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Systemic contact dermatitis after oral exposure to nickel: A review with a modified meta-analysis

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Systemic contact dermatitis can be elicited experimentally in nickel-sensitive individuals by oral nickel exposure. A crucial point interpreting such experiments has been the relevance of nickel exposure from drinking water and diet. The aim of this meta-analysis study on former nickel-exposure investigations was to provide the best possible estimation of threshold values of nickel doses that may cause systemic contact dermatitis in nickel-sensitive patients. 17 relevant investigations were identified, and statistical analyses were performed in a stepwise procedure. 9 studies were included in the final dose-response analysis, which divided the studies into a homogenous middle group of 5 studies and 2 groups of 2 studies with a higher and lower response frequency, respectively, described by logistic dose-response curves shifted in parallel. On the basis of these curves, calculations were made of the doses that, theoretically, would cause systemic contact dermatitis in exposed nickel-sensitive patients. The results from the 2 most sensitive groups show that 1% of these individuals may react with systemic contact dermatitis at normal daily nickel exposure from drinking water and diet, i.e. 0.22-0.35 mg nickel.
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Review Article
Systemic contact dermatitis after oral exposure to
nickel: a review with a modified meta-analysis
CHRISTIAN STAB JENSEN
1
,TORKIL MENNE
´
2
AND JEANNE DUUS JOHANSEN
1
1
National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark,
2
Department of Dermatology, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
Systemic contact dermatitis can be elicited experimentally in nickel-sensitive individuals by oral
nickel exposure. A crucial point interpreting such experiments has been the relevance of nickel
exposure from drinking water and diet. The aim of this meta-analysis study on former nickel-
exposure investigations was to provide the best possible estimation of threshold values of nickel
doses that may cause systemic contact dermatitis in nickel-sensitive patients. 17 relevant investiga-
tions were identified, and statistical analyses were performed in a stepwise procedure. 9 studies were
included in the final dose–response analysis, which divided the studies into a homogenous middle
group of 5 studies and 2 groups of 2 studies with a higher and lower response frequency, respec-
tively, described by logistic dose–response curves shifted in parallel. On the basis of these curves,
calculations were made of the doses that, theoretically, would cause systemic contact dermatitis in
exposed nickel-sensitive patients. The results from the 2 most sensitive groups show that 1% of
these individuals may react with systemic contact dermatitis at normal daily nickel exposure from
drinking water and diet, i.e. 0.22–0.35 mg nickel.
Keywords: nickel allergy; oral exposure; systemic contact dermatitis. #2006 The Authors. Journal
compilation #2006 Blackwell Munksgaard.
Accepted for publication 31 October 2005
Systemic contact dermatitis is seen as flare-up of
previous dermatitis or de novo dermatitis similar
to allergic contact dermatitis. While systemic
contact dermatitis from medicaments is a well-
established entity, systemic reactions to metals,
particularly to nickel, has been regarded as con-
troversial (1, 2). 1 reason for this is that reactions
to a ubiquitous hapten, such as nickel, are not
easily identified with certainty because it is diffi-
cult to measure and control daily exposure
through drinking water and diet.
However, there is significant evidence that oral
intake of nickel can induce systemic contact der-
matitis in nickel-sensitive individuals. Flare-up
reactions of previous nickel patch test sites after
systemic oral exposure appear to be hapten spe-
cific (3). There appears to be a dose–response
relationship, and the overall trend from several
oral exposure studies is that the severity of the
reaction after exposure and the number of react-
ing nickel-sensitive individuals increase with
higher exposure doses (Table 1) (4–20). Until
now, nobody has tried to summarize the data
from the oral exposure studies to determine an
oral nickel exposure threshold for elicitation of
systemic contact dermatitis. A complicating fac-
tor, making it difficult to draw definite conclu-
sions, is the great variation in the protocols of the
different studies and in the degree and extension
of the individual’s clinical reactions.
Whether or not the nickel exposure from
drinking water and the diet can induce systemic
reactions is still controversial, as unphysiologi-
cally high nickel doses were used in most of the
conducted studies. The doses used in the studies
vary from 0.3 mg to 5.6 mg nickel (Table 1),
while normal daily dietary nickel intake has
been found to vary from 0.02 mg to 0.48 mg
nickel (21–32). However, some studies have
shown that an exposure dose equivalent to the
maximal nickel exposure through the diet (0.9 mg
nickel per day) (21) can induce systemic reactions
in some nickel-sensitive individuals (6, 8, 9, 13,
20). Additionally, dietary intervention studies
(5, 33–36) indicate that exposure to nickel in diet
and drinking water could be a contributing factor
to systemic contact dermatitis.
