover
n=5
Apply a few drops
No area size suggested
n=1
Apply a sufficient amount on
1 cm2
Do not touch or cover
n=1
Apply some colour cream on
1 × 1 cm
Do not touch or cover
n=1
Apply a little of the mixture
No size of area suggested
n=2
Apply a little of the cream
No area size mentioned
n=2
Apply a small amount of the
colorant with an equal amount
of developer
No area size suggested
n=1
Apply a mixture of the colorant
and the developer on 1 × 1 cm
n=1
Apply a small quantity of the
colorant covering on 1 × 1 cm
n=1
Total
Re-application
suggested
Resting time (hr)
After it has dried,
repeat three times
None
48
Red or itchy skin
After it has dried,
repeat two to three
times
No
None
48
Redness, itching, oedema
After 45 min
48
None
48
Not defined
n=2
Rash, redness, burning or itch
n=3
Redness, irritation or burning
After it has dried,
repeat two to three
times
After 48 hr
48
Not defined
No
After 48 hr
48
Redness, itching, or oedema
After it has dried,
re-apply
None
48
Redness, irritation, or swelling
After it has dried,
repeat three times
None
48
No
None
24
Redness or itching
n=1
Redness, itching, bullae, or
suppuration
n=1
Swelling, redness, itching,
eczema, blistering, etc.
No
None
48
Redness, burning, or itching
After it has dried,
repeat twice
None
48
Redness, itching, or swelling
No
the area’, ‘a little amount’, ‘some’, or ‘a sufficient amount’.
For 11 products, the consumer was instructed to re-apply
the product up to three times. In one product, rinsing
after 45 min was suggested, whereas in two products,
rinsing after 48 hr was suggested. In the remaining products, rinsing was not suggested at all. Test readings were
recommended after 48 hr in 19 of the products, but after
24 hr in one product. No uniform description of skin reactions was given (Table 2), and in three products, the term
‘reaction’ was used but not defined. In the case of a positive
skin test reaction, the consumer was advised to ‘rinse the
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
Definition of positive allergic
reaction
Rinsing
20
skin and not to dye their hair’ in three products, and ‘not
to use the product/or dye hair’ in 17 products. According
to the instructions, the consumer was advised to ‘contact
a doctor if in doubt’ in one product, ‘see a physician in case
a reaction develops’ in one product, and finally ‘ask a dermatologist if in doubt’ in another product. In summary,
instructions varied markedly, even among different hair
dye products from the same manufacturer, and it is our
impression that most were not really recommendations,
but rather mandatory steps that should be followed by
the consumer. It is interesting that some PPD-sensitized
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SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
individuals tend to keep dyeing their hair despite the risk of
developing dermatitis and swelling (22). Hence, the intention of the industry to prevent hair dye reactions through
the use of a self-test may not reach its target audience at all.
Screening Tests–General Aspects
Screening is used in medicine to detect a disease
in individuals without signs or symptoms of that
disease. This is generally performed in an attempt to
reduce morbidity, mortality, and overall healthcare costs.
Although screening may lead to an earlier diagnosis,
nearly all screening tests may result in false-positive and
false-negative results. For these reasons, a test used in
a screening programme, especially for a disease with
a low prevalence, must have high specificity (i.e. the
proportion of true-negative reactions correctly identified
by the screening test) and moderate to high sensitivity
(i.e. the proportion of true-positive reactions correctly
identified by the screening test). The balance between
sensitivity and specificity that one should strive for must
also depend on the seriousness of the disease, and the
impact of early detection on prognosis. The advantage of
screening is clearly that one may detect a condition at
an early stage, resulting in early treatment and cure. The
disadvantages are numerous, and include:
• adverse effects from the screening procedure, such as
uncertainty, stress, discomfort, systemic side-effects,
and chemical exposure;
• unnecessary investigations and treatments following false-positive test outcomes, potentially resulting
in stress, anxiety, and even morbidity;
• a false sense of security following false-negative
test outcomes, potentially resulting in a delay in
diagnosis.
The UK National Screening Committee defines screening as ‘a process of identifying apparently healthy people
who may be at increased risk of a disease or condition’
(http://www.screening.nhs.uk/screening#fileid7942).
Importantly, it also states in its definition that individuals
‘can then be offered information, further tests and appropriate treatment to reduce their risk and/or any complications arising from the disease or condition’. The World
Health Organization developed criteria for screening programmes in 1968, and these are still applicable today
(http://whqlibdoc.who.int/php/WHO_PHP_34.pdf).
However, the UK National Screening Committee provides an updated and more comprehensive list of criteria
appraising the viability, effectiveness and appropriateness
of a screening programme (http://www.screening.nhs.
uk/criteria) (Table 3).
