Biocompatibility of dental casting alloys: A review

John C. Wataha, D M D , PhD a

Medical College of Georgia, School of Dentistry, Augusta, Ga.
S t a t e m e n t o f p r o b l e m . Dental casting alloys are widely used in applications that place them into contact
with oral tissues for many years. With the development of new dental alloys over the past 15 years, many
questions remain about their biologic safety. Practitioners must choose among hundreds of alloy composi-
tions, often without regard to biologic properties.
P u r p o s e . This article is an evidence-based tutorial for clinicians. Concepts and current issues relevant to
the biologic effects of dental casting alloys are presented.
Sununary. The single most relevant property of a casting alloy to its biologic safety is its corrosion. Sys-
temic and local toxicity, allergy, and carcinogenicity all result f?om elements in the alloy being released into
the mouth during corrosion. Little evidence supports concerns of casting alloys causing systemic toxicity.
The occurrence of local toxic effects (adjacent to the alloy) is not well documented, but is a higher risk, pri-
marily because local tissues are exposed to much higher concentrations of released metal ions. Several ele-
ments such as nickel and cobalt have relatively high potential to cause allergy, but the true risk of using
alloys containing these elements remains undefined. Prudence dictates that alloys containing these elements
be avoided if possible. Several elements in casting alloys are known mutagens, and a few such as beryllium
and cadmium are known carcinogens in different chemical forms. Despite these facts, carcinogenic effects
from dental casting alloys have not been demonstrated. Prudent practitioners should avoid alloys containing
these known carcinogens.
C o n c l u s i o n . To minimize biologic risks, dentists should select alloys that have the lowest release of ele-
ments (lowest corrosion). This goal can be achieved by using high-noble or noble alloys with single-phase
microstructures. However, there are exceptions to this generality, and selection of an alloy should be made
on a case-by-case basis using corrosion and biologic data from dental manufacturers. (J Prosthet Dent
2000;83:223-34.)

Dental casting alloys are widely used in applica-
tions that place them into contact with the oral epithe-
lium, connective tissue, or bone for many years. Given
these long-term roles, it is paramount that the biocom-
patibility o f casting alloys be measured and understood.
In the past 15 years, much has been learned about the
biocompatibility o f casting alloys. However, research in
this area has generated as m a n y questions as it has
answered, and there is little d o u b t that m u c h m o r e
needs to be learned about the biocompatibility o f these
materials. Becausc the biocompatibility o f alloys is not
completely known, it can be frustrating for practition-
ers to choose an alloy on the basis o f biologic safety.
The purpose o f this article is to review the biocom-
patibility o f dental casting alloys. The article is n o t
aAssociateProfessor,Departmentof Oral Rehabilitation.
i n t e n d e d to be an exhaustive literature review, but
rather an evidence-based tutorial for clinicians on the
state o f knowledge in this area. The article presents sev-
eral important physical properties o f casting alloys that
have biologic relevance, then addresses potential sys-
temic and local toxicity o f these alloys, their allergic
effects, and their mutagenic or carcinogenic effects.
Finally, several r e c o m m e n d a t i o n s for the practitioner
are presented.
BIOLOGICALLY RELEVANT
PROPERTIES OF CASTING ALLOYS
Alloy composition and microstructure
An alloy is any mixture o f 2 or more metals. In den-
tistry, alloys usually contain at least 4 metals, and often
6 or more. Thus, dental alloys are complex metallurgi-
cally. Alloy compositions are diverse, and much o f this

