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J Am Dent Assoc, Vol 139, No 2, 138-145. © 2008 American Dental Association

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Seven years of longitudinal observations in a randomized trial

	ABSTRACT

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Background. Although large-scale, randomized trials involving children have been completed and their results demonstrate an absence of neurobehavioral effects from clinical exposure to mercury amalgam, neurological findings from such studies have not been reported.

Methods. The authors conducted a randomized, prospective trial examining the safety of dental amalgam in which 507 children aged 8 through 12 years were assigned to treatment with either amalgam or resin-based composite. During seven years of follow-up, the authors performed annual clinical neurological examinations, including an evaluation of neurological hard signs (NHSs), presence of tremor and neurological soft signs (NSSs).

Results. The authors found no significant differences between treatment groups in any of the neurological measures. Groups did not differ with respect to the presence or absence of NHSs or tremor, nor the presence or absence or severity of NSSs at any point. As expected, NSS severity scores diminished with increasing age.

Conclusions. Even at the levels of amalgam exposure in this study (a mean of 7.7–10.7 amalgam surfaces per subject across the seven years of follow-up), the authors conclude that exposure to mercury from dental amalgam does not adversely affect neurological status.

Clinical Implications. The current evidence is that potential neurobehavioral or neurological effects from dental amalgam mercury exposure in children are inconsequential.

Key Words: Mercury; amalgam; neurological; children

Abbreviations: IRB: Institutional review board. • NHS: Neurological hard sign. • NSS: Neurological soft sign.

For the past 150 years dental amalgam, formulated from approximately 50 percent elemental mercury, has been used in dental restorations. Controversy exists, however, as to whether detrimental effects on brain development in children occur as a function of low-level exposures to mercury from amalgam.^1,2 In two recent long-term, randomized, controlled clinical trials of elementary school children, investigators found no significant differences in neurobehavioral performance between children who received amalgam restorations and those who received only resin-based composite restorations.^3,4

The nervous system and the kidney are the two main sites in which any toxic effects of mercury might be expected to occur, according to results from studies of high-level mercury exposure.^1,5 The neurological examination provides one method of assessing the integrity of the central nervous system. In children, it includes observations of neurological hard signs (NHSs) and neurological soft signs (NSSs). NHSs indicate damage to specific neural structures and, in clinical practice, are used to localize the site of lesion or dysfunction—for example, right homonymous hemianopsia as a sign for left occipital lobe lesion. Screening for NHSs, consists of a brief neurological examination, including the evaluation of mental status, cranial nerves, gross motor and sensory function.^6,7

NSSs, on the other hand, are subtle signs of central nervous system dysfunction that have no localizing value—that is, they may merely point to immature sensory-motor skills and not to any structural damage or localization in the brain, such as showing clumsiness in rapid sequences of fine finger movements. In healthy children, their frequency and severity tend to decrease with age, along with central nervous system maturation.^8–10 In addition, their prevalence is increased in a number of conditions, such as low birth weight, mental or cognitive disturbances, emotional disturbances, low IQ, attention-deficit/hyperactivity disorder, obsessive-compulsive disorders and schizophrenia.^11–16 Although the physiopathology of NSSs is not fully understood, the fact that they are associated with or might be predictive of certain disorders makes them useful as nonspecific probes for disturbances of neurological development.

In previously reported findings, our research team found no significant differences in neurobehavioral performance or nerve conduction velocity (the primary study endpoints) between children who received only amalgam restorations and children who received only resin-based composite restorations.^4,17 This article reports additional findings on secondary endpoints from systematic neurological examinations of the same cohort of 507 children, randomly assigned to receive dental treatment with either amalgam or resin-based composite for posterior restorations (and composite for all anterior restorations) and studied across a seven-year follow-up period. The aim of the neurological examination was to identify evidence of focal lesions or diffuse dysfunction of the nervous system to determine whether dental restoration with amalgam has a deleterious effect on neurological development. The presence of tremor was specifically recorded, in addition to the results of the routine neurological examination, because it is one of the common manifestations of mercury toxicity.^2,3,5

	PARTICIPANTS, METHODS AND MATERIALS

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Participants. The study participants were 507 children from the Casa Pia school system in Lisbon, Portugal, who were 8 to 12 years old at the time of enrollment in the study, which began in January 1997. Inclusion criteria for the study were having at baseline at least one carious lesion in a permanent tooth, no previous exposure to amalgam treatments, urinary mercury level less than 10 micrograms per liter, blood lead level less than 15 µg per deciliter, IQ equal to or greater than 67 as obtained with the Comprehensive Test of Nonverbal Intelligence¹⁸ and no interfering health condition, such as progressive neurological disease or renal insufficiency. Participants were randomly assigned to receive either dental amalgam for posterior restorations (and resin-based composite restorations elsewhere) or resin-based composite restorations only. The study design has been described in detail previously.^4,17,19

Institutional review board (IRB) approval was obtained at both the University of Washington, Seattle, and the University of Lisbon, Portugal. (Author’s note: Please see a note at the end of this article regarding this IRB approval.) We obtained parental or guardian consent, as well as assent from each child (although assent was not required). Neurological examinations were obtained before the beginning of dental treatment at baseline and at yearly follow-up examinations for seven subsequent years.

