D. International Reviews on Safety of Amalgam Fillings

    There have been a number of major reviews by international
authorities of the nature and magnitude of health risks associated with
dental amalgam restorations. The majority of these assessments are
based upon extensive reviews of the available body of relevant
scientific literature and consensus among leading researchers and
renowned experts from the fields of {*filter*}health, toxicology, medicine,
and other related disciplines. The following overview identifies these
individual reviews and provides the overall conclusions of each.
    In 1994, an expert group convened by Sweden's National Board of
Health and Welfare took the position that: ``Scrutiny of the results of
recent research *  *  * has not shown that mercury from amalgam has an
adverse effect on health, with the exception of isolated cases of
allergic reactions'' (Ref. 6).
    At the request of senior U.S. health officials, in 1994, a
delegation of PHS scientists and regulators organized a nine-country
information exchange forum in Berlin, Germany for the purpose of
determining the scientific bases for national policies governing the
use of dental amalgam. In 1998, a report memorializing the conclusions
of this group was published. The report concluded that: (1) No systemic
dose-dependent toxic effects have been shown to be related to amalgam;
(2) local reactions to dental amalgam fillings do occur but are
relatively rare; (3) the benefits of restoring teeth with dental
amalgam outweigh significantly the documented risks; and (4) there is
no indication that clinically satisfactory dental amalgam fillings
should be removed (Ref. 7).
    In 1995, Canadian health authorities released a report on amalgam
safety (Ref. 8), which concluded:
    Dental amalgam contributes detectable amounts of mercury to the
[human] body, and is the largest source of mercury exposure for
average Canadians. However, this exposure is not causing illness in
the general population. Current evidence does not indicate that
mercury contributes to Alzheimer's disease, amyotrophic lateral
sclerosis, multiple sclerosis or Parkinson's disease.
    In 1996, the University of Otego's Wellington School of Medicine in
New Zealand, which serves as the World Health Organization (WHO)
Collaborating Centre in {*filter*}Health, enlisted four prominent
researchers to conduct a review of available scientific reports on
amalgam safety. In a draft report, three of the researchers concluded:
``* * * the assumption of a cause-and-effect relationship between
amalgam and cases of ill health is evidence of an overreaction and
unwise, considering the endemic prevalence of amalgam in the
population'' (Ref. 9).
    In 1997, the Canadian province of Quebec undertook its own
evaluation of the state of the science relating to amalgam safety.
Taking a somewhat equivocal stance, Quebec authorities stated:
    The mainstream scientific view holds that mercury exposure, even
at very low levels attributable to dental amalgam, might be
affecting people adversely, but the evidence currently available is
inadequate to determine if this is the case. Existing evidence is
weak, but the information base is inadequate to conclude that dental
amalgam has no effects that might be of concern (Ref. 10).
    In early 1997, WHO convened a ``consultation meeting'' at its
headquarters in Geneva, Switzerland to re-visit WHO's policy on dental
amalgam use with the current science. In attendance were government
officials, scientists, and representatives from the dental profession
and dental trade industry from 10 of the world's major industrialized
nations and 2 of WHO's regional offices. At the end of this meeting,
the participants issued the following consensus statement:
    Dental amalgam restorations are considered safe, but components
of amalgam and other dental restorative materials may, in rare
instances, cause local side effects or allergic reactions. The small
amount of mercury released from amalgam restorations, especially
during placement and removal, has not been shown to cause any other
adverse health effects. (Ref 11).
    In 1997, the {*filter*}Health section of WHO's Division of Non-
Communicable Diseases issued a publication based upon the working
papers and presentations by participants at the 1997 WHO conference
noted above. The publication included and gave WHO sanction to the
consensus statement adopted by the participants at the 1997 WHO
consultation meeting and provided supporting technical and scientific
evidence on a wide range of discrete issues relating to dental amalgam
(Ref. 11).
    For example, in a section entitled ``Direct Restorative Dental
Materials in {*filter*}Health Care Amalgam, Composites and Glass Ionomers,''
the document states:
    Expert groups, convened by the Swedish National Board of Health
and Welfare and the Swedish Medical Research Council (SOS, 1987) and
the Department of Health and Human Services, USA (1993), have
studied possible health effects of the use of mercury-containing
amalgam. These study groups concluded that while it is well
documented that individuals with amalgam fillings have higher
concentrations of mercury in all tissues studied than those who have
no amalgam fillings, there is no direct evidence of an adverse
effect of mercury from amalgam tooth fillings on general health
(Ref. 11).
    In the section titled ``Toxic and Allergenic Risks Due to Dental
Biomaterials'', the document states:
    Mercury from dental amalgam has been accused of being a toxic
agent causing serious consequences to health, including various
sclerosis, Alzheimer's disease, myalgic encephalitis, epilepsy, etc.
without any proof having ever been presented. On the other hand, we
know that certain allergies to mercury are involved in the
appearance of lichenoid reactions, even if they are not the only
responsible cause. The very rare epidemiological estimation of risk
of allergy gives us percentages that go from 0.04% to

