Contact Dermatitis • Original Article COD

Contact Dermatitis

Occupations at risk of developing contact allergy to isothiazolinones

in Danish contact dermatitis patients: results from a Danish
multicentre study (2009–2012)
Jakob F. Schwensen1 , Torkil Menné1 , Klaus E. Andersen2 , Mette Sommerlund3
and Jeanne D. Johansen1
1
Department of Dermato-Allergology, National Allergy Research Centre, Copenhagen University Hospital Gentofte, 2900, Hellerup, Denmark, 2 Department
of Dermatology and Allergy Centre, Odense University Hospital, 5000, Odense C,Denmark, and 3 Department of Dermatology, Aarhus University Hospital,

Printed by [Universidad Del Valle - 045.005.167.037 - /doi/epdf/10.1111/cod.12286] at [25/08/2021].

8000, Aarhus, Denmark

doi:10.1111/cod.12286

Summary Background. In recent years, the prevalence of contact allergy to isothiazolinones

has reached epidemic levels. Few studies have presented data on occupations at risk of
developing contact allergy to isothiazolinones.
Objectives. To present demographics and examine risk factors for sensitization to
methylisothiazolinone (MI), methylchloroisothiazolinone (MCI) in combination with MI
and benzisothiazolinone (BIT) in Danish dermatitis patients.
Materials and methods. A retrospective epidemiological analysis of data from three
Danish hospitals departments was conducted. All patients consecutively patch tested with
MI, MCI/MI and BIT between 2009 and 2013 were included.
Results. MI contact allergy showed a signicantly increased trend in prevalence from
1.8% in 2009 to 4.2% in 2012 (p < 0.001). Females with facial dermatitis mainly drove
the increase in 2012. Adjusted logistic regression analysis showed that MI sensitization
was signicantly associated with occupational exposures, hand and facial dermatitis,
age > 40 years, and the occupational groups of tile setters/terrazzo workers, machine
operators, and painters. MCI/MI contact allergy was signicantly associated with the
following high-risk occupations: painting, welding (blacksmiths), machine operating,
and cosmetology. The occupational group of painting was frequent in the group of
patients with BIT contact allergy.
Conclusion. Several high-risk occupations for sensitization to isothiazolinones exist.
Regulation on the allowed concentration of isothiazolinones, and especially MI, in both
consumer products and industrial products is needed.

Key words: allergic contact dermatitis; benzisothiazolinone; epidemiology;

methylchloroisothiazolinone; methylisothiazolinone; occupational; painters;
preservatives.

Isothiazolinones are antimicrobial agents, and have

Correspondence: Jakob F. Schwensen, Department of Dermato-Allergology,
National Allergy Research Centre, Copenhagen University Hospital Gentofte,
Niels Andersens Vej 65, 2900 Hellerup, Denmark. Tel: +45 39777303; Fax:
+45 39777118. E-mail: jakob.ferloev.schwensen.03@regionh.dk
Accepted for publication 17 June 2014
been used as preservatives in both consumer and indus-
trial products since the early 1980s (1). Until recently,
methylisothiazolinone (MI) (CAS no. 2682-20-4) was
employed in a xed combination with methylchloroisoth-
iazolinone (MCI) in a 3:1 combination (MCI CAS no.
26172-55-4). In consumer products, MCI/MI has been