304
Validity of the Hair Dye Self-Test
In general, a screening test should be validated by
comparison against an established gold standard in an
appropriate spectrum of subjects representing the target
population. Ten questions have been developed that one
should ask when reading a paper that claims to validate a
screening test, to ensure that the necessary requirements
have been met (23) (Table 4). Hitherto, four studies have
attempted to investigate the validity of hair dye allergy
self-tests, but only two of them included controls. When
a screening test is being evaluated, controls without
the condition are considered to be a prerequisite for
determining the test’s validity, making two of the studies
useless for the purpose of validation. Also, a screening
test should be validated in the target population for its
future use (in this case, individuals from the general
population who intend to dye their hair, and not PPDallergic patients). As this has not yet been done in any
published study, one may conclude that the hair dye selftest has been very inadequately validated, and that proper
validation in the target population is required before
healthcare providers can use the data. The intention
behind the hair dye self-test is that the consumer or
the hairdresser should read and interpret the reaction.
No published study has yet evaluated how well these
groups perform, which, again, is a prerequisite in the
validation process. Finally, no information is given about
unwanted side-effects, such as active sensitization, which
is necessary knowledge for healthcare providers. Despite
the numerous limitations, we provide a short overview of
the four published studies to clarify some of the weaknesses
and strengths of the hair dye self-test (Table 5).
Krasteva et al. performed an open test in 30 dermatitis
patients with diagnosed PPD allergy and 30 sex-matched
and age-matched controls without PPD allergy (25).
The test material was a marketed hair dye product
representative of the current L’Or´eal hair colouring
technology, containing 1.8% PPD and six other hair
dye substances. It was applied without mixing with
a developer. The test material was applied to the
retro-auricular area on one side, the other side was used
as a negative control, and the hair dye was left open
for 48 hr without washing. The reactions were read in a
non-blinded manner 1 hr after application, and on day 2
and day 4. About half of the patients in both groups had
skin changes characterized by erythema after 1 hr. On
day 2, all 30 PPD-allergic individuals had erythema and
infiltration, and 25 had vesicles. Three individuals in the
control group had erythema and one had a papule, but
all reactions were considered to be negative (n = 29) or
doubtful (n = 1). On day 4, reactivity had decreased in
most PPD-allergic individuals. A major criticism of this
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
Table 3. Abbreviated version of the screening programme appraisal criteria defined by the UK National Screening Committee
(http://www.screening.nhs.uk/criteria)
Criteria for appraising the viability, effectiveness and appropriateness of a screening programme
The Condition:
• The condition should be an important health problem
• The epidemiology and natural history of the condition, including development from latent to declared disease, should be
adequately understood and there should be a detectable risk factor, disease marker, latent period, or early symptomatic stage
• All the cost-effective primary prevention interventions should have been implemented as far as practicable
The Test:
• There should be a simple, safe, precise and validated screening test
• The distribution of test values in the target population should be known and a suitable cut-off level defined and agreed
• The test should be acceptable to the population
• There should be an agreed policy on the further diagnostic investigation of individuals with a positive test result and on the
choices available to those individuals
The Treatment:
• There should be an effective treatment or intervention for patients identified through early detection, with evidence of early
treatment leading to better outcomes than late treatment
The Screening Programme:
• There should be evidence from high-quality randomized controlled trials that the screening programme is effective in
reducing mortality or morbidity. Where screening is aimed solely at providing information to allow the person being screened
to make an ‘informed choice’ (e.g. Down’s syndrome, cystic fibrosis carrier screening), there must be evidence from
high-quality trials that the test accurately measures risk. The information that is provided about the test and its outcome must
be of value and readily understood by the individual being screened
• There should be evidence that the complete screening programme (test, diagnostic procedures, treatment/intervention) is
clinically, socially and ethically acceptable to health professionals and the public
• The benefit from the screening programme should outweigh the physical and psychological harm (caused by the test,
diagnostic procedures, and treatment)
• The opportunity cost of the screening programme (including testing, diagnosis and treatment, administration, training, and
quality assurance) should be economically balanced in relation to expenditure on medical care as a whole (i.e. value for
money). Assessment against this criterion should have regard to evidence from cost benefit and/or cost-effectiveness analyses
and have regard to the effective use of available resources
• All other options for managing the condition should have been considered (e.g. improving treatment, providing other
services), to ensure that no more cost-effective intervention could be introduced or current interventions increased within the
resources available
• There should be a plan for managing and monitoring the screening programme and an agreed set of quality assurance
standards
• Evidence-based information, explaining the consequences of testing, investigation, and treatment, should be made available
to potential participants to assist them in making an informed choice
Hair dye self-test
√
√
—
—
—
Unknown
—
√
—
—
—
Unknown
—
—
—
√
, criteria fulfilled; —, criteria not fulfilled.
Ideally all the following criteria should be met before screening for a condition is initiated.
study, apart from the fact that it was non-blinded, was the
absence of information on the strength of PPD reactivity
in the PPD-allergic patients who were included. This is a
requirement in validation studies (Table 4). Also, followup beyond day 4 had provided an opportunity to detect
late reactions.
