Journal of Oral Rehabilitation 1996 23; 309-320
Review
Biological effects of palladium and risk of using palladium in
dental casting alloys
J . C . W A T A H A * & C T . H A N K S + *The Medical College of Georgia School of Dentistry, Augusta, Georgia and v^;
University of Michigan School of Dentistry, Ann Arbor, Michigan, U.S.A. :.. .
SUMMARY In dentistry, palladium is a very common
component of dental casting alloys of all types, and
its use has increased over the past several decades
in response to the increased cost of gold. However,
there have been recent controversies, particularly in
Germany, over possible adverse biological effects of
using palladium in dental alloys. Therefore, the pur-
pose of this paper is to review the known biological
effects of palladium and the likelihood that these
effects can be caused by dental alloys w^hich contain
palladium. In an ionic form and at sufficiently high
concentrations, palladium has toxic and allergic
Introduction
In dentistry, palladium is a very common component of
dental easting alloys of all types, and its use has increased
over the past several decades in response to the increased
eost of gold. However, there have been reeent contro-
versies, particularly in Germany, over possible adverse
biological effects of using palladium in dental alloys.
Therefore, the purpose of this paper is to review the
known biological effects of palladium and the like-
lihood that these effects can be caused by dental alloys
which contain palladium. This section of this paper
reviews the abundance and uses of palladium, as well as
its physical and chemical properties. Subsequent sections
review the biological effects of palladium, including
toxicity, allergenicity, carcinogenicity and therapeutic
effects, and a final section reviews the literature on the
release of palladium from dental alloys, both in vivo and
in vitro.
1996 Blackwell Science Ltd
^ ^r..,,f.'-yfrr,^rmr ^^
: - ,;...... . ^, A. ....,: ..-•y^ii-
effects on biological systems. Palladium allergy almost
always occurs in individuals w^ho are sensitive t o
nickel. The carcinogenic potential of the palladium
ion is still unclear, although there is some evidence
that it is capable of acting as a mutagen. How^ever,
there are no well documented cases of adverse bio-
logical reactions to palladium in the metallic state.
Furthermore, in spite of the potential adverse bio-
logical effects of palladium ions, t h e risk of using
palladium in dental casting alloys appears to be
extremely low because of the low dissolution rate of
palladium ions from these alloys.
Abundance and uses • " " • • ' - • • • : - ' ••'••
Palladium (Pd) is a member of the platinum group metals
which include, in addition to palladium, platinum (Pt),
rhodium (Rh), ruthenium (Ru), iridium (Ir), and osmium
(Os). These elements are in low concentrations in the
earth's crust compared to other elements, ranging from
0-01 parts per million (p.p.m.) for Pd to 0-001 p.p.m. for
Os (National Research Council, 1977). When compared
to the concentration of aluminum at 18,000 p.p.m.
or silicon at 280,000 p.p.m., the concentration of Pd is
very low, approaching the concentration of gold at
0-005 p.p.m. (Williams, 1981). The largest deposits of Pd
occur in Russia, South Africa and Canada. The South
African deposits are the most concentrated in the
platinum group metals (4-10 p.p.m.), but the Russian
source has the greatest concentration of Pd, estimated at
60% by weight. American deposits of Pd are scarce, but
there is a significant deposit of platinum group metals
309
310 J . C . WATAHA & C.T. H A N K S
which is rich in Pd in Montana (National Research
Council, 1977).
There are diverse uses for palladium. In recent years,
its largest use has been for catalytic converters in auto-
mobiles. Since these devices emit an estimated 1-3 |ig of
Pd and Pt per mile (National Research Council, 1977)
there has been concern about the environmental con-
sequences of Pd emission, and much of the research
about the biological effects of Pd has been done to ad-
dress these concerns. Other uses of Pd include electrical
contacts in the electronics industry, as a catalyst in the
chemical and petroleum industries, and as a component
of jewelery (Brubaker et al, 1975; Moore et al, 1975;
Downey, 1989; Wahlberg & Boman, 1992; Aberer etal,
1993). In medicine, Pd is used in alloys for orthopaedics
and dentistry, and there has been some research into
using Pd-based organometallic compounds as anti-
neoplastic agents similar to the Pt-based agents which
have been in use for many years (National Research
Council, 1977).
Physical and chemical properties
Palladium was discovered by Wollaston in 1803
(Budavari, 1989). It is a group VIIIB transition metal
with atomic number 46 and a molecular weight of
approximately 106-4 (King, Caldwell, & Williams, 1972).
It is also considered to be one of the noble metals (which
consists of the platinum group metals and gold). The most
common oxidation states of Pd are +2 and +4, but Pd(+2)
is the most common of these. The specific gravity of Pd is
11-4 which makes it considerably less dense than gold or
platinum. Pd melts at 1555°C which is significantly higher
than other common components of dental casting alloys
such as gold, copper, silver or zinc, but is the lowest
among the platinum group metals (Craig, 1989). The
Brinell hardness is 61-0 kg/mm^ (Budavari, 1989).
Palladium is a silvery-white metal with face-centred
cubic structure. It reacts with chlorine or fluorine at red
heat to form chloride or fluoride salts which are
somewhat water soluble. It reacts with nitric, sulphuric
and somewhat with concentrated hydrochloric acids. It
will also form sulphides or phosphides (Budavari, 1989).
Palladium will absorb a significant amount of hydrogen,
which can be a liability because of hydrogen embrittle-
ment in casting alloys (Craig, 1989). However, these
absorptive properties have been used to an advantage in
dental impression materials, where Pd powder is added
to sequester unwanted hydrogen gas which is released
during the polymerization reaction, and which would
otherwise diffuse into the die material and form bubbles
(Craig, 1989). The oxide of Pd (PdO) is not water soluble,
which is significant in biological systems since it cannot
readily bond to biological molecules (Budavari, 1989).
In metallurgy, Pd forms a series of solid solutions with
both gold and copper, and this property has been ex-
ploited in the development of dental casting alloys,
especially since it is substantially cheaper than gold. In
dental alloys, Pd is used to raise the melting range of
alloys and increase hardness without reducing the
nobility of the alloys. Interestingly, Pd whitens dental
alloys in concentrations as low as 5 wt.% (Craig, 1989).
Biological effects of palladium
Basie prineiples
Although the biological effects of metals are very diverse,
there are several principles that should be kept in mind.
With metals, the biochemical form of the element
significantly affects its biological properties. Mercury
illustrates this concept better than any other metal. In its
metallic state, elemental mercury has a significant vapour
pressure, is lipid soluble, and can pass from inspired air
into the bloodstream. Elemental mercury has an affinity
for red blood cells and nervous tissue. In its ionic form,
mercury has no vapour pressure and is water soluble,
which makes absorption from the intestine inefficient
because the ionic form cannot easily penetrate the lipid
membranes of the intestinal epithelium. Methyl-mercury
is the most potent toxin of all forms of mercury and is
distributed similarly to the elemental form, but has far
greater negative biological effects (Goyer, 1986).
In general, the toxicity of metal salts follows their water
solubility, but water solubility in itself does not imply
toxicity. Lipid solubility, usually via an organic-metal
complex, allows the metal to gain access to the cells
through the lipid membrane and can contribute to the
toxic effect (National Research Council, 1977). In contrast
to the metal salts, no platinum group metal has been
documented to cause any allergic or toxic reaction in its
elemental form (National Research Council, 1977).
Implicit in this statement is the hypothesis that to cause
biological effects, metals must dissolve from their metallic
state. This statement is of fundamental importance to
the biological effects of Pd or Pd-containing alloys, since
Pd shows very limited dissolution in the body (see section
on release of Pd from dental casting alloys).
1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320