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Contact Dermatitis, 71, 295–302 295
CONTACT ALLERGY TO ISOTHIAZOLINONES AND OCCUPATIONS AT RISK • SCHWENSEN ET AL.
limited to a concentration of 15 ppm. Since the EU per-
mitted the use of MI as a stand-alone preservative and
allowed a concentration of MI in consumer products of
up to 100 ppm (2), several European studies have shown
an epidemic increase in MI contact allergy throughout
the continent over a short period of time (3–10). Some
case reports of severe allergic reactions to MI have pri-
marily identied occupational cases, for example work
with paints and glue, which has been found to cause MI
sensitization (11, 12).
It has previously been suggested that MI is increasingly
being used as a preservative in consumer products, for
example different leave-on and leave-off products, and a
recent Danish analysis concluded, in a market survey, that
the use of MI in cosmetics had increased from 1.5% to
3.3% of all cosmetics on the Danish retail market (5, 13).
The use of benzisothiazolinone (BIT) (CAS no.
2634-33-5) is allowed in industrial products, but is
not permitted in consumer products, which may be the
reason why a more modest prevalence of BIT contact
allergy is observed (5). Nevertheless, allergic reactions to
BIT have been identied resulting from exposure to indus-
trial products containing BIT, for example paint, glues,
car care products, and varnishes (11, 14, 15). In a recent
analysis, it was shown that BIT was the predominant
isothiazolinone in data obtained from the Danish Prod-
uct Register, as BIT was registered in 985 products, as
compared with 884 products for MI and 611 products for
MCI/MI (14). The Danish Product register is a database in
which the composition of primarily hazardous chemical
products for occupational use is registered (14).
Overall, the epidemiological studies conducted have
focused on the increased level of MI contact allergy
throughout Europe (3–6). Retrospective epidemiological
analyses that have investigated occupations at risk of
developing MI sensitization are few in number (3), and
none have presented occupations at risk of sensitization
to the three most commonly registered isothiazoli-
nones as a whole (MI, MCI/MI, and BIT) based on
national data.
The aim of this study was to conduct a detailed retro-
spective epidemiological analysis of risk factors associated
with contact allergy to MI, MCI/MI, and BIT, with a special
focus on occupations at risk.
Materials and Methods
The National Database for Contact Allergy is a database
created by the Danish Contact Dermatitis Group with
the purpose of monitoring contact allergy throughout
Denmark. Contributors to the database are hospital
departments and dermatologists in private practice. Data
296
from the following hospitals were extracted: Gentofte Uni-
versity Hospital, Aarhus University Hospital, and Odense
University Hospital. The study population comprised
6744 consecutively patch tested patients with contact
dermatitis patch tested with MCI/MI, MI or BIT between
2009 and 2012.
Data concerning patients tested at Gentofte Univer-
sity Hospital with MCI/MI, MI and BIT (two periods:
2006–2010 and 2009–2012) and data concerning
patients at Odense University Hospital tested with MCI/MI
and MI (2011–2013) have been published previously (5,
Printed by [Universidad Del Valle - 045.005.167.037 - /doi/epdf/10.1111/cod.12286] at [25/08/2021].
16, 17).
Information available from the database included age,
occupation, MOALHFA index (Male, Occupation, Atopic
dermatitis, Leg dermatitis, Hand dermatitis, Facial der-
matitis, and Age > 40 years), and patch test results.
At the time of patch testing, all patients were given
an occupational code according to the Danish Interna-
tional System Standard Classication of Occupations
(DISCO-88). DISCO-88 divides occupations into 10 major
groups (one-digit code), which are further organized
into sub-major groups (two digits), minor groups (three
digits), and unit groups (four digits).
Occupational codes according to DISCO-88 were
aggregated to an occupational classication system on
the basis of well-known subgroups. Each unit group
was individually aggregated to an occupational group;
for example, aggregating the following DISCO-88 codes
created the occupational groups of painting and machine
operating: ‘7140, 7141 and 7142’ and ‘8000, 8100,
8140, 8160, 8170, 8200, 8210, 8220, 8224, 8230,
8231, 8240, 8260, 8262, 8270, 8279, 8281, and
8290’, respectively. This has previously been explained
(18, 19). A total of 19 occupational groups were created.
Occupations not tting into any of the 19 occupational
groups were aggregated into ‘others’.
Patch testing
The study population comprised consecutively registered
patients with patch test results of 6722 patients patch
tested with MCI/MI, 5290 patients patch tested with MI,
and 3636 patients patch tested with BIT. Only consecu-
tively tested patients were included in the analysis. Periods
of targeted testing with any of the allergens were excluded
from the analysis (e.g. targeted testing with MI at Odense
University Hospital in 2009).
MCI/MI was consecutively patch tested at a concentra-
tion of 100 ppm MCI/MI aq. or as part of the TRUE Test ®
(4 μg/cm 2 ) at all three hospitals between 2009 and 2012.
MI was consecutively patch tested at Gentofte University
Hospital (2000 ppm MI aq., 2009–2012), at Aarhus Uni-