A non-blinded follow-up study by Krasteva et al.
included 34 PPD-allergic individuals [previous PPD
reactivity was 1+ (n = 2), 2+ (n = 24), and 3+ (n = 8)]
and 49 sex-matched and age-matched controls (14).
The open test was performed in the same manner
as in the first study, but this time hair dyes with
increasing concentrations of PPD (A = 0.1%, B = 0.5%,
C = 1.0%, and D = 1.5%) were tested consecutively, and
a negative control substance (0% PPD) was included.
The PPD-negative control subjects were tested with one
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
concentration of PPD. The experiment showed that 27 of
34 PPD-allergic individuals reacted to product A (0.1%
PPD), 3 of the 7 remaining PPD-allergic individuals
reacted to further testing with product B (0.5% PPD),
3 of the 4 remaining PPD-allergic individuals reacted to
further testing with product C (1.0% PPD), and the last
individual, without reactions to products A–C, reacted to
product D (1.5% PPD). No controls reacted to products
A–D. In both studies, reactivity was generally stronger
on day 2 after application than on to day 4.
Inspired by a PPD-allergic patient who performed
inadequate pretesting with the PPD-based home patch
test kit Colourstart® (Trichocare Diagnostics Ltd) and
who afterwards had a reaction from hair dyeing, Orton
tested 7 consecutive patients reporting hair dye reactions
with the Colourstart® self-test as well as with the standard
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SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
Table 4. Evaluation of studies that have attempted to validate the hair dye self test using questions that have been recommended for assessing
papers claiming to validate screening tests (1–10, 23) and another point included by the authors (11)
Question
Criteria judged to be
fulfilled for the hair
dye self-test?
1. Is this test potentially relevant to my practice?
?
2. Has the test been compared with a true gold
standard?
+
3. Did this validation study include an appropriate
spectrum of subjects?
−
4. Has workup bias been avoided?
+
5. Has expectation bias been avoided?
−
6. Was the test shown to be reproducible?
−
7. What are the features of the test as derived from
this validation study?
8. Were confidence intervals given?
—
9. Has a sensible ‘normal range’ been derived?
10. Has this test been placed in the context of other
potential tests in the diagnostic sequence?
11. Has active sensitization been considered in the
design and conduct of the study, e.g. through
late readings?
−
Not applicable
Not applicable
−
Comments
The answer depends on who you ask (consumers,
industry, regulators, or dermatologists). Industry’s
target population comprises consumers who have
not experienced any previous adverse skin
reaction from hair dyeing. This group has not
been tested
Criteria met for PPD, as the patch test is considered
to be the gold standard. However, no studies
have attempted to test other oxidative hair dye
chemicals
Only the study by Basketter and English (24)
included a collection of PPD-allergic individuals
with an equal distribution of patch test reactivity.
However, women were very overrepresented, and
all age groups were not represented. No
validation study has been performed in the target
population addressed by industry. Again, only
PPD has undergone a validation attempt
Criteria met, as all who were tested with the
self-test were also tested with the gold standard
None of the studies was blinded. A major concern is
that in none of the studies were the tests read by
the target group, i.e. consumers intending to dye
their hair
None of the studies reported repeated interpretation
of test reactions
The sensitivity and specificity have not been settled.
Please refer to the main text
No confidence intervals have been reported. It is
particularly important to provide confidence
intervals in studies with small samples
—
—
None of the studies attempted to investigate the
magnitude of active sensitization, which is
considered to be critical for risk assessment
purposes
PPD, p-phenylenediamine; +, criteria met; – , criteria not met; ?, unknown.
patch test (26). He observed positive reactions to 0.1%
PPD in 1 patient, to 1% PPD in 5 patients, and to 1%
PTD in 1 patient. However, negative reactions to the
Colourstart® kit were noted in 4 patients.
Later, Basketter and English described a non-blinded
study of the Colourstart® kit in 30 PPD-allergic
individuals; 10 with 1+, 10 with 2+ and 10 with 3+
reactivity (24). Overall, 19 of 30 patients reacted to the
Colourstart® kit; 10 of 10 patients with 3+ reactivity
to PPD reacted to the Colourstart® kit, 8 of 10 patients
with 2+ reactivity reacted, and 1 of 10 patients with
1+ reactivity reacted. These findings clearly showed
that this self-test could only identify those with strong
306
reactivity, and not those with weaker reactions; that is, it
has considerable shortcomings regarding sensitivity and
negative predictive value.