Like most drugs, the route of exposure of metals to
the body is also important to their biological effects
(Goyer, 1986). Intravenous exposure, which can result
during dialysis or as a contaminant in other administered
drugs, is generally the most damaging route of exposure
when considering systemic effects of the metals.
Inhalation and intratracheal exposure are equivalent but
less potent than intravenous exposure, and the least toxic
route of exposure is generally by oral ingestion. The toxic
concentration of a metal can be several hundred times
greater by an oral exposure than by an intravenous
exposure. This principle is also fundamentally important
to dental casting alloys since any dissolved metals are
generally exposing the body through the oral route.
Finally, the way by which the body eliminates the metal
is important. The rate of elimination will determine how
much metal will accumulate in the body, given a certain
ingestion rate. The route of elimination will determine
the organ systems which are at risk for toxic effects.
Elimination rates and routes are complex, and depend
upon the ingestion rate, diet, disease states, exposure to
other metals, and other factors (Goyer, 1986). Further-
more, metals can partition themselves into other areas
of the body such as bone or fat, and this partitioning
affects elimination of the metals as well. In general, the
elimination of salts of the platinum group metals which
are ingested (orally) is rapid and almost complete. Within
3 days, 99% of most platinum group metal salts will be
eliminated primarily from the faeces with some elimina-
tion from the urine. Elimination of metals administered
through the intravenous route is slower (half-life of 14
days), with the kidney, liver and spleen retaining most
of the metals (National Research Council, 1977).
Toxic effects
The toxic effects of Pd were first studied in the 1930s
and 40s (Orestano, 1933; Meek, Harrold & McCord,
1943), and the measurement of the toxicity of Pd has
been approached by animal, cell culture, and enzymology
studies. Several previous reviews of Pd toxicity are
available (National Research Council, 1977; Goyer, 1986).
Reports of Pd toxicity in animals followed the intro-
duction of Pd-containing automotive catalytic converters
in the early 1970s (Table 1). Reports of animal toxicity
appear to be restricted to mice and rats and, to test the
effects of Pd ions, these animals have been exposed through
the oral, intraperitoneal, intratracheal or intravenous routes.
Many studies have included intratracheal exposure
1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320
B I O L O G I C A L E F F E C T S OF P A L L A D I U M 311
because of the concerns regarding Pd emissions from
automobile catalytic converters. The durations of the
exposures have been diverse, ranging from hours with
intravenous exposure (Wiester, 1975) to the lifetime of
the animal after weaning for oral exposure (Schroeder
&Mitchener, 1971).
The biological fate of Pd ions appears to depend upon
the route of administration (Moore etal, 1974). In rats,
greater than 99% of a single dose of radioactive Pd (as
'^^PdCl^) was eliminated after 3 days if administered oral-
ly. When the Pd was administered intratracheally, 95%
of the ions were eliminated after 40 days, whereas after
intravenous administration only 80% of the ions were
eliminated in the same time period. Orally administered
Pd was eliminated primarily though the faeces, whereas
intravenous Pd was eliminated through both the urine
and the faeces. Pd did not move readily across the
placenta, but was present in the milk. In the intravenous
group, the highest tissue concentrations of Pd occurred
in the spleen, liver, lung and bone. The rapid elimination
of Pd ions from the oral route is noteworthy since release
of ions from Pd-containing dental restorations is essen-
tially an oral administration.
Various means have been used to assess the effects of
Pd ions on animal systems. A common method has been
the determination of a dose which will kill 50% of the
animals in a given time period (LD50). LD50 values for
Pd ions have been determined for the different routes of
administration for both rats (Moore etal, 1975; Wiester,
1975) and mice (Phielepeit etal, 1989). In rats, the LD50
values range from 5 mg/kg for the intravenous route to
200 mg/kg for the oral route, whereas in mice these
values were 87 mg/kg for the intraperitoneal route and
1000 mg/kg for the oral route. Care should be taken when
comparing such studies to note the duration of exposure,
since a shorter duration of exposure will generally require
higher doses to cause death of 50% of the animals.
Another method used to measure the effects of Pd ions
on animals is the assessment of body weight and life span
(Schroeder & Mitchener, 1971). When mice were ex-
posed to 5 mg/L of Pd"^^ in the drinking water from
weaning until natural death, animals in the test group
were slightly lighter upon death, but ironically lived
longer than those in the control groups. These trends
were true for both males and females. Other investigators
have measured the effects of Pd ions on different organ
systems, either by measuring the rate of DNA synthesis
in the organs, the organ weight, or by noting the
frequency of histological irregularity. In mice, Pd ions
312 J . C . WATAHA & C.T. H A N K S

