The plan was divided into three fundamental areas of activity—research, education and regulation—and a different USPHS agency was assigned the lead for each one. Endorsed by each Agency Head and the Assistant Secretary for Health, the plan set forth a broad range of risk management activities whose implementation costs were absorbed by each agency. In some cases, completion has been reached. In other cases, work is ongoing. In still others, new directions have been pursued in light of new information and budgetary considerations.

In the 1993 USPHS report on dental amalgam, priority was given to research aimed at establishing:

• whether low-level mercury effects are prevalent in the general population and whether they can be attributed to amalgam;
• which special population groups, (e.g., children, pregnant women, or people with renal disease), if any, might be especially sensitive to mercury effects;
• how human studies could be designed to assess the potential effects of dental amalgam;
• whether existing dental amalgam restorations should be replaced and, if so, under what circumstances;
• how the mercury in dental amalgam might be stabilized to minimize release into the body; and
• the safety and effectiveness of existing alternatives to dental amalgam.

With this in mind, the USPHS, led chiefly by the National Institute of Dental Research (NIDR) of the National Institutes of Health, which is investing more than $30 million per year to support a range of intramural and extramural studies, is vigorously addressing the questions and research goals outlined in the 1993 report. (*In FY 1996, the NIDR expended $33 million for extramural research alone, directed at epidemiological and materials development research.)

Dental Amalgam Safety Study
There is a paucity of epidemiological studies of health effects of dental amalgam in patient populations. Even among the few studies that have been published, it has been difficult to discern any patterns of effects due to the relatively small sample sizes and the different definitions used for predictor and outcome measures.

A U.S. Air Force Health Study, begun in 1982 to determine if Air Force personnel who aerially dispersed the herbicide Agent Orange during the war in Vietnam (an activity known as Operation Ranch Hand) are experiencing health effects traceable to exposure to the defoliant, provided NIDR with an opportunity to conduct an epidemiological study on a large and well-defined cohort for whom extensive medical and oral health information is available. The study entails a 20-year follow-up of exposed personnel and consists of mortality and morbidity components based on a matched cohort design (i.e., age, race, and military occupation).

A database on the nearly 1,200 study participants contains extensive medical information relating to the central nervous system; renal, immune, and endocrine function; and psychological conditions. Supplementary information includes occupational exposure to heavy metals as well as dietary information such as fish consumption. Oral health information includes the presence or absence of soft tissue lesions, coronal caries, DFS (Decayed or Filled Surfaces) scores, the number of restorations and the type of restorative material used. Dental records from military archives enable researchers to pinpoint the time since amalgam restorations were initially performed. Measures of total and inorganic mercury levels in blood and urine are available as well.

The dental component of the study, into which NIDR is investing $1.75 million over a an 8-year period, will entail two experimental designs. The first will be a cross-sectional approach in which the association of current levels of mercury vapor exposure from amalgam and the occurrence of several health conditions will be determined. The other design will involve a longitudinal cohort study in which the number of amalgam restorations among the approximately 1,200 cohorts are determined retrospectively and comparisons of the prevalence and/or incidence of various health outcomes are made between subgroups having high exposure levels for several years with those of non-exposed or low-exposed individuals.

At present, data are available for 1,166 subjects. The average number of amalgam surfaces is 20, a number that is relatively high in comparison to the general U.S. population. Mercury concentration levels in both blood and urine, however, appear to be lower than those found in the general population, i.e., 2.9 and 3.1 micro-grams per liter, respectively. An association between the number of amalgam fillings and mercury concentrations in urine has been made; a similar association has not been established for blood.

To date, preliminary data show no adverse health effects. Final results of ongoing data analyses are expected by 1998.

Children's Amalgam Trial
In 1994, the NIDR publicly invited researchers to propose clinical trials on dental amalgam use among children in the mixed dentition stage. The target population was selected for several reasons. The first was the need to establish a baseline level of mercury in a group with little or no history of exposure to mercury. Second, it was important to study a population that, on the whole, experiences a higher rate of caries and thus are candidates for amalgam treatments. (Among the enrollment criteria will be that subjects have received little or no restorative treatment prior to entry into the trial.) And finally, using children in the study will allow at least 7 years of follow-up in order to detect possible subtle and long-term health effects.

Ten (10) applications were submitted to the NIDR. Once peer reviewed, two were selected in September 1996 for $1.4 million in NIDR funding. Enrollment of study subjects will begin in 1997. The two-armed trials will entail both cross-sectional and longitudinal comparisons and will focus on: (1) potential neurological, psychological and behavioral, renal, endocrine, and other relevant organ system impairments and dysfunctions; (2) mercury concentrations in urine, blood, and other relevant tissues; and (3) progression of mercury in urine, blood and other tissues over time following amalgam treatments. Both trials, while independent, will use the same amalgam and composite materials, similar clinical decision protocols, and a common set of neuropsychological, cognitive, and behavioral tests.

One trial will be a collaborative investigation by scientists at the University of Washington (Seattle) and the University of Portugal (Lisbon), and will involve 500 children between the ages of 8 and 10 who attend the Casa Pia Schools in Lisbon. The second trial is being conducted by a consortium of scientists from the New England Research Institutes (Cambridge, MA), Forsyth Dental Clinic and Harvard University (Boston, MA) and the University of Rochester (Rochester, NY). The study population will be 500 children, age 6-8, from the Boston/Cambridge area and the State of Maine, who require at least three fillings. Initial results of these two studies are anticipated by the year 2003.

