Journal of Oral Rehabilitation 1996 23; 309-320

Review
Biological effects of palladium and risk of using palladium in
dental casting alloys ^ ^r..,,f.'-yfrr,^rmr ^^
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. :.. . : - ,;...... . ^, A. ....,: ..-•y^ii-

SUMMARY In dentistry, palladium is a very common effects on biological systems. Palladium allergy almost
component of dental casting alloys of all types, and always occurs in individuals w^ho are sensitive t o
its use has increased over the past several decades nickel. The carcinogenic potential of the palladium
in response to the increased cost of gold. However, ion is still unclear, although there is some evidence
there have been recent controversies, particularly in that it is capable of acting as a mutagen. How^ever,
Germany, over possible adverse biological effects of there are no well documented cases of adverse bio-
using palladium in dental alloys. Therefore, the pur- logical reactions to palladium in the metallic state.
pose of this paper is to review the known biological Furthermore, in spite of the potential adverse bio-
effects of palladium and the likelihood that these logical effects of palladium ions, t h e risk of using
effects can be caused by dental alloys w^hich contain palladium in dental casting alloys appears to be
palladium. In an ionic form and at sufficiently high extremely low because of the low dissolution rate of
concentrations, palladium has toxic and allergic palladium ions from these alloys.

Introduction Abundance and uses • " " • • ' - • • • : - ' ••'••

In dentistry, palladium is a very common component of Palladium (Pd) is a member of the platinum group metals
dental easting alloys of all types, and its use has increased which include, in addition to palladium, platinum (Pt),
over the past several decades in response to the increased rhodium (Rh), ruthenium (Ru), iridium (Ir), and osmium
eost of gold. However, there have been reeent contro- (Os). These elements are in low concentrations in the
versies, particularly in Germany, over possible adverse earth's crust compared to other elements, ranging from
biological effects of using palladium in dental alloys. 0-01 parts per million (p.p.m.) for Pd to 0-001 p.p.m. for
Therefore, the purpose of this paper is to review the Os (National Research Council, 1977). When compared
known biological effects of palladium and the like- to the concentration of aluminum at 18,000 p.p.m.
lihood that these effects can be caused by dental alloys or silicon at 280,000 p.p.m., the concentration of Pd is
which contain palladium. This section of this paper very low, approaching the concentration of gold at
reviews the abundance and uses of palladium, as well as 0-005 p.p.m. (Williams, 1981). The largest deposits of Pd
its physical and chemical properties. Subsequent sections occur in Russia, South Africa and Canada. The South
review the biological effects of palladium, including African deposits are the most concentrated in the
toxicity, allergenicity, carcinogenicity and therapeutic platinum group metals (4-10 p.p.m.), but the Russian
effects, and a final section reviews the literature on the source has the greatest concentration of Pd, estimated at
release of palladium from dental alloys, both in vivo and 60% by weight. American deposits of Pd are scarce, but
in vitro. there is a significant deposit of platinum group metals