Table 1. Summary of animal studies which have measured palladium toxicity

Authors Year Animal Description Results

Schroeder & Mitchener 1971 Mice 5 mg/L of Pd*^ in water Mice exposed to Pd lived longer,
fed from weaning until but had an increased frequency of
death amyloidosis in the kidney, liver,
spleen, and heart
Moore et al. 1974 Rats Single dose of ^ Orally: >99% eliminated in 3 days
given orally, i.t., or i.p.*; i.t.: 95% eliminated after 40 days
followed excretion i.v.: 80% eliminated after 40 days
Moore et al. 1975 Rats Pd"^- given orally, i.v., LD50 for oral, i.v., i.p., or i.t. were
i.p., or i.t. for 14 days. 200, 70, 6, or 5 mg/kg. Not all
Determined LD30** Pd*^ salts were of equivalent
potency
Fisher et al. 1975 Rats Measured DNA 14 |a,mol/kg (3-2 mg/kg)
synthesis in organs after inhibited DNA synthesis in
i.p. dose of spleen, liver, and kidney by 33,
40, and 26% after 2 h. Testes
were not affected
Wiester 1975 Rats Pd+^ salts injected i.v. at Pd+^ induced immediate
0-25-2-0 mg/kg. arrhythmias, particularly
Several salts used. premature ventricular contractions
which led to ventricular
fibrillation. Not all salts were
Rats equivalent
Holhrook et al. 1975 Fed Pd*- salts orally up 2H2O was most potent
to 13 weeks. Chloride, with LD50 of 2-7 mmol/kg (0-6
sulphate and oxide salts g/kg), followed by PdCl^ and
used. PdSO^ at 7 mmol/kg (1-6 g/kg)
and PdO at 40 mmol/kg (9 2 g/kg)
Phielepeit et al. 1989 Mice Mice exposed to ^ i.p. LD50 = 87 mg/kg
either orally or i.p. for 5 days OralLD50 = 1000 mg/kg

i.v. = intravenously; i.p. = intraperitoneally; i.t. = intratracheally; ** LD50 = lethal dose for 50% of the animals.

caused increased frequency of amyoidosis in kidney, liver,
spleen and heart (Schroeder & Mitchener, 1971), whereas
in rats, DNA synthesis in spleen, liver and kidney were
reduced up to 40% after only 2 h of intraperitoneal
exposure to 3-2 mg/kg (Fisher et al, 1975). In the latter
study the testes were not affected. No differences in the
organ weights of rats were observed after exposure to Pd
ions for 13 weeks (Holbrook et al, 1975). The effects of
Pd ions on heart rhythm have also been determined. After
only 1 h, rats which were exposed to between 0-25 and
2 mg/kg of Pd ions intravenously exhibited ventricular
arrhythmias, ventricular tachycardia from multiple foci,
and ventricular fibrillation (Wiester, 1975).
The inorganic form of Pd appears to affect its toxicity.
Although PdCl^ has been the most common salt used in
animal experiments,
2, PdO, and PdCl^ - 2H2O have also been studied
© 1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320
(Moore etal, 1974; Holbrook et al, 1976). In general,
the chloride salt-hydrate appeared to be the most potent,
and the oxide the least potent, with other salts some-
where between depending upon the route of admin-
istration and duration of exposure.
Several studies have investigated the effects of Pd in
cell culture (Table 2). These studies have used primarily
mouse cells, but there has been at least one report using
human cells (Nordlind, 1986). In all reported cases, Pd
ions were administered as PdCl^. As with animal studies,
care must be taken to note the duration of exposures
when comparing studies.
In sufficient concentrations, Pd ions inhibit most major
cellular functions. For mouse fibroblasts, the concen-
trations required to inhibit DNA synthesis, protein
synthesis, mitochondrial activity, and total cell mass
by 50% after 24 h exposure were 300, 340, 360, and
 BIOLOGICAL EFFECTS OF PALLADIUM 313