The aim of the conducted study was to deter-
mine the best possible threshold values for oral
nickel exposure which would elicit allergic
Contact Dermatitis 2006: 54: 79–86 #2006 The Authors
Printed in Singapore. All rights reserved Journal compilation #2006 Blackwell Munksgaard
CONTACT DERMATITIS
Table 1. Characteristics of the different studies
Criteria’s of inclusion Study design Group size Dose (mg Ni) Type of exposure and conditions Definition of positive reactions Time before evaluation References
PPT, HNA and HE DB, SE 1 12 0, 5.6 NiSO
4
in capsule, not fasting FUE, WHE and EB 6 + 30 hr Christensen and
Mo
¨ller (4)
PPT and HE DB, SE 1 28 0, 2.5 NiSO
4
in capsule, not fasting FUE and/or WHE 2–72 hr Kaaber et al. (5)
PPT, HNA and HE DB, SE 1 11 0, 0.6, 1.2, 2.5 NiSO
4
in capsule, not fasting FUE , WHE and EB 48–72 hr Kaaber et al. (6)
NPT* and HNA NB, SE 1 4, 1 7 4.0 NiSO
4
in capsule, not fasting FUE, WHE and EB 72 hr Veien and Kaaber (7)
PPT and HE DB, DE 1 10 0, 0.5 NiSO
4
in capsule, not fasting WHE 0–48 hr Jordan and King (8)
PPT and HE NB, SE 3 5 0.6, 1.25, 2.5 NiSO
4
in capsule, over night
fasting and 1 hr after
FUL, WHE and EB 0–72 hr Cronin et al. (9)
PPT and HE DB, DE 1 22 0, 2.0, 4.0 NiSO
4
in capsule, not fasting WHE 24 + 72 hr Burrows et al. (10)
Not documented DB, SE 1 49 0, 2.24 Not documented Not documented Not documented Bedello et al. (11)
Not documented DB, SE 1 20 0, 2.4 Not documented Not documented Not documented Sertoli et al. (12)
PPT, HNA and HE DB, SE
and DE
16, 2 10 0, 0.4, 2.5, 5.6 NiSO
4
in capsule, not fasting FUE and/or FUL and/or EK 72 hr Gawkrodger et al. (13)
PPT, HNA
and/or HE
NB, SE 1 10, 1 19 0, 2.5 NiSO
4
in capsule, not fasting FUE and/or FUPT and/or EB 24 + 48 hr Roduner et al. (14)
PPT and HNA DB, SE 1 131 0, 2.5 Ni-salt in tablet; not fasting FUE and/or FUPT and/or EB 0–96 hr Veien et al. (15)
PPT and HNA NB, SE 1 25 2.24 NiSO
4
in capsule, not fasting FUE and/or FUPT and/or EB 0–48 hr Santucci et al. (16)
PPT and ECZ DB, SE 1 19, 1 9 0, 2.5 NiSO
4
in capsule, not fasting FUE and FUPT 0–24 hr Mo
¨ller et al. (17)
PPT, HNA and HE NB, SE 2 20 0.8†
61
Ni in water, fasting 12 hr
before and 4 hr after
FUE and/or WHE and/or EK 0–72 hr Nielsen et al. (18)
PPT DB, SE 2 10, 1 9 0, 1.0, 4.0 NiSO
4
in capsule, over night
fasting and 1 hr after
FUPT 24 hours Hindse
´n et al. (19)
PPT and HE DB, SE 4 10 0, 0.3, 1.0, 4.0 NiSO
4
in capsule, fasting
12 hr before
FUE and/or FUPT and/or EB 24 hr Jensen et al. (20)
Inclusion criteria: ECZ ¼eczema; HE ¼hand eczema; HNA ¼history of nickel allergy; NPT ¼negative patch test; PPT ¼positive patch test; design DB ¼double blinded; NB ¼not
blinded; SE ¼single-exposure; DE ¼double exposure over 2 days. Definition of positive reaction: FUE ¼flare-up of former eczema; FUPT ¼flare-up of former patch test; WHE ¼
worsening of hand eczema; EB ¼erythema on the body.
*Patients with negative routine patch tests were challenged orally with nickel.
†Average exposure dose. Persons were exposed to 12 mg/kg bodyweight.
80 JENSEN ET AL. Contact Dermatitis 2006: 54: 79–86
contact dermatitis in nickel-sensitive individuals
by combining the data from published oral expo-
sure studies in a meta-analysis.
Methods and Statistical Analyses
Relevant studies published from January 1966 to
November 2004 were identified by searching
MEDLINE, EMBASE and BIOSIS using the
words: nickel, oral, challenge, exposure, hyper-
sensitivity, sensitivity, allergy, systemic provo-
cation and contact dermatitis in different
combinations. Additionally, the databases were
searched by the use of the ‘Related Articles’ func-
tion and by searching the publications by specific
authors in the scientific area. Finally, relevant
references were localized by the use of the refer-
ence lists in review articles. Though probably
most of the relevant publications were localized
by these methods, this study is not a formal
meta-analysis (or series of meta-analyses), which
includes all publications on the subject.
Standard statistical methods based on the
binomial distribution of the number of positive
reactions were used for the calculation of confi-
dence intervals for response frequency and for
tests of differences in response between doses
within the same study or between 2 studies at
the same dose.
Logistic regression analysis was applied to esti-
mate dose–response relations and for comparison
of dose–response relations between studies. These
methods are based on the assumption that
patients are randomly divided into the various
dose groups. It should be pointed out that the
dose–response modelling analysis does not apply
to the experimental situation where the same
group of patients is tested with different doses,
including a dose of 0 mg nickel (placebo). In this
case, it would be a natural assumption that if a
patient has shown a positive reaction to a given
dose, that person will also show a positive reac-
tion to all higher doses. This may be checked by
inspection of the individual responses to the
doses in question, but the reported response
rates do not contain this information except
when none or all patients react.
Paired responses to 2 different doses were com-
pared by McNemar’s test, while Fisher’s test or
Chi-square tests were used for unpaired responses
(data not shown). Multiple logistic regression
analysis was applied to determine which studies
deviate significantly from the mean under the
assumption that the slopes of the dose–response
curves were similar. However, since it is not cor-
rect to include the same patients more than once
in this analysis, it was chosen only to use the
response rate closest to 50% from the studies
where a single group of patients were tested
with more than 1 nickel dose. The analysis was
performed according to the backwards elimina-
tion procedure as well as the forward selection
procedure. In the backwards elimination, the
study that deviates the least as well as insigni-
ficantly (P>0.05) from the mean of the others is
regarded as representing the mean, and in the
next step the least non-significantly deviation
group among the remaining studies is accepted
as representing the mean, etc. This pooling of
studies stops when only significantly deviating
studies remain. These studies may also be identi-
fied by the forward selection procedure, where
the study (or the nickel dose–response effect)
that deviates most and significantly from the
mean is selected first. In the next step, the most
significant among those remaining is selected, etc.
The selection stops when none of the remaining
studies are statistically significant, i.e. P>0.05.
Finally, estimates of ED
50
and other lower
(threshold) doses were calculated from the logis-
tic dose–response curves by the use of Fieller’s
method. The statistical analyses were with
APL2000
1
software (Maneugistics, Rockville,
MD, USA) validated relative to SAS
1
version
8.2 procedures (Proc Freq and Proc Univariate,
SAS Institute, Cary, USA, 2001).