Ancillary Studies
Capitalizing on the availability of the two children study populations, the NIDR is pursuing the conduct of three separate studies. One will examine the immune function after placement of dental amalgam restorations. A second will focus on changes in antibiotic resistance among children with amalgam fillings. And the third will address the contribution of mercury from amalgam to the overall body burden of mercury through labeling mercury with a stable isotope. As with the endpoints in the clinical trials, these ancillary studies will provide for both cross-sectional and longitudinal comparisons. These studies are expected to begin in 1997 and produce results by 2003.

Alternative Materials Development
In keeping with the goal of improving dental care treatment, the NIDR is underwriting research designed to produce clinically and commercially viable alternatives to amalgam. Work in this area is proceeding on two fronts. In fiscal year 1996, for example, NIDR funded 35 research projects totaling $7 million for the development of resin composites, ceramics, glass ionomers, and other metal alloys.

Chief among these was a call for new labeling requirements for amalgam and all dental restorative products to provide dental care providers with information to more accurately pinpoint the source(s) of allergic reactions among the patients they treat and to select suitable substitutes when necessary, as well as avoid the use of certain treatment materials for patients with known, pre-existing sensitivities. Apart from ensuring that dental practitioners have the requisite information to provide quality care, this "truth in labeling" approach was suggested with the public's right to know in mind: in other words, to arm individuals with the facts necessary to make informed treatment choices. As part of this labeling initiative, the USPHS report also recommended that labeling materials should include statements concerning the safe handling and use of dental amalgam, in addition to clean-up of spills and storage and disposal of this material.

Given the relative dearth of adverse effects reports, notwithstanding the existence of a voluntary reporting system known as Medwatch—managed by the Food and Drug Administration and accessible to all health professionals and consumers—the USPHS report highlighted the need for broader educational and promotional efforts to make dentists, dental auxiliaries, and patients more aware of the reporting system and to foster incident reporting on a broader scale. Doing so, it was felt, could help shed additional light on the nature and degree of risk patients may be exposed to when undergoing amalgam placement procedures.

Finally, in light of the emergence and widespread clinical use of pre-encapsulated amalgam, the 1993 report focused on FDA's regulatory coverage of amalgam-related products. Historically, FDA had regulated elemental (or dental) mercury separately from and less rigorously than the alloy. To rectify this situation and "classify" the modern-day pre-encapsulated form, the report called upon FDA to regulate the three discrete entities as "class II" medical devices, meaning that special labeling and other regulatory controls could be imposed on these products.

Beginning in December 1993 and extending through the following year, FDA consulted experts from the fields of dentistry and toxicology, dental trade groups, and consumers with an interest in these areas who served on the agency's dental products advisory panel. Input was also elicited from other Federal agencies such as the Centers for Disease Control and Prevention, the NIH National Institute of Dental Research and the Labor Department's Occupational Safety and Health Administration. A careful review was made of OSHA's Material Safety Data Sheets program (this program requires dental offices to maintain records of all hazardous substances used in their individual practices as well as corresponding emergency decontamination instructions as a means to protect office workers) to guard against duplicative Federal regulatory mandates.

Based upon these consultations, FDA proceeded to promulgate new regulatory proposals to consolidate amalgam-related products into a single regulatory "class" as well as embark on a labeling program that will over time encompass all dental devices, including dental amalgam (ingredient labeling for dental amalgam has been given first priority due to its widespread use and well known composition, long duration of human tissue contact and reports of sensitization reactions among patients). These proposals were formally unveiled in early 1997.

With respect to ingredient labeling for dental amalgam, the FDA's guidance recommends that manufacturers disclose all component materials in descending order of content by weight percentage without compromising commercial confidentiality. In addition, manufacturers will be expected to include lot numbers, appropriate warnings and precautions, special handling instructions and expiration dating. Because of the longstanding use of dental amalgam, whose component ingredients are widely known among users, the guidance will be particularly beneficial in the case of newly developed alternative restorative materials, whose chemical composition, toxicological characteristics and potential for allergic reactions and other adverse health effects are considerably less well known.

Although FDA's ingredient labeling guidance will not establish legally enforceable rights or responsibilities and will not bind the industry or the agency, it will prescribe a uniform approach to marketing dental restorative materials, one that FDA product reviewers will take into account in performing market clearance evaluations.

In the area of adverse event reporting, the FDA, CDC, and NIH are working cooperatively to encourage dental professionals and consumers to make greater use of FDA's voluntary MedWatch and mandatory Medical Device Reporting programs to alert Federal health officials to untoward events involving the use of dental restorative materials. Doing so will help to supplement reports that dental product manufacturers are required to submit to FDA under a separate, mandatory Medical Device Reporting (MDR) program.

In the 1980's-early 1990's, FDA received hundreds of complaints related to amalgam, most of which were anecdotal reports purporting a link between dental amalgam and a wide variety of non-specific symptoms and systemic conditions. Lacking confirmatory clinical evidence and given the absence of identifiable patterns or trends in the reported effects, no definitive correlations could be drawn between amalgam and the case reports. In the last 4 years, the number of reports has precipitously declined: only eight reports have been submitted. Of these, five involved patient reports of alleviated physical symptoms and feelings of well-being after removal of amalgam fillings.