Table 2. Summary of studies which have measured in vitro effects of palladium

Authors Year In vitro system Description Results

Spikes & Hodgson 1969 Extracellular Effect of PdClj on catalase, Only trypsin and chymotrypsin
enzymes a-chymotrypsin, lysozyme, were inactivated 500 |a,mol/L of
peroxidase, ribonuclease, Pd-"^ in less than 10 min at pH •
trypsin 4-2. At pH 8-9 trypsin was not
inactivated, chymotrypsin was
80% suppressed over 40 min
Rapaka et al. 1976 Extracellular Effect of 370 nmol/L of PdSO^ strongly and irreversibly
prolyl PdSO^ on hydroxylation of inhibited prolyl hydroxylase. ;
hydroxylase proline. This reaction is Ki** was 0-02 mmol/L. Binding
from chick important in collagen of Pd*^ was competitive for the
cartilage synthesis normal Fe*^ binding site
Holbrook et al. 1976 Microsomal Effect of up to 113 )a,mol/kg Pd decreased levels of these
enzymes from of Pd(NOj)2 on aminopyrine enzymes, but less than other '
rat liver demethylase and cytochrome metals such as cadmium or lead.
P450 after 2 days Pd*^ also reduced liver function.
Low exposure of Pd*^ over
several weeks caused no alteration
in liver enzymes
Liu et al. 1979a Creatine kinase Effect of PdCl^ on creatine Pd*^ irreversibly inhibited both
purified from kinase activity; binding of rabbit and human creatine kinase.
rabbit muscle or Pd*^ to creatine kinase Ki** was 0-16 |imol/L. Higher
human serum concentrations were necessary to
inhibit the human enzyme
Liu et al. 1979b Purified enzymes Effect of PdClj on aldolase, All enzymes were inhibited by
from various succinic dehydrogenase, Pd*^. Inhibition was
animals alkaline phosphatase, competitive in several cases and
carbonic anhydrase and prolyl noncompetitive in others. Ki's
hydroxylase activities ranged from 0-16-20 |amol/l
Nordlind 1986 Human Effect of PdCl^ on DNA 100 ^mol/L of Pd*2 inhibited
lymphoid cells synthesis after 5 days thymocyte DNA synthesis. At 3
days, lQ |imol/L stimulated DNA
synthesis by 38%. Similar ^g
findings for lymphocytes , i^.^^
Phielepeit et al. 1989 Mouse liver Locus of Pd+^ in liver cells 2 After 2 days, Pd*^ was found 4;
cells and 5 days after a single dose primarily in the nuclei and
of 50 mg/kg mitochondria. After 5 days, no
cellular Pd*^ was detected
Wataha et al. 1991 Mouse Effect of PdCl^ on DNA TC50* values for
fibroblasts synthesis, protein synthesis, DNA synthesis: 300 |amol/L
mitochondrial activity and protein synthesis: 340 fimol/L
total protein after 24 h mitochondrial Act.: 360 |xmol/L
total protein: 370 |j.mol/L
Wataha et al. 1993 Mouse Uptake rate of Pd*^ over 8 h Upake rate of Pd+^ was 0-21
fibroblasts fmol/cell/h compared with 24-0
for Ag*' and 38-0 for Cd*^