versity Hospital (200 ppm MI aq., 2010–2012), and at
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Contact Dermatitis, 71, 295–302
 CONTACT ALLERGY TO ISOTHIAZOLINONES AND OCCUPATIONS AT RISK • SCHWENSEN ET AL.
Odense University Hospital (200 ppm MI aq. from Septem-
ber 2010 to May 2011, and 2000 ppm MI aq. from May
2011 to December 2012). BIT was consecutively patch
tested at Gentofte University Hospital (2415 patients
patch tested with 1000 ppm BIT aq., 2010–2012) and
Aarhus University Hospital (1221 patients patch tested
with 500 ppm BIT aq., 2009–2012). Odense University
Hospital did not consecutively patch test with BIT in the
years 2009–2012. Patch test data from Odense Uni-
versity Hospital regarding BIT were not included in the
analysis, owing to targeted testing.
Patch tests were applied to the upper back. The occlu-
sion time was 48 hr, and readings were performed at D2,
D3/D4 and D7 in accordance with the recommendations
of the ICDRG (20). Reactions of strength 1+, 2+ and 3+
were interpreted as positive responses. Readings of ‘Not
tested: sensitized’ were categorized as positive reactions.
Irritant reactions, doubtful reactions and negative reac-
tions were interpreted as negative responses. In cases of
retesting, patch test data obtained at the rst visit were
used in the analysis.
Statistics
The data were processed with SPSS (SPSS™ Statistics,
Chicago, IL, USA; IBM PASW Statistics) for Windows™,
edition 19.0. Median and interquartile range (IQR)
(Q 1 –Q3 ) were used to determine the difference in median
age for the populations with and without contact allergy
to MCI/MI, MI, or BIT.
Contact allergy across patch test years was tested
with linear-by-linear association by the chi-square trend
test. The chi-square test was applied for analysis of the
MOAHLFA index for all allergens. Fisher’s exact test was
used when observed values were below 5.
Contact allergy to MCI/MI and MI was analysed by
logistic regression analyses, with the allergen’s positive
patch test result as the dependent variable, and male
(yes/no), hand dermatitis (yes/no), related to occupa-
tional exposures (yes/no), age > 40 years (yes/no) and
occupation (e.g. healthcare worker: yes/no) or test year
as the explanatory variables. Associations were expressed
by means of odds ratios (ORs) with 95% condence inter-
vals (CIs). BIT contact allergy was not analysed by logistic
regression, owing to the more moderate sample size.
All p-values are two-sided, and 0.05 was chosen for
statistical signicance.
Results
A total of 6744 contact dermatitis patients (4462 females
and 2282 males) were retrospectively included in the
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Contact Dermatitis, 71, 295–302
Table 1. Prevalence of contact allergy to methylisothiazolinone
(MI), methylchloroisothiazolinone (MCI)/MI and benzisothiazoli-
none (BIT) in the years 2009 –2012
MCI/MI, % MI, % BIT, %
(n/total) (n/total) (n/total)
2009 3.3 (50/1538) 1.8 (13/727) 3.3 (10/399)
2010 2.2 (35/1603) 1.9 (20/1027) 0.4 (3/781)
2011 3.5 (61/1768) 3.5 (61/1745) 0.7 (9/1278)
2012 3.7 (67/1813) 4.2 (76/1791) 0.9 (12/1278)
p = 0.154 p < 0.001 p = 0.067
Printed by [Universidad Del Valle - 045.005.167.037 - /doi/epdf/10.1111/cod.12286] at [25/08/2021].
Chi-square test linear-by-linear association was used to test for
trends over the time period.
analysis. In total, 3.2% (213/6722) had MCI/MI con-
tact allergy, 0.9% (34/3636) had BIT contact allergy, and
3.2% (170/5290) had MI contact allergy.
Of all positive reactions to MCI/MI, 34.7% (74/213)
were weakly positive (1+), 51.6% (110/213) were
strongly positive (2+), and 6.1% (13/213) were extremely
positive (3+) (16 patients out of 213 were ‘Not tested: sen-
sitized’). Of the positive reactions to BIT, 79.4% (27/34)
were weakly positive reaction (1+), and 14.7% (5/34)
were strongly positive (2+) (2 patients out of 34 were ‘Not
tested: sensitized). Of all positive reactions to MI, 42.4%
(72/170) were weakly positive (1+), 45.9% (78/170)
were strongly positive (2+), and 4.1% (7/170) were
extremely positive (3+) (13 patients out of 213 were ‘Not
tested: sensitized’).
The median age of the patients with MCI/MI contact
allergy was 50 years (IQR 39–57 years), and that of the
patients negative for MCI/MI was 46 years (IQR 32–60
years). The median age of the patients with MI contact
allergy was 51 years (IQR 41–59 years), and that of the
patients negative for MI was 46 years (IQR 32–60 years).
The median age of the patients with BIT contact allergy
was 50 years (IQR 38–60 years), and that of the patients
negative for BIT was 47 years (IQR 32–60 years).
The prevalence rates of sensitization to MCI/MI, MI
and BIT are shown in Table 1. Overall, MCI/MI con-
tact allergy did not show any signicant trend over the
years (p = 0.154). MI sensitization showed a signi-
cantly increased trend over the years, to 4.2% in 2012
(p < 0.001). BIT sensitization did not show any signicant
trend (p = 0.067).
The coupled reactivity to MCI/MI, MI and BIT is shown
in Fig. 1. MI-positive patients had a concomitant reac-
tion to MCI/MI and BIT in 62.1% (105/170) and 5.9%
(10/170) of cases, respectively. MI and BIT coupled reac-
tivity was occupationally related in 80% (8/10) of the
patients, with the following occupational classication:
4 painters, 2 machine operators, 1 worker in the food
297
CONTACT ALLERGY TO ISOTHIAZOLINONES AND OCCUPATIONS AT RISK • SCHWENSEN ET AL.