The table shows the number of participants in each of the randomly assigned groups who underwent neurological examinations at baseline (before receiving dental treatment) and at follow-up years 1 through 7, together with their sex, ethnicity and age. Similar to what was reported previously for the neurobehavioral endpoints,⁴ among those with neurological examinations there were no significant differences between the two randomized groups in sex, ethnicity or mean age at the study’s inception.

 
The number of participants who received a neurological examination in a given year sometimes is less than the number for whom we had data at primary endpoints because the neurological examinations took place in schools and the children sometimes could not leave their classrooms at the time the neurological evaluations were scheduled. The number of participants was not uniform across study years because of dropouts and missed appointments.

The table also shows the average numbers of surfaces filled with amalgam that were present at the time of each neurological examination for those in the amalgam group. The overall average number of amalgam surfaces filled during the study was previously reported,⁴ but the numbers presented here are specific to those who underwent neurological examinations at each year. As is shown, those in the amalgam group had a relatively large number of surfaces treated with amalgam in the first year and maintained during follow-up, so that those in the amalgam group who had neurological examinations averaged between 7.7 and 10.7 surfaces of amalgam present during the seven years of follow-up neurological examinations. The resin-based composite group, on the other hand, did not have any exposure to amalgam. (Technically, two participants in the composite group received amalgam restorations through inadvertent protocol violations. Although those two participants originally were included in the composite group as called for in intent-to-treat analyses, the results presented here, for purposes of clarity, do not include any outcomes from those two participants after they received the erroneous amalgam restorations. Their inclusion or exclusion did not change the results of the analysis.)

Methods. One of two neurologists (either I.P.M. or M.L.) performed neurological examinations for NHSs at baseline and annually for the seven years of follow-up. A category for recording adventitious movements (including tremor) was added to the examination midway through year 1 of follow-up. We introduced screening for NSSs in follow-up year 2 and continued it throughout the remaining five years of the study. NSS severity scores were added starting in follow-up year 3. The neurologists performed the complete neurological examination at one visit, and all examinations took place at the participants’ school.

At any point in the study, the difference between the youngest and the oldest children of the sample was four years. The children were examined once per year, with an interval of approximately one year between the follow-ups. During the course of the study, the sample became smaller because of dropouts and because not all subjects were able to undergo every follow-up examination owing to incompatibility with their school schedules. The loss of participants throughout the seven-year period, however, was in the acceptable range for sufficient statistical power.

The neurological examination was performed according to standard practice.⁷ It included a brief evaluation of mental status (consciousness; language; and orientation to person, time and place), observation of the function of the 12 cranial nerves, gross motor function (muscle strength and tone and deep tendon reflexes), plantar responses, cerebellar functions (including limb and gait coordination), touch, joint position and vibration senses and recording of involuntary movements (such as athetosis or chorea). The neurologists scored NHSs in eight different categories. They evaluated the presence of tremor separately from the other NHSs. For analysis purposes, they denoted NHSs (including tremor) as present if any were present or absent if none were present. Because of the relationship of positional or kinetic tremor to mercury toxicity, its presence or absence also was reported separately.

We introduced screening for NSSs in follow-up year 2. We adapted the NSS evaluation from the examination described by Peters and colleagues.²⁰ Six items of that examination have shown a high correlation with cognitive performance and school achievement¹⁰; therefore, we selected them for our study. All of these items were motor signs that had a better interrater and test-retest reliability than did sensory tasks²¹: the presence of mirror movements, synkinesias, clumsiness of fine finger movements, clumsiness of heel-to-toe walking (tandem gait), motor impersistence and restlessness or hyperactivity. The neurologists scored each item from 0 (absent) to 3 (maximum deviation) points, depending on the degree of deviation observed. There were two scores: one for the presence or absence of any NSSs and an overall NSS score calculated by summing the score of the six individual items. The latter ranged from 0 to 18 points, with higher scores corresponding to the presence of more, or more evident, NSSs than lower scores. (A detailed description of NSS scoring is reported in the supplemental data section of the online version of this article, available at "http://jada.ada.org".)