FEBRUARY 2000 THE JOURNAl. OF PROSTHETIC DENTISTRY 223

THE JOURNAL OF PROSTHETIC DENTISTRY
A compatibility difficult because any element in an alloy
B 76 wt% gold, but only 57% o f its atoms are actually gold
Fig. 1. Scanning electron micrographs (backscattered elec-
tron images) of high-noble single-phase casting alloy (A) and
predominately base metal multiple-phase casting alloy (B).
Alloys were not etched with acid before viewing, and there-
fore grain boundaries are not visible in (A). Single-phase
alloy has no discernible microstructure, except polishing
scratches because its composition is essentially homoge-
neous. However, clear areas of different microstructure are
visible on multiple-phase alloy. Each area (phase) has dis-
tinct composition. Each image is approximately 40 ~m
wide.
diversity has developed in the past 20 years as the price
o f gold has increased and the functional and biologic
demands on these alloys have increased. For many
years, most dental alloy compositions were based on
gold; that is, they contained gold as their major ele-
ment. However, dental alloys may be based on gold,
palladium, silver, nickel, cobalt, or titanium (Table I). 1
224
WATAHA
Table I. Components of casting alloys used in dentistry
Alloy Typical components
Gold-based Ag, Au, Cu, In, Pd, Pt, Zn
Palladium-based Ag, Pd, Ga, Cu
Silver-based Ag, Pd
Cobalt-based Co, Cr, Mo, Fe, C, Si, Mn
Nickel-based Co, Ni, Mo, Fe, C, Be, Mn
"Pure" titanium (cp-titanium) Ti, O, N, C, Fe, H
Adapted from reference 1.
Minor elements in these alloys are even more diverse.
More than 25 elements in the periodic table o f ele-
ments can be used in dental alloys. The complexity and
diversity o f these alloys make understanding their bio-
may be released and may influence the body. Further-
more, because o f their rapid evolution, the full biolog-
ic properties o f many dental alloys are not yet known.
Dental alloys are commonly described by their com-
position. However, composition can be expressed 2
ways, either as weight percentage (wt%) of elements or
percentage o f the number of atoms of each element in
the alloy (atomic percentage = at%). Weight percentage
is the most common way o f describing an alloy's com-
position, and is used by alloy manufacturers and by stan-
dards organizations. However, biologic properties are
best understood by knowing the atomic percentage
composition. Atomic percentage better predicts the
number of atoms available to be released and affect the
body. The wt% and at% o f an alloy may be substantially
different from one another.1 Table II presents wt% and
at% for 3 common casting alloys. The gold-based alloy is
atoms. Thus, the true amount of gold in this alloy is
nearly 20% less than one might think. Similarly, the wt%
of Cu is only 11%, but 24% of the atoms are copper.
Differences between wt% and at% are greatest when
a large difference exists among the atomic weights o f
the c o m p o n e n t elements. Thus, because gold atoms
have a large atomic weight relative to the other ele-
ments in the alloy, they constitute a disproportionally
large amount o f the alloy's mass. For the silver-palladi-
um alloy in Table II, the at% and wt% are similar
because the atomic weights o f the component elements
are similar. For the nickel-based alloy, the atomic per-
centages o f aluminum and beryllium are 2 to 5 times
what would be expected, based on the weight percent-
ages, because aluminum and beryllium are light ele-
ments relative to the other alloy components.
Another way o f describing an alloy is by its phase
structure. Phases are areas within an alloy that have the
same composition and crystal structure. Single-phase
alloys have, more or less, a similar composition
throughout their structure. However, elements in mul-
VOLUME 83 NUMBER 2
WATAHA
Table II. Atomic (at) versus weight (wt) percentage composition for three types of dental casting alloys*
Gold-based alloy
Element Wt% At% Element
Ag 10 14 Ag
Au 76 57 Pd
Cu 11 24 Zn
Pd 2 3
Pt 0.1 0.1
Zn 1 2
*Compositions may not add to exactly 100% because of rounding error in the conversion from wt% to at%.
tiple-phase alloys combine in such a way that some
areas differ in composition from other areas. Thus, the
alloy is not homogeneous t h r o u g h o u t its structure.
Figure 1 illustrates SEMs of alloys with single and mul-
tiple phases. Cross-sections of a single-phase alloy at
the microscopic level show that all the alloy has essen-
tially the same composition (Fig. 1, A). Thus, the alloy
has no visible microstructure other than polishing
scratches. However, Figure 1, B illustrates a multiple-
phase alloy and reveals areas of different composition
that are visible. These other phases may have character-
istic structures, and 2, 3, or more types of phases may
coexist in the alloy. The phase structure of an alloy is
critical to its corrosion properties and its biocompati-
bility.2 The interaction between the biologic environ-
ment and the phase structure is what determines which
elements will be released and therefore how the body
will respond to the alloy.
What is corrosion? Why is it important to
biocompatibility?
Corrosion of alloys occurs when elements in the
alloy ionize. 1 Thus, the elements that are initially
uncharged inside the alloy lose electrons and become
positively charged ions as they are released into solution
(Fig. 2). Corrosion is a chemical property that has con-
sequences for other alloy properties, such as esthetics,
strength, and biocompatibility. From a biocompatibili-
ty standpoint, the corrosion of an alloy indicates that
some of the elements are available to affect the tissues
around it.
Corrosion is measured in a number of ways. It may
be measured visually by observing the alloy surface, by
many forms of electrochemical tests that measure ele-
mental release indirectly t h r o u g h the flow o f the
released electrons, 3 or by tests that measure the release
of the elements directly by spectroscopic methodsA
Corrosion p h e n o m e n a are extremely complex, and
depend on a variety of physical and chemical factors.
For example, the combination of 2 different alloys in a
FEBRUARY 2000
THE J O U R N A L O F PROSTHETIC DENTISTRY
Silver-based alloy Nickel-based alloy
Wt% At% Element Wt% At%
73 71 Ni 65.9 58.1
15 15 Cr 17.0 16.9
2 3 AI 5.0 9.6
Mo 5.0 2.7
Mn 5.0 4.7
Be 1.0 5.7
Fe 0.5 0.4
Si 0.5 1.3
C 0.1 0.4
solder joint may enhance corrosion, or the presence of
pits or crevices in a single alloy may enhance corro-
sion. s-7 Perhaps the most relevant measure of corrosion
from the standpoint of biocompatibility is identifying
and quantifying the elements that are released. Corro-
sion of an alloy is of fundamental importance to its bio-
compatibility because the release of elements from the
alloy is nearly always necessary for adverse biologic
effects such as toxicity, allergy, or mutagenicity. The
biologic response to released elements depends on
which element is released, the quantity released, the
duration of exposure to tissues, and other factors. 8
Thus, corrosion is a necessary but not a sufficient con-
dition for adverse biologic effects of dental alloys.
Do casting alloys release elements?
On the basis of the literature, there is little doubt
that elements are released from all dental casting alloys
into the oral cavity.2, 9-11 However, an alloy does not
necessarily release elements in proportion to its com-
position (Fig. 3). A high-noble single-phase casting
alloy may have 50 at% gold, but less than 2% of the total
mass released is gold. On the other hand, only 32 at%
of the atoms in this alloy are copper, yet 85% of the
mass released is copper. Similar statements can be made
for the other alloys illustrated in Figure 3.
Several statements can be made about release of ele-
ments from dental casting based on measurements of
elemental release from many different alloy composi-
tions,2, 9-12 although these generalizations are some-
times n o t accurate. First, multiple phases will often
increase the elemental release from alloys. Figure 3
depicts 2 high-noble alloys, 1 single and 1 multiple
phase. Despite near equivalent amounts of gold atoms,
total mass released from the multiple-phase alloy is 30
times (69 gg) that from the single-phase alloy (1.9 gg).
Second, certain elements have an inherently higher ten-
dency to be released from dental alloys, regardless of
alloy composition. This tendency of an element to be
released is sometimes referred to as its lability. Figure 3
225
THE JOURNAL OF PROSTHETIC DENTISTRY WATAHA

