The prevalence of chromium allergy in Denmark ... - Wiley Online Library

C O N T A C T DE R M A T I T I S AN D A L L E R GY

BJD

British Journal of Dermatology

The prevalence of chromium allergy in Denmark is currently increasing as a result of leather exposure J.P. Thyssen, P. Jensen, B.C. Carlsen, K. Engkilde, T. Menne´ and J.D. Johansen Department of Dermato-Allergology, National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

Summary Correspondence Jacob Pontoppidan Thyssen. E-mail: [email protected]

Accepted for publication 13 March 2009

Key words allergy, chromate, chromium, dermatitis, epidemiology, patch testing, prevalence

Conflicts of interest The authors have no conflicts of interest to disclose. DOI 10.1111/j.1365-2133.2009.09405.x

Background Chromium allergy has traditionally been caused by occupational skin contact with cement. In 1983, Danish legislation made the addition of ferrous sulphate compulsory in cement to reduce the water-soluble chromium content to not more than 2 ppm. An effect from this intervention has previously been demonstrated among Danish construction workers. Objectives To investigate the development of chromium allergy among patients with dermatitis tested between 1985 and 2007 in Denmark. Furthermore, to determine causative exposures in patients with chromium allergy. Patients and methods A retrospective analysis of patch test data was performed (n = 16 228) and charts from patients with chromium allergy were reviewed. Comparisons were made using a v2 test. Logistic regression analyses were used to test for associations. Results The prevalence of chromium allergy decreased significantly from 3Æ6% in 1985 to 1% in 1995 (Ptrend < 0Æ001) but increased to 3Æ3% in 2007 (Ptrend < 0Æ001). The frequency of clinically relevant cement exposure decreased significantly among patients with chromium allergy from 12Æ7% in 1989–1994 to 3Æ0% (P < 0Æ01) in 1995–2007, whereas the frequency of relevant leather exposure increased significantly from 24Æ1% during 1989–1994 to 45Æ5% during 1995–2007 (P < 0Æ02). Conclusions Chromium allergy is currently increasing in Denmark due to leather exposure.

Chromium allergy and dermatitis have traditionally been caused by occupational skin contact with cement1–3 as well as exposure to leather, metal, paint and plywood. In 1983, Danish legislation made the addition of ferrous sulphate compulsory in cement in order to reduce the water-soluble chromate content to not more than 2 ppm.1,4 An effect from this intervention was noted as the prevalence of chromium allergy decreased among construction workers in Denmark.5 In countries that did not pass similar legislation, cement exposure continued to cause occupational chromium dermatitis.6 Hence, a European Union (EU) Directive based on the Danish legislation came into effect in 2005.7 Zachariae et al.8 investigated the cause of chromium allergy among Danish patients with dermatitis tested between 1989 and 1994. The authors found that leather was the most frequent cause followed by cement. Because cement exposure mainly occurred before the chromium legislation was introduced (1983), the study emphasized that leather products should be regarded as an important source of chromium allergy. This finding was later supported by Hansen et al.,9 who investigated Danish

patients with chromium allergy patch tested between 2002 and 2004. They found that foot dermatitis caused by leather shoes and boots was the most frequent clinical picture. The Federal Institute for Risk Assessment in Germany recently recommended that the levels of chromium in leather goods should be strictly limited as the regulatory authorities of the federal states found that more than half of 850 leather goods contained hexavalent chromium, and that in one-sixth, the levels were higher than 10 mg kg)1 leather (http:// www.bfr.bund.de/cd/9575, last accessed 14 June 2009). The present study investigated the development of chromium allergy among Danish patients with dermatitis in order to determine the magnitude and causes of chromium allergy.

Patients and methods Study population and design All patients with dermatitis patch tested at the Department of Dermato-Allergology, Gentofte Hospital, University of 2009 The Authors

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The development of chromium allergy, J.P. Thyssen et al. 1289

