Principles of biocompatibility for dental practitioners

John C. Wataha, DMD, PhDa

School of Dentistry, Medical College of Georgia, Augusta, Ga.
This article is an evidence-based tutorial on the principles of biocompatibility. Although the tech-
nical issues of biocompatibility may seem beyond the scope of most practicing dentists, knowledge
of these issues is fundamentally important to ensure the health of patients, dental staff members
(including laboratory personnel), and practitioners themselves. Furthermore, the legal liability of
dentists is often linked to biocompatibility issues. The biocompatibility of a material is not
absolute; it must be measured with regard to the way the material is used. Measuring biocompati-
bility is a complex process that involves in vitro and in vivo tests. These tests contribute to
understanding biologic responses to a material but cannot define the material’s biocompatibility
with 100% certainty. Practitioners should understand enough about biocompatibility testing meth-
ods to critically judge advertising claims and ask relevant questions of manufacturers. Because
there is no infallible way to assess biologic response to a material, decisions about the clinical use
of a material ultimately must weigh the biologic risks of a material against its potential benefits.
(J Prosthet Dent 2001;86:203-9.)

T he complexity and technical nature of biocompat-

ibility issues may appear beyond the scope of practicing
dentists. However, these issues have profound ethical,
social, technical, and legal effects on prosthodontic
practice. Because of the nature of prosthodontic thera-
pies, dentists rely heavily on dental biomaterials. This
reliance on materials makes biocompatibility issues
especially relevant to prosthodontists and other restora-
tive dentists. This article provides an overview of the
biocompatibility principles that practicing dentists
should understand. A definition of biocompatibility, its
relevance to clinical practice, and an overview of how it
is measured are presented.
WHAT IS BIOCOMPATIBILITY?
Given the importance of biocompatibility to
prosthodontics and prosthodontic materials, it is sur-
prising how few practitioners understand what
biocompatibility really is. One widely accepted defini-
tion of biocompatibility is “the ability of a material to
elicit an appropriate biological response in a given
application.”1 If examined closely, this definition Fig. 1. Interactions between host, material, and application of
implies an interaction among a host, a material, and an material are important in biocompatibility. Biocompatibility
expected function of the material (Fig. 1). All 3 factors exists only when all 3 factors are considered, and it can
must be in harmony before the material can be con- change if any of these factors change.
sidered biocompatible. A discussion of 3 key concepts
about this definition will reinforce this idea.
living tissue, interactions with the complex biologic
Biomaterials are not biologically inert
systems around it occur, and those interactions
Practitioners should understand that there are no result in some sort of biologic response. The inter-
“inert” materials.2 When a material is placed into actions depend on the material, the host, and the
forces and conditions placed on the material (its
Financial support provided by Metalor, Medical College of Georgia function). Regardless, the material affects the host
Biocompatibility Program. and the host affects the material. Inertness of mate-
aProfessor, Department of Oral Rehabilitation.
rials implies an absence of such interactions. Most