[[Page 7624]]

0.00001%. In this respect, the present data concerning mercury are
perfectly characteristic of the risks of chronic intoxication and of
allergies caused by dental therapies, i.e., extremely low (Ref. 11).
    A third paper presented in the WHO publication entitled ``Mercury
Exposure From Dental Amalgam Fillings: Absorbed Dose and the Potential
for Adverse Health Effects'' stated: ``It is concluded that no signs of
renal toxicity could be found in conjunction with mercury released from
amalgam fillings.'' Additionally, the paper recited the findings of a
number of researchers who conducted studies on human subjects with
symptoms allegedly caused by amalgam fillings. One study found that:
``No symptom group had a higher estimated daily uptake of inhaled
mercury vapor, or any higher mercury concentrations in {*filter*} and urine
than the control group.'' Another study reported:
    No significant differences regarding release of mercury vapor
[sic] from the amalgam fillings before and after gum-chewing between
the test subjects and the matched controls in a few spot
measurements were found. Furthermore, no significant differences
were found regarding urinary mercury levels and total excretion of
proteins in urine. No damage in renal function was noted.
Yet another study cited in the WHO document found ``*  *  * no
correlation between the total number of amalgam surfaces and fatigue, a
symptom described as a mercury toxicity symptom'' (Ref. 11).
    December 1998 marked the culmination of a 2-year long study by an
ad hoc working group constituted by the European Commission (the
Commission) on amalgam safety and regulatory policies among the
Commission's 15 member states. Comprised of leading dental
professionals, researchers, and academics from western Europe, and with
oversight by the Commission's medical devices expert group, the ad hoc
working group issued a comprehensive assessment containing a number of
conclusions, as follows:
    In recent years, toxicological and biocompatibility aspects of
dental amalgam have been reviewed extensively, both nationally and
internationally, and risk analyses carried out. Currently available
data indicate that mercury from dental amalgam will not cause an
unacceptable health risk to the general population. * * * levels of
mercury found in tissues, {*filter*} and urine and associated with dental
amalgam fillings are considerably below the levels at which systemic
dependent toxic effects have been shown to occur * * *. The
hypothesis that there is a significant toxicological risk from
dental amalgam fillings cannot be substantiated by the available
evidence * * *. Local reactions to dental amalgam fillings and other
dental restorative materials do occur but are relatively rare * * *.
There is no scientific evidence that the use of dental amalgam is
related to adverse effects on pre- and post-natal health or
fertility.
Although there is not complete unanimity within the world community on
either the potential health consequences arising from the use of dental
amalgam or the appropriate posture that national health authorities
should take with respect to regulating its use, there is overwhelming
agreement among major health authorities that have assessed these risks
that there is no evidence of a serious threat to the general population
whose dental caries are treated with amalgam (Ref. 11).
    Notwithstanding general international consensus about the level of
risk, some Nordic countries, such as Denmark, Finland, Norway, and
Sweden, have placed legal restrictions on dental amalgam for
environmental concerns (Refs. 7 and 11). In addition, several European
countries have taken very conservative approaches.