* TC50 = Concentration required to reduce activity to 50% of controls; ** Ki is a measure of binding affinity. A low Ki implies a tightly
bound molecule.
370 jLimol/L, respectively (Wataha, Hanks & Craig, 1991). present in dental casting alloys. With human thymocytes.
In this study, palladium salts were among the least toxic PdCl^ inhibited DNA synthesis in the 0-1 mmol/L range
of the nine metal ions tested, including most elements after 5 days of exposure (Nordlind, 1986). Interestingly,
1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320
314 J . C . WATAHA & C.T. H A N K S
when the duration of exposure was reduced to 3 days, a
38% increase in DNA synthesis was noted at the same
concentration. For human peripheral blood lymphocytes,
a 20% stimulation of DNA synthesis was observed at
lower PdCl^ concentrations, while higher concentra-
tions inhibited DNA synthesis as with the thymocytes
(Nordlind, 1986).
The uptake of Pd""^ by mouse cells has been measured
and compared to other metal ions present in dental
casting alloys (Wataha, Hanks & Craig, 1993). Uptake of
Pd""^ by fibroblasts was 0-21 femtomoles/cell/h, which was
the slowest of the all-metal ions tested, including silver,
gold, cadmium, copper, indium, nickel and zinc. Once
taken up, the fate of Pd ions appears to vary with time
(Phielepeit etal, 1989). In mouse liver cells, a single dose
of Pd""^ was distributed primarily to the nuclei and
mitochondria after 2 days' exposure. Interestingly, after
5 days' exposure, no cellular Pd could be detected.
Several investigators have reported the cellular effects
of Pd-organic compounds. Pd-organic complexes appear
to inhibit macrophage chemotaxis in culture, affecting
the membranes of the macrophages at 0°C and the
nuclear DNA at physiological temperatures (Aresta et al,
1982). In addition, Pd-organic complexes inhibited
transcription in rat hepatocytes by 80% at 1-5 mmol/L
(Mital et al, 1992). These effects were investigated in
hope of identifying new anti-neoplastic drug analogues
to cis-platinum with lower cytotoxicity. Since most
investigators believe that the therapeutic action of the
cis-platinum drugs is by inhibition of DNA replication or
transcription, transcription rates have been chosen to
assess potentially beneficial drugs. It has also been report-
ed that the Pd-organic complexes inhibit transcription
by altering the DNA template and inhibiting the enzymes
involved in transcription (Mital et al, 1992).
There have been a number of investigations into the
effect of Pd on different cellular enzymes (Table 2), and
a wide variety of enzymes have been studied from several
animal systems. At sufficient concentrations, most en-
zymes are inactivated by Pd ions. Inhibition can be time
and pH dependent or independent (Spikes & Hodgson,
1969) and appears to be irreversible in many cases
(Rapaka et al, 1976; Liu, Khayan-Bashi & Bhatnagar,
1979; Liu, Lee & Bhatnagar, 1979). In one case, the
mechanisms of inhibition appeared to be a replacement
of Fe""^ with Pd""^ at the active site of prolyl hydroxylase,
an enzyme crucial for normal collagen formation (Rapaka
et al, 1976). In another report, the authors speculated
' that Pd inhibited enzymes by binding sulphahydril or
© 1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320
cystine groups on the protein (Spikes & Hodgson, 1969),
although no direct evidence was available to support this
theory. The binding of Pd to enzymes would appear to
be supported by studies which show that such binding
alters the electrophoretic mobility of some enzymes,
indicating significant conformational change (Rapaka
et al, 1976). The affinity of Pd""^ for different enzymes
has been quantified by the dissociation constant of the
enzyme-inhibitor complex (Ki). This equilibrium
constant is small when the inhibitor is tightly bound. Ki
values for Pd""^ range from 0-02 to 0-6 mmol/L, which is
small and indicates a tenaciously bound inhibitor.
Protection against the effects of Pd ions have also been
reported in liver cells if the palladium is administered in
lower doses over several weeks (Holbrook et al, 1976;
Phielepeit etal, 1989). These protective effects have been
attributed to the induction of metallothioneins which are
well known to bind and sequester other metal ions in
liver and other cells.
Allergie effects
Although platinum has been recognized as a potent
allergen for many years (Goyer, 1986), other elements
in the platinum group family, including Pd, have been
less well studied as allergens. The literature on this topic
consists of numerous cases reports and several group
studies which have attempted to define the frequency of
Pd allergy and cross-reactivity with other metals.
Case reports of Pd allergy began to appear in the
literature in 1981, when Van Ketel and Niebber reported
a case of a 19-year-old female who had swelling of the
right cheek and pain in the mouth at the site of a dental
bridge placed 6 months earlier (Van Ketel & Niebber,
1981). The patient also complained of generalized itching
and dizziness. The bridge contained gold, silver, platinum,
palladium (5 wt%), copper, zinc, magnesium, bismuth
and tin. The patch tests to pure metals gave positive
reactions to Ni and Co, with a borderline reaction to Cr.
However, when solutions of the metal salts were tested,
only Pd caused a strong reaction. When the bridge was
replaced 'without any metal', the symptoms disappeared.
Further details were not given. A second case report was
published in 1987 by Castelain & Castelain, who reported
a woman who tested allergic only to Pd in a standard
patch test battery which included methacrylate resins,
benzoyl peroxide, and other dental resins. These tests
were performed after placement of a metallic crown on
a single tooth produced swelling of the lower lip and