1996 Blackwell Science Ltd 309

310 J . C . WATAHA & C.T. H A N K S

which is rich in Pd in Montana (National Research during the polymerization reaction, and which would
Council, 1977). otherwise diffuse into the die material and form bubbles
There are diverse uses for palladium. In recent years, (Craig, 1989). The oxide of Pd (PdO) is not water soluble,
its largest use has been for catalytic converters in auto- which is significant in biological systems since it cannot
mobiles. Since these devices emit an estimated 1-3 |ig of readily bond to biological molecules (Budavari, 1989).
Pd and Pt per mile (National Research Council, 1977) In metallurgy, Pd forms a series of solid solutions with
there has been concern about the environmental con- both gold and copper, and this property has been ex-
sequences of Pd emission, and much of the research ploited in the development of dental casting alloys,
about the biological effects of Pd has been done to ad- especially since it is substantially cheaper than gold. In
dress these concerns. Other uses of Pd include electrical dental alloys, Pd is used to raise the melting range of
contacts in the electronics industry, as a catalyst in the alloys and increase hardness without reducing the
chemical and petroleum industries, and as a component nobility of the alloys. Interestingly, Pd whitens dental
of jewelery (Brubaker et al, 1975; Moore et al, 1975; alloys in concentrations as low as 5 wt.% (Craig, 1989).
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 Biological effects of palladium
using Pd-based organometallic compounds as anti-
neoplastic agents similar to the Pt-based agents which Basie prineiples
have been in use for many years (National Research Although the biological effects of metals are very diverse,
Council, 1977). there are several principles that should be kept in mind.
With metals, the biochemical form of the element
significantly affects its biological properties. Mercury
Physical and chemical properties
illustrates this concept better than any other metal. In its
Palladium was discovered by Wollaston in 1803 metallic state, elemental mercury has a significant vapour
(Budavari, 1989). It is a group VIIIB transition metal pressure, is lipid soluble, and can pass from inspired air
with atomic number 46 and a molecular weight of into the bloodstream. Elemental mercury has an affinity
approximately 106-4 (King, Caldwell, & Williams, 1972). for red blood cells and nervous tissue. In its ionic form,
It is also considered to be one of the noble metals (which mercury has no vapour pressure and is water soluble,
consists of the platinum group metals and gold). The most which makes absorption from the intestine inefficient
common oxidation states of Pd are +2 and +4, but Pd(+2) because the ionic form cannot easily penetrate the lipid
is the most common of these. The specific gravity of Pd is membranes of the intestinal epithelium. Methyl-mercury
11-4 which makes it considerably less dense than gold or is the most potent toxin of all forms of mercury and is
platinum. Pd melts at 1555°C which is significantly higher distributed similarly to the elemental form, but has far
than other common components of dental casting alloys greater negative biological effects (Goyer, 1986).
such as gold, copper, silver or zinc, but is the lowest In general, the toxicity of metal salts follows their water
among the platinum group metals (Craig, 1989). The solubility, but water solubility in itself does not imply
Brinell hardness is 61-0 kg/mm^ (Budavari, 1989). toxicity. Lipid solubility, usually via an organic-metal
Palladium is a silvery-white metal with face-centred complex, allows the metal to gain access to the cells
cubic structure. It reacts with chlorine or fluorine at red through the lipid membrane and can contribute to the
heat to form chloride or fluoride salts which are toxic effect (National Research Council, 1977). In contrast
somewhat water soluble. It reacts with nitric, sulphuric to the metal salts, no platinum group metal has been
and somewhat with concentrated hydrochloric acids. It documented to cause any allergic or toxic reaction in its
will also form sulphides or phosphides (Budavari, 1989). elemental form (National Research Council, 1977).
Palladium will absorb a significant amount of hydrogen, Implicit in this statement is the hypothesis that to cause
which can be a liability because of hydrogen embrittle- biological effects, metals must dissolve from their metallic
ment in casting alloys (Craig, 1989). However, these state. This statement is of fundamental importance to
absorptive properties have been used to an advantage in the biological effects of Pd or Pd-containing alloys, since
dental impression materials, where Pd powder is added Pd shows very limited dissolution in the body (see section
to sequester unwanted hydrogen gas which is released on release of Pd from dental casting alloys).

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 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