On the basis of the four available studies, the sensitivity [(true positives/(true positives + false negatives)]
and specificity [true negatives/(true negatives + false
positives)] of the diagnostic self-test can be calculated,
although the studies, as mentioned, had critical limitations, including lack of: (i) controls, (ii) an appropriate
spectrum of participants, (iii) blinding, (iv) information
on reproducibility (27), and (v) information on adverse
effects (Tables 4 and 5). The specificity as assessed from
the two small studies appears to be very high (100%),
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
Table 5. The sensitivity and specificity of the self-test derived from published studies
No. of PPD-allergic
individuals
No. of
controls
Concentration
of PPD, %
Sensitivity, %
(95% CI)
Krasteva et al. (25)
30
30
1.8
100 (88.4–100)
Krasteva et al. (14)
34
34
34
34
7
49
49
49
49
—
0.1
0.5
1.0
1.5
79.4 (62.1–91.2)
88.2 (72.5–96.7)
97.1 (84.7–100)
100 (89.7–100)
42.9 (9.9–81.6)
30
10c
10d
10e
—
—
—
—
b
Author
Orton (26)
Basketter and
English (24)
b
b
b
b
63.3 (43.9–80.1)
100 (69.2–100)
80.0 (44.4–97.5)
10.0 (2.5–44.5)
Specificity, %
(95% CI)a
Comments
100 (88.4–100) No information was given about the
strength of patch test reactivity to
PPD
100 (92.7–100) Study results suggest that high PPD
concentrations are necessary to
increase sensitivity
—
—
—
—
—
The test is not very sensitive in a
mixed patient population
The sensitivity of the test relies
heavily on the degree of
sensitization in those tested
PPD, p-phenylenediamine.
Exact 95% confidence intervals (CIs) calculated by the authors. See the main text for the critical limitations of these studies and where we list
factors suggesting inadequate validation.
a
It is the authors’ opinion that the sensitivity and specificity estimates derived from these studies cannot be used or generalized, and that the
studies have very critical limitations. See the text for details.
b
The Colourstart® product contains approximately 15 μg of PPD applied uniformly across an area of 0.5 cm2 , leading to a dose of 30 μg/cm2 .
c
Individuals with 3+ reactivity to PPD.
d
Individuals with 2+ reactivity to PPD.
e
Individuals with 1+ reactivity to PPD.
preventing false-positive reactions. However, it should
be acknowledged that false-positive reactions will be
expected to appear if the test is used in a population with
a lower prevalence of contact sensitization to hair dyes.
The sensitivity was high when high PPD concentrations
were used or when a strongly sensitized population was
tested, but low when weaker PPD concentrations were
used or when patients with weaker reactivity to PPD were
examined. On the basis of the available data, self-testing
in patients may therefore result in very few false-positive
reactions but in false-negative reactions of an unknown
extent. In this case, one may question whether it is more
desirable to have a moderate specificity (as false-positive
reactions would, in the worst case, prevent people from
dyeing their hair) and a high sensitivity (as false-negative
reactions may result in severe reactions that are potentially life-threatening). Hence, it may be considered more
appropriate to detect every PPD-allergic individual who
would otherwise develop severe reactions to hair dyes
than to save hundreds/thousands of individuals from the
psychological/social effects of not dyeing their hair. However, this would require an increase in the applied PPD
test concentration, potentially increasing the risk of active
sensitization to PPD.
Given the above, the ideal screening test for hair dye
allergy has not yet been developed, but should be both
very sensitive and specific but without causing active
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
sensitization, a combination that may be very difficult
to obtain. The sizes of published studies are inadequate
to determine the sensitivity and specificity of the hair
dye self-test with sufficient precision. Moreover, there
are important aspects of validation studies that have
not been addressed properly in published studies, as
described above and in Table 4. In particular, it should
be remembered that the above data have been generated
by testing dermatitis patients and not consumers without
symptoms. This means that the figures represent the selftest’s performance as a diagnostic test rather than as a
screening test. It is likely that validation in the true target
group (healthy consumers) would give quite different
values – certainly for the predictive values, which depend
on the true prevalence in the target population. It is
crucial that screening test validation studies be performed
in accordance with high methodological standards, and
that the benefits of an in vivo screening test outweigh the
risk, which is clearly not the case for the hair dye self-test.
Clinical and Ethical Considerations Regarding
the Hair Dye Self-Test
When the hair dye industry instructs consumers to perform a self-test to diagnose contact allergy to hair dyes
prior to hair dyeing, several clinical and ethical considerations should be addressed when evaluating its use and
307
SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
potential consequences. PPD is ranked as ‘category A’ in
a ranking of the allergenic potency of chemicals, which
means that ‘it is a significant contact allergen because
of proven strong contact allergenic effect in humans
after short and/or almost negligible exposure’ (28). A
number of sensitization tests have been performed in
humans. Kligman showed that repeated application of
10% PPD sensitized all 24 subjects in a human maximization test (29). Marzulli and Maibach performed a
PPD sensitization study using the Draize procedure, and
showed that 7.2% of 97 healthy volunteers were sensitized to 0.01% PPD, 11.2 to 0.1% PPD, and 53.4 to
1% (10 000 ppm) PPD (30). Basketter et al. performed a
human repeat insult patch test (HRIPT) with 1% PPD
in 98 healthy subjects without PPD allergy, and showed
that 3 reacted when later exposed to 1% PPD (31). In
the same study, subjects were instructed to dye their hair
with hair dye products containing 0.5% PPD and applied
for 5 min/day on the first 4 days and then once weekly for
6 months (n = 1107) (group 1), or a permanent hair dye
product containing 1.5% PPD and applied for 30–40 min
once monthly for 6 months (n = 548) (group 2), or no
hair dye product (n = 516) (group 3). At the end of
the 6-month period, patch testing with 1% PPD showed
that the prevalence of PPD allergy was 7.2% in group 1,
1.3% in group 2, and 0.4% in group 3. These data indicated that repeated short-time exposure to hair dyes with
a low concentration of PPD increased the risk of PPD
sensitization more than prolonged exposure to a higher
concentration of PPD, but with a longer time interval.