industry, and 1 classied in ‘others’. BIT-positive patients Table 3. Occupations with positive reactions to methylchloroisoth-
also had a concomitant reaction to MCI/MI in 17.6% iazolinone (MCI)/methylisothiazolinone (MI), MI, and benzisothia-
zolinone (BIT). All occupations are listed
(6/34) of cases. Of these 6 BIT-positive and MCI/MI-
positive patients, 3 were painters, 2 were machine oper- MCI/MI MI BIT
ators, and 1 was a mechanic. All 6 BIT-positive and % (n/total % (n/total % (n/total
MCI/MI-positive patients had occupationally related con- Occupation tested) tested) tested)
tact dermatitis. In total, 5 patients (3 painters and 2 Agricultural worker 4.4 (5/114) 2.6 (2/77) 0.0 (0/56)
machine operators) had positive patch test reactions to Blacksmith 11.4 (5/44) 2.9 (1/35) 0.0 (0/27)
MCI/MI, MI, and BIT, all with occupationally related con- Cleaner 3.1 (8/259) 2.1 (4/190) 1.3 (2/157)
tact dermatitis. Construction worker 0.0 (0/76) 3.3 (2/61) 0.0 (0/42)
The ndings for the MOAHLFA index are shown in Cosmetologist 15.8 (3/19) 6.3 (1/16) 0.0 (0/12)