AUGUST 2001 THE JOURNAL OF PROSTHETIC DENTISTRY 203

THE JOURNAL OF PROSTHETIC DENTISTRY
Fig. 2. Color of material depends on interaction of material
with light and observer’s interpretation of affected light.
Changes in light source, characteristics of material, or
observer will change perceived color. Thus, color is proper-
ty of material interacting with its environment.
Biocompatibility is also property of material interacting with
its environment.
scientists today agree that no material is truly inert
in the body.2
Biocompatibility is a dynamic process
Biocompatibility is a dynamic, ongoing process, not
a static one. A dental implant that is osseointegrated
today may or may not be osseointegrated in the future.
The response of the body to a material is dynamic
because the body may change through disease or
aging, the material may change through corrosion or
fatigue, or the loads placed on the material may change
through changes in the occlusion or diet. Any of these
changes may alter the conditions that initially promot-
ed an appropriate and desired biologic response. The
interactions among material, host, and function con-
tinue over time; therefore, the biologic response to a
material is an ongoing process.
Biocompatibility is a property of a material
and its environment
Biocompatibility is a property not only of a material,
but also of a material interacting with its environment.
In this sense, biocompatibility is like color (Fig. 2). We
often ascribe color to a material, but color is a property
of both the material and the material’s interaction with
light (its environment). Without the light interaction,
there is no color. Ultimately, the color of the material
depends on the light source, how the light interacts with
the material, and the bias of the observer.
Consider an example of this concept with dental
implants. Under the proper conditions, a titanium
alloy implant will osseointegrate with the bone over
time.3 This means that the bone will approximate to
within 100 Å of the implant with no intervening
fibrous tissue. If a cobalt-chromium alloy is placed into
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the same situation—same host, same placement tech-
nique, same load—no osseointegration will occur.
Conversely, if a titanium alloy is used as the ball por-
tion of a femoral hip joint, it will wear against the
acetabulum into small particles that ultimately will
cause the hip to fail.4,5 Yet the cobalt-chromium alloy,
which wears less, will do better. Because biocompati-
bility depends on the interaction of the material with
its environment, it is inappropriate to label the titani-
um alloy a “biocompatible material” and the
cobalt-chromium alloy an “incompatible material.”
One cannot define the biocompatibility of a material
without defining the location and function of the
material.
The complexities mentioned in the previous para-
graphs may leave the practitioner wondering about the
relevance of the definition of biocompatibility to den-
tal practice. Yet there are profound consequences of
this definition for practitioners. For example, the prac-
titioner must always consider the health and habits of
the patient when assessing the biologic response to
materials. Is the patient diabetic? Does the patient
smoke? If so, the response of the gingiva to placement
of a crown may be affected. Does the patient drink
many acidic liquids? The corrosion properties of par-
tial denture alloys and the tissue response may be
different. The practitioner must consider what he or
she is asking the material to do and must not assume
that, because a material is biologically acceptable in 1
role, it will be acceptable in a different role. Resin
materials that are biologically acceptable as denture
bases may or may not be acceptable as resin-based
cements. Finally, the practitioner must monitor the
patient over time. A patient who is not allergic to nick-
el today may become allergic in the future, from either
oral exposure or exposure through other sources (jew-
elry, for example).
HOW IS BIOCOMPATIBILITY
RELEVANT TO DENTISTS?
Dentists’ potential concerns about biocompatibility
can be organized into 4 areas: safety of the patient,
safety of the dental staff, regulatory compliance issues,
and legal liability.
Safety of the patient
One of the primary concerns of any dental practi-
tioner is to avoid harming the patient. Evidence has
shown that, although adverse reactions to dental mate-
rials are not common, they can occur for many types
of materials, including alloys, resins, and cements.6-8 A
national registry in Norway, where there are 4.3 mil-
lion people and 3800 dentists, reported 674 adverse
reactions to dental materials from 1993 to 1997.6
These adverse events occurred locally and systemically
and involved all classes of dental materials. A 1 in 2600
VOLUME 86 NUMBER 2
WATAHA
frequency of problems has been reported for dental
casting alloys, including nickel-based alloys.7 Yet the
number of adverse reactions may be underreported,
and existing reports may not be accurate.8 Better doc-
umentation of the extent of these reactions is needed.7
One biocompatibility/patient safety issue that has
been prominent in dentistry in recent years is the
hypersensitivity of patients to dental biomaterials.
Classically, this concern has focused on allergy to mate-
rials such as nickel or methacrylates. The incidence of
nickel allergy in the general population ranges between
10% and 20% and is far more common in females than
