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University of Groningen

The dark side of p-PhenylenediamineVogel, Tatiana Alexandra

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Publication date:2016

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Citation for published version (APA):Vogel, T. A. (2016). The dark side of p-Phenylenediamine: Biological aspects and prevalence of contactallergy to an extraordinary molecule [Groningen]: Rijksuniversiteit Groningen

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Chapter 4Two decades of p-Phenylenediamine and

2,5 -Toluenediamine patch testing – Focus on co-sensitizations in the European

Baseline Series and cross-reactions with chemically related substances

Tatiana A. Vogel, Rakita W. Heijnen, Pieter-Jan Coenraads, Marie-Lousie A. Schuttelaar

University Medical Center Groningen, University of Groningen, Department of Dermatology, Hanzeplein 1, 9700 RB Groningen

Re-submitted


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AbstractBackground: Cross-reaction and co-sensitizations are of great importance in understanding contact allergy and exposure sources. Objectives: To investigate common cross-reactions and co-sensitizations in p-phenylene diamine (PPD) and 2,5-toluenediamine (TDA) sensitized individuals.Methods: From our patch test population 8 036 patients patch tested with the European Baseline Series, were extracted. Readings had to be performed at least on D3, regarding the ICDRG guidelines. Results: 251 patients were sensitized to PPD and/or TDA; 231 patients were sensitized to PPD, 109 to TDA. A significant difference was observed regarding the different patch test reaction strength to PPD and number of cross-reactions. In TDA this difference was found between all reaction strengths except between + and ++ strengths. PPD sensitized individuals were more likely to be sensitized to carbamix, cobalt chloride, colophony, p-tertbutylfenolformaldehyde resin, parabens mix and methylisothiazolinone. TDA sensitized individuals were more oftensensitized to carbamix.Conclusions: Cross-reactivity was commonly found among individuals sensitized to PPD or TDA and was strongly related to the patch test strength. Regarding co-sensitizations, a frequently appearing or common exposure source could not be determined. However, modification of the allergen by e.g. the skin microbiota can have caused the formation of molecules that are for the human immune system indistinguishable from PPD.


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4. Two decades of p-Phenylenediamine and 2,5-Toluenediamine patch testing

IntroductionThe aromatic amines p-phenylenediamine (PPD, 1,4-diaminobenzene, CAS no. 106-50-3) and 2,5-toluenediamine (TDA, 1,4-diamino-2-methylbenzene, CAS no. 95-70-5; synonym p-toluenediamine, PTD) are both important components of permanent hair dye products. Their low molecular weight and strong protein binding capacity enable these haptens to penetrate deeply into the hair shaft, resulting in permanent staining of the hair. Moreover, these capacities make them extremely sensitizing components. 1 For this reason the PPD dose in permanent hair dyes is maximized at 2% in the final product (amending Annex III to Regulation (EC) No 1223/2009 of the European Parliament and of the Council on cosmetic products). The prevalence of contact allergy in both general and patch tested population remains high, respectively 1.3% and 3.3% in the population of the Netherlands. 2

Cross-reactions between PPD and TDA are often recognized, as described by Basketter and Goodwin in 1988. 3 Cross-reactivity can result from the almost identical molecular structure of both chemicals. The immune system is cannot differentiate between the chemical to which someone had been sensitized or to the molecular similar chemicals. This phenomenon of cross-reactions of PPD with structurally related chemicals other than TDA is also well-known and was recently described by Thomas et al.. 4 They investigated the relation between the strength of the patch test reaction to PPD and cross-reactions with three structurally related substances, which were local anaesthetics , i.e. caine mix, a component of black rubber, i.e. N-isopropyl-N’-phenyl-p-phenylenediamine (IPPD) and the textile dye disperse yellow. 3 They found an increase in likelyhood of reactions to all three substances in relation to an increasing strength of the PPD patch test reaction.

In the present study we analyzed the patch test strength to both PPD and TDA in relation to the number of positive patch test reactions to cross-reacting substances in a two decade period.Co-sensitization has been defined as a simultaneous appearing sensitization to two or more molecularly unrelated substances. This can be observed after synchronous exposure to different chemicals in e.g. hair dye products (m-aminophenol, p-aminophenol, resorcinol). 5

Co-sensitization is a less studied phenomenon regarding PPD and TDA contact allergy. Therefore, the secondary objective of this study was to identify the co-sensitizations in both PPD and TDA contact allergy.