Results
From the literature search, 17 studies on oral
nickel exposure in nickel-sensitive patients were
identified (Table 1). Additional 2 studies were
found (37, 38), but these were excluded because
the nickel-exposure doses used varied both intra-
and interindividually. The aim of the statistical
analysis was to conduct a comparative quantita-
tive dose–response analysis including as many of
the identified studies, which was proven difficult
because of the heterogeneity amongst the identi-
fied studies. The 17 studies included 496 indi-
viduals and varied in size from 11 to 131
individuals. Different protocols have been used
in the various studies, and so the observed differ-
ences between the studies may be caused by dif-
ferences in testing and evaluation methods as well
as differences in the tested patient populations.
The distribution of the number of positive
reactions with 95% confidence limits plotted
against the dose in logarithmic scale showed
that the limits in most cases were rather wide
due to the relative small number of patients
(data not shown). There was a clear tendency to
increasing reaction rate with increasing dose, but
a more detailed analysis was needed to evaluate
Contact Dermatitis 2006: 54: 79–86 SYSTEMIC CONTACT DERMATITIS 81
how the dose–response relations might differ
between the studies.
Some of the studies had positive responses to
placebo [studies 8, 10, part of 13 (the study con-
sisted of both single and double exposure), 15, 17
and 20]. A comparison of these reactions demon-
strated differences between single studies and
groups of studies both among studies using
double exposure and single exposure (data not
shown). Since the majority of the studies used
single exposure, it was more rational to continue
the analyses with these studies. This meant that
the data from studies 8, 10 and parts of 13 were
not included (Table 1).
A stepwise multiple logistic regression analysis
was performed on the relevant data from 401
patients in the 15 studies where single exposure
was used. The result showed a statistically signif-
icant dose–response effect (P<0.0001), and it
was found that the studies 9, 14, 15 and 17
deviated significantly from the remaining 11
studies, which showed an acceptable agreement
(Fig. 1). The 4 deviating studies could be divided
into 1 group with 3 studies (studies 14, 15 and 17)
and 1 separate study (study 9). The group com-
prising the 11 studies had an intermediary dose–
response curve, while the group of 3 had a lower
dose–response curve, and the separate study had
a higher response rate. The hypothesis of parallel
dose–response curves was acceptable. However,
the analysis has 2 weaknesses. The data included
2 studies without placebo testing (studies 16 and
18), and it contained 3 studies (studies 15, 17 and
20) which had positive responses to placebo.
It is an open question whether it from a biolo-
gical and statistical point of view is meaningful to
compare the dose–response relations from all the
single-exposure studies, when the response rates
to placebo is positive in some studies, and when
some studies have no placebo testing included.
Therefore, after exclusion of these 5 studies, an
additional analysis was performed on the data
from the remaining 9 studies comprising 171
patients. This altered the result of the stepwise
multiple logistic regression analysis. In a homo-
geneous group (studies 5, 6, 7, 11 and 13), an
intermediary dose–response curve was found,
while 2 groups each comprising 2 studies had a
higher (studies 4 and 14) or a lover dose–response
curve (studies 12 and 19) (Fig. 2). These 2 groups
included only 1 of the deviating studies from the
previous analysis.
On the basis of the result from the last analysis,
exposure doses corresponding to response rates
of 50% (ED
50
), 25% (ED
25
), 10% (ED
10
), 5%
(ED
5
) and 1% (ED
1
) of exposed nickel-sensitive
eczema patients were calculated (Table 2). These
calculations predict that an oral nickel exposure
with 0.22 mg, 0.35 mg or 0.53 mg nickel
(depending on which dose–response curve is
used) will make 1% of nickel-sensitive patients
respond. Similarly, 2% of these patients will react
if they are exposed orally to nickel doses of
0.29 mg, 0.45 mg or 0.70 mg, 5% will react to
0.41 mg, 0.65 mg or 1.0 mg nickel, while an
exposure to 0.55 mg, 0.87 mg or 1.33 mg nickel
will make 10% of the patients react with signs of
a systemic contact dermatitis.
Discussion
An extensive literature search identified dose–
response data from 17 published studies of oral
0.1 1 10
Ni dose lo
g
scale (m
g
)
0
20
40
60
80
100
Per cent
0.2 0.5 2 5 Study 20
Study 19
Study 18
Study 17
Study 16
Study 15
Study 14
Study 13
Study 12
Study 11
Study 9
Study 7
Study 6
Study 5
Study 4
Fig. 1. Observed rates of response with 95% confidence
limits and fitted dose–response curves in studies with single
exposure. Studies 4, 5, 6, 7, 11, 12, 13, 16, 18, 19 and 20 form
a homogenous group with a common dose–response curve
(in black), studies 14, 15 and 17 form another homogeneous
group (in green) and study 9 forms a third group (in red),
which are all significantly different.
10
Ni dose in lo
g
scale (m
g
)
0
20
40
60
80
100
Per cent
210.50.20.1 5
Study 19
Study 14
Study 13
Study 12
Study 11
Study 7
Study 6
Study 5
Study 4
Fig. 2. Observed rates of response with 95% confidence
limits and fitted dose–response curves in studies with single
exposure and no placebo reactions. Studies 5, 6, 7, 11 and 13
form a homogenous group with a common dose–response
curve (in black), studies 4 and 14 form another homogenous
group (in green), and studies 12 and 19 form a third group
(in red), which are all significantly different.
82 JENSEN ET AL. Contact Dermatitis 2006: 54: 79–86
nickel exposure on patients sensitive towards
nickel. These studies varied in criteria of inclu-
sion, design of the exposure protocol, numbers of
exposure boluses, how the same patients were
tested, inclusion of and reactions to placebo, fast-
ing condition prior to exposure, definition of
positive reaction to exposure and the time of
evaluation after exposure, which made a strict
meta-analysis including all studies impossible.