Copenhagen, Denmark between 1 January 1985 and 31 December 2007 were included in the study. Medical charts from patients with chromium allergy seen between 1995 and 2007 were examined retrospectively. This was done to obtain information about the relevance of positive patch reactions (current, previous or unknown), relevant exposures (leather shoes, leather gloves, other leather exposure, cement, plywood, cosmetics, graphic work and paint), and finally the anatomical location of dermatitis reactions (hand, leg, foot, face, universal, missing). Definitions The relevance of positive patch test reactions to chromium was assessed by the consulting physician: ‘current relevance’ was registered when a patient presented with a dermatitis reaction in combination with a history of current exposure to a source of chromium; ‘past relevance’ was registered when a patient had a positive patch test reaction to chromium in combination with a medical history of a past dermatitis reaction caused by exposure to a source of chromium; ‘unknown relevance’ or ‘missing’ was registered in patients with dermatitis and chromium allergy where no relation to current or past chromium exposure could be assessed, or where no registrations had been performed by the physician. Relevant causative exposures were based on the physician’s notes in medical charts. Patch testing Patch testing was performed with the European baseline series using Finn Chambers (8 mm; Epitest Ltd, Oy, Finland) on Scanpor tape (Norgesplaster A ⁄S; Alpharma, Vennesla, Norway). Potassium dichromate 0Æ5% was used for testing in petrolatum. The patch tests were applied to the upper back and were occluded for 48 h. Readings were done on day 2, 3 or 4, and day 7 according to the recommendation from the International Contact Dermatitis Research Group.10 Thus, homogeneous redness and infiltration in the entire test area was scored as a 1+ reaction. Homogeneous redness, infiltration and vesicles in the test area were scored as a 2+ reaction, and homogeneous redness, infiltration and coalescing vesicles in the test area as a 3+ reaction. A 1+, 2+ or 3+ reading was interpreted as a positive response. An irritant response, a doubtful (+?), or a negative reading was interpreted as a negative response. Statistics Comparisons were made using the v2 test. A v2 trend test was used to test for possible significant trends across test years. A logistic regression model was performed with ‘chromium allergy’ as the dependent variable, and sex, age group (‘0– 18 years’, ‘19–40 years’, ‘41–60’, ‘> 60 years’) and test year (‘1985–1990’, ‘1991–1996’, ‘1997–2001’, ‘2002–2007’) as the independent variables. In this model, a test for interaction

between test year and age group was performed by using a log-likelihood ratio test. A similar logistic regression model was performed but in this model, the interaction term was set between test year and sex. All results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Patch test data were analysed with the Statistical Products and Service Solutions package (SPSS Inc., Chicago, IL, U.S.A.) for Windows (Release 15.0).

Results A total of 16 228 patients with dermatitis (63Æ7% females and 36Æ3% males) aged 4–99 years were patch tested between 1985 and 2007. Their characteristics have previously been described.11 The overall prevalence of chromium allergy was 2Æ5% (2Æ5% in women and 2Æ4% in men). Two similar logistic regression analyses with chromium allergy as the dependent variable and with sex, age group and test year as the explanatory variables were performed. In the first model, an interaction term between sex and test year was inserted. It showed that the change in prevalence of chromium allergy was not significantly dependent on sex (the P-value for interaction between sex and test year was 0Æ06). This means that the change in the prevalence of chromium allergy from 1985 to 2007 may be presented as one overall estimate (Fig. 1). However, the decrease of chromium allergy during the mid 1990s was not as dramatic among women as observed among men (Table 1). Thus, the prevalence of chromium allergy among women was 2Æ1% during 1997–2001 compared with 1Æ4% among men (P < 0Æ02). In the second model, an interaction term between age group and test year was inserted. The P-value of the interaction term was 0Æ23, which means that stratification by age group was not necessary when evaluating changes in the prevalence over time. However, the overall prevalence of chromium allergy was highest among middleaged patients (Table 1). When chromium allergy in men and women was stratified by age group it revealed that the prevalence of chromium allergy was significantly higher among women aged 19–40 years than men in the same age group (2Æ0% vs. 1Æ0%, P < 0Æ009) whereas men above 60 years had a higher prevalence than women (3Æ3% vs. 2Æ4%, P < 0Æ06). However, the prevalence was consistently higher among older men than women during the entire study period. Finally, the study showed that the prevalence of chromium allergy decreased significantly from 3Æ6% in 1985 to 1Æ0% in 1995 (Ptrend < 0Æ001), which was the year with the lowest prevalence of chromium allergy. However, this decrease was followed by an increase that reached 3Æ3% in 2007 (Ptrend < 0Æ001) (Fig. 1). Table 2 shows the clinical characteristics of 197 patients with chromium allergy tested between 1995 and 2007. The total number of patients with positive patch test reactions during the 13-year period was 235 but only 197 (83Æ8%) medical charts were retrieved. The MOAHLFA index (see Table 2) showed that occupational dermatitis as well as hand dermatitis occurred significantly more often in men than women. The

2009 The Authors Journal Compilation 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp1288–1293

1290 The development of chromium allergy, J.P. Thyssen et al.

4 3·6 3·5

3·3 3·1

3·1

3

3

Percentage (%)