:rons High-Noble, Single Phase

2%30/0 1% ....E] Au 2%4% 8% 1%
2+ Ag @
a Cu
Pd
D Zn 8
12% IB Pt Total Mass
Fig. 2. Process of corrosion from alloy involves conversion Composition (At,%) Released: 1.9 ~g
of uncharged alloy component (shown here as Cu) to
charged form (Cu2÷) with simultaneous release of electrons. High-Noble, Multiple Phase
Corrosion can be measured by (1) looking on alloy for visi- 4%3%
ble effects of loss of atoms, (2) measuring current flow from
loss of electrons, or (3) measuring released elements them- 28% Q ea I 38%°
selves. Most biocompatibility risks of casting alloys are asso-
ciated with issue of elemental release.
13% ~ M , I 62
ComposlUon (At.%) I W m I Total Mass
shows that copper, nickel, and gallium are labile ele- Released: 69 #g
ments. Cadmium and zinc also have relatively high Noble (Au-based), Single Phase
lability and will tend to be easily released. 2 Silver has a
6% 3% 4% 6%1%
moderate lability and shows less tendency to be
released from dental alloys. Gold, palladium, and plat-
inum have low labilities and are unlikely to be released 24% IE] Au
at high levels. However, elemental labilities are not iCu
absolute. An element's lability may be altered by the [] Pd 89
other elements in the alloy. For example, palladium has
37% [ ] Zn Total Mass
been shown to reduce the lability of copper from gold- Composition (At,%) Released: 6 ~g
based dental alloys. 13 Third, certain environmental
conditions around the alloy will affect release of ele- Noble (Pd), Multiple Phase
ments. A reduction in p H (acid conditions) will
3% 1%2%
increase elemental release from dental alloys. This
effect is especially pronounced fbr nickel-based O
alloys)0a 4 Because dental plaque often adheres to den-
tal alloys and produces a reduced pH, the effects of
acids on dental alloys are relevant to biocompatibility 19' 50%"~m~_~ .'J
concerns.
Composition (At,%) Total Mass
SYSTEMIC TOXICITY OF CASTING Released: 3 ~tg
ALLOYS
Fig. 3. Comparison of the abundance of elements in several
More often than not, the biocompatibilities of cast- common types of casting alloys (left pie charts) with elemen-
ing alloys used in dentistry are not fully known. Thus, tal release from those alloys (right pie charts) after 72 hours
it is impossible to give a practitioner a list of "good" exposure to protein containing medium at pH 7.2 and 37°C.
and "bad" alloys for dental applications. Rather, the Percentage abundance in an alloy is not good predictor of
goal of the tbllowing sections is to present principles elemental release. Multiple-phase alloys may release more
that will guide the reader to make informed judgments mass, but not always. Certain elements such as Ag, Cu, Ni,
about biocompatibility as new information becomes Ga, and Zn have greater tendency to be released compared
available and new alloys are developed. One fundamen- with elements such as Au and Pd. For this reason, high-noble
tal concern about the safety of casting alloys is their and noble alloys have relatively superior corrosion properties.
Data for this figure was adapted from reference 2.)
ability to cause systemic toxicity in the body. The prac-
titioner must be aware of several key concepts that
address this concern.
inside the body. This fact is true for both local and sys-
Key concepts
temic toxicity. Elements that are released from alloys
Released metals may not be inside the body. Elements into the oral cavity may gain access to the inside of the
released from a casting alloy into the oral cavity are not body through the epithelium in the gut, through the