Therefore, it was necessary to modify the analysis
and exclude data from studies which differed
significantly from the majority to be able to
determine the best possible threshold values for
oral nickel exposure, which would elicit allergic
contact dermatitis in nickel-sensitive individuals.
In the overall evaluation of the identified
studies, there seem to be a tendency that increas-
ing exposure doses results in increasing reaction
rates, but a more detailed analysis was needed to
evaluate how the dose–response relations might
differ between the studies.
After conducting several analyses and exclud-
ing studies with double exposure, studies with
responses to placebo and studies without placebo
testing, the final model included 9 studies with
oral nickel exposure conducted on a total of 171
individuals. The result was a homogeneous group
including 5 studies (studies 5, 6, 7, 11 and 13)
with an intermediary dose–response curve, while
2 groups each including 2 studies had a higher
(studies 4 and 14) or a lower dose–response
curve.
On the basis of the result of the last modified
meta-analysis, theoretical exposure doses predict
that an oral nickel exposure with 0.22 mg,
0.35 mg or 0.53 mg nickel (depending of which
dose–response curve is used) will make 1% of
nickel-sensitive patients respond. Similarly, 10%
of these patients will react if they are exposed
orally to nickel doses of 0.55 mg, 0.87 mg or
1.33 mg nickel (Table 2).
It should be emphasized that the tested individ-
uals included in the studies do not represent
the majority of the population but are persons
allergic to nickel, who have consulted a
dermatologist. In the majority of the cases, the
patients had symptoms which could indicate a
systemic component in their disease, and many
patients had had chronic hand eczema (Table 1)
which flared up after the oral exposure. Using
the 2 ‘most sensitive’ statistical calculations, the
model predicts that 1% of these patients can be
expected to get a systemic reaction to the nickel
content of a normal diet, e.g. exposures between
0.22 mg and 0.35 mg nickel and that 10% of
them would react to exposures between 0.55 mg
and 0.89 mg nickel which theoretically could be
attained by consuming food with a high level of
nickel, by drinking water contaminated with
nickel from the pipes or taps and/or by drinking
a large volume of water containing a high level of
nickel while fasting.
Nickel exposure from drinking water and other
beverages is usually considered to be negligible,
although exceptions occur. In most studies, the
nickel levels in groundwater and drinking water
have been in the range of 1–10 mg per litre
(39–45). However, some studies have found
water samples containing higher levels.
Andersen et al. (44) found the nickel levels in
most of the tap water samples from the
Copenhagen area to be lower than 35 mg per
litre, but there were considerable variations in
the amount of nickel at different times of day,
from tap to tap and in hot versus cold water.
A statutory order on water quality and inspection
of water supply facilities from 2001, the Danish
Ministry of Environment (46) lowered the max-
imum level of nickel permitted in drinking water
from 50 mg per litre to 20 mg per litre. A recent
survey (47) found that the nickel concentrations
in the water in 2 out of 20 water supply facilities
and in 2 out of 37 sources exceeded the demands
to the quality of the drinking water. Andersen
et al. (44) found that an additional factor which
increases the nickel level in drinking water is
that the longer the water is allowed to be in the
pipes and the taps the more nickel will be
dissolved from the metal to the water. They
found concentrations of nickel up to 490 mg per
Table 2. Estimated doses of ED
50
and lower responses with 95% confidence limits
Studies 12 and 19 Studies 5, 6, 7, 11 and 13 Studies 4 and 14
Ni doses (mg) Estimate 95% limits Estimate 95% limits Estimate 95% limits
ED
50
1.27 0.77–172 2.00 1.47–2.35 3.06 2.15–4.30
ED
25
0.83 0.37–1.19 1.32 0.68–1.69 2.01 1.13–2.74
ED
10
0.55 0.17–0.86 0.87 0.31–1.26 1.33 0.53–1.94
ED
5
0.41 0.10–0.70 0.65 0.18–1.04 1.00 0.31–1.57
ED
2
0.29 0.05–0.54 0.45 0.09–0.81 0.70 0.16–1.21
ED
1
0.22 0.03–0.45 0.35 0.05–0.67 0.53 0.09–1.00
Contact Dermatitis 2006: 54: 79–86 SYSTEMIC CONTACT DERMATITIS 83
litre in the first 250 ml of drinking water. After
having the tap run for 5 min, they found much
lower nickel levels, which could indicate that
nickel is released from the pipes and taps and
concentrated in still water.
If only the maximum level of nickel permitted
in drinking water in Denmark at the moment is
obtained (20 mg per litre), a person can consume
up to 40–60 mg nickel per day through the drink-
ing water. According to the findings in the final
model, this will be the equivalent of 1/4 of the
dosage of nickel which will make 1% of the most
sensitive nickel-allergic patients seen by derma-
tologists react with a systemic contact dermatitis
response. If a relatively large part of the daily
water intake is consumed on an empty stomach,
e.g. if a person starts the day with a cup of coffee
or tea before eating breakfast, the uptake and
contribution of nickel from the drinking water
will probably be of relatively more importance
and therefore contribute more than 1/4 of the
dosage that can result in a systemic response.