MethodsPopulationA total of 8 036 consecutive patients were patch-tested with the extended European Baseline Series between January 1994 to December 2013 at the Dermatology department of the University Medical Center Groningen (UMCG). Data were retrieved from the local European Surveillance System of Contact Allergies (ESSCA) database regarding patch test strength, demographic information (gender, age), history of atopic dermatitis and polysensitization.


�0

Patch testingPatch tests had been performed with the European Baseline Series (EBS, TRUE test® panel 1 and 2, Mekos Laboratories AS, Hillerød, Denmark, and partly chamber-loaded) and our extended chamber-loaded Baseline series (supplied by Chemotechnique®, Vellinge, Sweden; tested in Van der Bend Chambers, Brielle, The Netherlands). PPD was tested with the T.R.U.E. test in a concentration of 0.090 mg/cm2, TDA was tested chamber-loaded as 1% in pet. Tests were read according to the criteria of the ICDRG on D2 and D3 from January 1994 until November 2008. From November 2008 until December 2013, the readings were performed on D3 and D7 to pre-empt late reactions. The registered reaction strength was defined as the strongest positive reaction during one of these readings. Weak (+), strong (++) and extremely strong (+++) positive patch test reactions were considered as positive.

Data analyses and statisticsData were analyzed using IBM SPSS® version 22 for WindowsTM. Outcomes with a p-value of <0.05 were considered as a statistically significant difference. In case of multiple testing a Bonferroni correction was applied.

Prevalences of PPD and TDA contact allergies in the patch-tested population were calculated. Demographic and clinical characteristics were compared between PPD and TDA sensitized groups. Cross-reactions with either PPD or TDA were calculated within our extended EBS. The selected cross-reacting substances were caine mix (including the local anesthetics benzocaine, dibucaine hydrochloride and tetracaine hydrochloride), black rubber mix (N-isopropyl-N’-phenyl-p-phenylenediamine, N-cyclohexyl-N-phenyl-p-phenylenediamine and N-diaphenyl paraphenylene diamine), Disperse Orange 3, Disperse Yellow 3, 4-aminoazobenzene and4,4-diaminediphenylmethane.Caine mix and black rubber mix were both present in the EBS during almost the whole study period. All other cross-reacting chemicals were in our extended EBS for shorter periods. To calculate differences in PPD or TDA patch test strength regarding cross-reactivity of both PPD and TDA the Kruskal-Wallis test was used.

Co-sensitizations were calculated within the EBS (TRUE test® and budesonide, fragrance mix II, hydroxylisohexyl 3-cyclohexene, methyldibromo glutaronitrile, methylisothiazolinone (MI), sesquiterpene lactone mix, tixocortol-21-butyrate) in the period January 1994 to December 2013. When substances were not tested as a part of the EBS during the full period, they were tested in an adjusted period. Unique co-sensitizing substances as well as polysensitized cases were identified. Individuals in who less than 16 substances from the EBS were tested were excluded for analysis. Furthermore, black rubber mix, caine mix, PPD or TDA were excluded from the determination of polysensitization, as these allergens are molecular related substances. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a logistic regression analysis with a correction for gender and age.


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ResultsDemographic characteristicsIn the two investigated decades (1994-2014), 8 036 subjects were patch tested. 251 patients had had a positive patch test to either PPD or TDA or both PPD and TDA. A positive patch test reaction to PPD was seen in 231 subjects (prevalence: 2.9%) and 109 had a positive patch test reaction to TDA (prevalence: 1.4%). Of 251 subjects, 214 were tested for both PPD and TDA. 110 were solely sensitized to PPD, 15 to TDA and 89 were sensitized to both PPD and TDA.

Table 1 shows the characteristics of groups that were tested to both PPD and TDA. Based on the demographic characteristics, that are gender, history of atopic dermatitis, primary location hand, leg, face or arm, no statistically significant differences could be determined between those sensitized to PPD, TDA or both PPD and TDA.

Table 1: Demographic characteristics of 214 patients, who were tested for both PPD and TDA. 110 individuals were sensitized to PPD but not to TDA, 15 were sensitized to TDA but not to PPD and 89 patients were sensitized to both PPD and TDA. Groups were comparable based on their demographic characteristics. No statistical significant differences were found, calculated by Fisher’s Exact test (2-sided).

Strength of the PPD and TDA elicitation reaction and the number of cross-reactionsThe number of positive patch test reactions of cross-reacting substances is strongly related with the strength of the PPD patch test reaction (Table 2 and Figure 1). A statistically significant difference was determined between the different patch test strengths of PPD and the number of cross-reactions (p<0.001 for all groups). The relation between the number of cross-reactions and the patch test strength of TDA was also obvious, though less than with PPD (Figure 2). Statistically significant differences were found between ++ and +++ reactors and + and +++ reactors (respectively p= 0.049 and p= 0.003). The difference between + and ++ was not significant (p= 0.081).