Like most drugs, the route of exposure of metals to because of the concerns regarding Pd emissions from
the body is also important to their biological effects automobile catalytic converters. The durations of the
(Goyer, 1986). Intravenous exposure, which can result exposures have been diverse, ranging from hours with
during dialysis or as a contaminant in other administered intravenous exposure (Wiester, 1975) to the lifetime of
drugs, is generally the most damaging route of exposure the animal after weaning for oral exposure (Schroeder
when considering systemic effects of the metals. &Mitchener, 1971).
Inhalation and intratracheal exposure are equivalent but The biological fate of Pd ions appears to depend upon
less potent than intravenous exposure, and the least toxic the route of administration (Moore etal, 1974). In rats,
route of exposure is generally by oral ingestion. The toxic greater than 99% of a single dose of radioactive Pd (as
concentration of a metal can be several hundred times '^^PdCl^) was eliminated after 3 days if administered oral-
greater by an oral exposure than by an intravenous ly. When the Pd was administered intratracheally, 95%
exposure. This principle is also fundamentally important of the ions were eliminated after 40 days, whereas after
to dental casting alloys since any dissolved metals are intravenous administration only 80% of the ions were
generally exposing the body through the oral route. eliminated in the same time period. Orally administered
Finally, the way by which the body eliminates the metal Pd was eliminated primarily though the faeces, whereas
is important. The rate of elimination will determine how intravenous Pd was eliminated through both the urine
much metal will accumulate in the body, given a certain and the faeces. Pd did not move readily across the
ingestion rate. The route of elimination will determine placenta, but was present in the milk. In the intravenous
the organ systems which are at risk for toxic effects. group, the highest tissue concentrations of Pd occurred
Elimination rates and routes are complex, and depend in the spleen, liver, lung and bone. The rapid elimination
upon the ingestion rate, diet, disease states, exposure to of Pd ions from the oral route is noteworthy since release
other metals, and other factors (Goyer, 1986). Further- of ions from Pd-containing dental restorations is essen-
more, metals can partition themselves into other areas tially an oral administration.
of the body such as bone or fat, and this partitioning Various means have been used to assess the effects of
affects elimination of the metals as well. In general, the Pd ions on animal systems. A common method has been
elimination of salts of the platinum group metals which the determination of a dose which will kill 50% of the
are ingested (orally) is rapid and almost complete. Within animals in a given time period (LD50). LD50 values for
3 days, 99% of most platinum group metal salts will be Pd ions have been determined for the different routes of
eliminated primarily from the faeces with some elimina- administration for both rats (Moore etal, 1975; Wiester,
tion from the urine. Elimination of metals administered 1975) and mice (Phielepeit etal, 1989). In rats, the LD50
through the intravenous route is slower (half-life of 14 values range from 5 mg/kg for the intravenous route to
days), with the kidney, liver and spleen retaining most 200 mg/kg for the oral route, whereas in mice these
of the metals (National Research Council, 1977). 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,
Toxic effects since a shorter duration of exposure will generally require
The toxic effects of Pd were first studied in the 1930s higher doses to cause death of 50% of the animals.
and 40s (Orestano, 1933; Meek, Harrold & McCord, Another method used to measure the effects of Pd ions
1943), and the measurement of the toxicity of Pd has on animals is the assessment of body weight and life span
been approached by animal, cell culture, and enzymology (Schroeder & Mitchener, 1971). When mice were ex-
studies. Several previous reviews of Pd toxicity are posed to 5 mg/L of Pd"^^ in the drinking water from
available (National Research Council, 1977; Goyer, 1986). weaning until natural death, animals in the test group
Reports of Pd toxicity in animals followed the intro- were slightly lighter upon death, but ironically lived
duction of Pd-containing automotive catalytic converters longer than those in the control groups. These trends
in the early 1970s (Table 1). Reports of animal toxicity were true for both males and females. Other investigators
appear to be restricted to mice and rats and, to test the have measured the effects of Pd ions on different organ
effects of Pd ions, these animals have been exposed through systems, either by measuring the rate of DNA synthesis
the oral, intraperitoneal, intratracheal or intravenous routes. in the organs, the organ weight, or by noting the
Many studies have included intratracheal exposure frequency of histological irregularity. In mice, Pd ions