Predictive human sensitization tests, such as the human
maximization test, the Draize procedure, and the HRIPT,
attempt to induce long-lasting or permanent sensitization
in the individual. Because of ethical considerations, the
SCCS and the former SCCP share the opinion of the former SCCNFP that predictive human sensitization tests of
potentially cutaneous sensitizing cosmetic ingredients or
mixtures of ingredients should not be undertaken (http://
ec.europa.eu/health/ph_risk/committees/04_sccp/docs/
sccp_s_01.pdf and http://ec.europa.eu/health/scientific_
committees/consumer_safety/opinions/sccnfp_opinions_
97_04/sccp_out102_en.htm). Repeated hair dye application on the skin with the consumer self-test may, in its
current form, be compared with experimental human sensitization tests. As PPD and other hair dye chemicals are
strong and extreme sensitizers, their use in screening tests
should be carefully considered and probably discouraged.
Clinical and Ethical Considerations
• False-negative readings. Positive patch test reactions
to PPD may sometimes appear after several days.
308
Hence, when reading of patch tests and allergy selftests is restricted to day 2, false-negative readings
are expected to appear to an unknown degree.
• Risk of active sensitization. PPD is an extreme sensitizer, and allergy skin testing with this chemical
should be carefully performed, owing to the recognized risk of active sensitization (32–37). The concentration of PPD in hair dye products is restricted
to a maximum of 2% PPD on the head, calculated
as free base, but very high exposure concentrations
might be applied in the hair dye self-test. Furthermore, other sensitizers, such as PTD (maximum 4%
on the head), and several other extreme and potent
sensitizers are used in hair dyes, and may cause sensitization following repeated exposure. Experimental
studies have clearly shown that the risk of sensitization increases with allergen dose per unit area,
frequency of exposure, duration of exposure, occlusion, the presence of penetration-enhancing factors,
and impairment of skin barrier function, and is
related to anatomical site (38–40). The hair dye selftest carries a significant risk of sensitization, as can
be seen in Table 6. It is important to understand that,
as it is the dose of allergen per unit area that is critical
for sensitization, application of an allergen to a small
skin area does not diminish the risk of sensitization
when compared with a larger skin area with the
same dose per area. Hence, even though the self-test
is applied to a small skin area, it still carries the same
risk of sensitization. It is also of major importance
that a recent experimental study showed that three
exposures to 10 μg/cm2 2,4-dinitrochlorobenzene
(DNCB), that is, 30 μg/cm2 cumulatively, led to
the same degree of sensitization as one exposure
to 60 μg/cm2 DNCB (41). Thus, repeated exposure
to low doses of contact sensitizers, as occurs when
the hair self-test is performed, may considerably
increase the risk of sensitization. In fact, individuals who dye their hair may need to do so at least
every 4–8 weeks to avoid noticeable differences in
hair colour. In a worst case scenario, an individual
performing the hair dye self-test every fourth week
applies up to 2% PPD on the skin each time, in addition to other sensitizers in the product. Such gross
exposures strongly contrast with the norms of clinical diagnostic patch testing, when the practice is
to attempt to reduce repeated allergen exposures
from patch testing, owing to the risk of active
sensitization. Also, the patch test concentration of
PPD has been lowered in, for example, Germany to
reduce active sensitization. Patients are infrequently
patch tested on more than one occasion, and if they
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
Table 6. An overview of factors associated with increased risk of sensitization
Factors increasing the risk
of contact sensitization
Factors associated with the
hair dye self-test
Allergenic potency
Dose per unit area
Frequency of exposure
+
+
+
Duration
±
Occlusion
±
Presence of
penetration-enhancing
factors
Mixture of allergens
+
Impaired skin barrier
functions
±
+
Comments
PPD and several other hair dye substances are extreme or strong sensitizers
High concentrations are used
Hair dyeing is frequently performed, resulting in repeated performance of the
self-test
Exposure time is variable, depending on the product. It is expected to be short only
if hair dye is rinsed off promptly after application, which is not part of the
instructions
No occlusion if located behind the ear, but possible intermittent occlusion if
located in the elbow flexure, and occlusion if covered by plaster
Hair dyes often contain penetration enhancers, e.g. sodium lauryl sulfate
Hair dyes contain many chemicals that may result in a cocktail effect, increasing
sensitization
Depending on genetic predisposition
PPD, p-phenylenediamine.
are, they are tested at most once every 1–2 years.
