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26 The Open Chemical and Biomedical Methods Journal, 2009, 2, 26-34
1875-0389/09 2009 Bentham Open
Open Access
The Epidemiology of Contact Allergy to Metals in the General Population:
Prevalence and New Evidences
Beatrice Bocca and Giovanni Forte*
Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
Abstract: Aluminium, Au, Be, Co, Cr, Cu, Hg, Ir, Ni, Pd, Pt, Rh and Ti represent causes of metal-induced allergic contact
dermatitis (ACD) which expresses in a broad spectrum of cutaneous adverse manifestations. The exposure is primarily by
skin contact with various items and products such as jewellery and piercing, cosmetics and tattoos, detergents, body im-
plants and dental prostheses. To reduce the growth of the metal ACD among people, the European Union issued directives
that limit the total Ni content in jewellery alloys and ban metals in cosmetics. Despite th ese regulations, the diffusion of
metal ACD remained quite high. On this basis, a review of the epidemiological evidence of the metal-induced ACD is re-
ported discussing the sources, the prevalence and the prescriptions.
Keywords: Allergic contact dermatitis, epidemiology, metals, metal contact allergy.
1. INTRODUCTION
Metals are ubiquitous in the environment; they are nor-
mally present in the Earth’s crusts, in food and water. Today,
metals are involved in several fields such as in industrial
productions and in consumer products like for example jew-
ellery, cosmetics, dyes, leather, dental/body implants and
household products where they can be present as main com-
ponents or as contaminants. It is for their numerous appli-
ance fields that metals and their salts (Ni, chromate and Hg
are examples) are able to cause the allergic contact dermatitis
(ACD). In Europe, the Ni, Cr and Co ACD prevalence rates
are of ca. 20%, 4% and 7%, respectively [1]. These data are
similar to those evid enced in the USA with a prevalence of
about 14% for Ni, 4% for Cr and 9% for Co [2, 3]. Females
are affected by Ni and Co ACD more than males due to ear
piercings and jewellery; while Cr ACD affects mainly males
because of occupational exposure [4]. Moreover, it has been
demonstrated that the incidence of Ni and Co ACD is higher
at younger age, while the prevalence of Cr ACD remained
high for the whole life [5]. In addition, other elements such
as Al, Au, Be, Cu, Ir, Pd, Pt, Rh and Ti are of growing inter-
est for their capability to act as allergens, even if the reaso n
why these metals are able to create sensitization or the pat-
tern of multip le metal reactivity are still not totally clear [4].
The ACD is characterized by a broad spectrum of skin
symptoms ranging from dryness, chapping and inflammation
to eczema and blisters. Discomfort is caused by skin in-
flammation and itching [6]. There are usually social stigmas
present due to the discolourations and eruptions of local ar-
eas of the skin that are visible to others. For this reason, the
importance of the ACD is not only related to the high num-
ber of affected people, but also to psychological - worsening
of the quality of life of patients - and economical - increase
*Address correspondence to this author at the Istituto Superiore di Sanità,
Viale Regina Elena 299, 00161 Rome, Italy; Fax: (39) 06 4990 2011;
E-mail: giovanni.forte@iss.it
expenses of each national health service - issues. In the USA,
the cost for treating the ACD is more than 1 billion of dollar
annually [7, 8], and people with ACD of the face and hands
and, in some cases obliged to change their job, reported the
worst life quality [9].
Nowadays, in the European Union (EU) are existing
regulations for limiting metals in products destined for skin
contact. In particular, the Council Directive 94/27/EC and
the more restrictive Commission Directive 2004/96/EC lim-
ited the total Ni content in alloys, and the Council Directive
76/768/EEC (implemented by the Commission Directive
2004/93/EC) banned certain metals in cosmetic formulations
[10-13]. However, more efforts should be undertaken to re-
duce and prevent metal ACD. Understanding the potency
and prevalence of sensitizers, developing new diagnostic
tests and informing about skincare strategies such as hy-
giene, gloves and protective creams can represent key points
for the management of the risk to metal ACD [14]. In th is
context, this paper reviewed the epidemiological state-of-the-
art on the sensitization and contact dermatitis caused by the
skin contact with Al, Au, Be, Co, Cr, Cu, Hg, Ir, Ni, Pd, Pt,
Rh and Ti contained in daily used products and items. The
sources, prevalence rates and the prescriptions to avoid con-
tact are discussed.