mucocutaneous lesions on the lip. Symptoms disappeared
after removal of the crown. The composition of the alloy
was not reported.
Guerra et al. (1988) reported two patients who tested
positive to nickel sulphate and palladium chloride. The
first patient was treated for erythematous vesicular lesions
of the forearms, presumably caused by heavy exposure
to the metals from handling firearms. The second patient
showed similar lesions on the neck, forearms and legs
which the authors speculated were caused by exposure
to metals during weight lifting. No further details were
provided. In 1989, Downey reported two instances of
patients who exhibited lichen-planus-like reactions
adjacent to recently placed crowns containing 79 wt%
Pd. Both patients tested positive to a PdCl^ solution in a
standard patch test, and both patients improved when
the crowns were removed. Van Joost & Roesyanto-
Mahadi (1990) reported a 28-year-old female who
developed disseminated urticaria after placement of a dental
bridge containing 90% palladium and 10% nickel by weight.
The patient tested positive to nickel and palladium in
standard patch tests. The investigators were not able to
identify which metal was responsible for the reaction.
In addition to case reports, a number of surveys have
been published on the frequency of Pd allergy (Table 3).
Allergy to Pd is most often tested by means of a patch
test, where a small patch containing a solution of PdCl^
is placed next to the skin for several days. Alternatively,
a drop of the solution is placed on a small prick in the
skin (skin-prick method). The reported frequency of
sensitivity in these types of studies must be interpreted
carefully, noting particularly the manner by which the
patient pool was selected for the study and the size of
the study, as well as the method of application. For
example, some studies have selected populations where
Pd sensitivity might be elevated due to employment in
platinum refineries (Murdoch & Pepys, 1987) or due to
history of other allergy (van Loon etal, 1984; van Loon
etal, 1988; Rebandel & Rudzki, 1990; Aberer rfa/., 1993).
The frequency of Pd sensitivity appears to range from
2% to 18% depending on these variables.
The presence of nickel sensitivity appears to be critical
to assessing Pd sensitivity, since the overwhelming
majority (93-100%) of people who are sensitive to Pd
ions are also sensitive to nickel (Augthun, Lichtenstein
& Kammerer, 1990; Rebandel & Rudzki, 1990; Camarasa
etal, 1991; Todd & Burrows, 1992; Aberer ^f a/., 1993).
There is still controversy whether a true cross-sensitivity
exists between nickel and Pd. It has been reported that
© 1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320
B I O L O G I C A L E F F E C T S OF P A L L A D I U M 315
traces of nickel in the palladium solutions may be
responsible for this phenomenon (Camarasa etal, 1991),
but others report that such contamination is not the cause
of the apparent cross-reactivity (Wahlberg & Boman,
1992). It should be emphasized that the frequency of
sensitivity exclusively to Pd ions is relatively rare (Table
3). There is some evidence of limited cross-reactivity
between platinum and Pd sensitivity (Biagini etal, 1985;
Murdoch & Pepys, 1987).
Although the vast majority of sensitivity tests have been
done using Pd ions, there are several reports of tests which
use Pd metal on the skin or in the mouth (van Loon
etal, 1984; van Loon etal, 1988; Augthun etal, 1990;
Todd £r Burrows, 1992). It is noteworthy that even in
patients with sensitivity to Pd ions, most (0-7%) will
not react to Pd metal. Most authors have interpreted this
observation as evidence that little or no Pd is released
from the Pd metal. In studies where histological
examination of tissues adjacent to Pd metal were
performed, tissue reaction is far more subdued than those
seen with Ni-containing alloys (van Loon et al, 1988).
Carcinogenic effects
Compared to studies which have assessed the toxic and
allergic effects of Pd, there are few studies which have
determined the carcinogenic effects of this metal. The
earliest study was reported by Schroeder & Mitchener in
1971, who assessed the carcinogenic potential of
palladium chloride. Mice were fed 5 parts per million
PdCl^ from weaning until 'natural' death. Seventy nine
of the 110 mice were autopsied and 19 tumours were
found, 18 of which were malignant. In the control group,
100 mice were autopsied, 13 tumours were found, 11 of
which were malignant. The authors concluded that Pd
appeared to exhibit a 'slight' carcinogenic activity in mice
because the rate of tumour formation in the Pd group
was marginally statistically significant. Pillai & Nandi
(1977) have reported that Pd interacts with the
phosphates and bases of DNA causing a 'considerable'
conformation change, and implicating Pd as a potential
mutagen. However, no information regarding DNA
mutations was reported.
In a review of the effects of platinum group metals in
1977, the National Research Council reported several
Japanese studies on the carcinogenicity of Pd (National
Research Council, 1977). In one study, a silver-palladium-
gold dental alloy was imbedded subcutaneously for 504
days in rats. Tumour formation was noted in seven of
316 J . C . W A T A H A & C.T. HANKS

Table 3. Summary of studies which have reported the incidence of palladium allergy

Number
Authors Year in study Description Results

van Loon et al. 1984 17 Skin (patch) test of ^ Three out of 17 patches tested positive to
Pd foil tested on cheek Pd*^. No patient tested positive
mucosa. Patients selected on to Pd foil
basis of history of allergic
reactions
Murdoch & Pepys 1987 306 Platinum refinery workers 2 % of workers were sensitive to
patch tested for PdCl^ PdCl^. Ni sensitivity not tested.
sensitivity No Pt-sensitive worker was also
sensitive to Pd*^
van Loon et al. 1988 IS Selected 15 patients with Slight increase in T cells and
positive patch tests to Ni. Langerhans cells after 7 days. Far
Tested for allergy to intraoral less reaction than for other metals
Pd metal (nickel)
Namikoshi et al. 1990 95 Patients selected at random. No patient showed a positive test
Skin patch tested to 15 metals to PdCl^. Eight of the 17 patients with
salts, including PdCl^ positive tests to other metal salts
had a history of dermatitis
Augthun et al. 1990 486 Patients patch tested for 7-4% (36) of patients were
sensitivity to metal salts, sensitive to PdCl^. 34 of these
including patients were also sensitive to
NiCl^. Only one of the 36 were
sensitive to Pd metal
Rebandel & Rudzki 1990 100 Patients had history of Ten patients were sensitive to both
dermatitis. Patch tested for Ni*^ and Pd*^. No patients were
and only sensitive to Pd*^
Camarasa et al. 1991 1521 Patch tested patients for 42 patients (2-8%) were sensitive
to Pd*^. 39 of these were female.
39 of these were also sensitive to