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Electrician 2.6 (1/39) 3.2 (1/31) 0.0 (0/24)
Table 2. MCI/MI contact allergy was signicantly associ-
Engineer 0.0 (0/51) 0.0 (0/36) 0.0 (0/32)
ated with occupational exposures, hand dermatitis, and Hairdresser 2.4 (4/166) 1.5 (2/136) 0.0 (0/89)
age > 40 years. MI sensitization was signicantly associ- Healthcare worker 3.4 (34/1014) 2.7 (22/803) 1.1 (6/559)
ated with occupational exposures, hand dermatitis, facial Machine operator 9.6 (8/83) 10.2 (6/59) 5.0 (2/40)
dermatitis, and age > 40 years. BIT contact allergy was, in Mechanic 4.5 (4/88) 1.4 (1/71 3.2 (2/62)
the unadjusted analysis, not signicantly associated with Office worker 3.5 (40/1135) 3.6 (35/974) 0.3 (2/662)
Painter 11.1 (7/63) 22.4 (11/49) 15.4 (6/39)
any of the variables in the MOAHLFA index.
Teacher 4.2 (7/167) 2.9 (4/136) 1.2 (1/85)
The MOALHFA index was further stratied for test year Tecnician 2.2 (3/134) 1.8 (2/112) 1.3 (1/79)
within each group of allergens, for example positivity Tile setter/terazzo worker 5.7 (2/35) 11.5 (3/26) 0.0 (0/20)
of MI reactions across the MOALHFA index. Within the Worker in food industry 2.1 (5/237) 2.5 (5/198) 0.8 (1/132)
period 2009–2012 for positive reactions to MI, the preva- Worker in transportation 3.5 (5/141) 3.1 (3/97) 0.0 (0/60)
lence of facial dermatitis increased from 21.3% in 2009 to or security
Worker in metal 1.9 (1/54) 0.0 (0/47) 4.2 (1/24)
48.7% in 2012 (p < 0.001; linear-by-linear association by processing industry
the chi-square trend test). The same signicantly increas- Others 2.5 (71/2803) 3.0 (65/2136) 0.7 (10/1435)
ing trend was found for positivity to MCI/MI regard-
ing face dermatitis (20% in 2009 to 46.3% in 2012,
p < 0.001), and a decreasing trend was found for hand
dermatitis (68.0% in 2009 to 46.3% in 2012, p = 0.005). frequencies of positive reactions to MI, BIT, and MCI/MI.
Regarding positivity for BIT, no statistical analysis was Furthermore, it was found that painters had a frequency
performed, as the sample sizes were too small across the of concomitant reactions between MI and MCI/MI of
MOALHFA index. 54.5% (6/11), and a frequency of concomitant reactions
The frequency of positive reactions to MCI/MI, MI or between BIT and MCI/MI of 50.0% (3/6).
BIT within the occupational groups is shown in Table 3, Table 4 shows the prevalence of patch test reac-
to give an overview of positive reactions in the specied tions to MCI/MI and MI dened according to selected
occupations. Painters and machine operators had high variables from the MOALHFA index and occupation.