2. MOST REPORTED ALLERGENS
Nickel
Nickel is present in consumer products such as deter-
gents, cosmetics, coins, jewellery, buttons, zippers, eye-
glasses, buckles, clasps, inks, dental prosthesis, cookies and
so on [4]. In consideration of its ubiquity, Ni allergy is the
most prev alent of the metal allergies all over the world. In
2004, the ESSCA working group collected data from 31
dermatological departments in 11 European Countries (Aus-
tria, Denmark, Germany, Italy, Lithuania, Poland, Spain,
Switzerland, Sweden, The Netherlands and United King-
dom) and reported positive responses to Ni in the 20.1% of
The Epidemiology of Contact Allergy to Metals in the General Population The Open Chemical and Biomedical Methods Journal, 2009, Volume 2 27
the 10,000 patch tested subjects. In this study, Ni ranked at
the first place among the allergens, the lowest percentage of
Ni allergy being found in Denmark (9.7%) and the highest in
Italy (32.2%) [1]. Similar results were obtained in other stud-
ies performed in different countries of the world. In fact, in
Australia, Czech Republic, Hong Kong, India, Iran, Israel,
Norway, Singapore, Turkey and USA the incidence was well
above the 10-20% [3, 15-21]. In addition, patients who re-
acted to Ni were more likely to be females; a mean value of
25.1% of females were positive to path test against the 7.4%
among males [15-21]. This was due to the growing popular-
ity of ear piercing in combination with the use of imitation
jewellery. Moreover, the same works reported that the preva-
lence of Ni allergy decreased with the increasing of age,
probably because of a decrease in exposure to Ni contained
in that objects. The EU recognized the possibility to regulate
the presence of Ni in metallic objects destined to the contact
with the human skin. The so-called “Ni Directive” and its
more restrictive amendment were issu ed with the aim to pre-
vent sensitisation to Ni (primary prevention) and to prevent
exacerbation of ACD in pre-sensitized subjects (secondary
prevention). The Directive limits the total content of Ni in
metallic objects in direct and prolonged contact with the skin
at no more than the 0.05% and, in addition, the same objects
with the skin shall not release more than 0.5 g/cm2/week of
Ni in sweat [10, 11]. At present, the effectiveness of the
regulatory limit in reducing metal ACD is under debate. In
fact, if on the one hand a decrease in Ni allergy after the Di-
rective implementation was observed in two population
groups passing from 24.8% to 9.2% and from 36.7% to
25.8%, respectively [22, 23], on the other hand, a study re-
vealed a similar percentage (about 50%) of subjects sensi-
tised to Ni before and after the Directive [24]. These last
Authors evidenced that the Ni released in artificial sweat
from cheap earrings available on the Italian market was over
the regulatory limit from 10 to 450 times, posing a serious
risk in the development of sensitization. Another factor able
to pose a risk in the development of Ni ACD is represented
by the relatively high presence of this metal in the Euro
coins. This is the case of Italy where the Ni present in the
Euro is much higher than in the old nation al current Lira
arising the percentage of sensitised people [25].
Moreover, despite the EU has banned the use of Ni and
Ni salts in cosmetic products [12, 13], cases of skin contact
with Ni from cosmetics do exist. Sainio et al. determined to-
tal Ni in 88 different eye shadows and 51 products contained
Ni above the safe allergizing limit of 5 g/g and other 27 had
Ni ranging 1-5 g/g. These levels are far to provoke sys-
temic tox icological effects, but they are able to gen erate risk
of ACD in pre-sensitized people [26]. Kang and Lee quanti-
fied Ni in 7 out 15 henna tattoo mixtures in the range 2.94-
3.96 g/g. These levels are thought to generate sensitisation
giving a contribution to the ACD occurrence [27]. Moreover,
in 11 body creams sold as “Ni-tested” the highest amount of
found Ni was 153 ng/g, but these levels were well below the
threshold for sensitization [28].
Another route of sensitisation is represented by the Ni
present in orthodontic devices such as wires, braces, bridges,
crowns or amalgams. The continuative contact with saliva,
the particular pH of the oral cav ity, the temperature of the
environment or also the friction of the metallic parts can
cause the release of the metal. In this context, 15 patients
with lichenoid oral manifestations showed positive reactions
when patch tested and the positivity to Ni represented the
12.9% of all positive reactions. The substitution of the fixed
replacements of white metal and crowns and dental bridges
improved the healing of the disease [29]. Moreover, an Is-
raelian study involved 121 patients with face and oral mani-
festations due to contact to dental materials. The frequent
symptoms were related to cheilitis, perioral dermatitis, burn-
ing mouth syndrome (BMS), lichenoid reaction and orofacial
granulomatosis and Ni one of the most common allergens
with the 13.2% of cases [30]. Similar results was observed in
a recent American study where patients suffering from dif-
ferent oral diseases reported positive reactions to Ni patch
test equal to the 12.5% [31]. Interesting studies in adolescent
population (Danish and Finnish) showed that the application
of dental braces prior to ear piercing was associated with a
significantly reduced prevalence of Ni allergy [32, 33]. Fi-
nally, it has been reported that the adoption of particular al-
loys (stainless steel, Ni-Ti or Ti alone and gold plated) or
materials (ceramic or polycarbonate) in the production of
dental devices can significantly reduce the release of Ni and
the oral symptoms [34].