2·7 2·5

2·3

2·2

2·3

1·9 2 1·6 1·5 1

1

0·5

0 1985

1987

1989

1991

1993

1995 1997 Test year

1999

2001

2003

2005

2007

Table 1 The prevalence of chromium allergy among 16 228 patients with dermatitis stratified by age group and patch test year

Chromium allergy % (n ⁄ total) Frequency of variables Age group (years) 0–18 19–40 41–60 > 60 Patch test year 1985–90 1991–96 1997–2001 2002–07 a

All

Male patients

0Æ7 1Æ7 3Æ2 2Æ8

(5 ⁄ 736) (94 ⁄ 5545) (184 ⁄ 5765) (116 ⁄ 4182)

0Æ8 1Æ0 3Æ0 3Æ3

(2 ⁄ 238) (19 ⁄ 1811) (65 ⁄ 2168) (56 ⁄ 1676)

3Æ0 1Æ7 2Æ1 3Æ1

(109 ⁄ 3692) (76 ⁄ 4378) (84 ⁄ 3998) (130 ⁄ 4160)

3Æ4 1Æ7 1Æ4 3Æ2

(47 ⁄ 1372) (28 ⁄ 1622) (19 ⁄ 1401) (48 ⁄ 1498)

Fig 1. The prevalence of chromium allergy among patients with dermatitis patch tested between 1985 and 2007 at Gentofte University Hospital, Denmark. A v2 trend test was performed to test for significant changes over time. The decreasing prevalence observed between 1985 and 1995 was significant (Ptrend < 0Æ001). The increasing prevalence observed between 1995 and 2007 was also significant (Ptrend < 0Æ001).

Female patients 0Æ6 2Æ0 3Æ3 2Æ4

P-valuea

(3 ⁄ 498) (75 ⁄ 3734) (119 ⁄ 3597) (60 ⁄ 2506)

0Æ7 0Æ009 0Æ8 0Æ06

(62 ⁄ 2320) (48 ⁄ 2756) (65 ⁄ 2597) (82 ⁄ 2662)

0Æ2 0Æ9 0Æ02 0Æ8

2Æ7 1Æ7 2Æ5 3Æ1

P-value of v2 test comparing male and female patients.

relevance of positive patch test reactions to chromium was generally high as approximately 50% and 23% were registered as being of current and past relevance, respectively. Current relevance was more often noted in men in comparison to women although the difference was not significant (60Æ7% vs. 46Æ3%, P < 0Æ06). Current relevance was high for leather shoes (92Æ9%) but low for cement (14Æ3%). Relevant exposures included leather shoes (35Æ5%), leather gloves (10Æ7%), other leather exposures such as furniture, jackets and bags (8Æ1%), as well as cement (3Æ6%). Cement and leather glove exposures were mainly registered in men. Finally, the anatomical location of the dermatitis reaction was most often noted on the hands (69Æ5%) and feet (47Æ7%) but universal dermatitis was not uncommon (11Æ7%). Obviously, some patients had dermatitis in more than one location. Table 3 shows changes of chromium exposure among Danish patients with dermatitis tested at Gentofte Hospital in 1989–1994 and 1995–2007. The frequency of clinically relevant cement exposure decreased significantly among patients with chromium allergy from 12Æ7% during 1989–1994 to 3Æ0% during 1995–2007 (P < 0Æ01) whereas the frequency of

overall leather exposure increased significantly from 24Æ1% to 45Æ5% (P < 0Æ02).

Discussion This study showed that the prevalence of chromium allergy decreased significantly between 1985 and 1995 and that it was followed by a significant increase between 1995 and 2007 (Fig. 1). The V-shaped pattern was independent of age group and sex although the 1995 decrease was more marked in men than women. The prevalence of chromium allergy was higher in older age groups, which may be explained by the fact that older patients have had a longer exposure time than younger patients. Furthermore, some may have been exposed to chromium in cement before the imposition of the 1983 regulation on chromium. We identified a significant change of chromium exposure over time (Table 3). Thus, relevant cement exposure was reported significantly more often between 1989 and 1994 than between 1995 and 2007 among patients with dermatitis and chromium allergy. Also, the proportion of current relevance regarding cement exposure was 2009 The Authors