males.9 In patients sensitive to nickel, oral exposure to
nickel may or may not elicit an allergic response, but
these responses may be spectacular.8 There is also
growing concern about the hypersensitivity of patients
to resin-based materials10 and to latex.11 Although
uncommon, patients can have severe or even fatal (ana-
phylactic) reactions to these materials.3 There have
been recent reports of a growing incidence of contact
sensitivity in children to a variety of substances, includ-
ing dental materials. One report found that 49% of
children had sensitivity to some type of material or
food.12 The growing allergic history in children may
portend an increasing need for dentists to be more
aware of material allergies in adults in the future.
Thus, there is evidence that the biomaterials used
by dental practitioners can pose safety risks to patients.
However, the evidence about harmful effects from
materials is, more often than not, equivocal or incom-
plete. It therefore is every practitioner’s responsibility
to decide whether the existing evidence has merit and
to assess the risks of these issues in his or her own prac-
tice, taking into account each patient’s unique history.
Safety of the dental staff
In many situations, the risk of adverse effects of bio-
materials is much higher for the dental staff than for
the patient. The staff may be chronically exposed to
materials when they are being manipulated or setting.
The classic example of this problem is dental amalgam
because the release of mercury vapor from amalgam
during placement or removal is substantially higher
than when it is undisturbed in the mouth.13 However,
these types of issues also are relevant to casting alloys,
resins, and other dental materials used in prosthodon-
tics. For example, risks for dental staff appear to result
from chronic contact with latex- and resin-based mate-
rials. Adverse effects from these materials range from
cumulative irritation to allergenic responses.8
Ironically, gloves do not protect against contact with
some materials because the materials are capable of
moving through gloves.8,14 Furthermore, the gloves
themselves may be a source of the problem. One study
in Sweden reported that 15% of dentists (vs 9% in the
general population) experienced itching on the hands
AUGUST 2001
THE JOURNAL OF PROSTHETIC DENTISTRY
in response to gloves, particularly latex gloves.14
Another study reported that 6.2% of dental staff were
allergic to latex.11
The mechanisms by which materials cause problems
through chronic exposure are not known, but there is
evidence that some resin components such as
2-hydroxyethyl methacrylate (HEMA),15,16 tetraeth-
ylene glycol dimethacrylate (TEGDMA),15 and
camphoroquinone17 are capable of directly activating
immune cells. If the dental team also grinds laborato-
ry materials such as acrylic resin, metals, or gypsum,
then there is a risk from inhalation of particulates.
Because particles less than 10 µm in diameter cannot
be filtered by the respiratory system,18 it is prudent to
wear a mask when grinding or polishing any material.
If laboratory personnel cast alloys containing berylli-
um, precautions must be taken to limit exposure to
vapor from the alloy, as the vapor can cause berylliosis
in the lungs.19,20 Reactions to many types of prostho-
dontic materials can be severe, career-threatening, and
even life-threatening in rare instances.8
Regulatory compliance issues
Biocompatibility issues are closely linked to regula-
tions that affect dental practice. An example of this link
is related to dental amalgam. Because of the biologic
concerns about mercury, regulators have considered
monitoring and restricting the amount of mercury in
waste water from dental practices.21-23 This debate has
spurred considerable research on methods to eliminate
particulate and elemental mercury from dental
waste.21 Another example is the use of latex. Because
of allergic reactions to latex (discussed previously), sev-
eral US state legislatures have debated but not passed
bans on latex gloves in dental and medical practice.11
Legal liability
Biocompatibility issues also influence liability issues
that affect dental practitioners. Because dental materi-
als can affect the well-being of patients and dental
auxiliaries, practitioners assume a legal risk when using
these materials. Litigation as a result of biomaterials
causing harm to a patient is probably rare.
Nevertheless, when these problems occur, they are (at
best) emotionally and financially stressful to the prac-
titioner.
ASSESSING BIOCOMPATIBILITY
In the last 30 years, the public and various govern-
ment agencies have required some assurance that the
materials used in dentistry are biologically safe and
effective. Pressures to regulate materials have come
from many sources, including the movement toward
the ethical treatment of patients, an increased patient
awareness of the risks involved in health care, and
health practitioners’ concerns about litigation by
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THE JOURNAL OF PROSTHETIC DENTISTRY
patients. Unfortunately, assessment of the biocompat-
ibility of a material is a complicated matter that may
involve several sophisticated types of biologic tests,
tests of physical properties such as corrosion, and risk-
benefit analysis. The complexity of assessing the
biocompatibility of materials is often bewildering and
frustrating to practitioners and the general public.