Also, one should remember that consumers may forget to remove the hair dye self-test at the suggested
time (in fact, most instructions advise the consumer
to leave it on), resulting in prolonged exposure to a
high concentration of PPD, again increasing the risk
of sensitization. Despite some manufacturers recommending self-testing with a 45 min application of
hair dye products, the risk of sensitization remains,
as the test involves significant exposure to extreme
sensitizers and sufficient time to induce contact sensitization. Thus, short-time exposure can by no means
be considered to be a safe or warranted screening
method.
• Reading of the test results. Patch test reading is complex and sometimes very difficult. For this reason,
clinicians undergo specific training in this area, and
there is a continuous interest in inter-observer variability in the reading of an allergic reaction (42, 43).
A set of definitions have been established by the
International Contact Dermatitis Research Group,
and these should be carefully followed to standardize readings and distinguish irritant from allergic
reactions (44). It is very questionable whether individuals from the general population are able to
distinguish such reactions. In the article by Orton,
the PPD-allergic patient had not interpreted the
Colourstart® correctly (26), emphasizing that this
is a real concern. Misinterpretation may result in
false-positive and false-negative readings. Hence, as
stated, the hair dye self test has not been validated
yet, as this would require that consumers (study
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
participants) attempt to perform the test readings
themselves.
• Cosmetic or medicines. Article 2 of the Cosmetics
Directive states that a cosmetic product put on the
market within the Community must not cause damage to human health when applied under normal
or reasonably foreseeable conditions of use (http://
europa.eu/legislation_summaries/consumers/
product_labelling_and_packaging/l21191_en.ht).
In the hair dye allergy self-test, one must conclude
that the hair dyes are used as medicines rather
than as cosmetics. This is something that industry and European regulatory authorities have not
yet addressed, but they will inevitably have to do.
According to Directive 2001/83/EC [article 1(4b)],
hair dye allergy self-tests must be considered as
‘medicinal products’, as allergens are applied for
diagnostic purposes. At present, there is no market
authorization, and to obtain this, hair dye allergy
self-tests should first undergo clinical trials according
to the Clinical Trials Directive (2001/20/EC).
Concluding Remarks
The EU has more than 500 million citizens. Studies have
indicated that hair dyeing is frequent and recurring in
many people’s lives. If we apply figures from a Danish
adult questionnaire study, up to 80% of women and 20%
of men will dye their hair at some point (6). Also, teenagers
and even children dye their hair. The general use of a hair
dye allergy self-test prior to hair dyeing will therefore
result in unnecessary repeated exposure to PPD, PTD and
309
SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
Table 7. Example of abuse of the hair dye self-tests taken from real
life in France
A healthy young girl without any skin symptoms was seen by a
physician, as she intended to enroll in a hairdressing school. The
school had given her a printed document that she was instructed to
give to her general practitioner for signature. She was supposed to
initially visit a hairdresser, who should apply a solution used for
permanent curling and a solution used for permanent hair dyeing on
her skin. These should be left untouched for 48 hr, and the general
practitioner should inspect the skin area for allergic reactions. He
should afterwards note his findings on the document and sign it.
This proof of ‘non-allergy to products of hairdressing’ was a
prerequisite for enrolling in the hairdressing school.
other sensitizing chemicals in hundreds of millions of EU
citizens every year, increasing the risk of sensitization.
Once an individual is sensitized, elicitation concentrations
are much lower, and it is currently unknown whether it
may affect the propensity to develop other severe diseases.
The vulnerability of individuals to the development of
contact sensitization and allergic dermatitis is variable,
and has genetic determinants (45).
This review offers important information on the
requirements for correct validation of screening tests,
and concludes that, in its present form, the hair dye
self-test has severe limitations: (i) it is not a screening
test but a diagnostic test; (ii) it has not been validated
according to basic criteria defined by scientists; (iii) it has
been evaluated in the wrong population group; (iv) skin
reactions have been read by dermatologists and not by
the targeted group (consumers and hairdressers); (v) hair
dyes contain strong and extreme sensitizers that are left
on the skin in high concentrations, potentially resulting
in active sensitization; and (vi) recommendations and
instructions on how to perform the hair dye self-test vary
greatly, even among products from the same company,
again suggesting that the basis for safe use of the test has
not been determined. If the use of a hair dye self-test to
predict contact sensitization becomes widespread, there
is a severe risk that a tool has been marketed that may
cause morbidity in European consumers. Also, such a
test may be abused in different contexts; one example is
provided in Table 7. It is worth repeating that the UK
National Screening Committee states that, in cases of
positive screening test reactions, individuals ‘can then be
offered information, further tests and appropriate treatment to reduce their risk and/or any complications arising
from the disease or condition’. No such back-up system
is available in this industrially proposed screening programme. It is a political task to debate whether the hair
dye allergy self-tests should be removed from the market
or undergo strict validation according to the presented
criteria prior to release. Another important issue, which
we have not addressed, is responsibility. Politicians and
regulators should probably address this as well. There
are disturbing consequences, as illustrated by the case
described in Table 7. The present review summarizes the
main scientific evidence, and we hope that it may function
as the basis for future decision-making.