226 VOLUME 83 NUMBER 2

WATAHA
Table Ill. Estimates of daily intake (in ~tg) in the diet of
some elements in dental alloys*
Element Daily dietary intake (~g)
Cadmium 50
Chromium 240
Cobalt 250
Copper 3,110
Gold <7
Iron 23,250
Molybdenum 400
Nickel 400
Silver 25
Titanium 750
Zinc 14,250
*Adapted from reference 4.
gingiva or other oral tissues or, for elements that tbrm
vapors such as mercury, through the lungs. In contrast,
elements that are released from dental implants into the
bony tissues around the implant are, by definition,
inside the body. It is for this reason that elemental
release from implants is thought to be more critical bio-
logically than elemental release from dental alloys used
tbr prosthetic restorations.
Biologic effects of metals depend on route of access into
the body. The route by which an element gains access
inside the body is critical to its biologic effects. 1~ A
good example o f the importance o f route is the sys-
temic toxicity of palladium ions. If administered orally
to mice, palladium ions will have an LDs0 (lethal dose
that will kill 50% o f the animals) o f 1000 m g / k g . 16 If
administered into the peritoneum o f mice, the LDs0
drops to 87 m g / k g . 16 The toxic dose for intravenous
administration is an order o f magnitude lower yet
(approximately 2 m g / k g in rats). 17
Metals entering the body may be wide& distributed.
Once inside the body, metal ions can be distributed to
many tissues, each harboring a characteristic amount. 18
Metal ions may be distributed by diffusion through tis-
sues, the lymphatic system, or the bloodstream. Metal-
lic particles (0.5 to 10.0 ~tm) may also be ingested by
cells such as macrophages, which are themselves trans-
ported by the lymphatics or blood vessels. 19 The oxi-
dation state and chemical form o f the metal will signif-
icantly influence its absorption, distribution, retention
half-life, and excretion. The distribution o f a metallic
element is also critical to its ability to cause systemic
toxicity. Ultimately, the body generally eliminates met-
als through the urine, feces, or lungs. The elimination
of an element will depend on its route of access into the
body. For example, if palladium ions are given intra-
venously to rats, 20% o f the palladium will remain in
the rats after 40 days. However, if the same palladium
is administered orally, only 1% will remain in the rats
FEBRUARY 2000
THE J O U R N A L OF PROSTHETIC D E N T I S T R Y
Table IV. Release of mass from various dental casting alloys
(~g/cm2/day)
Average
mass released*
Type of alloy ADA classification Phases (~/cm2/day)
Au-Pt High noble M 0.071
Au-Pd High noble S 0.005
Pd-Cu-Ga Noble M 0.011
Pd-Ag Noble M 0.048
Au-Cu-Ag High noble S 0.152
Au-Ag-Cu Noble S 0.184
Ag-Pd Noble M 0.109
Ni-Cr Predominately M 0.021
base metal
S - Single; M - multiple.
*An averagedental crown would have 2 to 3 cm2 of surface area. (Basedon
10 mo of study, data adapted from reference 25.
after 3 days. 20 The rate o f elimination is unique to each
metallic element.]5, 21
Current issues
Do elements released from casting alloys into the oral
cavity gain access into the body? There is some evidence
that released elements can gain access through the gingi-
val tissues. In dogs, elevated gingival copper levels have
been demonstrated adjacent to crowns composed of
brass (copper-zinc). 22 It should be noted that brass is
extremely corrosion-prone in the mouth and not repre-
sentative of dental alloys used in most countries. Nickel
and cobalt have been measured in tongue and other oral
tissues in patients with removal partial dentures. 23 In
other studies, extremely sensitive analytical techniques
have been used to demonstrate the presence of compo-
nents of crowns and amalgams in human gingival tissues
adjacent to dental alloys.24 However, these levels are low.
There is little evidence that elements released from
casting alloys contribute significantly to the systemic
presence o f elements in the body. This result is not sur-
prising when the normal daily dietary intake o f metals
in dental alloys is considered 4 (Table III). In most sit-
uations, the amounts o f elements that are released t?om
dental alloys are tar below those taken in as a part o f the
diet. For example, the amount o f zinc released t?om a
dental alloy (< 0.1 btg/day) 25 is far below that eaten
(14,250 btg/day). A survey o f the total mass released
from casting alloys (Table IV) shows that mass release
does not approach the dietary intake.
The amount of release from any alloy is directly pro-
portional to the number o f castings present in the
mouth. However, nickel released from nickel-based
prostheses may approach the 400 btg/day daily intake
particularly if the nickel-based alloy is subjected to an
acidic environmcnt.4J 4 As Table IV indicates (Ni-Cr
alloy), in a neutral pH, the release o f nickel is much less.
Other evidence has shown that nickel release from nick-
227
THE J O U R N A L OF PROSTHETIC DENTISTRY
~ ,100
,o
1>
"N
20
o 0
0.1 1 10 100
Ag + Concentration (pmol/mL)
Fig. 4. Dose-response curve of mouse fibroblasts to Ag 1+
ions in vitro. Cell activity is unaffected up to silver+l con-
centration of 1 gmol/L. Above this concentration, cell activ-
ity drops to near zero. TC50 concentration is defined as con-
centration required to suppress cell activity by 50%. TC50
concentrations have been defined for all metals, allowing
comparison of toxic potential among metals (Table V). Ele-
ments with low TC50 concentrations and high risks for
release from an alloy hold greatest potential for adverse bio-
logic effects. (Data from this figure were adapted from refer-
ence 31 .)
el-based alloys is highly dependent on the chromium
content. 4 If chromium is less than 20 wt%, nickel release
under all conditions increases. Exposure to nickel from
nickel-containing silverware appears to be minimal. 26
It must be stressed that, if an alloy releases amounts
o f metal approaching those in the diet, it does not
implicate these alloys as having systemic biologic toxic-
ity (or other effects). The problem with using daily
dietary intakes as "rulers" for assessing the safety o f
dental alloys is that there is no information that the
dietary intake levels themselves have any meaning for
l o n g - t e r m biologic safety. The a m o u n t o f titanium
(750 gg/day, Table III) ingested in a diet may or may
not be safe. It is simply an empirical fact that this much
titanium is consumed. Thus, if an alloy releases this
much titanium (which it does not), we really do not
know if the alloy is safe. We are led into a false sense o f
security by this comparison because we observe that we
do not suffer ostensibly from the dietary intake. Again,
in terms o f risks and benefits, it is likely that the bene-
fits o f the titanium in the products we use (sunscreens,
drug fillers, cosmetics, foodstuffs) far outweigh the
risks o f any long-term exposure to the metal. This bal-
ance must be established for each metal.
Evidence from the o r t h o p e d i c implant literature
shows that elements that gain access to the body from
a local source (such as a hip implant) will be widely dis-
228
WATAHA
tributed. For example, titanium can be detected at ele-
vated levels in the serum and liver o f implant
patients.27, 28 Similar studies that used dental implants
have failed to show similar elevated levels at distant
sites, 29 probably because the surface area o f the
implants is less and there are no frictional forces applied
to dental implants. Furthermore, no studies with den-
tal casting alloys have shown that systemic metal levels
are elevated from the use o f dental crowns. Even with
the brasses previously mentioned, copper levels in the
liver were not elevated. 22
In summary, systemic toxicity from dental casting
alloys has not been demonstrated. There is evidence
that released metals can and do gain access to the body,
and these metals may be widely distributed. However,
no studies have shown that the presence of these met-
als systemically causes toxicity. Further studies will con-
tinue to assess the possibility o f systemic toxicity as
long-term data become available.
LOCAL TOXICITY OF CASTING ALLOYS
A second major concern about the safety o f dental
casting alloys is whether elements released can cause
toxicity locally, that is adjacent to the restoration.
Again, there are several key concepts that should aid
the practitioner in assessing the potential o f casting
alloys to cause local toxicity.
Key concepts
Microenvironments exist locally around casting alloys.