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Chemical Test concentration

(vehicle)

Overall prevalence allergen % (number

tested)

Number tested positive for PPD

Positive for Chemical and PPD, n

(%)

Number tested positive for TDA

Positive for Chemical and TDA, n (%)

Black Rubber mix 75 g/cm2a 0.9% (7780) 226 26 (11.5) 104 19 (18.3)

Caine mix 630 g/cm2 a 0.8% (7777) 225 18 (8.0) 105 9 (8.6)

Disperse Orange 3 1% (PET) 2.1% (6267) 184 111 (60.3) 91 67 (73.6)

Disperse Yellow 3 1% (PET) 0.6% (6260) 183 19 (10.4) 90 17 (18.9)

p-Phenylenediamine 90 g/cm2 a 2.9% (8024) N/A N/A 105 90 (85.7)

2,5-Toluenediamine 1% (PET) 1.4% (7124) 199a 52 (43.5) N/A N/A

4-Aminoazobenzene 0.25% (PET) 2.6% (6281) 182 141 (77.5) 90 77 (85.6)

4,4-Diaminodiphenylmethane 0.5% (PET) 1.2% (6344) 184 44 (23.9) 92 32 (34.8)

Table 2: Substances with well-known cross-reacting potential appearing in the extended EBS.

The overall prevalence of the contact allergy to the substance is presented in column 3, the prevalence of contact allergy to the substance in the presence a contact allergy to respectively PPD and TDA can be found in column 5 and 7. Note that some overlap appeared, as 89 individuals are sensitized to both PPD and TDA. N/A: not applicable. a: Substance tested as a part of the TRUE test®

Figure 1: Patch test strength of PPD (white: +, dashed: ++, black: +++) in relation to the number of cross reactions (black rubber mix, caine mix, 4-aminoazobenzene, disperse orange, disperse yellow and 4,4-diaminodiphenylmethane, PTD or none). 144 individuals were included for analysis, of which 87 weak reactors, 57 strong and 25 extremely strong. A statistically significant difference was found in the number of cross-reacting substances between all reaction strengths (p<0.001 for +/++, ++/+++, +/+++).


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Figure 2: PTD patch test strength (white: +, dashed: ++, black: +++) related to the number of cross reactions (black rubber mix, caine mix, 4-aminoazobenzene, disperse orange, disperse yellow and 4,4-diaminodiphenylmethane, PPD or none). The total number of patch tested individuals is 86, with respectively 56, 20, 10 weak, strong and extremely strong positive reactions. Differences were found in number of cross-reacting substances between ++/+++ and +/+++ (respectively p= 0.049 and p= 0.003). No difference was found between +/++ (p= 0.081).

The appearance of co-sensitizations with PPD and TDA in the EBSWithin the population of the 251 patients with a positive patch test to either PPD or TDA or both PPD and TDA all other sensitizations were analyzed and frequencies of appearance of positive patch test reactions to chemically unrelated allergens in the European Baseline series were compared to the entire patch test population. The results are shown in Table 3 and 4.

Patients that were at least sensitized to PPD were about two times more likely to be sensitized to carbamix (OR: 2.5 95% CI: 1.4-4.5; p= 0.002), cobalt chloride (OR: 2.0, 95% CI: 1.3-3.2; p= 0.002), colophony (OR: 2.4, 95% CI: 1.5-3.8; p <0.001), and p-tertbutylfenolformaldehyderesin (PTBFR) (OR: 2.7, 95% CI: 1.6-4.8; p <0.001), when compared to the entire patch test population. Individuals with positive patch test reaction to PPD had a ten times higher odds of being sensitized to parabens mix as well (OR: 10.0, 95% CI: 3.5-26.6; p <0.100). Since the



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recent introduction of MI in the EBS frequent co-sensitization with PPD has occurred, as PPD sensitized individuals have 26 times higher odds of being sensitized to MI as well (95% CI: 3.6-192.4; p= 0.001). However, MI has not been tested frequently as a part of the EBS (n=245).

A tendency towards higher odds of being sensitized to formaldehyde (OR: 2.743, 95% CI: 1.367-5.502; p= 0.004) and fragrance mix I (OR: 2,0, 95% CI: 1.3-3.1; p= 0.003) was observed in patients with a PPD sensitization. These co-sensitizations appear in respectively 3.9 and 9.5 percent of this group.