Todd & Burrows 1992 536 Patch tested patients for Thirteen patients (2-4%) tested positive
and NiCl,. Pd-sensitive for Pd*^, all of whom were also
patients were also tested with sensitive to Ni*^. Twelve of the 13
Pd metal patients were not sensitive to Pd
metal. One was not tested
Aberer et al. 1993 1382 Patients had history of 8-3% (115) of the patients
eczema. Patch tested with showed a positive reaction to
Pd*^ 107 of these patients were
also sensitive to Ni*^

the 14 rats. However, implants in the oral submucous
membrane of rabbits had 'only mild effects.' In another
study by Ridgway and Karnofsy (National Research
Council, 1977), PdCl^ was determined to be non-
tertatogenic in developing chicken eggs.
Therapeutic uses . 7 mg/day of the colloid suspension caused a 19 kg weight
Unlike platinum, which has been used in organometallic
compounds for the treatment of cancer for many years.
the use of Pd for cancer drugs or other therapeutic uses
have been limited (Das & Livingstone, 1978). There are
reports of PdCl^ being used unsuccessfully to treat
tuberculosis at a daily dosage of 18 mg (National Research
Council, 1977). Palladium chloride has also been used
as a germacide. Finally, palladium hydroxide has been
administered to patients to treat obesity. Injections of 5-
loss over 3 months and necrosis at the injection site
(National Research Council, 1977).

1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320


Release of palladium from dental casting
alloys
Most researchers agree that the toxic, allergic, carcino-
genic, or therapeutic effects of Pd require that the Pd be
in an ionic form (Williams, 1981; Van Joost & Roesyanto-
Mahadi, 1990). This hypothesis is of fundamental
importance to the biological effects of dental alloys since
it assumes that any effect of the alloy is caused by
ions which have dissolved. Thus, the release of palladium
ions from dental alloys is of interest and is reviewed
briefly here.
In vivo
There are few studies which have addressed the question
of Pd release from dental alloys in vivo, and these are
inconclusive. One report, a review by the US National
Research Council in 1977, apparently found Pd in teeth
that had been restored with an unidentified Pd-
containing alloy. In 1987, Bessing & Kallus implanted
two silver-palladium alloys subcutaneously into guinea-
pigs for 30-90 days. The tissue response to the alloys
was compared to low- and no-gold alloys. One alloy (Alba
V) showed several 'severe and extreme' reactions after
90 days. The other alloy (Albacast) showed the least tissue
response of any of the alloys or controls. The authors
attributed the tissue responses to elements which were
released from the alloys, but did not measure such release
themselves. In 1988, Kratzenstein, Sauer & Weber report-
ed that metal ions released from alloys which had been
present in the mouth for 0-5-8 years may be responsible
for hyperplastic tissue or other oral symptoms, such as
burning of the tongue or a metallic taste. However, they
did not measure the levels of these ions in the tissue and
were not able to discern which released elements might
be responsible for these reactions, or if these reactions
were caused by the metals.
In 1992, Downey published a case report of a woman
who developed acute intermittent porphyria after
placement of a dental alloy composed of 76% palladium,
2% gold and 10% copper. In spite of the high Pd content
of the alloy, it was determined that copper, not palladium,
was responsible for the patient's symptoms, which
included skin rashes, diarrhoea, metallic taste and short-
term memory loss, among others. Downey did not report
how palladium was ruled out, however. The patient
recovered fully after the alloy was removed. In an
abstract, Rechmann (1992) reported that a variety of
1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320
BIOLOGICAL EFFECTS OF PALLADIUM 317
elements, including Au, Pt, Ga and indium were found
in tissues adjacent to dental casting alloys, but he did not
report any Pd release.
In vitro . ' , . #.
Similar to in vivo studies, there are relatively few reports
addressing in vitro Pd release from dental alloys. Niemi,
Minni & Ivaska (1986) measured elemental release from
several types of dental casting alloys, including a multiple
phase Ag-Pd-Cu-Au alloy and single phase Cu-Pd and
Ag-Pd alloys (Fig. 1). The alloys were in contact with an
artificial saliva solution for 24 h before elemental release
was measured using atomic absorption spectroscopy.
Copper and silver dissolved from both the single and
multiple phase alloys. In each case. X-ray photoelectron
spectroscopy showed that as these elements dissolved,
the concentrations of gold and palladium increased at
the alloy surface. Neither gold nor palladium dissolved
from either the multiple phase or single phase alloys.
1000
1
100 r
1
10 r
1
li
CJ
1 r
1
o
U
1 ,
0-1
B
Pd
Ag Cu
Fig. 1. Alloys of silver, copper, palladium, gold and zinc were
exposed to an artificial saliva solution at 25°C for 24 h after which
the amount of elements released were measured by means of atomic
absorption spectroscopy. The ratio of alloy surface area to volume
of artificial saliva was 520 mm"/mL. Alloy A had a single phase
microstructure of 52-4% silver (by weight) with 23-4% palladium
and 21-7% copper. Alloy B had a multiple phase microstructure
with a nominal composition of 50-9% copper with 32-4% palladium
and 12-6% silver. Alloy C also had a multiple phase microstructure,
but had a nominal composition of 67% silver, 20% palladium and
9-8% copper. None of the alloys had greater than 3% gold. No
alloy released detectable amounts of palladium or gold into the
saliva. The detection limit for palladium was 2 |a.g/mL (horizontal
line).
318 J . C . WATAHA & C.T. H A N K S