Statistical analyses. We recorded for each year the proportions of patients in the two treatment groups who exhibited NHSs, tremor or any NSSs. We also computed means and standard deviations of the NSS severity scores within each treatment group for follow-up years 3 through 7. We made comparisons between treatment groups using the Fisher exact test for proportions and the two-sample Student t test for mean severity scores (using SPSS, Version 15, SPSS, Chicago). We report P values for each univariate test, without adjustment for multiple comparisons.

	RESULTS

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As is demonstrated in Figure 1, the percentage of participants exhibiting any NHSs before receiving dental treatment was 2.4 percent in the resin-based composite group and 3.6 percent in the amalgam group. Across time, there were slight differences between the two treatment groups in the percentages exhibiting any NHSs, but the directions of the differences were not consistent from year to year, and the differences were not statistically significant in any of the years. There was an overall slight increase in the percentage of participants exhibiting NHSs in both of the groups during the last three years, as high as 8.9 percent to 14.1 percent.

View larger version (58K): [in this window] [in a new window]   Figure 1. Presence of neurological hard signs (NHSs), according to treatment group (amalgam or resin-based composite).

 
We report every NHS registered in follow-up year 7 to illustrate the above-mentioned increase in NHSs. Among the 31 children with NHSs, 13 showed either kinetic tremor in the finger-nose test or postural tremor in the outstretched-arm test. Two children had congenital decreased auditory acuity, two had congenital nystagmus, and one child was blind in the right eye as a result of surgery at the age of 7 months. The neurologists observed one case of decreased level of tendon reflexes of the lower limb (present only in follow-up year 7) and four cases of loss of olfactory discrimination because of sinus disease. Two children showed an abnormal mental status with elevated affect, two children showed decreases in visual acuity, and in two other children, the motor examination finding was not normal owing to an acute trauma or surgical intervention. In the remaining two cases, the neurologists observed unilateral alteration of coordination and, in one child, a sensory loss in the right thumb and second finger. At the end of the study, we still were investigating the etiology of the latter two cases.

As is demonstrated in Figure 2, the percentage of participants exhibiting positional hand tremor started low (0–2 percent) in the first four years of follow-up and increased over the seven years of follow-up to a level between 4.4 percent and 4.9 percent. However, the increase was uniform in both groups, group differences were not consistently in one direction, and there were no significant differences between the amalgam and composite groups in any of the years.

View larger version (51K): [in this window] [in a new window]   Figure 2. Presence of positional tremor, according to treatment group (amalgam or resin-based composite).

 
Observation of NSSs began in follow-up year 2. As shown in Figure 3, in year 2, 68.0 percent of participants in the amalgam group and 78.4 percent of participants in the composite group exhibited one or more NSSs. That difference is marginally significant (P = .02), but in a situation in which one is testing differences across multiple (in this case, six) years, an appropriate adjustment for the multiple comparisons would be to multiply the P value by the number of comparisons, which would increase the P value to a non-significant .12. Regardless, the direction of the difference in year 2 (10 percent higher in the composite group) was opposite the direction one would expect if the mercury from amalgam was having a deleterious effect. For the remaining years, differences were small and in varying directions, and none was near statistical significance. There was a clear trend of decreasing percentages across time in both groups.

View larger version (56K): [in this window] [in a new window]   Figure 3. Presence of neurological soft signs (NSSs), according to treatment group (amalgam or resin-based composite).

 
For follow-up years 3 through 7, when the NSS severity scores were recorded, Figure 4 shows mean NSS severity scores for the amalgam and composite groups. In a trend similar to that of the NSS percentages presented in Figure 3, the average NSS severity scores for the two treatment groups differed only slightly from year to year, in varying directions, with none of the differences significant in any of the five years of follow-up for which the scores were recorded. And, similar to what is seen in the data on percentages of children exhibiting NSSs in Figure 3, there was a general trend in both groups for the average NSS severity score to decrease progressively across time (with age), as is expected in normally developing children.

View larger version (54K): [in this window] [in a new window]   Figure 4. Mean neurological soft sign score, according to treatment group (amalgam or resin-based composite).

 

	DISCUSSION

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This study’s results show clearly that children exposed to elemental mercury from dental amalgam, a substance potentially toxic to the nervous system,^1,2 do not differ from similar children without amalgam exposure in terms of gross and fine neurological development, as assessed in routine clinical neurological examinations. Thus, these data indicate the absence of a generalized negative effect on children’s nervous system functions stemming from the presence of dental amalgam, and while we cannot rule out potential adverse reactions in individual children, we found no indications of any.