V. 1993 and 1994 Panel Meeting Concerning Encapsulated Amalgam
Alloy and Dental Mercury

    The Dental Products Panel (hereinafter referred to as the Panel)
met on December 1, 2, and 3, 1993, and June 29, 1994, to discuss
amalgam products. In addition to testimony from FDA staff, the Panel
heard testimony from representatives of ADA, the American Dental Trade
Association, and PHS. The Panel also reviewed the 1993 PHS report and
an updated literature review. FDA requested that the Panel make a
classification recommendation only on the encapsulated dental amalgam
alloy and mercury.
    After considering this testimony and information, the Panel
unanimously recommended to classify encapsulated amalgam alloy and
mercury for the restoration of teeth into class II. Specifically, the
Panel recommended voluntary performance standards that could be issued
by a group such as the Association for the Advancement of Medical
Instrumentation (AAMI), voluntary testing guidelines, education, that
the product be used only upon the written or {*filter*}authorization of a
practitioner licensed by law to administer or use the device, and that
the device be used only by persons with training or expertise in its
use (Ref. 12).

A. Identification

    The Panel identified encapsulated amalgam alloy and mercury as a
device composed of elemental mercury and amalgam alloy separated by a
septum, which when placed in a dental amalgamator produces dental
amalgam that is intended for the restoration of teeth. This product is
hereinafter referred to in this document as encapsulated alloy/mercury.

B. Classification Recommendation of Encapsulated Alloy/Mercury

    Class II (special controls): The Panel recommended that the
establishment of special controls be a medium priority.

C. Summary of the Reasons for the Panel's Recommendation for
Encapsulated Alloy/Mercury

    The Panel, after considering the persons for whom the generic
device is intended, and the proposed conditions for use for the generic
device, gave the following reasons in support of its recommendation to
classify the encapsulated alloy/mercury into class II.
    1. General controls by themselves are insufficient to provide a
reasonable assurance of the safety and effectiveness of the device.
    2. There is sufficient information to establish special controls to
provide reasonable assurance of safety and effectiveness.
    3. Special controls will provide a reasonable assurance of safety
and effectiveness.

D. Summary of Data on Which the Panel's Recommendation Is Based

    The Panel based its recommendation on the review of the PHS report,
other published literature, on expert testimony presented to the Panel,
and on the Panel member's personal knowledge of, and experience with,
the devices. The PHS report has been summarized under section IV.A of
this document.
    The Panel also reviewed a wide range of literature during its
deliberation on the classification of encapsulated alloy/mercury in
addition to the data described in the PHS report. The majority of the
literature reviewed states that there is no compelling reason to change
the current usage patterns of dental amalgam. There is, however,
acknowledgement that continued research in the area is prudent. The
following paragraphs describe specific information detailing the
literature.
    One of the articles reviewed indicated that mercury vapor is
released from amalgam restorations. This article stated that there is
release of mercury vapor from restorations during chewing, tooth
brushing, and other {*filter*}activities. The author, however, indicated
that there is insufficient knowledge about the metabolism of mercury
vapor in the human to predict the health significance

[[Page 7625]]

of chronic exposure to this source of mercury (Ref. 13).
    Another article reviewed by the panel demonstrated that mercury
vapor can be analyzed in the {*filter*}cavity, especially following removal
of amalgams, and during the setting and polishing of the amalgam. This
study also demonstrated a significant direct correlation between the
size of the amalgam restoration and the amount of vapor released. The
study, however, concludes that mercury vapor exposure is of short
duration and infrequent and is well below the exposure limits that are
considered harmful (Ref. 14).
    Another article indicated that although there is evidence of
mercury vapor released from amalgam restorations there is no proof of a
causal link of this specific source of the heavy metal to any major
human health problem (Ref. 15).
    One article indicated that Dental Amalgam remains one of the most
versatile restorative materials in use (Ref. 16). The article further
stated that certain measures should be instituted to assure patient and
health care professional safety. These include the potential for
chemical sensitivity to any of the elements and compounds found in
dental amalgam. Similar concerns were also raised in the PHS report.
The article reported that the chemical sensitivity response to specific
compounds and elements in a dental amalgam are no different than other
sensitivity reactions (Ref. 16). It further stated that evidence
suggests that sensitivities to chemicals can occur within a small
portion of the population.
    Several articles addressed the benefits versus the risks of dental
amalgam, and these articles agreed that, although dental amalgam can
release minute amounts of elemental mercury, occupational studies
indicate that the severity of response to this heavy metal follows a
dose response pattern (Refs. 16 and 17). A dose response effect has not
been demonstrated at a level of exposure associated with dental
amalgams (Refs. 16 and 18). It also is noted that mercury is absorbed
from many sources, including cooking.net">food and air, and there has been no
demonstration that most people experience any clinical effects from
this small additional body burden of mercury from amalgams (Ref. 16).
The articles also stated that if there are adverse health effects from
mercury in dental amalgam they may be so subtle and nonspecific that
they would be difficult to detect, and noted that true allergies to
dental amalgam rarely have been reported but do exist (Refs. 16 and
19).
    One article directly examined the claims of mercury poisoning from
dental amalgam (Ref. 19). This article and others concluded that
although it is not possible to completely rule out adverse effects in a
minority of susceptible patients, there is insufficient evidence to
justify claims that mercury from dental amalgam restorations has an
adverse effect on health on the vast majority of patients (Refs. 16 and
19). Other articles indicated that, although mercury vapor in high
concentrations can have deleterious effects on organ systems, there is
no evidence of risk at the levels generated by chewing with amalgam
restorations (Refs. 13 and 15). The regulatory issues related to
amalgam were addressed in one article. This article emphasized the need
for continued surveillance and the need for practitioner input to
report problems in performance with dental devices (Ref. 20).