The different outcomes of the studies may
reflect variations in study design and in differ-
ences in the patch tested nickel-sensitive individ-
uals. Different protocols have been used in the
various studies, and some of the studies were not
conducted in a double-blind manner. In many of
the studies, only a very small number of subjects
have been tested. The criteria for the selection of
test persons have not been standardized. In some
studies, a positive patch test to nickel was the
only inclusion criterion; 1 study (study 7) was
performed on subjects with hand eczema but
with a negative patch test, in others the subjects
had a positive patch test and hand eczema and/or
a history of nickel dermatitis. Neither have the
criteria been standardized for identifying a posi-
tive reaction to the oral challenge. The time
between challenge and evaluation is not the
same in the various studies, varying from 0 hr
to 72 hr or more. In studies with the shortest
time frames, this could have led to an underesti-
mation of the number of subjects reacting to the
oral challenge. It has not always been specified
whether the subjects had fasted overnight or
whether there were other dietary restrictions. In
some studies, a single bolus challenge was used,
while in others they used a double bolus chal-
lenge. The absorption and biokinetics following
the bolus exposure employed in most oral chal-
lenge studies may be quite different from natu-
rally occurring, dietary exposure, where nickel is
absorbed incrementally throughout the day. The
natural dietary intake of nickel is difficult to
estimate, and in most of the oral challenge stud-
ies, it was not taken into account. Total dietary
nickel intake and absorption can be highly vari-
able and difficult to estimate precisely. This
depends both on the composition of the diet
and on such factors as how the food had been
prepared, whether it was fresh or canned food
and/or whether it was contaminated during pro-
cessing or by kitchen utensils. There may also be
regional differences in the nickel content of various
foods. In most cases, there is probably only a small
amount of nickel in drinking water, but as shown in
some studies, drinking water may be contaminated
with nickel. A particular problem in the performed
modified meta-analysis is that no distinction was
made between the different end points (definition
of positive reaction to exposure) in the various
studies. 1 used end point in some studies, flare-up
of a recurrent vesicular hand eczema, which is the
most common clinical manifestation of systemic
nickel contact dermatitis, isaverycomplexdisease
and may be precipitated by a number of stimulants.
It has not been attempted to extend the logistic
dose–response analysis to include variables
describing differences between the studies such
as those just mentioned. From a statistical point
of view, the main problem is undoubtedly the
variation in background responses between the
studies and in particular how to incorporate this
heterogeneity into a general dose–response ana-
lysis. Therefore, the decision was made to exclude
studies with positive responses to placebo and
studies without placebo testing, which meant
that some reliable studies may not have been
used in the final analysis (studies 15, 16, 17, 18
and 20). However, adjusting for a placebo effect
would probably shift a theoretical dose–response
curve in parallel to the right, resulting in higher
threshold values and thus making it impossible to
note responses to the lower exposure doses.
It is believed that the analyses performed
represent a reasonable and at the moment best
possible systematic approach given the limited
and rather heterogeneous data.
In conclusion, oral exposure to nickel may
lead to systemic contact dermatitis in a dose-
dependent fashion. The amount of nickel in
food and drinking water will under normal
circumstances only provoke a systemic reaction
in a minority of the nickel-allergic patients seen
be dermatologists.
Acknowledgements
We thank Aage Vølund, PhD, Department of
Biostatistics, Novo Nordisk, Bagsværd, for assistance
with the statistical analyses of the data. The study was
supported by a grant from the Danish Environmental
Protection Agency.
84 JENSEN ET AL. Contact Dermatitis 2006: 54: 79–86
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Address:
Christian Stab Jensen
National Allergy Research Centre
Gentofte Hospital
University of Copenhagen
Niels Andersensvej 65
DK-2900 Hellerup, Denmark
Tel: +45 39 77 73 00
Fax: +45 39 77 71 18
e-mail: csj@ssi.dk
86 JENSEN ET AL. Contact Dermatitis 2006: 54: 79–86
... In this study, we also tested nickel leaching from the faucets. Currently, nickel is not legally regulated in Japan; however, nickel in drinking water has been identified as a potential cause of systemic contact dermatitis in nickel-sensitized individuals ( Jensen et al. 2006;WHO 2022). Therefore, it can be said that appropriate monitoring of nickel leaching is important for protecting public health. ...
... This could be particularly problematic for nickel-sensitive individuals who suffer from contact dermatitis following oral exposure to nickel. According to a review published by Jensen et al. (2006), nickel intake by drinking water with a nickel concentration of 0.02 mg/L (the Japanese drinking water quality management target value and the maximum level permitted in drinking water in Denmark) corresponds to onefourth of the nickel dosage that could cause dermatitis response in 1% of the most sensitive individuals. One possible approach for alleviating the health impact on nickel-sensitive individuals is the preventive use of faucets not made primarily of copper alloys. ...
Article
Full-text available
In this study, metal leaching was investigated in commercially available faucets in Japan to clarify their compliance to Japanese regulations. We purchased 37 faucets from the market and analyzed the leaching of cadmium, mercury, selenium, lead (Pb), arsenic, hexavalent chromium, boron, zinc (Zn), copper, manganese, and nickel. The leaching tests were performed with and without a conditioning treatment, that simulated approximately 1-month intermittent use of faucets on weekdays, and the results were compared to estimate the changes in metal leaching during the use of faucets. The results revealed that metal leaching from most of the faucets complied with Japanese regulations. However, the levels of Pb leaching from several faucets produced by certain manufacturers exceeded the Japanese standard. The conditioning treatment was generally effective in reducing metal leaching. However, the reductions in Pb and Zn leaching tended to be lower than those of the other metals. Nickel is not legally regulated in Japan; although the number of cases where nickel concentration in leachate exceeded the water quality management target value was greater, such cases were limited to faucets primarily made of copper alloys. We believe that these results will be helpful to improve the public health associated with metal leaching from faucets. HIGHLIGHTS Metal leaching was tested in commercially available faucets in Japan.; Leaching with and without conditioning was tested to estimate time-course decline in metal leaching.; Faucets of a certain manufacturer repeatedly exceeded the Japanese standard.; The declines in Pb and Zn leaching by the conditioning were limited.; Using faucets not made mainly of copper alloys may be useful to reduce the effect of nickel leaching.;
... Fischer et al. (2005) showed that 5% of a sensitized population react to 0.44 µg Ni/cm 2 and 10% react to 1.04 µg Ni/cm 2 [27]. Jensen et al. (2006) performed a meta-analysis to find the estimated thresholds of nickel doses that may cause systemic contact dermatitis in nickel-sensitive patients [28]. The results showed that the most sensitive groups may react with systemic contact dermatitis at normal daily nickel exposure from drinking water, or food of 0.22-0.35 ...
