Research Work Group Leader:
Stanford Hamburger, D.D.S., M.P.H. Food and Drug Administration

Research Work Group Members:
Thomas Callahan, Ph.D. - Food and Drug Administration
Stephen Corbin, D.D.S., M.P.H. Centers for Disease Control and Prevention
Jeffery Gift, Ph.D. - Environmental Protection Agency
Peggy Hamilton - Food and Drug Administration
Annie Jarabek - Environmental Protection Agency
Mark McClanahan, Ph.D. - Centers for Disease Control and Prevention
Kevin Tonat, M.P.H. - National Institutes of Health

A major concern facing the public health and professional communities, as well as the public, is the potential for adverse health effects associated with the use of dental amalgam/mercury restorative materials. This concern has led the Public Health Service (PHS) to develop comprehensive scientific reviews of the risks and benefits of dental amalgam use. Pursuant to these reviews, the Committee to Coordinate Environmental and Health Related Programs (CCEHRP), through its Risk Management Subcommittee (RMS), formed three work groups to develop reports addressing professional and public education, regulation, and research recommendations related to the use of dental amalgam and human health. This report by the Research Work Group (RWG) is in response to five charges that were provided by the RMS as follows:

1. Evaluate the research recommendations presented in the risks and benefits report.
2. Develop rating criteria for identifying and prioritizing research initiatives.
3. Address the viability of developing an intramural tracking mechanism to ensure that meritorious research projects are properly considered and funded within the PHS.
4. Advise whether the use of dental sealants and other preventive restorations can further reduce the incidence of caries and, thus, the need for amalgam restorations.
5. In consultation with the Regulation Work Group, examine the relevance and utility of adverse effects information collected from FDA's Medical Device Reporting System and Problem Reporting Programs (MDRs and PRP, respectively) for ongoing and future research initiatives, and explore means for exporting such data to government and private researchers.

The RWG conducted extensive discussions of the charges which resulted in general agreement that the philosophical approach would be based on the public health aspect(s) of scientific research with an emphasis on what research would best address two important public health policy questions:

"Should dental amalgam continue to be recommended for use?" and, if not,

"Should existing dental amalgam restorations be removed and replaced with another material?"

These policy questions cannot be addressed with confidence until we obtain answers to several fundamental questions relative to potential adverse effects of mercury on human health that include:

• Is the population or any subpopulation at significant risk of adverse health effects from levels of body mercury cogently encountered?
• Does mercury follow the heavy metal paradigm, i.e., is there no threshold?
• Does mercury from dental amalgam make a significant contribution to total human exposure from all forms and sources of mercury with resultant adverse health effects?

• If mercury from dental amalgam does pose significant health risks, are there alternative restorative materials and methods that are adequate (safe and effective) for treating the range of dental restorative needs encountered in human populations?

Similar to the issues of lead neurotoxicity, mechanistic research on mercury toxicity and the dynamics of its release from dental amalgams is crucial given the limitations of epidemiologic evidence. Issues such as measuring doseresponse at very low levels, bioavailability, relative persistence of the effects of early exposures, and the identification of critical periods of sensitivity will not be identified by epidemiologic studies alone. Such studies are generally imprecise in terms of dose and they are frequently confounded by the multitude of variables present in human populations.

It is important to recognize that the changing manner of dental practice has a continuing impact on how dental amalgam is used and how its "risks" and "benefits" are assessed. Average caries scores, especially for children and adolescents, continue to diminish. This reduction is largely attributable to the widespread use of fluorides, especially community water fluoridation. Dental amalgam remains the most commonly used dental restorative material, with nearly 50 percent of dental restorative procedures still involving the use of dental amalgams. However, its use is declining as caries scores decline and alternative materials are substituted. Effective preventive methods (e.g. sealants) and the utilization of new and improved materials and techniques now permit a wider spectrum of clinical choices.

The members of the RWG reviewed and accepted the amalgam benefits and risks reports as expert reviews and used them as a starting point for identifying and characterizing research needs. Numerous research recommendations were included in the reports, some general and some specific.