The development of chromium allergy, J.P. Thyssen et al. 1291 Table 2 Clinical characteristics of 197 patients with dermatitis and chromate allergy treated between 1995 and 2007 Total (n = 197) % (n) MOAHLFA index Males 31Æ5 (62) Occupational dermatitis 25Æ4 (50) Atopic dermatitis 17Æ8 (35) Hand dermatitis 69Æ5 (137) Leg ulcers 2Æ5 (5) Facial dermatitis 8Æ6 (17) Age > 40 years 76Æ1 (150) Relevance of positive patch test reactions to chromium Current 50Æ8 (100) Past 23Æ4 (46) Unknown 26Æ4 (52) Relevant exposures Leather shoes 35Æ5 (70) Leather gloves 10Æ7 (21) Other leather exposureb 8Æ1 (16) Cement 3Æ6 (7) Plywood 1Æ0 (2) Cosmetics 1Æ0 (2) Graphic work and paint 1Æ5 (3) Anatomical location of dermatitis (apart from hand eczema)c Feet 47Æ7 (94) Legs 7Æ1 (14) Face 1Æ0 (2) Universal distribution 11Æ7 (23) Missing 29Æ4 (58)

Male patients (n = 61) % (n)

Female patients (n = 136) % (n)

P-valuea

– 39Æ3 11Æ5 80Æ3 1Æ6 11Æ5 86Æ9

– 19Æ1 20Æ6 64Æ7 2Æ9 7Æ4 71Æ3

– 0Æ003 0Æ1 0Æ03 0Æ6 0Æ3 0Æ2

(24) (7) (49) (1) (7) (53)

(26) (28) (88) (4) (10) (97)

60Æ7 (37) 18Æ0 (11) 24Æ6 (15)

46Æ3 (63) 25Æ7 (35) 27Æ2 (37)

0Æ06 0Æ2 0Æ7

27Æ9 23Æ0 11Æ5 11Æ5 3Æ3 0 4Æ9

(17) (14) (7) (7) (2)

39Æ0 5Æ1 6Æ6 0 0 1Æ5 0

(53) (7) (9)

0Æ1 0Æ001 0Æ3 0Æ001 0Æ03 0Æ3 0Æ01

44Æ3 8Æ2 0 13Æ1 31Æ1

(27) (5)

49Æ3 6Æ6 1Æ5 11Æ0 28Æ7

(67) (9) (2) (15) (39)

(3)

(8) (19)

(2)

0Æ4 0Æ7 0Æ3 0Æ7 0Æ7

a P-value of v2 test comparing male and female patients. bFurniture, watch strap, jacket, bag, belt, and cover for car wheel. cSome patients had dermatitis at more than one anatomical location.

Table 3 Sources of chromium exposure assessed in patients with dermatitis and chromium allergy patch tested during two different periods (1989–1994 and 1995–2007) at Gentofte Hospital, Denmark

Exposure sources Cement Leather shoes Leather gloves Leather, other sourcesb Leather, total Chromium, other sources Unknown

1989–19948 (n = 79) % (n)

1995–2007 (n = 235) % (n)

P-valuea

12Æ7 17Æ7 3Æ8 2Æ5

3Æ0 29Æ8 8Æ9 6Æ8

0Æ01 0Æ1 0Æ06 0Æ2

(10) (14) (3) (2)

(7) (70) (21) (16)

24Æ1 (19) 8Æ8 (7)

45Æ5 (107) 3Æ0 (7)

0Æ02 0Æ05

56Æ9 (45)

48Æ5 (114)

0Æ3

a

P-value of v2 test comparing ‘1989–1994’ with ‘1995–2007’. Furniture, watch strap, jacket, bag, belt, and cover for car wheel.

b

low (14Æ3%) among patients with chromium allergy tested between 1995 and 2007. Taken together, these findings confirm that occupational exposure to cement used to be a common

cause of chromium allergy and dermatitis, especially in men;1,5,8 and they suggest that the significant decrease of chromium allergy observed between 1985 and 1995 was likely to be a result of the Danish chromium regulation of 1983. However, one should be aware that general increased work hygiene in Denmark may also be of importance. The increasing prevalence of chromium allergy observed in both sexes between 1995 and 2007 was likely to be explained by increasing exposure to leather products such as shoes, gloves and furniture. In fact, approximately 55% of 197 patients with chromium allergy tested between 1995 and 2007 had a relevant leather exposure in their medical history compared with only 24Æ1% of 79 patients with chromium allergy tested between 1989 and 1994.8 Thus, a significant change occurred between the period 1989–1994 and the period 1995–2007 (Table 3). Data analysis showed that clinically relevant exposure to leather shoes was more frequent in women than men (39% vs. 27Æ9%) in the second study period (1995–2007), and that nearly half of all patients with chromium allergy had foot dermatitis (Table 2). Finally, current relevance was judged in 92Æ9% of patients with exposure to leather in shoes. In conclusion, current causative leather exposures were common in patients with chromium allergy, and often led to hand and ⁄or foot dermatitis.