Table 2. The MOAHLFA index for both positive and negative reactions for methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI), MI,
and benzisothiazolinone (BIT)

MCI/MI MI BIT

% (n) positive % (n) negative % (n) positive % (n) negative % (n) positive % (n) negative
Total tested (n = 213) (n = 6509) p-value** (n = 170) (n = 5120) p-value** (n = 34) (n = 3602) p-value**

M 30.5 (65) 34.0 (2211) > 0.05 31.2 (53) 33.0 (1690) > 0.05 38.2 (13) 34.1 (1229) > 0.05
O 29.1 (62) 17.9 (1163) < 0.001 33.5 (57) 19.5 (1000) < 0.001 32.4 (11) 22.2 (801) > 0.05
A 17.8 (38) 20.3 (1323) > 0.05 14.7 (25) 20.0 (1022) > 0.05 14.7 (5) 22.1 (796) > 0.05*
H 61.5 (131) 44.0 (2864) < 0.001 60.6 (103) 43.1 (2206) < 0.001 61.8 (21) 45.8 (1651) > 0.05
L 2.8 (6) 3.7 (244) > 0.05 2.9 (5) 3.2 (163) > 0.05 5.9 (2) 3.5 (126) > 0.05*
F 30.5 (65) 25.9 (1685) > 0.05 36.5 (62) 26.8 (1371) 0.005 23.5 (8) 26.0 (935) > 0.05
A 74.6 (159) 62.8 (4086) < 0.001 77.6 (132) 63.5 (3250) < 0.001 70.6 (24) 64.2 (2312) > 0.05

Signicant value are in bold type.

*Fisher’s exact test was used when n < 5.
**Pearson chi-square.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
298 Contact Dermatitis, 71, 295–302
 CONTACT ALLERGY TO ISOTHIAZOLINONES AND OCCUPATIONS AT RISK • SCHWENSEN ET AL.

Table 4. Percentages of positive reactions to methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) and MI in subgroups of patients
dened by male sex, hand dermatitis, occupationally related dermatitis, facial dermatitis, and occupational classication

MCI/MI MI

% (n/total tested) OR (95% CI) % (n/total tested) OR (95% CI)

Male 2.9 (65/2276) 0.71 (0.51–1.00) ∗ 3.0 (53/1743) 0.72 (0.49– 1.05)
Hand dermatitis 4.4 (131/2995) 2.03 (1.48– 2.78) 4.5 (103/2309) 2.16 (1.51–3.09)
Occupationally related dermatitis 5.1 (62/1225) 1.57 (1.09– 2.25) 5.4 (57/1057) 2.05 (1.36– 3.10)
Facial dermatitis 3.7 (65/1750) 1.54 (1.12– 2.10) 4.3 (62/1433) 1.98 (1.41– 2.79)
Age > 40 years 3.7 (159/4245) 1.98 (1.43– 2.73) 3.9 (132/3382) 2.33 (1.59– 3.41)

Printed by [Universidad Del Valle - 045.005.167.037 - /doi/epdf/10.1111/cod.12286] at [25/08/2021].