E. Risks to Health

    The Panel stated that there were no major risks associated with
encapsulated amalgam alloy/mercury when used as directed, but
recognized there was a small population of patients that may
demonstrate allergic reactions to the materials in amalgam. The Panel
noted that improper usage of the product also presented risks
associated with mercury toxicity. The Panel specifically identified
improper storage, trituration, and handling as contributing to this
risk.

VI. The Proposed Rule

    FDA is proposing classification actions in this document for dental
mercury and dental amalgam products. FDA believes that the uniform
regulation of all these products as class II devices, and the
application of certain uniform special controls is appropriate, given
the same risks are presented by the potential toxicity of mercury in
each of these devices. This approach is consistent with the
recommendation in the PHS report to regulate these products in a
uniform manner. FDA believes that sufficient information exists to
develop special controls, which will provide reasonable assurance of
the safety and effectiveness of these devices.
    With respect to encapsulated alloy/mercury, FDA agrees with the
Panel's recommendation and is proposing that this product be classified
into class II (special controls). Specifically, FDA is following the
Panel's recommendation and proposing that labeling guidance and
relevant recognized voluntary consensus standards be applied as special
controls to these products.
    FDA is also proposing to reclassify dental mercury as identified in
Sec. 872.3700 from class I to class II with labeling guidance and a
relevant recognized voluntary consensus standard as special controls.
    Lastly, FDA is proposing to add labeling guidance and a relevant
voluntary consensus standard as special controls for the existing class
II device, amalgam alloy, as identified in Sec.  872.3050. Currently,
no performance standard or other special controls are designated for
amalgam alloy.

A. Information FDA Reviewed Before Issuing This Proposal

    Before making this proposal, FDA carefully examined extensive
information about the safety and effectiveness of dental restorative
materials that contain mercury. As stated previously, public concern
about the safety of dental amalgam engendered several national and
international comprehensive reviews of scientific information about the
risks and benefits of these products. FDA examined the 1993 and 1995
PHS reports, information presented to the Panel and the Panel's
recommendations, information submitted in support of citizen petition's
requests, and numerous reports of international health organizations
and foreign countries that conducted comprehensive risk assessments of
dental products that contain mercury.
    In preparing the 1993 and 1995 PHS reports described in section
IV.A of this document, the experts convened by the PHS conducted a
comprehensive review of the scientific literature to assess the
benefits and risks posed by dental restorative materials containing
mercury (Ref. 1). In assessing the benefits of these products, the
Benefits Assessment Subcommittee performed a literature search using
the Medline system (Ref.1). The scientific material reviewed for this
report included well-qualified, prospective studies using objective
assessment methods; cross-sectional studies reporting data for a given
point or points in time; retrospective studies reporting the longevity
of dental restorations; and articles published in peer-reviewed
scientific journals (Ref. 1).
    In assessing the risks associated with dental restorative materials
containing mercury, the Risk Assessment Subcommittee viewed the body of
significant literature that described the evidence for possible health
effects produced from exposure to mercury from dental amalgam (Ref. l).
The Risk Assesment Subcommittee reviewed an extensive number of studies
relating to