Casting alloys are in long-term intimate contact with
local tissues, and there are often "microenvironments"
formed between the alloy and the tissues. For example,
a dental crown often extends below the level o f the gin-
giva, forming a sulcus between the gingiva and the
alloy. If elements from the alloy are released into this
sulcus, they may reach high concentrations because
they are not diluted by saliva or other digestive juices.
For example, the amount o f copper released from a
dental crown may approach 0.2 gg/day, 25 which is far
below the 3100 g g / d a y that we eat (Table III). How-
ever, in the gingival crevice adjacent to the crown, the
concentration o f copper might be much higher. Fur-
thermore, the concentration that is required to have a
local adverse effect may be much lower than concen-
trations necessary to cause systemic effects through the
oral route. An epithelial cell in the gingiva may begin to
suffer from copper levels as low as 10 btg/g, 3° even
though this concentration would be harmless if ingest-
ed. A similar situation exists underneath the metal
framework o f a removable partial denture. Elements
released toward the tissue side o f the framework may
not be diluted by oral fluids to the same extent as ele-
ments that are released from the opposite side o f the
framework. Consequently, metal ion concentrations
may be higher next to the tissue than in the saliva.
VOLUME 83 NUMBER 2
WATAHA
Table V. Concentrations of metal ions that suppress cell
activity by 50%
Metal cation (compound) TC50 value (lamol)
Ag1+ (AgNO3)
Au 3+ (HAuCI4.3 H20)
Cd 2+ (CdCI2)
Co 2+ (COCI2.6H20)
Cr3+ (CrCI2.6H20)
Cu 2÷ (CuCI2.2H20)
Ga 3÷ (GaCI3)
Hg 2+ (HgCI2)
In 3+ (InCI3)
Mn 2+ (MnCI2.4H20)
Mo 5+ (MoC15)
Ni 2+ (NiCI2.6H20)
Pd2÷ (PdCI2)
Pt4+ (H2PtCI6)
Sn2+ (SnCI2.2H20)
Zn 2+ (ZnCI2)
L-929 mouse fibroblasts, 24-h exposure,evaluated using succinic dehydro-
genase activity by MTT. Low numbers indicate higher toxicity. See also refer-
ences 31 and 32.
(Adapted from reference33.)
Metal ions can cause local toxicity. In vitro it is
clear that, if metal ions are present at high enough con-
centrations, they will alter or totally disable cellular
metabolism. The effect of silver ions on cellular mito-
chondrial activity is a case in point (Fig. 4). 31 The mito-
chondrial activity is often used because it is indicative of
the cell's ability to provide energy for all other cellular
processes. At low concentrations (<2.0 ~tmol/mL), cel-
lular mitochondrial activity is essentially unchanged
from normal. However, as the concentration o f silver
ions increases, cellular activity falls dramatically. Above
10 ~tmol/mL, activity is essentially zero. This example
o f the effects o f silver is indicative of almost all metal
ions, except that each metal ion has its own threshold
above which cellular activity deteriorates. Toxicity of
these metal ions is reported as the concentration to
depress cellular activity by 50%, or the toxic concentra-
tion 50% (TC50 value). TC50 values (after 24 hours of
exposure) for metal ions range from 6 to 3000 ~tmol/L,
depending on the cell type and toxicity parameter that
is measured (Table V). sl-ss
Increased exposure time increases toxicity. If the expo-
sure time o f a metal ion to cells is increased, the T C 5 0
value will decrease. 34 As Figure 5 illustrates for copper
ions, the TC50 value is a decreasing function o f time o f
exposure; namely, the longer the metal ions are in con-
tact with cells, the lower the amount o f metal ions are
required to cause cellular problems. The shape o f the
curve in Figure 5 will change for each metal ion, but
the trend is similar. Thus, alloys that release elements
over longer periods are more likely to cause local toxic
effects.
FEBRUARY 2000
THE JOURNAL OF PROSTHETIC DENTISTRY
250
200
4.8
21 ~ 1 ~0
10
100
1790 I O0
139
1530 Im ~0
11
2310
556 0
775 0 20 40 60 80
188 Duration of Exposure, Cu ~'* (h)
281
33
Fig. 5. Duration of exposure influences toxicity of release
3110
7
metal ion. TC50 concentration (see Fig. 4) drops by 10 times
as duration of exposure is increased from 18 to 72 hours.
Clinically, this phenomenon means that long-term elemental
release may have biologic effects at relatively low concen-
trations. (Data for this figure were adapted from reference
34.)
Current issues
Although the release o f elements from dental casting
alloys is well established in vitro and in vivo, the local
biologic effects o f these released elements is still a topic
o f intense debate. The central question in this debate is
whether the levels o f elements that are released are suf-
ficient to alter the normal biologic functions o f the
tissues around the alloys. Unfortunately, insufficient
evidence exists to definitively answer this question.
However, the following text will present evidence from
in vitro and in vivo studies.
In vitro studies have clearly established that some
dental alloys will damage cells in culture. Figure 6 illus-
trates an in vitro test that placed alloy samples in the
centers o f small cell-culture wells for 72 hours, s5 Each
row contained 6 replicates, and there was a different
alloy in each row o f wells. Cells were placed around the
alloy samples. After 72 hours, alloys were removed, and
the cells were treated with a dye that stained cells with
active mitochondria. In the top 2 rows, the alloys
caused significant damage to cells and little or no stain-
ing occurred. In the lower 2 rows, the cells were not
affected and formed a heavy layer o f stain.
Studies such as these have demonstrated that some
dental alloys can cause cellular damage. It has also been
possible to relate the cellular damage observed in these
tests to the release o f elements from the alloys into the
cell-culture medium.SA 2 Thus, for alloys that showed
cellular damage, it has been possible to measure metal-
lic ions in the cell-culture medium. For these alloys, the
metallic ions are at sufficient concentrations to cause
229
THE JOURNAL OF PROSTHETIC DENTISTRY
Fig. 6. Example of in vitro test for toxicity of casting alloys.
Six replicates of each alloy were placed into wells (1 alloy
per row) along with fibroblasts. After 72 hours, alloys were
removed and cells were exposed to chemical that turned
blue (shaded dark in figure) if cells had active mitochondri-
al function. Thus, alloys in top 2 rows had distinct negative
effect on cell function, whereas alloys in bottom 2 rows did
not. Experiments like these have demonstrated that alloys
may release sufficient elements to cause toxic effects. (Data
adapted from reference 35.)
cellular damage. A l t h o u g h metallic ions are also
released into medium for the alloys that showed no cel-
lular damage, the concentrations o f ions are insufficient
to cause cellular damage. These types o f studies have
clearly established that release o f metallic ions is neces-
sary for cellular damage but does not guarantee that
cellular damage will occur. Whether damage will occur
depends on the elemental species, the concentrations
released and the duration o f their exposures to the cells.
There are f~zw well-controlled in vivo studies that
d o c u m e n t the biologic response o f casting alloys in
clinically relevant contexts. I f brass (Cu-Zn) alloys with
high corrosion rates are placed as crowns on dog teeth,
gingival tissues will show significant inflammation in
response to the released elements. 22 However, m o s t
alloys used clinically today release 100 to 1000 times
less mass than brass, and it is not clear if these lower lev-
els o f elemental release are important clinically. Some
evidence supports the idea that dental alloys may cause
increased inflammation in humans, despite a low
plaque index on the alloys. 36-38 These studies are few
and they have n o t looked comprehensively at the
response to specific types o f alloys. O n the basis of clin-
ical use, we know there is significant tolerance in vivo
for low levels o f elements that are released from dental
alloys over the short term (months-years). Questions of
the long-term responses to these low levels o f elements
remain unanswered. The risk o f some chronic irritation
f r o m elemental release m u s t be weighed carefully
against the known benefits o f using these materials.
Because no materials exist that do n o t release some
230
WATAHA
mass into the oral cavity, the public must be willing to
assume this risk if it is to benefit from use of these
materials. Most researchers in this area would agree