However, despite its complexity, biocompatibility test-
ing of dental materials is currently the only means to
try to assure the safety of the patient and dental team.
One must always remember that the complexities of
the current methods are preferable to using a new
material not previously tested in humans.
Types of biocompatibility tests
Biocompatibility is measured with 3 types of bio-
logic tests: in vitro tests, animal tests, and usage
tests.24-26 It is unlikely that dentists will need to eval-
uate the results of these tests directly. However, it is
important that practitioners, who must assume the
direct legal risks of using materials in patients, under-
stand how materials are approved for use. The
following paragraphs describe the advantages and dis-
advantages of each type of biologic test so that
practitioners will have a foundation for understanding
biocompatibility issues.
In vitro tests. In vitro biocompatibility tests are per-
formed in a test tube, cell-culture dish, or otherwise
outside of a living organism. These tests are quite
diverse but generally place cells or bacteria in contact
with a material. For example, a strain of bacteria may
be used to assess the ability of a material to cause
mutations (the so-called Ames test27,28), or a strain of
fibroblasts may be grown on a culture plate and
exposed to liquid extracts from a material. The effect
of the material is generally determined by measuring
the number, growth rate, metabolic function, or other
cellular function of the cells exposed to the materials.
In vitro tests have the advantages of being experimen-
tally controllable, repeatable, fast, relatively
inexpensive, and relatively simple. In addition, these
tests generally avoid the ethical and legal issues that
surround the use of animals and humans for testing.
The primary disadvantage of in vitro tests is their ques-
tionable relevance to the use of a material in the
mouth. Because these tests are performed outside of
an intact organism, the many complex interactions that
make up the biologic response in the body are not pre-
sent. Consequently, in vitro tests may provide
misleading results about the ultimate biologic response
to the material.
Animal tests. Animal tests for biocompatibility are
different than in vitro tests because the material is
placed into an animal, usually a mammal. For example,
the material may be implanted into a mouse or placed
into the tooth of a rat, dog, cat, sheep, goat, or mon-
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key. By using a mammalian organism, this type of test
allows the many complex interactions between the bio-
logic environment and the material to occur. Thus, the
biologic response is more comprehensive and more
relevant than that obtained in in vitro tests. However,
it is often difficult to control variables in animal tests.
For example, the chewing habits of a sheep may alter
the material in ways that are not relevant to humans.
Furthermore, it often is difficult to quantitatively
assess the biologic response because it is so complex.
Ethical concerns and animal welfare issues are increas-
ingly important in these types of tests. These tests are
time-consuming and expensive. Finally, and most
importantly to the practitioner, the question of rele-
vance remains because there are always questions
about the appropriateness of an animal species to rep-
resent the human response.
Usage tests. Usage tests are essentially clinical trials
of a material. In these tests, the material is placed into
a human volunteer in its final intended use. The usage
test is, by definition, the most relevant biocompatibil-
ity test; all other tests must be measured against it for
relevance. However, usage tests have many complica-
tions and problems. They are expensive,
time-consuming, extraordinarily difficult to control,
and difficult to interpret, and they may be legally and
ethically complex.
Correlating biocompatibility tests
Several studies have shown the problems of corre-
lating in vitro, animal, and usage tests for
biocompatibility.29-31 A classic example relates to zinc
oxide–eugenol cements. Clinical experience and clini-
cal trials have shown conclusively that this cement has
virtually no adverse pulpal effects, yet tests in animals
(implanted subcutaneously) have shown significant
inflammation, and in vitro cell-culture tests have
shown that this cement can be severely toxic.
Discrepancies such as these have led some researchers
to question the usefulness of any test except the usage
test to evaluate dental biomaterials.30
Today, researchers and regulatory agencies recog-
nize that in vitro and animal tests play important roles
in the biologic evaluation of dental materials.1
However, it is also recognized that the structure of any
biocompatibility test is critical to its relevance. If
meaningful data are to be obtained from biocompati-
bility tests, then the test procedures must be closely
scrutinized to ensure that the testing conditions are as
relevant as possible. For example, because zinc
oxide–eugenol cement is placed on dentin in clinical
situations, in vitro or animal tests that do not replicate
the presence of dentin give misleading results. Studies
that have interposed a dentin barrier between the tis-
sues or cells and zinc oxide–eugenol cement better
correlate with clinical results.19,32 For in vitro tests, the
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type of cells used, conditions of exposure, and type of