Nickel can also come from household consumer prod-
ucts; actually, its presence is related to the development of
hand eczema in women. For this reason, in 1993, it was rec-
ommended that the amount of Ni in household products
should not exceed 5 μg/g to avoid elicitation; in 2003, the
limit was revisited and lowered to 1 μg/g [35]. This concen-
tration limit allowed the decrease of the Ni content in this
kind of products. In fact, in 1987, an Italian study reported a
Ni mean value of 9.20 g/g in 34 liquid or powder detergents
with a percentage of sensitised people equal to 21% [36]. Af-
ter the regulation, two studies reported Ni at level below 1
g/g in 50 and 95 detergents [37, 38].
New causes of Ni allergy are related to activities as the
use of cellular phone and the playing violin and trumpet. Pa-
tients showed erythema and papule in the hemilateral and
preauricular region due to the handling of the phone and re-
sulted positive to patch testing with nickel sulphate. In addi-
tion, the presence of free Ni on the surface of the phone was
confirmed by the dimethyglyoxime test. The covering of the
phone with a plastic case resolved the lesions [39-42]. A vio-
linist revealed a reaction to Ni contained in the violin string;
the substitution of the string was not the adequate solution
because the tone of the string was significantly different
form the original decreasing the quality of the sound [43]. A
musician revealed scaling and crusting cheilitis on the lips.
This condition was due to the presence of Ni in the mouth-
piece of his trumpet. In this case the release of Ni was fa-
voured by the contact of body fluids such as saliva and
sweat; the use of the gold mouthpiece favoured the healing
of the lip eczema [44].
Nickel allergies are also associated with metal button and
snaps on blue jeans. In this context, Suneja et al. evidenced
the presence of Ni in button of new and preworn blue jeans
with the dimethyglioxime test. Authors highlighted that the
presence of Ni was greater in new jeans than in preworn
ones. In addition, they reported that one clear coat nail polish
applied on the Ni containing button can prevent the metal
release through two wash/dry cycles in a test environment
[45]. In conclusion, mandatory labelling of jewellery, cloth-
28 The Open Chemical and Biomedical Methods Journal, 2009, Volume 2 Bocca and Forte
ing, cosmetic or household products (e.g., “Ni free” or “hy-
poallergenic”) could perhaps increase public awareness and
possibly protect future consumers from Ni sensitisation.
Chromium
Skin contact with Cr and Cr-compounds occurs by alloys,
cement, leather tanning, chemicals, anticorrosives, ceramic,
wood preservatives, paints and varnishes, textile mordants
and dyes, batteries, magnetic tapes, detergents and bleaches,
electroplating and so on [4]. Variation in toxicity is associ-
ated with Cr(III) and Cr(VI); the former has a percutaneous
permeability poorer than that of Cr(VI) resulting, thus, less
able to elicit ACD [46].
In the European general population, the Cr allergy rate
was approximately 4.5% in 2004, and both the lowest and
the highest values were recorded in UK with 1.3% in Shef-
field and 9.1% in Liverpool, respectively [1]. In Singapore
and Turkey, the rate was similar (i.e., 5%) where the main
sources of exposure were cement and tanned leather [21, 47].
Allergy in India has reached 10% and the cause was refer-
able to the use of shoes without socks [48]. In most cases,
the Cr allergy was more frequent in males than females. For
example, in Czech Republic, percentages equal to 5.93% in
males vs 2.81% in females were found and in Hong Kong
7.1% vs 2.3%; while in Turkey, the males were affected 2.3
times more than women, and in USA, this ratio was about 2
times in favour of males [15, 17, 21, 49].
The Cr(VI) is responsible for leather-induced dermatitis.
In this regards, a Danish investigation on the content of
Cr(VI) in 15 tanned leathers evidenced a concentration in the
range 4.1-16.9 mg/kg and 5 patients had positive skin reac-
tions after leather contact. Considering that no correlation
between eczema and Cr(VI) or Cr(III) alone in leather was
observed, it was suspected that skin responses were the result
of a combined Cr(III) and Cr(VI) allergy [50]. In India, there
were 155 cases of footwear dermatitis where the frequency
of positive patch tests to chromate was the 45.8% [51]. The
treatment to convert Cr(VI) in Cr(III) by soaking the tanned
leather in 5% Vitamin C solution might minimize contact
dermatitis [52].