Agricultural worker 4.4 (5/114) 1.50 (0.58– 3.86) 2.6 (2/77) 0.70 (0.17 –3.01)
Blacksmith 11.4 (5/44) 4.15 (1.52– 11.30) 2.9 (1/35) 0.77 (0.10– 5.87)
Cleaner 3.1 (8/259) 0.88 (0.41– 1.89) 2.1 (4/190) 0.43 (0.15–1.23)
Construction worker 0.0 (0/76) – 3.3 (2/61) 0.87 (0.20 –3.82)
Cosmetologist 15.8 (3/19) 5.85 (1.61– 21.24) 6.3 (1/16) 1.69 (0.21–13.56)
Electrician 2.6 (1/39) 0.98 (0.13 –7.39) 3.2 (1/31) 1.00 (0.13– 7.76)
Engineer 0.0 (0/51) – 0.0 (0/36) –
Hairdresser 2.4 (4/166) 0.74 (0.26– 2.13) 1.5 (2/136) 0.33 (0.08–1.41)
Healthcare worker 3.4 (34/1014) 1.00 (0.65– 1.55) 2.7 (22/803) 0.63 (0.38 –1.06)
Machine operator 9.6 (8/83) 3.09 (1.39 –6.91) 10.2 (6/59) 2.67 (1.05– 6.78)
Mechanic 4.5 (4/88) 1.59 (0.54 –4.69) 1.4 (1/71) 0.37 (0.05– 2.78)
Office worker 3.5 (40/1135) 1.27 (0.85– 1.88) 3.6 (35/974) 1.07 (0.70 –1.63)
Teacher 4.2 (7/167) 1.60 (0.72– 3.56) 2.9 (4/136) 0.92 (0.33–2.59)
Technician 2.2 (3/134) 0.69 (0.21– 2.26) 1.8 (2/112) 0.40 (0.10–1.70)
Painter 11.1 (7/63) 3.54 (1.48– 8.46) 22.4 (11/49) 5.81 (2.59 –13.03)
Tile setter/terazzo worker 5.7 (2/35) 2.29 (0.52 –9.99) 11.5 (3/26) 3.89 (1.08 –14.07)
Worker in food industry 2.1 (5/237) 0.66 (0.26– 1.69) 2.5 (5/198) 0.60 (0.23–1.58)
Worker in metal processing industry 1.9 (1/54) 0.59 (0.08– 4.41) 0.0 (0/47) –
Worker in transportation or security 3.5 (5/141) 1.33 (0.52 –3.40) 3.1 (3/97) 0.93 (0.28–3.08)
Others 2.5 (71/2803) 1.00 (reference) 3.0 (65/2136) 1.00 (reference)

OR, odds ratio; CI, condence interval.

Logistic regression analysis was used to calculate ORs and 95% CIs.
A logistic regression analysis was conducted for both MCI/MI and MI.
∗
Male sex was weakly but signicantly inversely associated with MCI/MI contact allergy (OR 0.710; 95% CI 0.506 –0.995).

MCI/MI contact allergy was signicantly associated with
female sex (OR 1.41; 95% CI 1.01–1.98), hand der-
matitis, facial dermatitis, and occupational exposures.
Mainly older individuals were affected by sensitiza-
tion to MCI/MI, as the prevalence of MCI/MI contact
allergy was higher among individuals aged > 40 years
of age than among individuals aged < 40 years (OR
1.98; 95% CI 1.43–2.73). Furthermore, it was found
that MCI/MI contact allergy was signicantly associ-
ated with the following occupations: painting, welding
(blacksmiths), machine operating, and cosmetology
(Table 4).
MI sensitization was associated with being female
(Table 4). MI contact allergy was signicantly associ-
ated with hand dermatitis, occupational exposures, and
facial dermatitis, and affected older individuals (aged
> 40 years) more often than younger individuals. Occu-
pations signicantly associated with MI contact allergy
were tile setting/terrazzo work, painting, and machine
operating.
Adjusted multivariate analyses for MI contact allergy,
with MI positivity as the dependent variable, showed that
the increased prevalence of MI contact allergy had a sig-
nicantly positive gain in 2011 and 2012 for all cases. In
2012, a signicantly positive gain was observed in females
(Table 5).
Furthermore, adjusted multivariate analyses for
non-occupational cases for females, with MI positivity as
the dependent variable, showed a positive and signicant
gain in 2012 (OR 3.02; 95% CI 1.28–7.14).
Adjusted multivariate analyses for non-occupational
cases for females aged > 40 years and aged < 40 years
of age did not show any signicant trend over the test
period. It should be noted that, for non-occupational cases
for females aged > 40 years with MI contact allergy, we
found a positive, but not signicant, gain of prevalence
in 2009 of 2.2–5.2% in 2012, with an OR of 2.39 (95%

