Sensitization trends for chromium and cobalt and causative exposures

Chromium and cobalt are common causes of contact allergy in the general population and amongpatients investigated for contact dermatitis. Since the 1990s, leather has become the single mostimportant source of chromium exposure in Denmark. In March 2014, the EU commission adopted aregulation restricting the content of hexavalent chromium to a maximum of 3 mg/kg (ppm) in leatherarticles coming into contact with the skin. The regulation was expected to be 80% effective inreducing the incidence of allergic contact dermatitis due to hexavalent chromium in leather.Regarding cobalt allergy, the prevalence remains relatively high and largely stable across time withlimited insight into relevant exposures. During recent years, a growing body of evidence hassuggested that leather might constitute a more frequent exposure in cobalt allergic patients thanhitherto recognized. In this thesis, we aimed at assessing whether the regulatory intervention againsthexavalent chromium in leather entailed temporal changes in the epidemiology (manuscript I) ofchromium allergy in Denmark and burden of disease (manuscript II) in those affected. Furthermore,trends in sensitization rates, clinical characteristics and causative exposures were explored acrosstime for patients with cobalt allergy (manuscript III). Additionally, as previous studies have reporteda potential association between metalwork - especially metalworking fluids - and metal allergy, weconducted a market survey exploring the presence of metal allergens in used and unusedmetalworking fluids collected from several metalworking plants in Copenhagen, Denmark(manuscript IV).In manuscript I, we performed a retrospective cross-sectional registry study including 13,379 adultpatients aged 18 to 99 with suspected allergic contact dermatitis patch tested at the Department ofDermatology and Allergy, Herlev-Gentofte Hospital, during 2002-2017. The overall prevalence ofchromium allergy was 2.2%. We found a decreasing trend in the prevalence of chromium allergy(ptrend<0.001) and foot dermatitis (ptrend=0.01) among chromium allergic patients during 2002-2017.Leather was recorded as the relevant source of exposure in nearly half of the chromium allergicpatients (48.3%). No cases of relevant cement exposure were recorded in patients with chromiumallergy.In manuscript II, a case-control questionnaire study was conducted including 172 adult dermatitispatients with chromium allergy and 587 age- and sex-matched dermatitis patients withoutchromium allergy. All patients were patch tested at the Department of Dermatology and Allergy, viiHerlev-Gentofte Hospital, during 2003-2018. Compared to controls, chromium allergic patientswere still more affected by current foot dermatitis (OR=3.82, 95% CI: 2.07-7.08) and handdermatitis (OR=1.98, 95% CI: 1.13-3.49) during 2013-2018. As regards self-reported leatherexposures causing dermatitis, no difference was found comparing chromium allergic patientsduring 2013-2018 versus 2003-2012 (66.1% vs. 71.0%, p=0.5). Furthermore, estimates onoccupational performance and disease-severity were similar in patients with chromium allergy for2013-2018 versus 2003-2012.In manuscript III, we conducted a retrospective cross-sectional registry study including 13,475 adultpatients aged 18 to 99 with suspected allergic contact dermatitis patch tested at the Department ofDermatology and Allergy, Herlev-Gentofte Hospital, during 2002-2017. The prevalence of overalland isolated cobalt allergy was, respectively, 3.3% and 1.5% and remained largely unchanged overtime. The proportion of cobalt allergic patients with relevant leather exposure increased significantlyfrom 3.7% in 2002-2009 to 8.3% 2010-2017 (ptrend<0.001). While exposures to jewellery (6.3%) andleather (6.0%) were most common in cobalt allergic dermatitis patients, a relevant source of exposurewas recorded in only one in five patients.In manuscript IV, the presence of metal allergens was examined in 80 used and unused metalworkingfluids collected from eight metalworking plants in Copenhagen, Denmark. Elemental analysis withgraphite furnace atomic absorption spectroscopy showed that 13 of 80 samples (16.3%) contained >1 mg/kg nickel (range: 6.4-17.7 mg/kg), 3 of 80 (3.8%) contained > 1 mg/kg chromium (range: 1.4-3.1 mg/kg) and 1 of 80 (1.3%) contained 1.3 mg/kg cobalt. While nickel was found in both used andunused oils, chromium and cobalt were found in used ones only. The handheld x-ray fluorescensdevice was a poor screening instrument for these metals in metalworking fluids.This thesis showed that the prevalence of chromium allergy has decreased, suggesting a positiveeffect of legislative actions against hexavalent chromium in leather. However, no sign ofimprovement was found regarding disease-burden nor in the proportion of self-reported leatherexposures leading to dermatitis in patients with chromium allergy, thus implying an inadequateprotection of those already sensitized. The prevalence of cobalt allergy remained unchanged and mostcases could not be linked to a relevant exposure. It is currently not possible to assess the need andpotential target for preventive measures. Lastly, considerable levels of metal allergens were detectedin some used and unused metalworking fluids suggesting that these might constitute a relevant sourceof exposure in metalworkers with metal contact allergy.