The 109 individuals that were at least sensitized to TDA had a 3.4-fold increased chance of being sensitized to carbamix as well (OR: 3.4, 95% CI: 1.6-7.2; p= 0.001). This co-sensitization was seen in 8 patients (7.6%). In these 109 patients a tendency towards a 2.5-fold increased chance of having a colophony sensitization (OR: 2.5, 95% CI: 1.3-4.8; p= 0.007).


��

Alle

rgen

from

the

EBS

Test

conc

entr

atio

n (V

ehic

le)

Ove

rall

prev

alen

ce E

BS

alle

rgen

(num

ber

test

ed)

Num

ber t

este

d fo

r PP

D

Num

ber p

osit

ive

in E

BS a

nd

PPD

(%)

p-va

lue

OR

( 95%

CI)

Myr

oxyl

on p

erei

rae

(Bal

sam

of

Peru

)80

0g/

cm2

2.2%

(803

5)

231

8 (3

.5)

0.24

7 1.

5 (0

.7-3

.2)

Bude

soni

de

0.1%

(PET

) 0.

8% (8

036)

22

8 2

(0.9

) 0.

835

1.2

(0.3

-4.8

) C

arba

mix

25

0 g/

cm2

2.4%

(777

8)

225

13 (5

.8)

0.00

2*

2.5

(1.4

-4.5

) M

ethy

lchl

oroi

soth

iazo

linon

e an

d m

ethy

lisot

hiaz

olin

one

(MC

I/MI)

4g/

cm2

4.3%

(777

7)

225

11 (4

.9)

0.80

8 1.

1 (0

.6-2

.0)

Cob

alt c

hlor

ide

20g/

cm2

5.0%

(800

5)

229

23 (1

0)

0.00

2*

2.0

(1.3

-3.2

) C

olop

honi

um (c

olop

hony

) 85

0 g/

cm2

3.8%

(801

7)

231

20 (8

.7)

<0.0

01*

2.4

(1.5

-3.8

) Ep

oxy

resin

50

g/cm

22.

2% (8

030)

23

1 9

(3.9

) 0.

046

2.0

(1.0

-4.0

) Et

hyle

nedi

amin

e di

hydr

ochl

orid

e 50

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20.

7% (7

770)

22

5 2

(0.9

) 0.

695

1.3

(0.3

-5.5

) Fo

rmal

dehy

de

180

g/cm

21.

4% (7

977)

23

1 9

(3.9

) 0.

004

2.7

(1.4

-5.5

) Fr

agra

nce

mix

I 43

0 g/

cm2

4.9%

(803

3)

231

22 (9

.5)

0.00

3 2.

0 (1

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Frag

ranc

e m

ix II

14

% (P

ET)

2.4%

(803

6)

92

11 (1

2.0)

0.

065

1.8

(1.0

-3.5

) H

ydro

xylis

ohex

yl 3

-cyc

lohe

xene

(L

yral

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(PET

) 1.

2% (8

036)

96

4

(4.2

) 0.

738

1.19

1 (0

.427

-3.

321)

La

nolin

alc

ohol

10

00

g/cm

21.

0% (8

033)

23

1 1

(0.4

) 0.

376

0.4

(0.1

-3.0

) M

erca

pto

mix

75

g/cm

21.

4% (8

035)

23

1 5

(2.2

) 0.

383

1.5

(0.6

-3.7

) M

erca

ptob

enzo

thia

zole

(MBT

) 75

g/cm

21.

1% (8

005)

22

9 5

(2.2

) 0.

437

1.5

(0.5

-4.1

) M

ethy

ldib

rom

o gl

utar

onitr

ile

(MD

BGN

) 0.

5% (P

ET)

3.1%

(803

6)

202

12 (5

.9)

0.05

6 1.

8 (1

.0-3

.3)

2-m

ethy

l-4-is

othi

azol

inon

e (M

I) 0.

01%

(AQ

U)

7.8%

(245

) 5

3 (6

0.0)

0.

001*

26

.3 (3

.6-1

92.4

) N

eom

ycin

sulfa

te

230

g/cm

20.

7% (8

036)

23

1 4

(1.7

) 0.

107

2.3

(0.8

-6.5

) N

icke

l sul

fate

20

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cm2

18.3

% (7

918)

22

6 61

(27)

0.

022

1.4

(1.1

-2.0

) Pa

rabe

ns m

ix

1000

g/

cm2

0.3%

(802

9)

230

5 (2

.2)

<0.0

01*

10.0

(3.5

-26.

6)

Pota

ssiu

m d

ichr

omat

e 23

g/cm

23.

7% (7

999)

23

1 16

(6.9

) 0.