... Fischer et al. (2005) showed that 5% of a sensitized population react to 0.44 µg Ni/cm 2 and 10% react to 1.04 µg Ni/cm 2 [27]. Jensen et al. (2006) performed a meta-analysis to find the estimated thresholds of nickel doses that may cause systemic contact dermatitis in nickel-sensitive patients [28]. The results showed that the most sensitive groups may react with systemic contact dermatitis at normal daily nickel exposure from drinking water, or food of 0.22-0.35 ...
Article
Full-text available
The aim of this study was to explore whether changes in the salivary pH influence mechanical properties, surface roughness, and ion release from NiTi archwires with various surface coatings, and discuss the clinical significance of the findings. The uncoated, rhodium-coated, and nitrified NiTi wires were immersed into artificial saliva of different pH values (4.8, 5.1, 5.5, and 6.6). Released nickel and titanium ions were measured with inductively coupled plasma-optical emission spectroscopy at the end of 28 days. Atomic force microscopy was used to measure the arithmetic average surface roughness Ra, the root-mean-square roughness Rq, and the maximum height of the asperities RZ. The nanoindentation hardness (HIT) and Young’s modulus (EIT) measurements were performed. The change in the pH of artificial saliva is inversely proportional to the release of titanium from both coated and uncoated wires, and the release of nickel from uncoated wires. The surface roughness parameters of both coated and uncoated wires are unaffected by the change in the pH of artificial saliva. The change in the pH of saliva has minor influence on the hardness and Young’s modulus of elasticity of both coated and uncoated wires. The concentration of released metal ions measured was below the recommended upper limit for daily intake; nevertheless, hypersensitivity effects cannot be excluded, even at lower concentrations and at low pH.
... Было установлено, что системные реакции на никель дозозависимы. Результаты исследований показывают, что у 1% людей может развиться системный контактный дерматит при ежедневном потреблении никеля, содержащегося в питьевой воде и пище в дозах от 0,22 до 0,35 мг [29]. При ведении пациентов с выявленной сенсибилизацией больным следует рекомендовать специальную диету с низким содержанием никеля [30]. ...
Article
The article provides basic information about nickel-associated allergic contact dermatitis (NACD). Nickel is a common metal that is commonly used in alloys for jewelry, accessories and household items. Contact with this metal often leads to the development of allergic contact dermatitis in sensitized individuals. The prevalence of NACD among the population is high: up to 19% among adults and about 10% among children and adolescents. It is noted that in female’s sensitization to nickel is observed several times more often than in males. On the risk of developing an allergic reaction to nickel, the integrity of the skin barrier, the frequency of contacts with nickel-containing household items, the presence of piercings, high humidity and hyperhidrosis are of decisive importance. Nickel ions entering the body through the alimentary route are capable of both sensitizing the body and forming tolerance to it. The pathogenesis of NACD is based on the classic delayed-type hypersensitivity reaction. The main clinical forms of this allergic dermatosis, as well as the characteristic features of the course of the disease are presented. The features of the course of NACD in patients with atopic dermatitis (AD) are analyzed in detail. The presented data clearly demonstrate that contact allergy to nickel can not only maintain, but also significantly aggravate the course of AD. The main criteria for the differential diagnosis between simple contact and allergic contact dermatitis are shown schematically. The need for early identification and termination of contact with nickel-containing household items is noted as the initial stage of NACD treatment. The main treatment for NACD is local therapy with topical glucocorticosteroids.
... Аллергический контактный дерматит встречается реже, чем раздражаю щий контактный дерматит, и возникает только у людей, у которых развилась контактная аллергия на определенные вещества, такие как латекс, моющие средства или металлы. Попавшие внутрь аллергены могут иногда спровоцировать экзему рук [19]. ...
Article
Hand eczema is a common disease – up to 5% in the general population. In addition, eczema is closely related to atopy and, like atopic dermatitis, to a mutation in the FLG gene. In addition to genetic factors, eczema is caused by external irritants and toxic substances. Eczema often occurs in families with atopic diseases, including asthma, allergic rhinitis/hay fever (and food allergies), and atopic dermatitis. These diseases share a common pathogenesis and often occur together in the same person and/or family. Eczematous rashes are often accompanied by itching. This symptom can lead not only to sleep disturbances but also to secondary infections. According to some data, the rate of infections in eczema can be more than 70%. In such cases, the drugs of choice are combined glucocorticosteroids (GC), which in addition to GC contain an antimycotic and an antibiotic. Our practical experience shows the high effectiveness of the combination of beclomethasone dipropionate, gentamicin, and clotrimazole not only in cases of eczema complicated by secondary infection but also in patients with other infected chronic dermatoses. This article reviews these and other practical aspects and problems in the treatment of hand eczema, discusses the etiological factors that lead to the development of the disease, and presents current data from clinical recommendations and guidelines for the treatment of eczema.
... Although high airborne exposures to nickel (Ni) compounds by production workers have been associated with chronic respiratory effects including cancer, Ni is generally of low toxicity for exposures to consumer products or implanted medical devices, for which the primary health concern is a delayed Type IV allergic reaction in sensitive individuals (IARC 1999;McGregor et al. 2000;Jensen et al. 2003Jensen et al. , 2006ATSDR 2005;FIOH 2010). The World Health Organization (WHO) derived a Tolerable Daily Intake (TDI) for oral exposure of 11 lg Ni/kg of body weight (bw) per day based on a noadverse-effect level for reproductive toxicity in a two-generation study in rats (WHO 2007). ...