Each RWG member was asked initially to review and evaluate these recommendations. Additionally, RWG members were asked to identify questions or items suggested in the text of those reports that were not specifically addressed in the recommendations sections. These, in addition to the NIH Technology Assessment Conference document entitled Dental Restorative Materials and the recent FDA Dental Panel Report, comprise a rather complete inventory on amalgam safety and benefit issues. Additionally, research recommendations from the WHO International Programme on Chemical Safety (IPSC) Environmental Health Criteria 118 Inorganic Mercury were also considered.

Based on recent literature reviews, we conclude that several critical parameters relating to mercury toxicity and human health are unresolved: the specific health effects of low level mercury exposure, if any; the relevant absorption, distribution, metabolism, and elimination; putative biological markers of exposure and effect; the medical consequences; and, the significance of blood, urine, or tissue levels of mercury. Observations from the source reports cited that support this conclusion include the following:

1. The putative human health effects of mercury are not well established or pathognomonic at low levels of exposure.
2. Reported exposure levels are not consistent and are widely divergent. There is probably no zero-level of human exposure to mercury.
3. Direct human data are inadequate and subject to confounding. Although, adverse human health effects from high mercury levels are documented from occupational exposure, these studies are not adequate for making decisions about risks from low-level exposure.
4. Experimental animal data are inadequate and/or not helpful (e.g., sheep and rodent data may not be relevant to humans) because principal exposure may not be due to the vapor components.
5. There are no consistently accepted criteria from which to assess the failure of a restoration.
6. The exact mechanism of action of neurotoxicity from mercury is not established.
7. No complete quantitative risk assessment, including risk chain has been presented.
8. The mercury exposure and related health effects that may accompany removal of dental amalgam restorations as compared to not removing existing amalgam restorations have not been clearly established.
9. Information supporting the safety of alternative materials may be no more sufficient than the information available on risks or benefits of exposure to dental amalgams.

The RWG discussed extensively the merits of developing a numerically based ranking system for purposes of establishing research priorities relative to dental amalgam. It was recognized that even if such a system were to be developed, its validity, objectivity, and usefulness would remain to be determined. Similar issue-specific systems or a generic system have not yet been developed for ranking research needs and opportunities in other CCEHRP areas of concern to the Work Group's knowledge. Additionally, it was apparent, after review of the risks and benefits reports, that there are so many areas meriting additional scientific research, developing a special ranking instrument at this time may be superfluous.

As an alternative approach, members of the RWG independently reviewed the risks and benefits reports, along with the abstracts from the NIH Technology Assessment Conference, and the WHO IPSC report and developed lists of research questions and needs. The RWG then employed an iterative delphi type process to develop a list of the most fundamental and important areas for research that could practically be pursued in the immediate future. These are areas felt to be most critical to sound public health decision-making. Notwithstanding this approach, a more extensive list of issues meriting additional research attention, reflecting an integration of individual RWG member efforts, are identified in Attachment 1 of this report.

Two major areas of research questions were identified—questions that were principally methodological or those that were substantive relative to the effects and mechanisms of mercury actions on human health, whether from dental amalgam or other sources.

• The prevalence of symptoms and signs in the general population of mercury intoxication
• Identification of low level mercury exposure effects and in relation to amalgam placement and removal
• Distinguishing between non-specific effects of mercury exposed and similar effects produced by other factors
• In the general population, the distribution of mercury release from dental amalgams
• Identification of valid/reproducible criteria for dental restoration replacement
• The effects of mercury exposure on high risk or more sensitive groups
• Increasing the stability of mercury in dental amalgam
• Development of standardized exposure measures
• Cross-sectional and prospective study designs to assess potential health effects from dental amalgam
• Long-term safety and efficacy of alternative materials

• Absorption, distribution, metabolism, and elimination of mercury from all sources, and dental amalgam in particular
• Mechanisms of action of mercury toxicity

Additional methodological concerns include:

• Are body burden levels of mercury to be physiologically or functionally determined?
• What are the relationships between in vitro and in viva and between animal and human results?
• What sources and forms of mercury are of greatest concern?
• What dose/concentration parameters should one use in assessing dose (e.g. mean values or the highest reported value) and what are the dose-time-response relationships?
• How useful are blood, urine, or tissue levels of mercury for assessing exposure levels to predict potential health risks?
• How does one account for prior organ accumulations of mercury?