017

1.9

(1.1

-3.2

) p-

tert

buty

lphe

nol

form

alde

hyde

resin

(PTB

FR)

40g/

cm2

2.2%

(798

2)

231

14 (6

.1)

<0.0

01*

2.7

(1.6

9-4.

8)

Qua

tern

ium

15

100

g/cm

21.

6% (8

035)

23

1 9

(3.9

) 0.

014

2.4

(1.2

-4.8

) Q

uino

line

mix

19

0 g/

cm2

0.3%

(803

5)

231

2 (0

.9)

0.10

0 3.

4 (0

.8-1

4.8)

Se

squi

terp

ene

lact

one

mix

0.

1% (P

ET)

1.1%

(803

6)

229

7 (3

0.6)

0.

013

2.7

(1.2

-6.0

) Th

iom

ersa

l 8

g/cm

21.

2% (8

022)

23

1 3

(1.3

) 0.

898

1.1

(0.3

-3.4

) Th

iura

m m

ix

25g/

cm2

2.2%

(803

4)

231

7 (3

.0)

0.20

8 1.

6 (0

.8-3

.3)

Tixo

cort

ol-2

1-pi

vala

te

0.1%

(PET

) 0.

7% (8

036)

22

9 2

(8.7

) 0.

784

1.2

(0.3

-5.0

)

Tabl

e 3:

Co-

sens

itiza

tions

of P

PD w

ith a

llerg

ens i

n th

e EB

S. O

dds r

atio

s (O

R) a

re ca

lcul

ated

usin

g lo

gist

ic re

gres

sion

anal

ysis

with

95%

confi

denc

e in

terv

als

(CI),

age

and

sex

sta

ndar

dize

d. IN

CI n

ames

are

use

d w

here

app

ropr

iate

. Con

cent

ratio

ns u

sed

are

acco

rdin

g to

the

guid

elin

es o

f the

Eu

rope

an S

ocie

ty o

f Con

tact

Der

mat

itis.

* Sta

tistic

al si

gnifi

cant

diff

eren

ces.

N/A

: not

app

licab

le.



��

Alle

rgen

from

the

EBS

Test

conc

entr

atio

n (v

ehic

le)

Ove

rall

prev

alen

ce E

BS

alle

rgen

(num

ber

test

ed)

Num

ber t

este

d fo

r TD

A

Num

ber p

osit

ive

in E

BS

and

TDA

(%)

p-va

lue

OR

( 95%

CI)

Myr

oxyl

on p

erei

rae

(Bal

sam

of

Peru

) 80

0g/

cm2

2.2%

(803

5)

108

3 (2

.8)

0.65

1 1.

3 (0

.4-4

.2)

Bude

soni

de

0.1%

(PET

) 0.

8% (8

036)

10

8 2

(1.9

) 0.

183

2.7

(0.6

-11.

2)

Car

bam

ix

250

g/cm

22.

4% (7

778)

10

5 8

(7.6

) 0.

001*

3.

4 (1

.6-7

.2)

Met

hylc

hlor

oiso

thia

zolin

one

and

met

hylis

othi

azol

inon

e (M

CI/M

I) 4

g/cm

24.

3% (7

777)

10

5 3

(2.9

) 0.

482

0.7

(0.2

-2.1

)

Cob

alt c

hlor

ide

20g/

cm2

5.0%

(800

5)

108

10 (9

.3)

0.08

1 1.

8 (0

.9-3

.5)

Col

opho

nium

(col

opho

ny)

850

g/cm

23.

8% (8

017)

10

8 10

(9.3

) 0.

007

2.5

(1.3

-4.8

) Ep

oxy

resin

50

g/cm

22.

2% (8

030)

10

8 1

(0.9

) 0.

439

0.5

(0.1

-3.3

) Et

hyle

nedi

amin

e di

hydr

ochl

orid

e 50

g/cm

20.

7% (7

770)

10

6 1

(1.0

) 0.

688

1.5

(0.2

-11.

1)

Form

alde

hyde

18

0 g/

cm2

1.4%

(797

7)

108

3 (2

.8)

0.31

0 1.

8 (0

.6-5

.9)

Frag

ranc

e m

ix I

430

g/cm

24.

9% (8

033)

10

8 7

(6.5

) 0.

589

1.2

(0.6

-2.7

) Fr

agra

nce

mix

II

14%

(PET

) 2.

4% (8

036)

35

4 (1

1.4)

0.

316

1.7

(0.6

-5.0

) H

ydro

xylis

ohex

yl 3

-cyc

lohe

xene

(L

yral

)5%

(PET

) 1.