response measured are critical. For animal tests, the
animal system, site of implantation of the material,
forces on the implant, and duration of the test are all
important features.25,26 a
Using different biocompatibility tests
together
For approximately 20 years, researchers have recog-
nized that the most efficient, cost-effective, relevant
way to evaluate the biocompatibility of materials is to
use a combination of in vitro, animal, and usage tests.33
However, the ways in which these tests are used togeth-
er and philosophies about the roles of each type of test
have changed somewhat over the years. Early b
researchers proposed a pyramid scheme of unspecific
toxicity, specific toxicity, and clinical trials (Fig. 3, a).34
Unspecific tests were those in which the conditions of
the test did not necessarily reflect those of the materi-
al’s use. Specific toxicity tests were those in which
testing conditions were more relevant to the clinical use
of the material. Approximately 10 years later, others
proposed a similar pyramid scheme divided into prima-
ry, secondary, and usage tests (Fig. 3, b).33 This newer c
scheme expanded the scope of the tests beyond toxici-
ty. Primary tests consisted of general cell toxicity,
systemic toxicity in animals, bacterial mutagenic tests,
and other types of in vitro tests. Secondary tests con-
sisted of animal tests to measure allergy, mucosal
irritation, and inflammation. Usage tests were equiva-
lent to clinical trials. Both schemes used the pyramidal
idea as a screening procedure. Only tests that passed
the lowest level of the pyramid were considered for fur-
ther testing. Likewise, only tests that passed the second d
tier were considered for clinical trials. Although effi-
cient in time and cost, these schemes did not
accommodate the reality that the initial tests were
fraught with false-positive and false-negative results.
Newer schemes have been developed that reflect
the complexity of biocompatibility testing of materi-
als (Fig. 3, c and d). 1,34 Two of these schemes
recognize several key points. First, all 3 types of bio- Fig. 3. Schemes for testing biocompatibility. Oldest scheme
compatibility tests continue to be useful throughout (a) used “unspecific” toxicity tests followed by “specific”
the evaluation of a material and during its clinical ser- toxicity tests and then clinical trials. Only materials that
passed 1 level were tested further. Unspecific tests were not
vice. An in vitro test may be useful in the initial stages
directly relevant to use of material. Second scheme (b) uses
of material development to “screen in” promising primary, secondary, and usage tests and is still commonly
materials, but it also may be useful to investigate a used today. Scheme b differs from scheme a because the
specific biologic response observed during clinical former emphasizes many cellular reactions in addition to
trials or after the introduction of a material to the toxicity. As in scheme a, each test level screens for tests
market. Second, both schemes recognize the danger above it. Primary tests measure basic biologic properties
of “screening out” a material with a single type of such as toxicity or mutagenicity of material. Secondary tests
test. Finally, both schemes recognize that the evalua- assess more advanced properties such as allergenicity.
tion of the biocompatibility of a material is an Usage tests are equivalent to clinical trials. Newer schemes
ongoing process that evolves with the clinical experi- (c and d) for biocompatibility testing recognize need to use
ence of the material. The practitioner must keep several types of tests together and treat evaluation of mate-
rial biocompatibility as ongoing process.
especially this last point in mind.