As for Ni, allergy to Cr may be related to daily activities
such as the use of cellular phone and playing guitar. In the
first case, this problem was caused by the chromate present
in the plating procedure of the phone [53], and, in the second
case, by the presence of Cr in the guitar strings [54]. Moreo-
ver, Cr has been found in 88 different eyeshadows (9 of them
contained soluble Cr above 2 g/g) and in 11 moisturizing
body creams (2 of them contained total Cr at 150 ng/g and
300 ng/g) [26, 28]. Also cheap earrings available on the Ital-
ian market released Cr in artificial sweat, with the highest
value equal to 0.253 g/cm2/week [24].
Chromium contained in detergents and bleaches can in-
crease the risk of ACD on the hand and forearm of women.
In Italy, 8.4% of 65 cases resulted to be sensitized to total Cr
contained in detergents at a mean concentration of 4.12 μg/g
[36]. Household products marketed in Israel had very high
total Cr concentration (i.e. above 5 g/g in 56% of products)
and the labelling of these products with regard to active in-
gredients was insufficient in most cases [55]. Basketter et al.
recommended that household products should contain Cr(VI)
< 5 g/g or for a better protection < 1 g/g in order to render
the elicitation of chromium related ACD highly improbable
[35].
Cobalt
Sources of Co include ceramics, enamels, paints as dry-
ing agent, catalysts, dental prosthesis, jewellery, p articular
adhesives, household products, hair dyes, fertilizers and
feeding for animal [4]. In 2004, the ESSCA working group
reports positive responses to Co in the 6.74% of the 10,000
patch tested subjects and Co is addressed as the third most
important allergen. The lowest percentage of Co allergy is
found in Denmark (1.1%) and the highest in Italy (17.6%)
[1]. These rates are similar to those of other countries for the
general population (i.e., the range reported is 5-10%);
moreover, Co dermatitis was mainly prevalent in females
than in males due to the wearing of jewels or personal
adornments and patient’s age did not significantly change the
distribution of Co positive reactions [20, 21, 49, 56, 57].
Hand eczema due to cobalt salts in those responsible for
domestic work has been observed [58]. A recent survey of
95 detergents and household cleaning products by the Dutch
authorities showed that approximately 90% contained < 1
μg/g of Co, and all were just below 5 μg/g. In those products,
the highest level of Co was 0.28 μg/g [37].
The release of Co in artificial sweat from a necklace
caused the development of vesicular eczema; the chain re-
leased a concentration of Co 40,000 times higher than the
minimal elicitation concentration dose. On normal skin, the
minimum eliciting concentration was 2.26 μg/ml [59]. Co-
balt contained in the alloy replaced Ni with the aim of being
in compliance with statutory requirements of the Directive
94/27/EC. Even so, the modification of the alloy resulted to
be unsafe [60]. Moreover, a Co-containing alloy for jewels
was developed and tested on the cobalt allergic patients and
18% of them were found to be positive after 7-8 days of ex-
posure [61]. Bocca et al. reported a release rate of Co ions in
the range 0.013-0.188 g/cm2/week from the 40% of cheap
earrings tested. These amounts are not likely to pose a risk
for skin sensitisation [24].
In the last years, tattooing and ear piercing practices in-
creased the incidence of Co-induced ACD among the juve-
nile population. A Swedish study performed on 520 young
men demonstrated that the 1% of them had cobalt ACD re-
lated to ear piercing and there was a higher prevalence of
sensitization in patients with pierced earlobes [62]. In Japan,
9 out of 106 pierced subjects had eczema and resulted to be
positive to Co patch test, even if they did not significantly
differ from non-pierced Co allergic patients [63]. Skin hy-
persensitivity caused by the presence of Co in the blue ink
used for tattoo was observed. In particular, the tattooed pa-
tient suffered from urticaria on the tattooed right deltoid
[64]. Kang et al. found Co in 4 different henna dyes at a
concentration of about 3 mg/kg and they concluded that this
amount can be able to provoke sensitisation but not contract
dermatitis [27]. In addition, Co was determined in 88 colors
of different brand of eye shadows, and ca. the 75% of the
products contained more than the safe limit of 1 μg/g of Co.
Although these amounts were low when systemic toxico-
logical effects were considered, the Author’s opinion was
that the risk of acquire allergy in unsensitized sub jects due to
the use of these products cannot be excluded [26]. In a series
The Epidemiology of Contact Allergy to Metals in the General Population The Open Chemical and Biomedical Methods Journal, 2009, Volume 2 29
of 11 body cream labelled as “Ni tested”, Co was quantified
in 9 of them and it was below 5 ng/g, while in 2 cases, ar-
rived at a concentration of 200 ng/g [28].