Very specific research questions/ studies/designs should be reviewed by experts in the topical subject areas. An extensive list of currently funded research projects is appended (Attachment 2) that reflects RWG consensus as bearing on many of the scientific questions at issue.

The RWG adopted the position that existing intramural research projects, whether conducted by PHS researchers or through extramural grants, are meritorious by virtue of the review processes they must undergo before approval or award.

A first approximation of research projects relevant to dental toxicity, mercury amalgam, and alternative dental restorative materials conducted throughout the PHS was obtained by conducting several searches of the PHS CRISP database (Attachment 2).

In order to ensure that duplicative efforts would be minimized, the RWG consulted with the CCEHRP Subcommittee on Research Needs on its concurrent efforts to develop a research tracking system for specific areas of interest to CCEHRP.

An Intramural tracking mechanism to identify and monitor research projects funded within the PHS is a viable undertaking. Alternative mechanisms of obtaining relevant information, such as CRISP (Attachment 3), are available but do not currently address the full requirement of this charge.

The system should be clearly distinguished from a system to track recipients of dental amalgam or a postmarket surveillance system. This system would essentially be a registry of research projects supported and/or sponsored by PHS agencies. The administration of a system is of prime importance. Since it is to encompass all of the PHS and is to be a tool for the Assistant Secretary for Health (ASH), it should be administered by that office and could be delegated by the ASH to a lead agency or committee. In order to be comprehensive, the system should include information from sister agencies (i.e., EPA, DOD) and the private sector.

A proposed intramural tracking system should incorporate, at a minimum the following information for each project:

1. Funding agency
2. Program title
3. Description of project
4. Purpose of this project
5. When results are expected
6. Linkages between anticipated outcome measures and actual findings
7. Milestones
8. Anticipated accomplishments
9. Categories: Basic sciences; Toxicology; Epidemiology; Clinical practice; Public health risk management (science. clinical)

All agencies would need access to the system in order to be able to identify areas of current and needed research and to decide how they would like to prioritize or solicit grant applications or project requests. Cooperation from participating agencies will be vital in order to establish a system that will be a viable tool for agency manages.

Dental amalgam restorations have long been the mainstay of dental restorative practice. In fact, in previous decades when dental caries scores were much higher than today, it was not uncommon for many individuals to have dental amalgam restorations in virtually all their posterior teeth. Declining caries scores are a result of widespread preventive efforts, largely fluorides in drinking water and dental products. Dental sealants, which have been available for two decades, have only recently come into increasing prominence. In 1989, approximately 13% of 8-year-olds and 17 percent of 14-year-olds had received dental sealants. The PHS, through the Healthy People 2000 initiative, has established the goal that by the Year 2000, 50 percent of children will have received dental sealants.

Sealants prevent caries by acting as barriers. Sealants fill surface pits and fissures that are prone to the development of caries. Caries protection may be determined by the sealants' ability to remain adhered to the tooth. As long as the sealant remains intact, caries will not develop beneath it. However, even where sealants have been partially lost, some protection may be gained from residual sealant occluding the depth of the pit or fissure. Still, the longevity of a sealant on a tooth is a prime determinant of success. Sealants are underused in both private and public health care delivery systems. Expanding the use of sealants would reduce the occurrence of dental caries in the population, and particularly among children.

The report on the benefits of dental amalgam has concluded, based on extensive scientific evidence, that dental sealants are extremely effective in preventing decay in the pits and fissures that are common to the chewing surfaces of the posterior teeth This is important since fluoride is only partially effective in preventing caries on these surfaces.