2% (8

036)

34

0 (0

) 0.

997

N.A

.

Lano

lin a

lcoh

ols

1000

g/

cm2

1.0%

(803

3)

108

1 (0

.9)

0.96

6 1.

0 (0

.1-7

.0)

Mer

capt

o m

ix

75g/

cm2

1.4%

(803

5)

108

4 (3

.7)

0.07

9 2.

5 (0

.9-6

.9)

Mer

capt

oben

zoth

iazo

le (M

BT)

75g/

cm2

1.1%

(800

5)

108

3 (2

.8)

0.55

4 1.

5 (0

.4-6

.3)

Met

hyld

ibro

mo

glut

aron

itrile

(M

DBG

N)

0.5%

(PET

) 3.

1% (8

036)

89

4 (4

.5)

0.61

1 1.

3 (0

.5-3

.6)

Met

hylis

othi

azol

inon

e (M

I) 0.

01%

(AQ

U)

7.8%

(245

) 6

2 (3

3.3)

0.

032

7.8

(1.2

-51.

1)

Neo

myc

in su

lfate

23

0 g/

cm2

0.7%

(803

6)

108

1 (0

.9)

0.80

7 1.

3 (0

.2-9

.4)

Nic

kel s

ulfa

te

200

g/cm

218

.3%

(791

8)

107

28 (2

6.2)

0.

265

1.3

(0.8

-2.0

) Pa

rabe

ns m

ix

1000

g/

cm2

0.3%

(802

9)

107

2 (1

.9)

0.01

1 6.

9 (1

.6-3

0.3)

Po

tass

ium

dic

hrom

ate

23g/

cm2

3.7%

(799

9)

108

7 (6

.5)

0.15

5 1.

8 (0

.8-3

.8)

4-te

rt-B

utyl

phen

ol

form

alde

hyde

resin

(PTB

FR)

40g/

cm2

2.2%

(798

2)

107

4 (3

.7)

0.33

1 1.

7 (0

.6-4

.6)

Qua

tern

ium

15

100

g/cm

21.

6% (8

035)

10

8 2

(1.9

) 0.

916

1.1

(0.3

-4.4

) Q

uino

line

mix

19

0 g/

cm2

0.3%

(803

5)

108

1 (0

.9)

0.21

4 3.

6 (0

.5-2

7.5)

Se

squi

terp

ene

lact

one

mix

0.

1% (P

ET)

1.1%

(803

6)

109

3 (2

.8)

0.17

5 2.

3 (0

.7-7

.4)

Thim

eros

al (t

hiom

ersa

l) 8

g/cm

21.

2% (8

022)

10

9 0

N/A

N/A

Thiu

ram

mix

25

g/cm

22.

2% (8

034)

10

8 2

(1.9

) 0.

732

1.2

(0.4

-3.9

) Ti

xoco

rtol

-21-

piva

late

0.

1% (P

ET)

0.7%

(803

6)

109

1 (0

.9)

0.85

3 1.

2 (0

.2-8

.8)

Tabl

e 4:

Co-

sens

itiza

tions

of T

DA

with

alle

rgen

s in

the

EBS

. Odd

s ra

tios

(OR)

are

cal

cula

ted

usin

g lo

gist

ic r

egre

ssio

n an

alys

is w

ith 9

5%

confi

denc

e in

terv

als

(CI),

age

and

sex

sta

ndar

dize

d. IN

CI n

ames

are

use

d w

here

app

ropr

iate

. Con

cent

ratio

ns u

sed

are

acco

rdin

g to

the

gu

idel

ines

of t

he E

urop

ean

Soci

ety o

f Con

tact

Der

mat

itis.

* Sta

tistic

al si

gnifi

cant

diff

eren

ces.

N/A

: not

app

licab

le.


��

DiscussionIn the present study we aimed to investigate the relationship between the strength of the patch test reaction to PPD, TDA and well-known cross-reacting chemicals. Furthermore, we investigated the presence of unexpected concomitant sensitizations to chemically unrelated substances.

Of all individuals sensitized to PPD, 45% was also sensitized to TDA, while 86% of all TDA sensitized individuals was also sensitized to PPD. Based on the chemical structure of PPD and TDA the percentage of cross-reactions with PPD in TDA sensitized individuals should be higher, as in our study. It is a good possibility that the 15% individuals that have a positive patch test reaction to TDA, but not to PPD, are sensitized to this specific part of the molecule and therefore the immune system does not recognize PPD. A comparable percentage was also found by Basketter and English in 2009. 6 Although this can explain the difference, the question whether the number of false negative tests using the TRUE test® or the number of false positive tests using chamber loaded tests does bias the findings remains. 7

The strength of the PPD or TDA patch test reaction is related to the number of cross-reacting substancesA stronger elicitation reaction to PPD is associated with significantly more positive reactions to cross-reacting, para-amino compounds, as is presented in Figure 1. This phenomenon is also seen in TDA sensitized individuals, in which significantly more cross-reactions were found amongst the extremely strong reactions.