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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, (Moore etal, 1974; Holbrook et al, 1976). In general,
spleen and heart (Schroeder & Mitchener, 1971), whereas the chloride salt-hydrate appeared to be the most potent,
in rats, DNA synthesis in spleen, liver and kidney were and the oxide the least potent, with other salts some-
reduced up to 40% after only 2 h of intraperitoneal where between depending upon the route of admin-
exposure to 3-2 mg/kg (Fisher et al, 1975). In the latter istration and duration of exposure.
study the testes were not affected. No differences in the Several studies have investigated the effects of Pd in
organ weights of rats were observed after exposure to Pd cell culture (Table 2). These studies have used primarily
ions for 13 weeks (Holbrook et al, 1975). The effects of mouse cells, but there has been at least one report using
Pd ions on heart rhythm have also been determined. After human cells (Nordlind, 1986). In all reported cases, Pd
only 1 h, rats which were exposed to between 0-25 and ions were administered as PdCl^. As with animal studies,
2 mg/kg of Pd ions intravenously exhibited ventricular care must be taken to note the duration of exposures
arrhythmias, ventricular tachycardia from multiple foci, when comparing studies.
and ventricular fibrillation (Wiester, 1975). In sufficient concentrations, Pd ions inhibit most major
The inorganic form of Pd appears to affect its toxicity. cellular functions. For mouse fibroblasts, the concen-
Although PdCl^ has been the most common salt used in trations required to inhibit DNA synthesis, protein
animal experiments, synthesis, mitochondrial activity, and total cell mass
2, PdO, and PdCl^ - 2H2O have also been studied by 50% after 24 h exposure were 300, 340, 360, and
© 1996 Blackwell Science Ltd, Journal of Oral Rehabilitation 23; 309-320
 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 cystine groups on the protein (Spikes & Hodgson, 1969),
38% increase in DNA synthesis was noted at the same although no direct evidence was available to support this
concentration. For human peripheral blood lymphocytes, theory. The binding of Pd to enzymes would appear to
a 20% stimulation of DNA synthesis was observed at be supported by studies which show that such binding
lower PdCl^ concentrations, while higher concentra- alters the electrophoretic mobility of some enzymes,
tions inhibited DNA synthesis as with the thymocytes indicating significant conformational change (Rapaka
(Nordlind, 1986). et al, 1976). The affinity of Pd""^ for different enzymes
The uptake of Pd""^ by mouse cells has been measured has been quantified by the dissociation constant of the
and compared to other metal ions present in dental enzyme-inhibitor complex (Ki). This equilibrium
casting alloys (Wataha, Hanks & Craig, 1993). Uptake of constant is small when the inhibitor is tightly bound. Ki
Pd""^ by fibroblasts was 0-21 femtomoles/cell/h, which was values for Pd""^ range from 0-02 to 0-6 mmol/L, which is
the slowest of the all-metal ions tested, including silver, small and indicates a tenaciously bound inhibitor.
gold, cadmium, copper, indium, nickel and zinc. Once Protection against the effects of Pd ions have also been
taken up, the fate of Pd ions appears to vary with time reported in liver cells if the palladium is administered in
(Phielepeit etal, 1989). In mouse liver cells, a single dose lower doses over several weeks (Holbrook et al, 1976;
of Pd""^ was distributed primarily to the nuclei and Phielepeit etal, 1989). These protective effects have been
mitochondria after 2 days' exposure. Interestingly, after attributed to the induction of metallothioneins which are
5 days' exposure, no cellular Pd could be detected. well known to bind and sequester other metal ions in
Several investigators have reported the cellular effects liver and other cells.
of Pd-organic compounds. Pd-organic complexes appear
to inhibit macrophage chemotaxis in culture, affecting
Allergie effects
the membranes of the macrophages at 0°C and the
nuclear DNA at physiological temperatures (Aresta et al, Although platinum has been recognized as a potent
1982). In addition, Pd-organic complexes inhibited allergen for many years (Goyer, 1986), other elements
transcription in rat hepatocytes by 80% at 1-5 mmol/L in the platinum group family, including Pd, have been
(Mital et al, 1992). These effects were investigated in less well studied as allergens. The literature on this topic
hope of identifying new anti-neoplastic drug analogues consists of numerous cases reports and several group
to cis-platinum with lower cytotoxicity. Since most studies which have attempted to define the frequency of
investigators believe that the therapeutic action of the Pd allergy and cross-reactivity with other metals.
cis-platinum drugs is by inhibition of DNA replication or Case reports of Pd allergy began to appear in the
transcription, transcription rates have been chosen to literature in 1981, when Van Ketel and Niebber reported
assess potentially beneficial drugs. It has also been report- a case of a 19-year-old female who had swelling of the
ed that the Pd-organic complexes inhibit transcription right cheek and pain in the mouth at the site of a dental
by altering the DNA template and inhibiting the enzymes bridge placed 6 months earlier (Van Ketel & Niebber,
involved in transcription (Mital et al, 1992). 1981). The patient also complained of generalized itching
There have been a number of investigations into the and dizziness. The bridge contained gold, silver, platinum,
effect of Pd on different cellular enzymes (Table 2), and palladium (5 wt%), copper, zinc, magnesium, bismuth
a wide variety of enzymes have been studied from several and tin. The patch tests to pure metals gave positive
animal systems. At sufficient concentrations, most en- reactions to Ni and Co, with a borderline reaction to Cr.
zymes are inactivated by Pd ions. Inhibition can be time However, when solutions of the metal salts were tested,
and pH dependent or independent (Spikes & Hodgson, only Pd caused a strong reaction. When the bridge was
1969) and appears to be irreversible in many cases replaced 'without any metal', the symptoms disappeared.
(Rapaka et al, 1976; Liu, Khayan-Bashi & Bhatnagar, Further details were not given. A second case report was
1979; Liu, Lee & Bhatnagar, 1979). In one case, the published in 1987 by Castelain & Castelain, who reported
mechanisms of inhibition appeared to be a replacement a woman who tested allergic only to Pd in a standard
of Fe""^ with Pd""^ at the active site of prolyl hydroxylase, patch test battery which included methacrylate resins,
an enzyme crucial for normal collagen formation (Rapaka benzoyl peroxide, and other dental resins. These tests
et al, 1976). In another report, the authors speculated were performed after placement of a metallic crown on
' that Pd inhibited enzymes by binding sulphahydril or a single tooth produced swelling of the lower lip and