Historically, the near universal choice for dental restorative material in the majority of restoration situations for posterior teeth has been amalgam. However, newer materials and techniques, most notably the preventive resin restoration, and improved composite materials are modifying the "standard" choice in defined situations. With an ever strengthening commitment to preserving as much sound tooth structure as possible, dentists are increasingly relying on non-amalgam restorative materials where the physical stress requirements of a particular restorative situation permit. Plastic filling materials can be used by themselves or in combination with sealants where the extent of caries is conservative. Acid etching techniques that enhance retention of the restorations are substituted for the creation of undercut areas in the tooth preparation to prevent dislodgement. This results in the removal of less sound tooth structure.

Another alternative to dental amalgam in defined restorative situations are the glass ionomers. Since these materials do not resist stress well, they cannot be used in areas of heavy occlusal contact. They offer an added advantage of containing fluoride that can leach out and provide a supplemental caries preventive effect. Glass ionomers, like resins, are tooth colored and thus superior to dental amalgam from an esthetics standpoint.

Still, it must be remembered that the majority of posterior restorative situations do not permit the use of plastic fillings or glass ionomers. This is particularly true of replacement restorations that may need to be large or that restore areas of heavy occlusal contact. With caries scores declining in children and with individual carious lesions being generally less extensive than in the past, there is likely to be increasing substitution of these alternative materials for dental amalgam in the future.

Expanding the use of dental sealants and alternative materials to dental amalgam, where appropriate, should be promoted to the public and the dental profession.

Historically, little use has been made of the reporting system for dentally-related concerns. Thus, it has been of little utility for research purposes.

The relevance and utility of adverse effects information collected from the Food and Drug Administrations's MDRs and PRP for ongoing and future research is limited. A plethora of reports have been filed with chief complaints that were claimed to be resolved with the removal of amalgam/mercury restorations.

These reports, on relatively few subjects, may reflect a "selection bias." Approximately 550 reports have been entered into the system. The patients were self-selected and not representative of the general population. Representativeness is a basic requirement underlying statistical analysis. Preliminary frequencies relative to age, geographical distribution, and symptoms can only be considered as counts. The lack of population based data for comparisons severely limits any useful determinations. Reporting on these systems is not intended to provide precise quantifications of actual population-based risks. The MDRs and PRP are most useful for preliminary assessments of whether more formal surveillance or specialized studies are merited.

Only aggregate data are available from the MDRs and PRP reporting systems. Because of the limitations cited above, their value to researchers or others is severely restricted. Therefore, efforts to make the data more widely available are not likely to be useful.

Based on comprehensive scientific reviews of the risks and benefits of dental amalgam, the RWG has identified an extensive list of research opportunities and needs relative to the safety and utility of dental amalgam and alternative dental restorative materials. Additionally, a smaller list of high priority research areas has been drawn from the comprehensive list, based on the potential to provide a sound basis for public health decision making about the continued use of dental amalgam.

There are enough areas of fundamental research merited, both in terms of low level mercury effects on human health in general and mercury vapor from dental amalgam in particular, that definitive answers will require research efforts over a period of many years. The available research evidence is not specific enough or strong enough to make sound pronouncements about human health risks from dental amalgam. Given the potential that end effects from low levy mercury exposure may well be subtle and non-specific and that the relative importance of various forms and sources of mercury are not clearly established, much work remains.

At the same time, it is encouraging that a wide range of research is already being conducted that should help to answer questions of potential mercury toxicity, as well as the safety and utility of alternative dental restorative materiels. A tracking system has been proposed that will permit the ongoing assessment of research efforts that bear on these questions. Agencies that carry out or sponsor research related to these questions could utilize the tracking system to assess how their resources could best be applied to addressing the most important scientific questions for making sound public policy decisions.

Unlike many areas of potential health risk where extensive research remains to be conducted, a marked decline in exposure to the potential risk agent is already taking place as a result of declining caries rates, improved dental materials and treatment methods, and preference of the public for tooth colored rather than metal colored restorations.