that the benefits far outweigh the risks tbr many alloys
currently used in dentistry.
ALLERGY TO CASTING ALLOYS
Key concepts
A n element must be released from an alloy to cause
alle~v. N o study has shown that allergy to alloys can
occur without corrosion and release of metallic ions. At
least 1 study has shown that, even in patients with a
documented allergy to palladium, placement of palladi-
u m in the m o u t h did not elicit an allergic reaction.39, 4°
Presumably, the lack o f response was caused by a lack of
corrosion o f the palladium. This principle further sup-
ports the importance of lmowing the corrosion proper-
ties of an alloy.
Metal ions cannot be allergens by themselves. As far as
is known, metal ions c a n n o t act as allergens them-
selves.15,41 Rather they act as haptens, binding to resi-
dent molecules and altering these molecules such that
the body "sees" the complex as tbreign. Because of
their ability to bind to many types o f molecules in the
body such as proteins, nucleic acids, or carbohydrates,
the potential fbr many types of allergenic complexes is
great. Little is known a b o u t the specific metal com-
plexes that cause the allergic response, or whether these
complexes are even similar a m o n g different allergic per-
sons. 42-44 Finally, the exposure of metal ions to the oral
mucosa may elicit different effects than if the ions are
exposed to the sldn. There has been at least 1 report
that oral exposure may actually induce tolerance to
chromium, although this fact has not been verified in
h u m a n models.45, 46 Other more recent reports show
that oral i m m u n e cells may be m o r e responsive to
immune challenges than cells in s k i n s
Allergy and toxic reactions are often difficult to dis-
tinguish. It is oRen difficult to determine whether an
inflammatory response to a metal ion is mediated by an
allergic mechanism or a toxic mechanism or some com-
bination o f both. The boundary between these 2 mech-
anisms is not always clear. Classically, allergic responses
are characterized by dose-independence, that is, the
reaction o f the b o d y is i n d e p e n d e n t o f the dose
applied. 41 Thus, low doses that would n o t cause
inflammation through toxicity would cause inflamma-
tion by activating immune cells. In reality the bound-
aries between toxicity and allergy are not that clear. The
absence o f a classic allergic response does not preclude
metals having an effect on immune cells. Metal ions
may alter or disrupt normal immune pathways, which
then causes an inflammatory response. 48-5° This type o f
interaction could be viewed as a toxic response, because
it does not involve recognition of a specific metal-pro-
tein complex.
VOLUME 83 NUMBER 2
WATAHA
The relationship between allergy and toxicity is still
an active areas of research. More recently, the concept
has been advanced that allergic reactions to metal ions
may also have a threshold below which no reaction
occurs, sl Only when this threshold is exceeded does
the dose-independence apply. Thus, it may be possible
for very low levels o f metal ions in an allergic person to
cause no measurable allergic response.
Patch tests for metal hypersensitivity are contro~,ersial.
Allergy to metals is assessed by either applying the
metal ion to the sldn in a patch or by injecting a small
amount o f the ion below the sldn. ~2 Even with proper
administration, the assessment of the response is diffi-
cult. With metal ions, the salt (anion) o f the metal ion
is important to the r e s p o n s e Y Thus, the chloride salt
may elicit a different response than the sulfate or
nitrate. The oxidation state o f the metal also affects the
outcome of the test. The metal salts are in some liquid
vehicle, and the vehicle will affect the results, whether
it is water, oil, or petrolatum. Even the type o f patch
can influence the results.
C u r r e n t issues
The incidence of hypersensitivity with clinical dental
products in general appears to be quite low. ~4 In 1
study, only I in 400 prosthodontic patients experienced
adverse effects to the materials. O f these, 27% were
related to base metal and to noble metal alloys. Red-
ness, swelling, pain, and lichenoid reactions were com-
mon signs and symptoms o f the responders. Some sys-
temic reactions were also reported. One problem in
assessing the incidence of problems to dental metals is
that the symptoms can be distant from the site of the
material. For example, of 139 adverse reactions to base
metal alloys reported in 1 study, 99 had local symp-
toms, 33 had distant symptoms, and 10 patients had
symptoms only at distant sites. The incidence o f hyper-
sensitivity reactions to dental materials deserves further
attention, s ,~,56
Studies indicate that about 15% o f the general pop-
ulation is sensitive to nickel, 8% is sensitive to cobalt,
and 8% to chromium. Documented allergies have also
been reported for mercury, copper, gold, platinum, pal-
ladium, tin, and zinc. s7 However, frequencies o f these
allergies are not well defined. There have been reports
o f allergic responses to other metals, although they are
less well documented. The frequency o f hypersensitivi-
ty to metal ions differs considerably among the metals.
The reasons for these differences are probably related
to the f~equency o f exposure of the population to the
metals, the likelihood that the metals are released as
ions from alloys, and the biologic interactions of the
metal ions with the tissues. For example, the high inci-
dence o f nickel allergy is probably a result of the high
frequency o f exposure through metallic jewelry, the
lability o f nickel ions from alloys, and the biologic
FEBRUARY 2000
THE JOURNAL OF PROSTHETIC DENTISTRY
interactions o f nickel ions with the tissues. 58 The pop-
ulation is also commonly exposed to gold jewelry, but
the incidence of allergy to gold is rare. This lower inci-
dence probably results from the low levels o f gold that
tend to be released and may result from the inability o f
gold ions to interact with tissues in a manner that pro-
motes the allergic response. The reasons some metal
ions cause allergy while others do not is not known.
There is probably a genetic component to the frequen-
cy o f metal allergy as well. 43 Further research is needed
in this area.
It is possible for metal ions to have cross-reactive
allergy. A cross-reaction occurs when antigens are suffi-
ciently similar that allergy to one antigen will guarantee
that the person will be allergic to the second antigen,
even with no previous exposure. Cross-reactivity is dif-
ficult to prove, but is suspected for palladium and nick-
el. 59,6° Some studies have reported that patients who
are sensitive to palladium are nearly always also sensitive
to nickel. O f course, there are big differences in the
tendency o f palladium and nickel to be released from
dental alloys. Because palladium is generally much less
likely to be released, the risk o f exhibiting palladium
allergy in patients sensitive to nickel is substantially
reduced. 61
MUTANGENICITY AND
CARCINOGENICITY OF CASTING
ALLOYS
Key concepts
Mutagenicity and carcinogenicit~ are not the same.
Mutagenicity describes an alteration o f the basepair
sequence o f DNA (a mutation). Carcinogenicity means
that alterations in the DNA have caused a cell to grow
and divide inappropriately. Carcinogenicity results from
several mutations. 62 It is important to understand that
not all mutagenic events lead to carcinogenesis. Many
mutations are repaired; others occur in irrelevant sec-
tions o f the DNA; and still others do not have any func-
tional consequence. Mutations occur routinely in our
DNA, and the body has n u m e r o u s mechanisms for
repairing and otherwise dealing with them. Another
important concept is that metals may not have to act
directly on DNA to cause mutations, but may generate
free radicals that may then alter the DNA. 63 Finally, the
measurement o f mutagenesis is much easier than that
o f carcinogenesis. The fbrmer can be measured with
several in vitro tests. The latter almost always requires
long-term epidemiologic studies.
Alloys must release elements for carcinogenici U or
mutagenici U to oec,t~ As with allergic responses, metal
ions mediate mutagenic and carcinogenic responses. 62
Therefore, an alloy's ability to cause mutagenesis or
carcinogenesis is directly related to its corrosion. How-
ever, it is important to realize that particles from alloys
may also gain access to the body indirectly through the
231
THE J O U R N A L OF PROSTHETIC DENTISTRY WATAHA