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Contact Dermatitis, 71, 295–302 299
CONTACT ALLERGY TO ISOTHIAZOLINONES AND OCCUPATIONS AT RISK • SCHWENSEN ET AL.
Table 5. Percentages of positive reactions to methylisothiazolinone (MI) in test year 2009 –2012. Adjusted logistic regression analysis was
applied to test for any time trend over the test years
Total
% (n/total) OR (95% CI) % (n/total)
2009 1.8 (13/727) Reference 1.8 (9/498)
2010 1.9 (20/1027) 1.09 (0.54 –2.21) 1.9 (13/693)
2011 3.5 (61/1745) 1.99 (1.09 –3.64) 3.4 (40/1168)
2012 4.2 (76/1791) 2.43 (1.34 –4.41) 4.6 (55/1188)
OR, odds ratio; CI, condence interval.
CI 0.99–5.74) (p = 0.053). The same adjusted analyses
for males were conducted, and did not show any signi-
cant trend over the test years. Adjusted logistic regression
analyses were also applied to MCI/MI and BIT, with pos-
itivity as the dependent variable. These analyses did not
show any signicant time trend over the test years.
Discussion
For the rst time, a detailed retrospective epidemiologi-
cal analysis presents risk factors associated with contact
allergy to MI, MCI/MI, and BIT with a special focus on
occupations at risk.
The prevalence of MI contact allergy increased signif-
icantly, from 1.8% in 2009 to 4.2% in 2012 (Table 1),
and, once again, the epidemic of MI sensitization is shown
in a large patient population (3, 4, 6, 8, 10). As previ-
ously shown for some of this population (5), MCI/MI con-
tact allergy increased steadily, although not signicantly,
over the time period, following, and probably linked to, the
same pattern of increase in the prevalence of MI sensitiza-
tion.
It has recently been shown that the recent rapid
increase in the prevalence of MI sensitization has a
strong association with being female, age > 40 years,
and facial dermatitis, which is partly in agreement with
our ndings (Tables 2, 4 and 5) (3, 21). In the adjusted
multivariate analysis for MI (Table 4), female sex was
not signicantly associated with MI contact allergy.
However, further adjusted multivariate analyses showed
that the increased prevalence of MI contact allergy had
a signicant positive gain in 2011 and 2012, mainly
driven by non-occupational cases of females with aller-
gic contact dermatitis caused by MI (Table 5). Further
adjusted analysis revealed a trend of an increase in the
prevalence of MI sensitization in females aged > 40 years,
as the prevalence increased from 2.2% in 2009 to 5.2%
in 2012 (OR 2.39; 95% CI 0.99–5.74) (p = 0.053). This
is in accordance with other studies (3, 21).
Occupations at risk of MI contact allergy and domes-
tic exposure to paints will probably fuel the MI epidemic
300
Females Males
OR (95% CI) % (n/total) OR (95% CI)
Reference 1.7 (4/229) Reference
1.04 (0.44 –2.45) 2.1 (7/334) 1.20 (0.35 –4.16)
1.93 (0.93– 4.00) 3.6 (21/577) 2.13 (0.72 –6.26)
2.64 (1.29– 5.38) 3.5 (21/603) 2.03 (0.69 –5.98)
Printed by [Universidad Del Valle - 045.005.167.037 - /doi/epdf/10.1111/cod.12286] at [25/08/2021].
even after the cosmetic industry has reduced the use of
MI in, for example, leave-on consumer products (22).
Furthermore, we present data indicating that the recent
rapid increase in MI contact allergy could have resulted
from cosmetics and air-borne exposures, for example from
paint, as test-year stratied analysis showed a trend of
a rapid increase in the prevalence of facial dermatitis
(21.3% in 2009 to 48.7% in 2012) (p < 0.001). This
nding is in accordance with previously published data,
although a facial dermatitis prevalence of 48.7% among
newly diagnosed individuals with MI contact allergy is
higher than previously observed, and is alarming (3).
No signicant change in BIT contact allergy was
observed. This may reect the fact that BIT is not legal for
use in cosmetics and/or the fact that BIT is less allergenic
than MI. A recent Danish study indicated that BIT is
widely used in industrial applications (14). Therefore, it is
important that dermatology departments start to patch
test with BIT on the slightest suspicion of BIT contact
allergy, especially if the patient has been in contact with
paint, varnishes, cleaning agents, and polishing agents
(14). Moreover, it is important to remember the possibility
of coupled reactivity between all three isothiazolinones
(Fig. 1).
MI as a primary sensitizer is once again pointed out,
as MI-positive patients had a concomitant reaction to
MCI/MI in only 62.1% of cases, which is similar to previ-
ous ndings (3, 5, 23). Patients with BIT contact allergy
also had a concomitant reaction to MCI/MI in 17.6% of
cases, and, in all of these 6 patients, the contact dermatitis
was associated with occupational exposures (painters,
machine operators, and one mechanic). The fact that the
frequency of BIT contact allergy without a concomitant
reaction to MCI/MI is 82.4% indicates that BIT is a pri-
mary sensitizer, causing a risk for the blue collar worker
(14). The data indicate that occupationally related con-
tact dermatitis is frequent for cases with coupled reactivity
between all three isothiazolinones.
In the unadjusted analysis, BIT contact allergy was not
associated with any of the variables across the MOAHLFA
index, which is probably attributable to the small
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Contact Dermatitis, 71, 295–302
 CONTACT ALLERGY TO ISOTHIAZOLINONES AND OCCUPATIONS AT RISK • SCHWENSEN ET AL.
Fig. 1. Observed positive reactions and coupled reactivity of
methylisothiazolinone, methylchloroisothiazolinone/
methylsiothiazolinone, and benzisothiazolinone.
population size of patients with positive patch test
reactions to BIT (Table 2).
Occupations with an increased risk for MCI/MI con-
tact allergy were mainly occupational groups belonging
to the blue collar worker and cosmetologist (Table 4)
categories; this is probably related to MI sensitization in
these occupations (19). Painters were at signicant risk
for developing contact allergy to MCI/MI and MI (Tables 3
and 4). This is in accordance with previous ndings of
painters being at risk for MI (and BIT) contact allergy
(3, 15), and correlates with the fact that BIT, MI and
MCI/MI are widely used in paint and varnish (14, 22).
Painters had the highest frequency of coupled reactions
between all three isothiazolinones (Fig. 1), and, in all of
those cases, the contact dermatitis was occupationally
related. It remains to be seen whether this frequency is
attributable to cross-reactivity or concomitant reactions,
although the high prevalence of MCI/MI contact allergy
observed in painters might result from the widespread use
of BIT and MI in, for example, paints, in contrast to the
more moderate use of MCI/MI (14).
Machine operating was associated with MI sensitiza-
tion (OR 2.67; 95% CI 1.05–6.78). This is a new and
interesting nding, and may reect the newly obtained
knowledge on the extended use of isothiazolinones in
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Contact Dermatitis, 71, 295–302
car care products and metal polishing agents, which has
shown that these products have the highest concentration
of MI (and BIT) in the Danish Product Register (14).
Moreover, MCI/MI contact allergy was signicantly
associated with machine operating and welding (black-
smiths) (Table 4). This could be attributable either to con-
comitant exposure to MCI/MI in industrial products or
cross-reactivity with MI or BIT (14). As a new nding,
it was shown that tile setters/terrazzo workers had an
increased risk of developing sensitization to both MCI/MI
and MI (Table 4). This has previously not been described
Printed by [Universidad Del Valle - 045.005.167.037 - /doi/epdf/10.1111/cod.12286] at [25/08/2021].
in the literature, although tile setters/terrazzo workers are
probably in contact on a daily basis with ooring mate-
rials, cleaning agents, and binding agents, all of which
contain high concentrations of MI (14).
The only occupation outside the group of blue collar
workers (19) with a signicant association with MCI/MI
contact allergy was cosmetology (Table 4). Cosmetology
was also associated with MI sensitization, but the associ-
ation was not signicant (Tables 3 and 4). However, both
associations should be interpreted with caution, owing to
the moderate sample size of cosmetologists with MI and
MCI/MI contact allergy. A German study has previously
reported that cosmetology is associated with MI sensiti-
zation (3). The signicant association found between cos-
metology and MCI/MI contact allergy is probably not a
result of a change in exposure to MCI/MI in consumer
products, but rather of cross-reactivity between contact
allergy to MI and to MCI/MI, for example when the cos-
metologist is applying concealer containing MI on a client
by hand. As postulated before, one might speculate that,
in private, cosmetologists tend to use a higher volume of
cosmetics than the female background population (3).
In conclusion, we once again show the general Euro-
pean trend of an epidemic increase in MI contact allergy
in a large patient population (4, 6, 7, 15, 23). Adjusted
multivariate analyses showed that the prevalence of MI
contact allergy had a signicantly positive gain in 2012,
as the MI epidemic gained more momentum. Moreover,
the prevalence of facial dermatitis in newly diagnosed
patients with MI contact allergy increased alarmingly
over the time period, indicating exposure to MI in either
consumer products or air-borne products, for example
paint.
Further adjusted analyses showed that contact allergy
to isothiazolinones is associated with several occupations,
for example painting and machine operating. This newly
obtained information on contact allergy to isothiazoli-
nones calls for urgent regulation on the allowed concen-
tration of isothiazolinones, and especially MI, in both con-
sumer products and industrial products.
301
CONTACT ALLERGY TO ISOTHIAZOLINONES AND OCCUPATIONS AT RISK • SCHWENSEN ET AL.
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