Article
Full-text available
Worker-specific Biological Exposure Action Levels (BEALs) for nickel (Ni) exposure are a urinary Ni concentration that reflects a dose that can be experienced on a daily basis without adverse systemic health effects. Several health-based reference values for systemic exposure to Ni have been derived as oral daily Ni dosing levels (e.g., 2007 WHO tolerable daily intake for Ni). To support evaluation of urinary nickel biomonitoring data in workers based on such health-based criteria, new human biokinetic models for nickel (Ni) were fit jointly to data obtained for 18 adult volunteers from four newly reported human studies and to data from two previously reported studies involving a total of 14 adult volunteers. This model and associated statistical analyses characterize and predict human Ni biokinetics after ingestion of Ni doses ≤ 20 µg/kg bw and associated inter-individual variation in urinary Ni excretion. Using this approach, we illustrate how available health-based reference values for daily Ni exposure by the oral route developed to protect against adverse health effects can be applied to derive urinary nickel BEALs for nickel workers based on their individual characteristics (e.g., shift pattern, body weight). Such worker-specific BEALs can provide health-based reference values to evaluate measures obtained through urinary Ni biomonitoring programs to complement existing industrial hygiene air monitoring programs.
... A subset of Ni-ACD patients (about 20%) also develops a more severe form of disease called systemic nickel allergy syndrome (SNAS) [2,3], with cutaneous and extra-cutaneous involvement (primarily of the gastrointestinal tract), especially after consumption of Nirich plant foods [4], and with cutaneous manifestations even in sites without direct contact [5,6]. ...
Article
Full-text available
Background: Restrictions due to the COVID-19 pandemic limited patients' access to hospital care. The aims of this study were to assess dietary nutritional status, quality of life (QoL), and adherence to dietary therapy before and after 30-day personalized diet therapy through telenutrition tools in patients with systemic nickel allergic syndrome (SNAS). Methods: Each SNAS patient underwent the following allergological procedures: (a) face-to-face visit (nutritional visit and QoL evaluation) with prescription of one out of five personalized and balanced dietary plans different for calorie intake, (b) video call visit for dietary evaluation and assessment of adherence to diet after 15 days, and (c) video call visit for dietary and QoL evaluation and assessment of adherence to diet therapy after 30 days (end of study). Results: We enrolled 20 SNAS patients. After 15 and 30 days, we found a statistically significant improvement in anthropometric findings after diet therapy, a significant adherence rate to low-nickel diet (60% and 80%, respectively), and an improvement in QoL with an increase in almost all psychometric indices. Conclusions: Our study demonstrates that telenutrition can be a valid tool to monitor nutritional status and adherence to balanced low-Ni diet positively affecting QoL in SNAS patients during the COVID-19 pandemic.
Article
Contact dermatitis (CD) is among the most common inflammatory dermatological conditions and includes allergic CD, photoallergic CD, irritant CD, photoirritant CD (also called phototoxic CD) and protein CD. Occupational CD can be of any type and is the most prevalent occupational skin disease. Each CD type is characterized by different immunological mechanisms and/or requisite exposures. Clinical manifestations of CD vary widely and multiple subtypes may occur simultaneously. The diagnosis relies on clinical presentation, thorough exposure assessment and evaluation with techniques such as patch testing and skin-prick testing. Management is based on patient education, avoidance strategies of specific substances, and topical treatments; in severe or recalcitrant cases, which can negatively affect the quality of life of patients, systemic medications may be needed. Contact dermatitis results from the exposure to exogenous allergens or irritants that stimulate immune responses leading to inflammation of the skin.
Chapter
The term systemic contact dermatitis is used to describe dermatitis in persons with contact sensitivity who are exposed to the hapten orally, rectally, transcutaneously, or intravenously or by inhalation. Well-known examples are eczematous eruptions seen after medicaments which have been administered to persons with contact sensitivity to the specific medicament. Other causes include the ingestion of the metals mercury, nickel, cobalt, and dichromate and plant allergens such as sesquiterpene lactones. Typical clinical features are flare-up reactions of previous dermatitis or previously positive patch test sites, widespread dermatitis, vesicular palmar, and/or plantar dermatitis and flexural dermatitis. Systemic contact dermatitis is rare compared with other types of contact dermatitis.
Chapter
Nickel, chromium, and cobalt remain the most frequent causes of contact allergy in the general population, certain occupational groups, and dermatitis patients. Consumer products and occupational exposure are the main sources of sensitization and elicitation, whereas the role of medical and surgical implant is unclear. Pure metals, alloys, platings, and compounds have different ability to cause sensitization and dermatitis. Nickel release from certain items in contact with the skin and hexavalent chromium in cement and leather are limited by EU regulation for allergy prevention. Strong indications concerning reduced exposure and health benefits have been noted following the implementation of the regulations; however, the problems are still very large. The presence of cobalt in leather and the association with dermatitis among cobalt allergic patients is a new understanding. Several other metals are less frequent sensitizers, and some cause cross-reactivity. New data on cocktail effects and reactivity to nickel following short-term exposure have been published. Spot tests remain useful in the assessment of metal exposure and exposure reduction, but clearly better techniques are needed for most metals.
Article
Full-text available
Of 28 patients with chronic nickel dermatitis 17 experienced aggravation following oral ingestion of 2.5 mg nickel, but not a placebo tablet. The dermatitis of 9 of the 17 patients improved during a period of 6 weeks on a low nickel diet. The dermatitis of 7 of the 9 patients flared again when a normal diet was resumed. Nickel excretion over a 24-h period was measured for 14 of the 17 patients by atomic absorption spectrophotometry before, during, and after the diet. Reduced excretion was seen during the diet with no statistically significant difference between patients whose dermatitis improved during the diet and those whose dermatitis showed no change.
A second national survey was done to ascertain the levels of Cd, Co, Cr, Cu, Ni, Pb, Zn, Ca, and Mg in Canadian drinking water supplies. Raw, treated, and distributed water samples collected from 71 municipalities across Canada were analyzed both by atomic absorption spectrophotometry using the direct method and by an APDC-MIBK extraction procedure. As in the first national survey, the amounts of trace metals found in the 3 types of water samples were essentially the same. Contamination of the water supplies with these metals except Cu and Zn was minimal during treatment and distribution. For Canadian drinking water, the median and extreme values expressed as ng metal/mL water were: Cd ≤0.02 (≤0.02-0.07), Co ≤2.0 (≤2.0-6.0), Cr ≤2.0 (≤2.0-4.1), Cu ≤10 (≤10-900), Ni ≤2.0 (≤2.0-69.0), Pb ≤1.0 (≤1.0-79.7), and Zn ≤10 (≤10-750). Hardness values as mg CaCO3/L, ranged from 6.7 in St. John’s, Newfoundland, to 328.3 in Portage La Prairie, Manitoba. The median values for the Canadian drinking water supplies were well below the maximum permissible limits set by Health and Welfare Canada and the World Health Organization.