1292 The development of chromium allergy, J.P. Thyssen et al.

This study showed that the prevalence of chromium allergy as well as the relevance of leather exposure in patients with chromium allergy has increased significantly since the late 1990s. However, it did not show whether this was caused by a more frequent exposure to leather goods or by exposure to higher concentrations of chromium. Possible explanations for increased leather (and chromium) exposure could be that (i) the fashion pattern has changed in Denmark, e.g. sneakers are increasingly replaced by leather shoes in men and women may tend to wear leather sandals more often; (ii) the sale of leather shoes (the average Danish household spent 130€ in 1999 on women’s shoes in comparison to 180€ in 2005 (http://www.statistikbanken.dk/statbank5a/default.asp?w=1024, last accessed 14 June 2009) has increased as a result of increasing wealth since the late 1990s; (iii) leather products may more easily release chromium today as a result of new tanning techniques; (iv) increased focus on leather allergy among dermatologists has resulted in enhanced diagnostic work-up of patients. A weakness of our study was that we did not have any information about atopic dermatitis. This disorder may in some cases lead to false positive reactions upon patch testing. However, both the decreasing and increasing trend of chromium allergy was unlikely to be explained by changing proportions of atopic dermatitis as the study population was fairly large and patch test readings were performed using identical methods and by the same staff through the study period. Furthermore, medical chart data supported a genuine change of exposure during the study period. The prevalence of chromium allergy in the general population and among patients with dermatitis has generally decreased over the past 50–60 years.12,13 Besides the potential effect of the regulation on chromium in cement, this decrease has been explained by increased work hygiene in combination with decreased manual contact with construction materials.14 In women, the decrease has also been associated with the replacement of dichromate containing bleaches with other detergents.15,16 Finally, the difference between the prevalence rates among male and female patients has decreased over time.13 In line with these findings, the prevalence of chromium allergy decreased within the North American Contact Dermatitis Group (NACDG) from more than 10% in the 1970s to 2Æ0% in 1995.17 However, this decrease was recently replaced by an increase to 6% in 1998–2000 and to 4% in 2001–2002.17 Similarly, in Singapore, the prevalence of chromium allergy decreased from 6Æ3% in 1984–1985 to 2Æ7% in 1986–1990 but increased again to 5Æ6% in 2001– 2003.18 These prevalence patterns are remarkably similar to the ones identified in this study from Denmark. Thus, it seems that the prevalence of chromium allergy is on the increase elsewhere too and perhaps also as a consequence of leather exposure. It is estimated that 90% of global leather production is tanned using chromium sulphates.19 Hence, chromium was recently found to constitute 98% of the total concentration of heavy metals in a large sample of finished leather tanned with

chromium.19 Leather not tanned by chromate is usually tanned by using other metal sulphates (mostly aluminium), vegetable tannins or a combination of both.19 Chromium is a transition metal that has several oxidation states of which only trivalent Cr(III) and hexavalent chromium Cr(VI) are sufficiently stable to act as haptens. Hexavalent chromium may easily pass through the epidermis whereas trivalent chromium tends to form stable complexes within the epidermis.20,21 Once hexavalent chromium has entered the skin, it is reduced to trivalent chromium which then binds to a protein. The hapten– protein complex may later be presented to T cells and the individual becomes sensitized to chromium.22 It was recently demonstrated that it was not only hexavalent chromium that was of significance in patients with chromium allergy; they also developed dermatitis upon exposure to trivalent chromium.23 Thus, exposure to both oxidative states of chromium should be considered although hexavalent chromium remains most allergenic. Despite the fact that only trivalent chromium is used for the tanning process, hexavalent chromium is often detected in leather, probably as a result of high heat and pH.24 Srinivas et al.25 recently showed that vitamin C could reduce hexavalent chromium to trivalent chromium in leather but also hypothesized that sweat would oxidize it back to hexavalent chromium. Thus, repeated or long-term skin contact with chromium tanned leather may lead to allergic contact dermatitis which is often located on the feet and hands where direct skin contact may occur.9,26 The significance of this may be appreciated by the fact that chromium allergy and foot dermatitis are highly prevalent in Africa and India, countries where warm weather results in a frequent use of sandals.26,27 The aetiology and epidemiology of chromium allergy in Denmark has changed from an occupational problem caused mainly by cement exposure to a consumer problem caused by leather exposure. A suggestion on threshold levels for Cr(III) release and Cr(VI) content in leather products has recently been raised in Germany as modifications in the leather manufacturing process can limit the content of trivalent and hexavalent chromium (http://www.bfr.bund.de/cd/9575, last accessed 14 June 2009). Such legislative initiatives may be necessary to protect European consumers.

Acknowledgment The authors acknowledge funding from the Copenhagen County Research Foundation.

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