Table VI. Metallic elements in dental alloys that have known mutagenic or carcinogenic properties

Element Form Mutagenic/carcinogenic

status Other comments

Beryllium
Be0 Carcinogenic Also beryllium derivatives
Be2÷ Carcinogenic Also beryllium derivatives
Cadmium
Cd0 Carcinogenic Also cadmium derivatives
Cd2+ Carcinogenic Also cadmium derivatives
Chromium
Cr3+ Not mutagenic Very reactive, kills cells before reaching nucleus
Cr6+ Carcinogenic
Cobalt
CoO Possibly carcinogenic
Co2+ Possibly carcinogenic
Copper
Cu1+ Unknown
Cu2+ Mutagenic but not carcinogenic
Gallium Gag+ Probably not mutagenic Data from in vitro studies
Gold Unknown Low risk in dental alloys due to very low corrosion, organic,
and inorganic forms probably not equivalent
Indium Unknown
Iron Fe2+ Mutagenic but not carcinogenic High dietary intake
Nickel
Ni ° Possibly carcinogenic
Ni2S3 Carcinogenic Nickel subsulfide
NiCI 2 Weakly mutagenic
NiS04 Weakly mutagenic
Palladium Pd2÷ Limited data, possibly mutagenic Low risk in dental alloys due to very low corrosion
Platinum Unknown Low risk in dental alloys due to very low corrosion, organic,
and inorganic forms probably not equivalent
Silver Ag1+ Limited data, probably not mutagenic
Tin
Sn2+ Mutagenic but not carcinogenic
Sn4+ Unknown
Zinc Zn2+ Not mutagenic High daily intake
Adaptedfrom references11, 63, 69, and 71.