Clothing and shoes can be sources of Co-based ACD. In
particular, a nurse with pruritic rush on the inner thighs and
posterior calves resu lted to be positive to Co due to the dyes
used for manufacturing the blue trousers of the uniform [65].
Another nurse working in an intensive care unit reported
itchy dermatitis on the dorsum of both feet and toes due to
Co contained in the green plastic shoes [66]. In both cases,
symptoms disappeared when the person stop to wear trousers
and shoes. In India, the incidence of footwear dermatitis was
24.2% and the occurrence for Co sensitization was the
38.1%. This outcome was traced back to the habit of wearing
shoes without socks [51].
Another cause of skin sensitisation is related to the pres-
ence of Co in polyester resins or in acrylonitrilebutadienesty-
rene (ABS) plastic. A cobalt catalyst, namely the cobalt
naphthenate, was used in the production of plastic for PC
mouse manufacture posing a risk for adverse skin reactions
[67]. A patient presented a glove-associated hand eczema; in
this case, the cobalt octoate was used as accelerator in the
polyester resin production. The patient presented a signifi-
cant improvement in his hand eczema by using cotton lined
PVC gloves [68].
Mercury
Primary routes of exposure to inorganic Hg are dental
amalgams and some preservatives that still contain Hg as a
component like for instance the thiomersal [69]. Generally
the skin rashes in the oral, head and neck area, itching, swol-
len lips, localized eczema-like lesions in the oral cavity
symptoms due to the amalgams resolved on th eir own with-
out treatment. In serious cases, instead, the replacement of
the Hg-amalgams with others in resin or porcelain become
mandatory to improve the disease in patients with patch test
positive to Hg [70]. In addition, Hg containing dental fillings
are considered to be the starting point for the development of
oral lichen planus [71], orofacial granulomatosis [72] and the
BMS [73] in Hg sensitized subjects. Thiomersal may be
found in topical medications (ophthalmic and nasal prepara-
tions), cosmetics and vaccines. Thiomersal resulted to be the
fifth most common allergen in patients with a positive patch
test and it was found to be “possibly relevant” in 7.8% of
those patients tested, with a single patient having “probable
relevance” [74].
The use of skin whitening products is popular in develop-
ing countries and can cause Hg poisoning. People from Tai-
wan reported complications such as facial dermatitis and ec-
zema; the two most detected allergens were Ni and Ammo-
niated Mercury (AM), and the majority of AM-sensitive
cases resulted from cosmetics [75]. The association between
the use of skin lightening creams and urinary or blood Hg
has been reported in 314 cream users and the symptomatic
Hg poisoning appeared at a concentration of Hg higher than
57,000 g/g [76]. In Indonesia, a woman with membranous
nephropathy habitually applied a Hg-containing skin whiten-
ing cream; testing showed her blood and urinary Hg levels
higher than normal and the clinical signs subsided when she
stopped using the cream [77]. A case report showed, in a 25-
year-old woman, an itchy erythematous bullous dermatitis in
the area of application of a Taiwanese whitening cream (i.e.
the region around the eyes and mouth). The Hg concentra-
tion in cosmetic resulted to be the 7.2% w /w, and patch test-
ing was positive to both mercury chloride and AM [78].
Tattoos, piercing and items made in polyvinyl chloride
(PVC) can potentially be a hidden source of Hg sensitization.
Metal salts that make up tattoo dyes can be responsible for
allergic reactions. In particular, red pigments in tattoos may
include the red isomer of mercury(II) sulfide (vermillion,
cinnabar) and are known to produce a delayed hypersensitiv-
ity reaction [79]. Mercury together with Cr and Co have also
initiated different types of skin reaction in tattooed areas
[80]. The number of positive reactions was more than dou-
bled among patients with pierced ear lobes than in those with
un-pierced ears [81]. Patients with baboon syndrome and Au
dermatitis due to ear-lobe piercing were tested with 0.05%
mercuric chloride applied for 2 days; 5 of 5 patients with ba-
boon syndrome were patch-test positive, 21 out 35 of those
had pierced ears [63]. Mercury contained in PVC boots al-
lowed the development of a severe ACD with exanthema in
legs, groins and lateral parts of the trunk in a 5 year-old child
affected by mercurochrome intolerance. Patch test revealed
positivity to organic and inorganic Hg [82].