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THE JOURNAL OF PROSTHETIC DENTISTRY
Regulatory approval of dental materials
Two regulations currently govern the use of den-
tal materials: the American National Standard
Institute/American Dental Association (ANSI/
ADA) document No. 41 (1979) and addendum No.
41A (1982) and the International Standards
Organization (ISO) 10993 document (1993).
Although these documents are different, the
ANSI/ADA document is currently under revision to
coordinate with the ISO document. The US Food
and Drug Administration (FDA) regards dental mate-
rials as devices35 and uses the ANSI/ADA and ISO
regulations as guidelines for determining the biologic
safety of dental materials. The ADA also maintains a
Seal Program for materials that pass the ADA’s rele-
vant specifications and standards.
The FDA, ISO, and ANSI/ADA do not require
specific biologic tests for approval of a new dental
material. Rather, they place the responsibility on the
manufacturer to present evidence for a compelling
case for approval. The evidence consists of in vitro,
animal, or usage tests that the manufacturer deems
relevant to the material. Often, there are guidelines
for the selection of these tests based on the type of
material and its intended use. For example, in the ISO
document, the types of recommended tests depend
on the type and duration of body contact. For a den-
tal casting alloy, body contact is viewed as an external
device that “communicates” with dentin on a perma-
nent (> 30 days) basis.36 For this type of device, the
ISO recommends implantation tests and tests to mea-
sure cytotoxicity, sensitization potential, and
genotoxicity. The structure of the specific tests also
may be subjected to guidelines, but it is up to the
manufacturer to defend any tests that are presented. It
is important to remember that, in addition to the bio-
logic tests, most materials also must meet
specifications for other physical and chemical proper-
ties. In some situations, the FDA will grant approval
based on a “grandfather” clause (510k). That is, a
material may be approved if the case can be made that
it is “substantially equivalent” to another material that
has already been approved.37 Again, it is up to the
manufacturer to defend the substantial equivalence
argument.
Critically evaluating new materials
How are these rather theoretical and technical
aspects of biocompatibility measurement useful to
dentists? Several points are appropriate. First, practi-
tioners must be careful when evaluating sales literature
that claims material biocompatibility. Marketing claims
must be scrutinized carefully. What tests were used to
evaluate the material? Does the company assume that
the new material will behave like a related material?
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This assumption is often not a good one. Second, new
materials may be marketed with little clinical experi-
ence, and companies may rely heavily on in vitro and
animal tests. In these cases, practitioners must ques-
tion the relevance of these tests to the clinical use of
the material, keeping in mind the limitations and pit-
falls outlined previously. Even if clinical trials have
been performed, practitioners must remember that
clinical trials may be only 1 to 2 years in duration. The
service life of many prosthodontic materials is much
longer, and long-term effects may not be apparent in
short-term trials. Third, practitioners must remember
that the biologic evaluation of materials is an ongoing
process. As more knowledge is acquired, opinions
about safety and risk may change; it is legally and eth-
ically dangerous to ignore new developments. Finally,
the decision to use a new material is ultimately a risk-
benefit decision that dentists must make for
themselves. Practitioners should search for published
evidence by unbiased researchers and consider the
dental needs, esthetic desires, health history, and risk
tolerance of their patients.
SUMMARY
Biocompatibility is especially relevant to prostho-
dontists and other restorative dentists because these
practitioners rely heavily on materials that remain in
intimate contact with living tissues for long periods.
Decisions about the biologic safety of prosthodontic
materials are as much philosophical as scientific.
Because no material can be proven 100% safe, the deci-
sion to use a material in the mouth must balance the
potential risks and benefits. Ultimately, each dentist
must determine whether the benefits outweigh the
risks for the patient under consideration. To avoid all
risk is to deny the patient the tremendous benefits that
materials have to offer. To assume too much risk may
harm the patient and put the practitioner at legal risk.
Technical tests and data, which improve over time, can
aid practitioners, but the decision is ultimately a philo-
sophical one that should involve the manufacturer, the
patient, and the practitioner.
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Reprint requests to:
DR JOHN C. WATAHA
DEPARTMENT OF ORAL REHABILITATION
SCHOOL OF DENTISTRY, MEDICAL COLLEGE
OF GEORGIA
1120 15TH ST
AUGUSTA, GA 30912-1260
FAX: (706)721-8349
E-MAIL: watahaj@mail.mcg.edu
Copyright © 2001 by The Editorial Council of The Journal of Prosthetic
Dentistry.
0022-3913/2001/$35.00 + 0. 10/1/117056
doi:10.1067/mpr.2001.117056

New product news

The January and July issues of the Journal carry information regarding new products of inter-
est to prosthodontists. Product information should be sent 1 month prior to ad closing date to:
Dr. Glen P. McGivney, Editor, UNC School of Dentistry, 414C Brauer Hall, CB #7450, Chapel
Hill, NC 27599-7450. Product information may be accepted in whole or in part at the discretion
of the Editor and is subject to editing. A black-and-white glossy photo may be submitted to
accompany product information.
Information and products reported are based on information provided by the manufacturer.
No endorsement is intended or implied by the Editorial Council of The Journal of Prosthetic
Dentistry, the editor, or the publisher.

AUGUST 2001 209