References
1 Thyssen J P, Linneberg A, Menn´e T,
Johansen J D. The epidemiology of contact
allergy in the general population–
prevalence and main findings. Contact
Dermatitis 2007: 57: 287–299.
2 Thyssen J P, Linneberg A, Menn´e T,
Nielsen N H, Johansen J D. Contact allergy
to allergens of the TRUE-test (panels 1 and
2) has decreased modestly in the general
population. Br J Dermatol 2009: 161:
1124–1129.
3 Schnuch A, Uter W, Geier J, Gefeller O.
Epidemiology of contact allergy: an
estimation of morbidity employing the
clinical epidemiology and drug-utilization
research (CE-DUR) approach. Contact
Dermatitis 2002: 47: 32–39.
4 Agner T, Andersen K E, Brandao F M et al.
Hand eczema severity and quality of life: a
cross-sectional, multicentre study of hand
eczema patients. Contact Dermatitis 2008:
59: 43–47.
5 Thyssen J P, Johansen J D, Menn´e T.
Contact allergy epidemics and their
310
6
7
8
9
10
controls. Contact Dermatitis 2007: 56:
185–195.
Søsted H, Hesse U, Menn´e T, Andersen
K E, Johansen J D. Contact dermatitis to
hair dyes in a Danish adult population: an
interview-based study. Br J Dermatol
2005: 153: 132–135.
Søsted H, Rastogi S C, Andersen K E,
Johansen J D, Menn´e T. Hair dye contact
allergy: quantitative exposure assessment
of selected products and clinical cases.
Contact Dermatitis 2004: 50: 344–348.
Søsted H, Basketter D A, Estrada E,
Johansen J D, Patlewicz G Y. Ranking of
hair dye substances according to predicted
sensitization potency: quantitative
structure–activity relationships. Contact
Dermatitis 2004: 51: 241–254.
Yazar K, Boman A, Lid´en C. Potent skin
sensitizers in oxidative hair dye products
on the Swedish market. Contact Dermatitis
2009: 61: 269–275.
Yazar K, Boman A, Lid´en C.
P-phenylenediamine and other hair dye
11
12
13
14
sensitizers in Spain. Contact Dermatitis
2012: 66: 27–32.
Thyssen J P, Andersen K E, Bruze M et al.
p-Phenylenediamine sensitization is more
prevalent in central and southern
European patch test centres than in
Scandinavian: results from a multicentre
study. Contact Dermatitis 2009: 60:
314–319.
Thyssen J P, White J M. Epidemiological
data on consumer allergy to
p-phenylenediamine. Contact Dermatitis
2008: 59: 327–343.
Uter W, Ramsch C, Aberer W et al. The
European baseline series in 10 European
countries, 2005/2006 – Results of the
European Surveillance System of Contact
Allergies (ESSCA). Contact Dermatitis
2009: 61: 31–38.
Krasteva M, Cottin M, Cristaudo A et al.
Sensitivity and specificity of the consumer
open skin allergy test as a method of
prediction of contact dermatitis to hair
dyes. Eur J Dermatol 2005: 15: 18–25.
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
SELF-TESTING FOR CONTACT SENSITIZATION TO HAIR DYES • THYSSEN ET AL.
15 Frosch P J, Kugler K, Geier J. Patch testing
with hydroxyethyl-p-phenylenediamine
sulfate – cross-reactivity with
p-phenylenediamine. Contact Dermatitis
2011: 65: 96–100.
16 Søsted H, Johansen J D, Andersen K E,
Menn´e T. Severe allergic hair dye
reactions in 8 children. Contact Dermatitis
2006: 54: 87–91.
17 Gago-Dominguez M, Castelao J E, Yuan
J M, Yu M C, Ross R K. Use of permanent
hair dyes and bladder-cancer risk. Int
J Cancer 2001: 91: 575–579.
18 Rubin I M, Dabelsteen S, Nielsen M M
et al. Repeated exposure to hair dye
induces regulatory T cells in mice. Br
J Dermatol 2010: 163: 992–998.
19 White J M, White I R. The role of self-tests
in the diagnosis of hair dye allergy. Br
J Dermatol 2007: 157: 847–848.
20 Morel O J X, Christie R M. Current trends
in the chemistry of permanent hair
dyeing. Chem Rev 2011: 111:
2537–2561.
21 European Commission and Scientific
Committee on Consumer Products.