[[Page 7626]]

possible risks presented by amalgam, including studies relating to:
Mercury forms, intake, uptake, metabolism and excretion; human exposure
to mercury from dental amalgam; factors affecting estimates of daily
intake of mercury vapor from dental amalgam; intra{*filter*}mercury vapor
production and estimation of daily intake; mercury levels in body
fluid; human and animal uptake of mercury from dental amalgam; hazard
identification; human exposure and response; occupational hazards
presented by dental amalgam exposure; hypersensitivity; psychological
outcomes associated with mercury levels in body fluids; and mercury
residues in neurological patients (Ref. 1). The PHS updated its review
of scientific literature on risks and benefits and issued a new report
in 1995 that confirmed its initial findings (Ref. 2).
    FDA also examined the information reviewed by its expert Panel in
1994, and the Panel's recommendation. In making its recommendation, the
Panel reviewed the 1993 PHS report, testimony from several professional
and health organizations, and additional scientific literature as
described in section V.D of this document.
    FDA also carefully examined numerous studies, as described in
section IV.B of this document, submitted by petitioners as evidence
that amalgam fillings cause detrimental physiological and psychological
effects.
    Lastly, FDA reviewed the comprehensive reports of several
international health organizations and foreign countries on the risks
associated with these products, described in section IV.D of this
document. In preparing these reports, these countries and organizations
conducted extensive reviews and assessments of existing literature and
scientific information.

B. Weighing Benefits and Risks

    For purposes of classification, FDA is to determine the safety and
effectiveness of a device, in part, by weighing the probable benefits
to health from use of the device against any probable risks of injury
or illness from such use (section 513(a)(2) of the act).
1. Benefits
    Over the past 100 years, amalgam fillings have provided great
benefit by restoring the structure of teeth of millions of individuals.
Products used to make amalgam fillings are used today in the following
situations (Ref. 1):
     Individuals of all ages;
     Stress-bearing areas and in small to moderate sized
cavities in the posterior teeth;
     Teeth with severe destruction of structure;
     For cast-metal, metal-ceramic, and ceramic restorations as
a foundation;
     When a patient's commitment to {*filter*}hygiene is poor; and
     When moisture control is problematic with patients.
    These products provide substantial benefits over other dental
restorative materials because amalgam fillings offer a broad range of
applicability in clinical situations, durability, ease of use and
relative insensitivity to variations in handling technique and {*filter*}
conditions (Ref. 1).
2. Risks
    Dental amalgam can release minute amounts of elemental mercury, a
metal whose toxicity at high exposure levels is well established.
Estimates of human uptake of mercury from amalgam fillings have ranged
between 1.24 and 27 micrograms (g) per day, a factor of more
than twentyfold. However, the widely varying experimental conditions
and assumptions in calculations undoubtedly contribute to the wide
range of results. Non-physiologic-based models resulted in estimates
likely being several times too high. Recalculations correcting for
these factors produced estimates of less than 5 g per day.
Studies have demonstrated higher {*filter*} and urine levels of mercury in
individuals with amalgam fillings. However, estimates of mean daily
mercury exposure from all sources vary (Ref. 1).
    There is also evidence that mercury levels in body fluids spike
during placement and removal of amalgam fillings and then decline over
time, but no controlled clinical studies of health consequences of this
phenomenon have been conducted. Occupational studies indicate that
subclinical effects may occur at exposure levels tenfold higher than
those typically experienced by the general population. Severity of
response generally follows a dose-response pattern. There is no valid
scientific evidence demonstrating specific adverse responses or a dose
effect in humans at levels of mercury exposure associated with dental
amalgam (Ref. 1).
    Mercury is absorbed from many sources, including cooking.net">food and air.
Because of the variability of exposures to mercury from all sources in
the population, the margin of safety for some persons may be lowered
when mercury from amalgam fillings is added. There is no valid
scientific evidence that the general population treated with dental
amalgam experiences any adverse clinical effects from this additional
body burden of mercury arising from amalgam use (Ref. 1).
    As stated previously, public concern has been expressed over the
toxic effects of mercury from amalgam fillings and certain persons have
attributed a variety of detrimental physiological and psychological
effects to mercury toxicity from amalgam fillings. In response to these
concerns, numerous national and international reviews have examined
reports of adverse effects from amalgam fillings, and FDA has reviewed
substantial information about amalgam risks, as described in sections
IV and V of this document.
    After review of the scientific evidence and review of numerous
studies submitted in support of banning or upclassifying dental
restorative products containing mercury, FDA does not find any
persuasive evidence that the physiological and psychological symptoms
attributed to amalgam fillings are caused by amalgam fillings.
Furthermore, FDA does not find any persuasive evidence that there is
any improvement of these symptoms after removal of amalgam fillings.
Although there are studies purporting to support the view that amalgam
products pose risks to persons beyond the small subpopulation of
hypersensitive individuals, conclusions cannot be drawn from these
studies because they are methodologically flawed.
    This position concerning the evidence of risks posed by amalgam
fillings is supported by the findings of the PHS reports (Ref. l),
international health organizations, foreign governments, and the
recommendations of FDA's expert advisory Panel as described in sections
IV and V of this document. FDA does believe that there are some risks
associated with dental products used in amalgam fillings from mercury
toxicity that are associated with improper storage, trituration, and
handling of the product. However, FDA does not believe that there are
any major risks associated with toxicity of mercury when these products
are used as directed. FDA believes there are also risks of allergic
reaction to these products in a small subpopulation of individuals.
3. Benefits Versus Risks
    FDA believes that valid scientific evidence, as defined in
Sec. 860.7(c)(2), exists to determine the safety and effectiveness of
dental amalgam: Namely, certain studies described in the PHS report;
the studies and reports upon which the Panel based its recommendation;
studies and reports reviewed by international health organizations and
foreign governments; and most notably the significant human