lungs during grinding and polishing. Once in the
lungs, these particles may be taken into the body by
macrophages or other cells. The subsequent intracellu-
lar corrosion o f these particles will then influence the
ability o f the alloy to cause mutations. 64 For this rea-
son, care should be taken to protect the lungs from
inhalation o f particles, especially those smaller than
10 ~m in diameter, which cannot be filtered by the res-
piratory system. 65
Carcinogenic activity of elements in dental alloys is
often unknown or poorly understood. Most evidence
about the mutagenic or carcinogenic activity o f metal-
lic elements has come from industrial settings where
large numbers o f workers have been exposed to metal-
lic compounds for years and show increased incidence
o f different neoplasias. There is little or no evidence
from the dental literature that indicates that dental
alloys are carcinogenic. 54 In other databases, however,
there is literature that indicates the mutagenic potential
o f metal ions. Mutagenesis can be measured in bacteri-
al systems 66 or in mammalian cells. 67 The reliability o f
these in vitro systems in predicting in vivo mutagenesis
or carcinogenesis is currently limited at best.
Current issues
As with toxic and allergic reactions, alloys probably
must release elements for mutagenesis to occur. Even
though an alloy may contain a metallic mutagen, the
metal cannot act on the DNA if it is not released from
the alloy.62 It is also imperative to realize that the form
o f the metal is critical to its mutagenic activity. For
example, the oxidation state o f chromium is critical to
understanding its mutagenic potential. Cr 3+ is not a
mutagen, but Cr 6+ is.62, 68 The molecular form o f the
metal ion is also important. Nickel ions are weak muta-
gens, but nickel subsulfide (Ni2S3) is highly muta-
genie. 69 Therefore, it is improper to state that a metal
is mutagenic or carcinogenic per se, because the muta-

232 VOLUME 83 NUMBER 2

WATAHA
genic activity will depend on the specifc form and oxi-
dation state of the metallic element in question. In den-
tal laboratories, the vapor forms of elements such as
beryllium are the most c o m m o n mutagenic threat.
These vapors are created during the casting and finish-
ing of prostheses.
Table VI lists the known effects of metal ions as
mutagens or carcinogens for a few elements in dental
alloys.n, 7° The data in this table have been collected
from many areas of research in the medical, environ-
mental, and industrial literature. Clearly, these data are
far from complete, and research is badly needed in this
area. As the table shows, metal ions may exist in sever-
al oxidation states or molecular forms, each having its
own mutagenic potential. In some cases like Cd 2+ ions,
the 2 forms (Cd ° and Cd 2+) have similar effects, each
known to be able to induce carcinogenesis. For other
elements the different forms may have different effects.
For example, with nickel subsulfide (Ni2S3) , there have
been studies linking exposure of the respiratory tract
with neoplasia. Thus, nickel subsulfide is a document-
ed carcinogen. For nickel chloride (NiC12) and nickel
sulfate (NiSO4) , the evidence is much less clear, and
only a weak mutagenic effect is suspected. 71 Some ions
such as Sn 2÷, Cu 2+, or Fe 2+ are known mutagens, but
have never been shown to induce neoplasia. It is likely
that the mutations induced by these metals are relative-
ly easy to repair by the body when compared with
mutations induced by other metal ions. Thus, the
mutations are less likely to lead to carcinogenesis. Mter-
natively, these metal ions may not induce mutations in
genes that tend to cause neoplasia. Data are simply not
available to answer these questions. Finally, for some
metal ions such as palladium, gold, indium, or plat-
inum, there are little data available concerning the
mutagenic or carcinogenic effects of the ions. Recent in
vitro studies on palladium and gallium chloride indicate
that the mutagenic potential of these ions is low. 62
Overall, there is no evidence that dental casting alloys
cause or contribute to neoplasia in the body. However,
it may be prudent for the practitioner to avoid alloys
containing elements such as cadmium, cobalt, and
beryllium.
CONCLUSIONS
Because it is not currently possible to know the com-
plete biologic effects of any dental alloy, practitioners
must rely on knowledge of the principles of biocom-
patibility to decide which dental casting alloys they will
use. This decision is not an easy one, and it will have
financial, legal, technical, and patient satisfaction con-
sequences for the practitioner. In many ways, the deci-
sion is philosophical, based on the possible biologic
risks of using a particular alloy versus its known clinical
benefits. The practitioner can help define risks by keep-
ing the following points in mind:
FEBRUARY 2000
THE JOURNAL OF PROSTHETIC DENTISTRY
1. Because elemental release is necessary for toxic,
inflammatory, allergic, or mutagenic reactions, practi-
tioners should be aware of the corrosion properties of
any alloy they use. In vitro data are commonly available
from most reputable alloy manufacturers. In particular,
the practitioner should find alloys that release the least
mass and know the complete composition of each alloy
used.
2. In the absence of detailed data on corrosion for an
alloy, use of high-noble and noble alloys of single-phase
microstructure will minimize biologic risk because ele-
mental release from these alloys is lower. However,
detailed elemental release data are preferable because
each alloy behaves somewhat differently, even if com-
positions are similar.
3. It is advisable to use alloys from a company with a
research and development division that manufactures the
alloys marketed. Testing should always include corrosion
testing for the release of elements and, if possible, basic
biocompatibility tests to determine whether the elemen-
tal release is biologically relevant. A review of basic bio-
compatibility tests has been published previously. 1
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Reprint requests to:
DR JOHN C. WATAHA
DEPARTMENTOF ORAL REHABILITATION
MEDICALCOLLEGEOF GEORGIASCHOOLOF DENTISTRY
AUGUSTA, GA 30912-1260
FAX: (706) 721-8349
E-MAIL: watahaj@maihmcg.edu
Copyright © 2000 by The Editorial Council of The Journal of Prosthetic
Dentisto~
0022~3913/2000/$12.00 + 0. 10/1/104278
VOLUME 83 NUMBER 2