3. EMERGING ALLERGENS
Gold
In 1998–2000, Au ranked as the sixth most frequent
cause of positive patch test reactions [83]. In Sweden, the
8.6% of 832 patients with suspected contact allergy on rou-
tine patch testing gave a positive response with gold sodium
thiosulfate (GST). Other patients with contact allergy to GST
also gave positive reactions to potassium dicyanoaurate, but
were negative to gold sodium thiomalate (GSTM) and metal-
lic Au [84]. In United Kingdom, the 4.6% of 278 patients
had positive reactions to GST on routine testing [85]. All of
these patients were females, with a mean ag e of 37 years and
the most frequent site of eczema was the head and neck. In
Japan, the 8.4% of 653 patients tested from 1990 to 2001
showed a positive reaction to gold chloride, and also in this
work significantly more women than men reacted [86].
Only recently studies have realized that a more mundane
use of Au in the form of the diverse alloys used in jewellery
could bring to sensitization problems. Dissolution of metallic
Au is notoriously difficult, but the process is facilitated by
the presence of other metals in the alloy or in the neighbour-
hood [87, 88]. Gold allergy often presents as dermatitis at the
site of jewellery contact, i.e., earlobes and fingers, but it also
may present solely as ey elid dermatitis [89]. More positive
reactions to 0.2% gold chloride in the patients with pierced
than in patients without pierced ears have been documented
[63]. In 1988, Fowler reported 2 women with eyelid dermati-
tis and positive patch tests to Au whose eruptions cleared
with avoidance of Au jewellery. It was postu lated that the
allergen was being transferred from the hands to the eyelid s
as is commonly seen with allergic reactions to tosylamide
formaldehyde resin [90]. In Portugal, contact allergy to GST
and to potassium dicyanoaurate was found in 23 patients, all
the reactors were women and had their ears pierced with Au
earrings [91]. Ehrlich and Belsito found that 7 of 15 Au-
allergic patients cleared their dermatitis by not wearing Au
jewellery [92]. In Spain it was described that a lady pre-
30 The Open Chemical and Biomedical Methods Journal, 2009, Volume 2 Bocca and Forte
sented Au-related ACD in the proximal root of a finger due
to her wedding ring [93].
The presence of Au in metallic form has been visualized
in human skin biopsies taken from areas of prolonged con-
tact with the metal such as rings and jewellery, confirming
absorption of the solubilized metal even through the intact
stratum corneum [87]. In some cases, hypersensitivity to Au
was associated with the formation of intracutaneous nodules
in the earlobes at the sites of piercing. The nodules at pierced
sites were described as lymphocytoma cutis, indicating the
formation of a benign lymphocytic infiltrate, which is distin-
guishable from malignant lymphoma. When this did not re-
solve over time, nodules had to be removed surgically [94,
95].
Platinum Group Elements (PGEs)
The platinum group elements (PGEs) - platinum (Pt), pal-
ladium (Pd), rhodium (Rh) and iridium (Ir) - are rare in the
earth’s crust in comparison with other elements, but their
specific physical and chemical properties have led to the de-
velopment of some highly sophisticated technical applica-
tions, especially in the field of catalysis. The skin contact
with PGEs is mainly via dental restorations and jewellery. A
case of contact dermatitis from wearing a Pt ring has been
reported [96]. Palladium is increasingly used in industry,
jewellery and dentistry since the European Directive re-
stricted the use of Ni. For this reason, during a 10-year pe-
riod, the trend of sensitization to Pd in a clinic population
increased to a maximum of 9.7% in the year 2000, with a
higher percentage in females than in males. In the majority
of cases, subjects were polysensitized (92.8%), but 7.2% of
subjects were positive to Pd alone. Of Pd-sensitized patients,
40.5% complained of hand dermatitis, 47.4% of body derma-
titis, and 1.7% of BMS [97]. In the study of Kanerva et al.,
7% of 700 schoolchildren had an allergic patch test reaction
to palladium chloride [98]. Two cases of sarcoidal-type al-
lergic contact granuloma due to Pd in ear piercing have been
presented; the first to Pd only, and the second to Pd in com-
bination to other metals [99]. Moreover, a case of developed
dermatitis at contact sites of metallic spectacle frames which
were declared as 99.7% Ti but with Au-plating using Au
(90%), Cu (3%) and Pd (7%) has been observed [100]. In
addition, Pd in dental restorations was the cause of oral
symptoms such as stomatitis, mucositis and oral lichen
planus [101-105]. Other works reported presence of swelling
of the lips and cheeks, dizziness, asthma and chronic urti-
caria and most of them improved with the replacement of a
metal-free dental devices [106-108].