Memorandum on Hair Dye Substances and
their Skin Sensitising Properties. European
Commission, Health and Consumer
Protection Directorate-General, 2006,
December 19.
22 Ho S C, Basketter D, Jefferies D, Rycroft R J,
White I R, McFadden J P. Analysis of
para-phenylenediamine allergic patients
in relation to strength of patch test
reaction. Br J Dermatol 2005: 153:
364–367.
23 Greenhalgh T. How to read a paper.
Papers that report diagnostic or screening
tests. BMJ 1997: 315: 540–543.
24 Basketter D A, English J. Pre-testing in
hair dye users: an assessment of the
Colourstart system. Eur J Dermatol 2009:
19: 232–237.
25 Krasteva M, Cristaudo A, Hall B et al.
Contact sensitivity to hair dyes can be
detected by the consumer open test. Eur
J Dermatol 2002: 12: 322–326.
© 2012 John Wiley & Sons A/S
Contact Dermatitis, 66, 300–311
26 Orton D I. A clinical assessment of a patch
test kit marketed to UK hairdressers for
detecting hair dye allergy. Br J Dermatol
2007: 157: 1017–1020.
27 Altman D G, Bland J M. Diagnostic tests. 1:
sensitivity and specificity. BMJ 1994:
308: 1552.
28 Schlede E, Aberer W, Fuchs T et al.
Chemical substances and contact
allergy – 244 substances ranked
according to allergenic potency.
Toxicology 2003: 193: 219–259.
29 Kligman A M. The identification of
contact allergens by human assay. 3. The
maximization test: a procedure for
screening and rating contact sensitizers.
J Invest Dermatol 1966: 47: 393–409.
30 Marzulli F N, Maibach H I. The use of
graded concentrations in studying skin
sensitizers: experimental contact
sensitization in man. Food Cosmet Toxicol
1974: 12: 219–227.
31 Basketter D A, Jefferies D, Safford B J et al.
The impact of exposure variables on the
induction of skin sensitization. Contact
Dermatitis 2006: 55: 178–185.
32 Dawe S A, White I R, Rycroft R J,
Basketter D A, McFadden J P. Active
sensitization to para-phenylenediamine
and its relevance: a 10-year review.
Contact Dermatitis 2004: 51: 96–97.
33 Gawkrodger D J, Paul L. Late patch test
reactions: delayed immune response
appears to be more common than active
sensitization. Contact Dermatitis 2008: 59:
185–187.
34 Hellinckx K, Goossens A. Late reactions to
para-phenylenediamine are not always an
indication of active sensitization: an
example. Contact Dermatitis 2008: 58:
110.
35 Hillen U, Jappe U, Frosch P J et al. Late
reactions to the patch-test preparations
para-phenylenediamine and epoxy resin:
a prospective multicentre investigation of
the German Contact Dermatitis Research
Group. Br J Dermatol 2006: 154:
665–670.
36 Thyssen J P, Menn´e T, Nielsen N H,
Linneberg A. Is there a risk of active
sensitization to PPD by patch testing the
general population? Contact Dermatitis
2007: 57: 133–134.
37 Uter W, Hillen U, Geier J. Is incident
sensitization to p-phenylenediamine
related to particular exposure patterns?
Results of a questionnaire study. Contact
Dermatitis 2007: 56: 266–270.
38 Friedmann P S. Contact sensitisation and
allergic contact dermatitis:
immunobiological mechanisms. Toxicol
Lett 2006: 162: 49–54.
39 Friedmann P S. The relationships between
exposure dose and response in induction
and elicitation of contact hypersensitivity
in humans. Br J Dermatol 2007: 157:
1093–1102.
40 Friedmann P S, Pickard C. Quantifying
human susceptibility to contact
sensitization; risk assessments now and in
the future. Contact Dermatitis 2010: 63:
237–247.
41 Paramasivan P, Lai C, Pickard C,
Ardern-Jones M, Healy E, Friedmann P S.
Repeated low-dose skin exposure is an
effective sensitizing stimulus, a factor to be
taken into account in predicting
sensitization risk. Br J Dermatol 2009:
162: 594–597.
42 Uter W, Becker D, Schnuch A, Gefeller O,
Frosch P J. The validity of rating patch test
reactions based on digital images. Contact
Dermatitis 2007: 57: 337–342.
43 Uter W, Frosch P J, Becker D, Schnuch A,
Pfahlberg A, Gefeller O. The importance of
context information in the diagnostic
rating of digital images of patch test
reactions. Br J Dermatol 2009: 57:
337–342.
44 Wilkinson D S, Fregert S, Magnusson B
et al. Terminology of contact dermatitis.
Acta Derm Venereol 1970: 50: 287–292.
45 Schnuch A, Westphal G, Mossner R,
Uter W, Reich K. Genetic factors in
contact allergy – review and future goals.
Contact Dermatitis 2011: 64: 2–23.
311