The detection limit for Pd was <2 ng/mL. Goehlich &

Marek (1990) found that Pd-Cu or Pd-Co alloys did not
release Pd into artificial saliva even when external
potentials were applied to the alloys for up to 64 h (Fig.
2). Like Niemi etal (1986), they also found that Pd was
enriched at the alloy surface. Wataha, Craig Er Hanks
(1991) reported that when a variety of dental casting
alloys were immersed in cell culture medium for 72 h,
no palladium or gold were found in the cell culture
medium, regardless of the abundance of these elements
in the alloys (Fig. 3). The compositions of these alloys
included high-, med-, and no-gold single phase alloys,
and a multiple phase silver-palladium alloy. The detection
limit for palladium was 35 ng/mL. In a second study,
Wataha, Craig & Hanks (1992) reported that palladium Fig. 3. Alloys of silver, copper, palladium, gold and zinc were
and gold were not released from these alloys even if the exposed to cell culture medium for 72 h after which the release of
alloys were not subjected to a cleaning treatment designed elements was measured. The surface area of the samples was 63 mm"
and the extration volume was 500 ^L (126 mm"/mL). No alloy re-
to disinfect the alloys prior to cell culture.
leased detectable levels of palladium into the medium. The detec-
tion limit for palladium was 0-035 |xg/mL. Alloy A was a high-gold,
single-phase alloy with 2-6 at% palladium. Alloy B was a low-gold
Conclusions single-phase alloy with 23-0% palladium. Alloy C was a no-gold,
single-phase alloy with 22-5% palladium, whereas alloy D was a
In an ionic form, Pd has toxic and allergic effects on no-gold, multiple-phase alloy with a nominal concentration of
biological systems. The carcinogenic potential of the Pd 22-8% palladium.
ion is still unclear, although there is some evidence that
it is capable of acting as a mutagen. The toxic effects of
the Pd ion are primarily from sources which are
administered parenterally. Oral ingestion of the ion has
relatively few effects because the majority of the Pd is
rapidly excreted in the faeces. The allergic effects of the
1
Pd ion seem to occur primarily in individuals who are

1•
sensitive to nickel, although there are a few cases of Pd
Pd sensitivity in individuals with no known nickel sensitivity.
Cu At present, there are no significant therapeutic uses for
Pd. Finally, there are no well documented cases of adverse
^ 0-6 biological reactions to palladium in the metallic state.
o In spite of the potential adverse biological effects of
-
1 ^'"^ palladium ions, the risk of using Pd in dental casting alloys
appears to be extremely low because of the low dissolu-
o tion rate of Pd from these alloys. In both in vivo and in
o 0-2
U vitro studies, there is little or no evidence that Pd dissolves
to any degree from a variety of alloy compositions,
0 1 '
including multiple phase compositions. Additional studies
24 h 64 h in this area are needed. The inertness of Pd in the metallic
Fig. 2. An alloy of 14-8 wt% copper and 85-2% palladium was form is further supported by a lack of allergic responses
immersed in artificial saliva. A potential of 0-6 volts was applied to to Pd or Pd-alloys by individuals who are known to be
the alloy for 24 or 64 h, after which the release of elements from
sensitive to the ionic form of the element. However, the
the alloy was measured by means of atomic absorption spectroscopy.
The surface area of the alloys were 260 mm", but the extraction
greatest risk of using Pd in these alloys appears to be of
volume was not given. The results indicated that palladium was an allergic response, although the indications are that
not released from the alloy in amounts greater than 0-02 [iglmL Pd sensitivity is rare in the general population (Henrsten-
(detection limit = horizontal line). Pettersen, 1992). There does seem to be an increased risk

1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320


of Pd sensitivity in individuals who are sensitive to nickel,
although a true cross-reactivity has not been established.
The risk of toxic or carcinogenic effects from Pd in dental
alloys appears extremely low based on the low dissolution
rate of Pd from its metallic state combined with the low
absorption rate of Pd from the gastrointestinal tract and
the relatively high doses required to induce these effects.
Acknowledgment
The authors thank Ivoclar North America for their
support of this work.
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