© 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

mucocutaneous lesions on the lip. Symptoms disappeared traces of nickel in the palladium solutions may be
after removal of the crown. The composition of the alloy responsible for this phenomenon (Camarasa etal, 1991),
was not reported. but others report that such contamination is not the cause
Guerra et al. (1988) reported two patients who tested of the apparent cross-reactivity (Wahlberg & Boman,
positive to nickel sulphate and palladium chloride. The 1992). It should be emphasized that the frequency of
first patient was treated for erythematous vesicular lesions sensitivity exclusively to Pd ions is relatively rare (Table
of the forearms, presumably caused by heavy exposure 3). There is some evidence of limited cross-reactivity
to the metals from handling firearms. The second patient between platinum and Pd sensitivity (Biagini etal, 1985;
showed similar lesions on the neck, forearms and legs Murdoch & Pepys, 1987).
which the authors speculated were caused by exposure Although the vast majority of sensitivity tests have been
to metals during weight lifting. No further details were done using Pd ions, there are several reports of tests which
provided. In 1989, Downey reported two instances of use Pd metal on the skin or in the mouth (van Loon
patients who exhibited lichen-planus-like reactions etal, 1984; van Loon etal, 1988; Augthun etal, 1990;
adjacent to recently placed crowns containing 79 wt% Todd £r Burrows, 1992). It is noteworthy that even in
Pd. Both patients tested positive to a PdCl^ solution in a patients with sensitivity to Pd ions, most (0-7%) will
standard patch test, and both patients improved when not react to Pd metal. Most authors have interpreted this
the crowns were removed. Van Joost & Roesyanto- observation as evidence that little or no Pd is released
Mahadi (1990) reported a 28-year-old female who from the Pd metal. In studies where histological
developed disseminated urticaria after placement of a dental examination of tissues adjacent to Pd metal were
bridge containing 90% palladium and 10% nickel by weight. performed, tissue reaction is far more subdued than those
The patient tested positive to nickel and palladium in seen with Ni-containing alloys (van Loon et al, 1988).
standard patch tests. The investigators were not able to
identify which metal was responsible for the reaction.
Carcinogenic effects
In addition to case reports, a number of surveys have
been published on the frequency of Pd allergy (Table 3). Compared to studies which have assessed the toxic and
Allergy to Pd is most often tested by means of a patch allergic effects of Pd, there are few studies which have
test, where a small patch containing a solution of PdCl^ determined the carcinogenic effects of this metal. The
is placed next to the skin for several days. Alternatively, earliest study was reported by Schroeder & Mitchener in
a drop of the solution is placed on a small prick in the 1971, who assessed the carcinogenic potential of
skin (skin-prick method). The reported frequency of palladium chloride. Mice were fed 5 parts per million
sensitivity in these types of studies must be interpreted PdCl^ from weaning until 'natural' death. Seventy nine
carefully, noting particularly the manner by which the of the 110 mice were autopsied and 19 tumours were
patient pool was selected for the study and the size of found, 18 of which were malignant. In the control group,
the study, as well as the method of application. For 100 mice were autopsied, 13 tumours were found, 11 of
example, some studies have selected populations where which were malignant. The authors concluded that Pd
Pd sensitivity might be elevated due to employment in appeared to exhibit a 'slight' carcinogenic activity in mice
platinum refineries (Murdoch & Pepys, 1987) or due to because the rate of tumour formation in the Pd group
history of other allergy (van Loon etal, 1984; van Loon was marginally statistically significant. Pillai & Nandi
etal, 1988; Rebandel & Rudzki, 1990; Aberer rfa/., 1993). (1977) have reported that Pd interacts with the
The frequency of Pd sensitivity appears to range from phosphates and bases of DNA causing a 'considerable'
2% to 18% depending on these variables. conformation change, and implicating Pd as a potential
The presence of nickel sensitivity appears to be critical mutagen. However, no information regarding DNA
to assessing Pd sensitivity, since the overwhelming mutations was reported.
majority (93-100%) of people who are sensitive to Pd In a review of the effects of platinum group metals in
ions are also sensitive to nickel (Augthun, Lichtenstein 1977, the National Research Council reported several
& Kammerer, 1990; Rebandel & Rudzki, 1990; Camarasa Japanese studies on the carcinogenicity of Pd (National
etal, 1991; Todd & Burrows, 1992; Aberer ^f a/., 1993). Research Council, 1977). In one study, a silver-palladium-
There is still controversy whether a true cross-sensitivity gold dental alloy was imbedded subcutaneously for 504
exists between nickel and Pd. It has been reported that days in rats. Tumour formation was noted in seven of