[[Page 7627]]

experience with amalgam for over 100 years.
    Although the degree of risk is not known to a certainty, FDA must
make an assessment to weigh the probable benefits with the probable
risks associated with the use of the device, in accordance with the
criteria for a reasonable assurance of safety under Sec.  860.7(d)(1).
The statute states that FDA's classification decisions are to be
predicated on a ``reasonable assurance of safety and effectiveness,''
not an absolute assurance of safety and effectiveness (section
513(a)(1) of the act). Moreover, the statute directs FDA, in
determining what is a ``reasonable assurance'' of safety and
effectiveness, to assess ``probable risk,'' not absolute risk (section
513(a)(2) of the act). FDA believes that the benefits and risks of
encapsulated alloy/mercury and amalgam alloy are sufficiently
characterized to make a determination that these products should be
classified into class II with special controls. FDA notes that there is
more significant human experience with dental amalgam than any other
restorative material, and that, accordingly, more is known about the
risks of dental amalgam than any other restorative material (Ref. 1).
    Given the known risks of untreated caries, the longstanding history
of successful use of dental amalgam restorations, the benefits of
products used in amalgam fillings over other alternative materials, and
the overall lack of valid scientific evidence that persons whose
carious teeth are treated with dental amalgam experience any adverse
health effects, other than a very small number of people who are
hypersensitive to mercury, FDA believes that the probable benefits of
restorative dental products containing mercury outweigh the probable
risks of using these products.
    The agency acknowledges that a small subpopulation of persons that
already have high body burdens of mercury or suffer from allergies may
respond adversely to the additional mercury exposure from amalgam
fillings. For these subpopulations, the agency believes the risks can
be addressed by labeling and by using alternative filling materials.
    FDA believes that special controls, such as those described below
by the Panel, will address those risks presented by dental amalgam
products, both to hypersensitive individuals and health care workers,
and that class II with special controls will provide a reasonable
assurance of the safety and effectiveness of dental amalgam products.
4. Proposed Special Controls to Address Risks Associated With the Use
of Dental Restorative Materials Containing Mercury
    FDA is proposing a labeling guidance and relevant recognized
voluntary consensus standards as special controls for dental mercury
and dental amalgam products. These special controls are consistent with
the Panel's recommendations for special controls for encapsulated
amalgam alloy and dental mercury, and FDA believes they address the
risks related to toxicity associated with improper handling of dental
mercury and dental amalgam products, and the risks for the small
subpopulation of individuals who are allergic to ingredients in these
products.