Rhodium and Ir are sometimes reported as sensitizers in
the form of salts, though not as metals, in subjects employed
in precious metals or jewellery industries [109, 110] or with
dental amalgams or prostheses [111, 112]. During 2001-
2002, 720 consecutive informed eczematous patients were
patch tested with 1% rhodium chloride and 1% iridium chlo-
ride, both in water. None of the 720 patch tested subjects
showed positive or irritant reactions to iridium chloride, but
2 were found to have a positive patch test to rhodium chlo-
ride as well as other metals. These study results suggested
that Rh and, above all, Ir are allergologically safe even in
patients sensitized to metals [113].
As regards prevention strategies, since PGEs-containing
dental or jewellery alloys have been identified as a possible
source of sensitization, protection of the public from related
adverse effects may be achieved either by limiting the use of
certain alloys or by the use of alloys with high corrosion sta-
bility and thus minimal release of PGEs.
4. RARE ALLERGENS
Aluminium, Beryllium, Copper, Titanium
Contact sensitivity to Al is rare. Sensitization occurs dur-
ing the frequent use of Al-containing antiperspirants or by
aluminium adjuvants in vaccines and pollen extracts. Two
types of reaction pattern are known: persistent granuloma at
the injection site and recurrent eczema [114]. In Sweden, a
patient who habitually apply an aluminium chloride roll-on
antiperspirant developed an itchy dermatitis in the ax illae
and patch tests with aluminium chloride were positive [115].
Another case of axillary eczema was observed in a 16-year-
old girl [116]. In addition, when Al is complexed with Zr
and glycine in antiperspirants cutaneous granuloma and skin
sensitivity have been observed [117]. Other two cases of
contact allergy to Al after the use of topical medications con-
taining aluminium acetotartrate were also reported [118].
Pruritus due to allergic conditions was seen after the usage of
a toothpaste containing 30-40% of aluminium oxide. The re-
placement of the incriminated toothpaste with a brand free of
Al resolved the pruritus in 1 month [119].
Only one case of contact urticaria to Al was recognized
because of the presence of Al in Norwegian coins; the metal
was present as a contaminant at the concentration of 0.01%
at maximum. The test on patient showed erythema and itch-
ing after 5 min; a vesicular infiltration appeared after 8 min,
and large crusts 2 days later [120]. Researchers have sug-
gested that tattoo pigments containing Al can induce granu-
lomatous reactions. In fact, in the 87% of 30 tattoo inks
tested, the most commonly identified element was Al [121].
A case study of a 21-year-old man with delayed hypersensi-
tivity granuloma formation in a tattoo has been reported.
Four weeks after tattooing, three separate tumorous areas ap-
peared in the violet areas of the tattoo. Intermittently pruritic
lesions had existed for 5 months from the first examination
[122].
The main sources of Be exposure are from the environ-
ment (i.e. the combustion of fossil fuel) or from corrosion of
dental metal alloys. The exposure to salts of Be, such as
fluoride, chloride, nitrate and sulphate, outcomes in local
toxicity responses that can include 5 groups of cutaneous
disease: ACD, irritant contact dermatitis, chemical ulcers,
ulcerating granulomas and allergic dermal granulomas [123].
When Be-containing casting alloys are used for dental pros-
theses, skin and oral contact with Be can not be overlooked
[124]. In this context, containing Be oral restorations pro-
voked gingivitis in 2 subjects and the cause was also con-
firmed by the positive reactions to beryllium sulphate (1% in
petrolatum) patch test [125], while other 3 patients showed
positive responses to beryllium chloride (l% petrolatum)
[126].
Copper is largely used in coins, jewellery, personal
adornments (clasps, pins, belt, necklaces, buttons, hooks,
etc.), dental restorations (oral prosthesis, bridges, band, wires
The Epidemiology of Contact Allergy to Metals in the General Population The Open Chemical and Biomedical Methods Journal, 2009, Volume 2 31
or cements) and intrauterine devices (IUDs). Copper salts are
also used in agriculture as algicides and fungicides [4]. Cop-
per has a low sensitizing power and, thus, it is a rare reason
of ACD growth. The most reported clinical symptoms of
ACD are related to the use of dental prosthesis and Cu-
containing IUDs. Wöhrl et al. suggested that a high percent-
age (15.2%) of children sensitized to Cu was because of the
increased use of this metal in dental amalgam [127]. In the
same way, a woman developed ACD of the oral mucosa
caused by the long-term exposure to Cu enriched dental
amalgam fillings [128]. A relationship between intraoral
metal ACD (i.e., mucositis) and pathogenesis of squamous
cell carcinoma was observed by Hougeir et al., and, as a
consequence of these findings, Cu was considered an addi-
tional risk factor in the evolution of cancer [129]. Addition-
ally, a woman showed lesions of oral lichen planus due to
the Cu contained in her prosthesis and the removal of the
prosthesis made the lesions improved [130]. A bingo-hall
worker’s developed ACD caused by the presence of Cu in
the 2-Euro coins and a woman was affected by ACD due to
the Cu container in the composition of a microphone used in
an ambulatory [131, 132]. A woman wearing a IUD reported
skin eruption some day before menstrual cycle and the sever-
ity improved with the onset of the bleeding [133]. In another
case, a patient showed diffused urticaria, angioedema of the
eyelids and the labia majora and minora [134]. In both cases,
the IUD users positively reacted to copper sulphate and re-
moval of the IUD led to the disappearance of clinical signs.