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

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

Release of palladium from dental casting in tissues adjacent to dental casting alloys, but he did not
alloys report any Pd release.
Most researchers agree that the toxic, allergic, carcino-
genic, or therapeutic effects of Pd require that the Pd be In vitro . ' , . #.
in an ionic form (Williams, 1981; Van Joost & Roesyanto-
Similar to in vivo studies, there are relatively few reports
Mahadi, 1990). This hypothesis is of fundamental
addressing in vitro Pd release from dental alloys. Niemi,
importance to the biological effects of dental alloys since
Minni & Ivaska (1986) measured elemental release from
it assumes that any effect of the alloy is caused by
several types of dental casting alloys, including a multiple
ions which have dissolved. Thus, the release of palladium
phase Ag-Pd-Cu-Au alloy and single phase Cu-Pd and
ions from dental alloys is of interest and is reviewed
Ag-Pd alloys (Fig. 1). The alloys were in contact with an
briefly here.
artificial saliva solution for 24 h before elemental release
was measured using atomic absorption spectroscopy.
In vivo
Copper and silver dissolved from both the single and
There are few studies which have addressed the question multiple phase alloys. In each case. X-ray photoelectron
of Pd release from dental alloys in vivo, and these are spectroscopy showed that as these elements dissolved,
inconclusive. One report, a review by the US National the concentrations of gold and palladium increased at
Research Council in 1977, apparently found Pd in teeth the alloy surface. Neither gold nor palladium dissolved
that had been restored with an unidentified Pd- from either the multiple phase or single phase alloys.
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 1000
was compared to low- and no-gold alloys. One alloy (Alba

1
V) showed several 'severe and extreme' reactions after
90 days. The other alloy (Albacast) showed the least tissue 100 r
1

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 10 r
1

themselves. In 1988, Kratzenstein, Sauer & Weber report-

ed that metal ions released from alloys which had been

li
CJ
1 r
1

present in the mouth for 0-5-8 years may be responsible o

for hyperplastic tissue or other oral symptoms, such as U
1 ,

burning of the tongue or a metallic taste. However, they 0-1

did not measure the levels of these ions in the tissue and B
were not able to discern which released elements might Pd
Ag Cu
be responsible for these reactions, or if these reactions
were caused by the metals. Fig. 1. Alloys of silver, copper, palladium, gold and zinc were
In 1992, Downey published a case report of a woman 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
who developed acute intermittent porphyria after
absorption spectroscopy. The ratio of alloy surface area to volume
placement of a dental alloy composed of 76% palladium, of artificial saliva was 520 mm"/mL. Alloy A had a single phase
2% gold and 10% copper. In spite of the high Pd content microstructure of 52-4% silver (by weight) with 23-4% palladium
of the alloy, it was determined that copper, not palladium, and 21-7% copper. Alloy B had a multiple phase microstructure
was responsible for the patient's symptoms, which with a nominal composition of 50-9% copper with 32-4% palladium
included skin rashes, diarrhoea, metallic taste and short- and 12-6% silver. Alloy C also had a multiple phase microstructure,
but had a nominal composition of 67% silver, 20% palladium and
term memory loss, among others. Downey did not report
9-8% copper. None of the alloys had greater than 3% gold. No
how palladium was ruled out, however. The patient alloy released detectable amounts of palladium or gold into the
recovered fully after the alloy was removed. In an saliva. The detection limit for palladium was 2 |a.g/mL (horizontal
abstract, Rechmann (1992) reported that a variety of line).

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

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

 BIOLOGICAL EFFECTS OF PALLADIUM 319

of Pd sensitivity in individuals who are sensitive to nickel, GOEHLICH, V. &• MAREK, M . (1990) Gorrosion behavior of Pd-Gu arid
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GovER, R.A. (1986) Toxic effects of metals. In: Toxicology: The Basic
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© 1996 Blackwell Science Lid, Journal of Oral Rehabilitation 23; 309-320