The relation between the patch test strength and cross-reactivity to related molecules, as we found in the present study, has already been described by Thomas et al.. 4 They showed a clear relation between the strength of the patch test reaction to PPD and the number of sensitizations to molecular similar compounds.

Uter et al. discussed that it is often difficult to discriminate between cross-reactivity and co-sensitization, as not all individuals with a PPD sensitization react to all para-amino compounds. As these compounds often appear together, such as PPD, TDA, m-aminophenol and p-aminophenol, it is complex to find out whether the immune system recognizes a similar molecular structure. A previous exposure with independent sensitization can also occur. This seems more plausible, as not all individuals are sensitized to all cross-reacting molecules.8 As mentioned before, the individual can be sensitized to another part of the molecule. Furthermore, haptens must have a different spacial geometry and size and are not recognized by the same receptor. 9 Accurate studying of cross-reactivity is only possible when the exposure to suspected haptens is controlled.

A probable explanation of the less marked relation between the TDA patch test strength and the number of cross-reactions, especially in weakly sensitized individuals, can be the



��

difference in the molecular structure between TDA and PPD, which makes the molecule a little less potent sensitiser. 10 However, due to the low number of investigated individuals in our study, it is difficult to draw firm conclusions.

Co-sensitizations with PPD and TDA within the European Baseline SeriesWhen studying co-sensitization, the relation between positive patch test reactions can be unclear, as common exposure sources are often difficult to determine.

PPD sensitized individuals had statistically significant higher odds of being sensitized to both carbamix, cobalt chloride, colophony, parabens mix and PTBFR compared to the entire patch test population. Furthermore, fragrance mix I and formaldehyde showed almost statistically significant higher odds of appearing more often in the PPD sensitized population. It is possible that subjects that dyed their hair are more exposed to hair styling, make-up or skin care products. From this point of view, it could be explained that patients with a PPD sensitization are more likely to be sensitized to fragrance mix I.The higher chance of being sensitized to parabens mix, when also sensitized to PPD, has already been described by Turchin et al.. 11 Though the odds they found were lower than the 10-fold higher chance of being sensitized in our population, they found a similar prevalence of PPD/parabens mix prevalence of 2.4 percent. They have a hydroxyl group instead of an amino group in para position. This is, however, debatable, as research on this topic has shown some lack of consistency up till now.

Since a few years an “epidemic” of MI sensitization has been observed. In the present study we found individuals 26 times more likely to be sensitized to both PPD and methylisothiazolinone than to methylisothiazolinone alone. However, the numbers are very small, as only 5 individuals were tested positive for PPD and were tested for MI and only 3 were tested positive for both PPD and MI. This relation was not observed when testing MCI/MI. MI can be present in hair dye products and these hair dye products are often used in combination with other hair cosmetics that also may contain MI in both an occupational setting (hairdressers) and a non-occupational setting (consumers).12

A relation between sensitization to either colophony, PTBFR, formaldehyde or cobalt chloride is unclear. Schnuch et al. already found a co-sensitization with PPD and colophony and PTBFR as well. They attributed this concomitant sensitization to occupational exposure in the leather/textile industry. 13 In our population this is unlikely, as leather/textile industry cannot be found in our region.

Both individuals with a PPD or a TDA sensitization are more likely to be sensitized to carbamix. This co-sensitization can occur in an occupational setting, due to exposure to rubber chemicals, or in a non-occupational setting. 14 Concomitant exposure to the accelators present in the carbamix and to rubber additives, present in the black rubber mix, can also have occurred.


�9

Carba mix (diphenylguanidine) Parabens mix (5 types of para-

hydroxybenzoates)

Colophony (abietic acid) PTBFR Eugenol

(fragrance mix I)

When concomitant exposure to substances is not plausible, other mechanisms might underlie these co-sensitizations. One of these mechanisms can be the conversion of two very different molecules into two similar metabolites. 9,15 A well-known example of this conversion is that of the synthetic azo-dyes being converted into aromatic amines. Around the late 1990s and early 2000s it was described that skin bacteria can cleave these azo-dyes into, sometimes very toxic, aromatic amines, among which PPD. 16,17

Some of the chemicals that appeared to co-sensitize with PPD, have an aromatic ring (Figure 3). The role of the microbiota of the skin is of increasing importance in the development and the prevention of diseases. One can presume that this microbiota can also convert or reduce the co-sensitizing molecules into molecules that are for the human immune system indistinguishable from PPD. And therefore the microbiota can play a role in the development of contact allergy as well.