Article
A provocation study was performed in twelve female patients with contact allergy to nickel and hand eczema of the pompholyx type. Intense handling of nickel-contaminated metal objects did not induce any visible eczematous activity. Oral administration of nickel in a double-blind test provoked an aggravation of the hand eczema in nine of the twelve patients, and in seven of the patients this was accompanied by secondary eruptions including outbreaks of earlier, healed eczema. The nickel dose given is probably in the upper limit of the presently known daily intake of the metal, but should be considered to be within the physiologic range. It is concluded that ingestion of small amounts of nickel may be of greater importance in maintaining the hand eczema than external contacts with the metal.
Article
Daily diet from 20 nursing homes for the elderly in the German state of Hessen were collected over a period of seven days. After weighing and protocoling, the components of the meals were combined to one sample per day. The homogenized samples were analyzed for the minerals sodium, potassium, calcium, magnesium, phosphorus, iron, zinc, manganese, copper, nickel, and chromium. For evaluation of the nutrient value the mineral contents were compared to the recommendations of the German Association for Nutrition (Deutsche Gesellschaft für Ernährung) for nutrient intake of the elderly. Whereas mean content of sodium and of calculated sodium chloride per day drastically exceeded the recommendation, the magnesium and chromium recommendations were not reached by far. Regarding high nutrient density requirements with respect to a lower energy demand, only a few diets could reach the recommendations for calcium, magnesium, iron, and zinc density given for the elderly.
Article
The evidence on the effect of oral nickel on hand dermatitis in nickel sensitive patients is conflicting. The evidence of this study suggests that the amount in an ordinary diet plays no part in the chronicity of nickel dermatitis although this conclusion must be made with reservations because of the small number of patients in the present study. It may be that larger doses not found in a normal diet may have some aggravating effect. Low nickel diets are difficult due to the widespread distribution of nickel in food. There is no evidence that current metals on plastic hips sensitize to nickel or aggravate existing dermatitis. Nickel allergy is not a factor in rejection so patients who are allergic to metal do not necessarily require titanium hips and pre-operative patch testing is unnecessary.
Article
In a controlled double-blind experimental study, patients with contact allergy to nickel or gold were exposed systemically to their contact allergen. Nickel sulfate was given orally, gold sodium thiomalate intramuscularly, and placebo by both routes. Clinical reactions including body temperature were followed and 7 plasma cytokines and acute phase reactants were assayed before and 24 h after provocation. Clinical flare-up, with reactivation of healing patch tests and/or toxicoderma-like reactions, was observed in patients receiving their specific allergen. A transient fever was noted in patients allergic to gold when exposed to gold, not in others. There was a significant increase in plasma tumour necrosis factor-α, soluble tumour necrosis factor receptor 1, inter leukin-1 receptor antagonist, and neutrophil gelatinase associated lipocalin in patients allergic to gold when exposed to gold allergen. Furthermore, in patients allergic to nickel exposed to nickel allergen there was a highly significant increase in plasma soluble tumour necrosis factor receptor 1. Interferon-gamma, interleukin-4, and C-reactive protein did not increase in any of the patient groups. Clinical reactions during flare-up in contact allergy are accompanied by release in the blood of several cytokines. This release is not a consequence of a toxic effect or bound to a particular allergen. Instead, the cytokine release should be considered a general phenomenon characteristic of the flare-up in contact allergy.
Article
Sixteen patients with negative routine patch tests were challenged orally in a controlled trial with 2.5 mg nickel, 1 mg cobalt, and 2.5 mg chromium given as salts of the respective metals. All of the patients had symmetrical, vesicular hand dermatitis and in some cases also foot involvement. The dermatitis of two patients flared after challenge with cobalt; in two patients flare occurred following chromate ingestion. Prior to the oral challenge all the patients were patch tested with nickel sulphate, cobalt chloride and potassium dichromate after adhesive tape stripping. Solutions of the same metal salts were used for intradermal testing. The intradermal test sites were read after 20 minutes and 48 hours, the patch tests after 48 h. Skin test reactivity correlated poorly to the results of the oral challenge, possibly due to nonspecific skin test reactivity. It is concluded that oral challenge is a valuable adjunctive diagnostic procedure in patients with pompholyx who have negative routine patch tests.
Article
Ten women with vesicular hand eczema and delayed hypersensitivity to nickel were given 0.5 mg nickel supplements to their diets. The double-blind controlled supplements were given on Monday and Tuesday of each week for at least 1 month. The nickel supplement was lower than that used in previous studies, and only one subject had reproducible flaring of her vesicular dermatitis. We conclude that dietary restriction of nickel is not warranted based on nickel supplement studies, but nickel's role in hand eczema could be clarified by depleting nickel from body stores with chelating agents.
Article
Eleven nickel-hypersensitive patients with chronic, dyshidrotic hand eczema aggravated by oral challenge with 0.6–2.5 mg nickel were treated with 100 mg tetraethylthiuramdisulfide (Antabuse®) two to four times daily for 4–10 weeks. Nine of the patients experienced a flare of the dermatitis shortly after initiation of the treatment. During the course of treatment the dermatitis of seven patients, cleared, improvement was seen in two patients, and in two the dermatitis remained unchanged. Flare was seen in six patients when the treatment was discontinued. Seven patients experienced side effects such as fatigue, headache and dizziness. The treatment of four patients was discontinued due to side effects. During the treatment high levels of nickel were found in the serum and urine.