It has been reported that sensitization is achieved by combi-
nation of Cu and Ni ions. In 30 patients, the severity of patch
test reaction to a Cu/Ni mix ture was greater than to Ni alone,
suggesting that Cu ions enhanced the sensitivity reaction to
Ni [135]. According to the possible Cu-Ni cross-
sensitization, it is risky to cover Ni goods with a layer of Cu
to protect individuals allergic to Ni [127].
Titanium and its alloys are used for medical appliances
like osteosynthesis, arthroplasty, pacemaker encasing, teeth
and arch-wires, or in daily-use articles like body piercing and
spectacle frames. The relationship between Ti and ACD is
still under debate due to the lacking of adequate patch test
preparations. Two cases of women wearing Au-pierced ear-
rings reported lymphocytoma cutis; zinc was detected by
scanning electron microscopy-energy dispersive X-ray spec-
troscopy (SEM-EDX) microanalysis from the specimen of
case 1 and Au and Ti from case 2. This study demonstrated
the existence of metal fragments in the lesion, which may
suggest the permanence of metal for 20 years [136]. Moreo-
ver, a 68-year-old man who had pierced his ears approxi-
mately 10-years earlier developed nodules at the sites of
piercings. Microscopic examination demonstrated epithelial-
ized tracts surrounded by a granulomatous infiltrate of
macrophages, lymphocytes, and plasma cells; a closer ex-
amination revealed minute brown-black particles within
macrophages and SEM-EDX microanalysis demonstrated
the particles to be composed of Ti, Al and V [137]. Contact
dermatitis from topical exposure to Ti compounds is un-
common. In one report, patients presented an adverse reac-
tion to titanium lactate used in a deodorant [138]; another
paper observed generalized eczema in a patient working with
melted Ti in a confined space [139]. Nanoparticles of tita-
nium dioxide are added to various paints and tattoo pigments
as a brightening agent; Ti is also a common ingredient in
sunscreens as a physical blocker of UV light. In a recent
study, a commercially available blue ink contained a high
concentration of Ti (36.82%) [140].
CONCLUSIONS
Millions of people worldwide are affected by ACD. Dif-
ferent immunological responses can develop and be so se-
vere to impact the working ability and to worsen the whole
quality of patient’s life. Metals are considered a major risk
factor in ACD development; Ni, Co and Cr are the allergens
with the highest occurrence while Al, Au, Be, Cu, Hg, PGEs
and Ti are emerging. The items containing metals are jewel-
lery, ear piercing, personal adornments (clasps, belts, pins,
buttons), coins, dental restorations, body prosthesis, inks and
tattoos, household products, hair dyes and leather tanning. In
daily life people come in contact with the above and, thus,
can be at risk of sensitization. Every contact with the aller-
gen should be avoided to prevent the development of metal
ACD in sensitized people; if this is not possible, personal
care is suggested like for instance the use of cotton gloves or
active and protective creams. Adequate warnings to costu-
mer through products labelling and improvements, in terms
of composition and/or plating, in industrial productions of
alloys may be other possible ways of prevention. Even
though some EU regulations have been issued to protect
consumer’s health, a high number of subjects still suffer
metal-induced ACD. For this reason, further research should
be done to identify the sources of the exposure to metal sen-
sitizers, to characterize metal allergological strength and to
develop new diagnostic in vivo and in vitro methods. The
activity in this field should give support to create a common
base of knowledge on this important health problem and to
adopt successful prevention programs.
ABBREVIATIONS
ABS = Acrylonitrilebutadiene styrene
ACD = Allergic contact dermatitis
AM = Ammoniated mercury
BMS = Burning mouth syndrome
ESSCA = The European Surveillance System of Contact
Allergies
EU = European Union
GST = Gold sodium thiosulfate
GSTM = Gold sodium thiomalate
IUDs = Intrauterine devices
PGEs = Platinum group elements
PVC = Poly(vinyl chloride)
SEM-EDX = Scanning electron microscopy – energy
dispersive X-ray spectroscopy
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Received: December 20, 2008 Revised: January 5, 2009 Accepted: January 10, 2009
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