Figure 3: Structure formulas of some co sensitizing chemicals.

ConclusionThe well-known phenomenon of cross-reactivity between chemically related molecules and PPD and TDA was confirmed in the present study. Cross-reactivity was strongly related to the patch test strength. Co-sensitizations to cobalt chloride, colophony, parabens mix and PTBFR are found more often in PPD sensitized patients, and both PPD and TDA sensitized individuals have significantly higher odds of being sensitized to carbamix as well. These co-sensitizations cannot be attributed to a frequently appearing or well-known exposure source. However, it is a good possibility that different molecules are conversed into chemically similar molecules, e.g. by the human skin microbiota. The latter should be investigated into more depth.



�0

LiteratureKrasteva M, Bons B, Ryan C, Gerberick GF. Consumer allergy to oxidative hair coloring products: epidemiologic data in the literature. Dermatitis 2009; 20:123-41.Vogel TA, Coenraads PJ, Bijkersma LM, et al. p-Phenylenediamine exposure in real life - a case-control study on sensitization rate, mode and elicitation reactions in the northern Netherlands. Contact Dermatitis 2015; .Basketter DA, Goodwin BF. Investigation of the prohapten concept. Cross reactions between 1,4-substituted benzene derivatives in the guinea pig. Contact Dermatitis 1988; 19:248-53.Thomas BR, White IR, McFadden JP, Banerjee P. Positive relationship - intensity of response to p-phenylenediamine on patch testing and cross-reactions with related allergens. Contact Dermatitis 2014; 71:98-101.Sosted H, Rustemeyer T, Goncalo M, et al. Contact allergy to common ingredients in hair dyes. Contact Dermatitis 2013; 69:32-9. Basketter DA, English J. Cross-reactions among hair dye allergens. Cutaneous and ocular toxicology 2009; 28:104-6.Goh C. Comparative study of TRUE Test and Finn Chamber patch test techniques in Singapore. Contact Derm 1992; 27:84-9.Uter W, Lessmann H, Geier J, et al. The spectrum of allergic (cross-)sensitivity in clinical patch testing with ‘para amino’ compounds. Allergy 2002; 57:319-22.Basketter D, Dooms-Goossens A, Karlberg AT, Lepoittevin JP. The chemistry of contact allergy: why is a molecule allergenic? Contact Dermatitis 1995; 32:65-73.Basketter DA, English J. Cross-reactions among hair dye allergens. Cutan Ocul Toxicol 2009; 28:104-6.Turchin I, Moreau L, Warshaw E, Sasseville D. Cross-reactions among parabens, para-phenylenediamine, and benzocaine: a retrospective analysis of patch testing. Dermatitis 2006; 17:192-5.Travassos AR, Claes L, Boey L, et al. Non-fragrance allergens in specific cosmetic products. Contact Dermatitis 2011; 65:276-85.Schnuch A, Lessmann H, Frosch PJ, Uter W. para-Phenylenediamine: the profile of an important allergen. Results of the IVDK. Br J Dermatol 2008; 159:379-86.Moritz K, Sesztak-Greinecker G, Wantke F, et al. Allergic contact dermatitis due to rubber in sports equipment. Contact Dermatitis 2007; 57:131-2.Benezra C, Maibach H. True cross-sensitization, false cross-sensitization and otherwise. Contact Dermatitis 1984; 11:65-9.Chung KT, Stevens SE,Jr, Cerniglia CE. The reduction of azo dyes by the intestinal microflora. Crit Rev Microbiol 1992; 18:175-90.Platzek T, Lang C, Grohmann G, et al. Formation of a carcinogenic aromatic amine from an azo dye by

human skin bacteria in vitro. Hum Exp Toxicol 1999; 18:552-9.

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Chapter 5The attitude of patients with a

p-phenylenediamine or 2,5-toluenediaminecontact allergy towards hair dyeing

Tatiana A. Vogel1, Thalina M. Prins1, A. Dijkstra2, Pieter-Jan Coenraads1, Marie-Lousie A. Schuttelaar1

1 University Medical Center Groningen, University of Groningen, Department of Dermatology,

Hanzeplein 1, 9700 RB Groningen2 University of Groningen, Department of Psychology,

Grote Kruisstraat 2/1, 9712 TS Groningen

Submitted

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