An unexpected finding is the increased frequency of NHSs in both groups across the course of the study. These signs usually indicate structural damage to or dysfunction of either the central or the peripheral nervous system. They usually begin with adverse life or health events and may occur at any point during life, and they may persist (adding up in consecutive evaluations) or disappear. The 31 NHSs observed in follow-up year 7 appear to stem from from differing causative backgrounds. With 13 cases, almost one-half of the NHSs in follow-up year 7 is explained by the presence of tremor. In our sample, the prevalence of tremor in follow-up year 7 is 4.7 percent. Throughout the whole study, tremor accounts for 24 percent of all NHSs. The prevalence of essential tremor in the general population ranges between 2 and 5 percent. The prevalence of essential tremor shows a bimodal distribution, with a peak in the second and sixth decades.^22–25 Although not all of the children in the sample will develop essential tremor, the remarkable increase of tremor seems to be related to essential tremor. Furthermore, the severity of physiological tremor is influenced by emotional tension or stress and may increase during a medical examination, becoming more obvious to the observer.

Another 13 incidences of NHSs were first observations or reflected transient pathological conditions, such as decrease of olfactory discrimination owing to constipation or occasionally low tendon reflex level caused by insufficient relaxation or low environmental temperature. The eight first observations of a NHS in follow-up year 7 were related to adverse life events such as traumas or surgical interventions, changes of visual acuity or changes of mood as a symptom of a possible first manifestation of a psychiatric illness. At baseline, approximately 3 percent of the children demonstrated NHSs that were scored continuously throughout the study. As children became older, the probability of their showing manifestations of chronic diseases increased. Furthermore, teenagers are more inclined to demonstrate risky behavior, thus increasing their risk of injury.

The incidence of NSSs decreased across the course of the study. This is consistent with maturation of the nervous system and the fact that NSSs tend to diminish or disappear with increasing age.^9,10 In addition, the severity of NSSs decreased steadily across time in the whole group of participants and within each treatment group, reflecting progressive neural development and maturation with time.

A large 2005 study of 1,663 adults examined the relationship of mercury from dental amalgam exposure to neurological function and found that there were no associations between amalgam exposure and neurological signs (including tremor) or clinically evident peripheral neuropathy.²⁶ These findings are consistent with those among the children in our study.

Because ours was a large-scale, randomized trial, the exposure to mercury from all sources besides dental amalgam should have been equivalent between the two treatment groups. The primary outside source would be dietary, so we performed a dietary survey and analyses of seafood samples eaten by the children to examine the contribution of dietary mercury²⁷ to total mercury exposure and found that dietary mercury was not a significant source of mercury exposure in the study population. A second source of mercury exposure in children is vaccines. All children in the study received the routine series of vaccines used in Portugal, which is similar to that used in the United States, so there was no difference between groups for this source either.

Studies of neurological parameters in dental personnel exposed to mercury from both occupational sources and amalgam restorations in their mouths have been performed as well, and investigators have not found that clinically evident neurological findings (including those examined in our study) have been present.^28,29

	CONCLUSION

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Because there are concerns that both developmental and psychiatric disorders may result from environmental toxic exposures (such as to mercury), it is important to understand the possible effect of such exposures on NSSs. This study fails to show that exposure to mercury in childhood as a consequence of treatment with amalgam restorations is associated with a higher frequency of NSSs in childhood and adolescence.

From a prognostic point of view, the decrease of the NSS scores observed in this study group could serve as a baseline for comparison with single subjects in a clinical arena. The persistence of NSSs may correlate with diverse negative neurobehavioral and emotional outcomes, but in our large longitudinal randomized trial, we found no indication that it is associated with exposure to mercury from dental amalgam.

	Amalgam ban reported in Norway

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Norway has acted to discontinue the use of dental amalgam, the American Dental Association reported in an eGram sent Jan. 4 to more than 75,000 members who have provided their e-mail addresses to the Association.

The eGram noted that Norway acted on amalgam shortly after the new year as part of a sweeping effort to restrict the use of mercury—action reportedly taken chiefly for environmental reasons and with some limited exceptions that still allow amalgam to be used.

It is possible, the eGram also stated, that Sweden may have taken similar action, although this could not be verified at the time the eGram was prepared.

The ADA noted, too, that no new scientific studies or other new data have been cited as calling for this action, which is not likely to have an economic impact in these countries because of their national health care systems.

INFORMATION ON AMALGAM For information about amalgam, dentists can visit the ADA’s Web site, ADA.org, at "www.ada.org/prof/resources/topics/amalgam.asp".

Patients seeking credible information on amalgam can visit the public side of ADA.org at "www.ada.org/public/topics/fillings.asp".

NEW PATIENT BROCHURE The ADA also has posted a new, free-of-charge patient education brochure on dental restorative materials that dentists may wish to download and have available for patients. Visit Dental Fillings Facts (abstract) at "www.ada.org/prof/resources//topics/materials/dental_fillings_facts_abstract.pdf" or Dental Filling Facts (full) at "www.ada.org/prof/resources/topics/materials/dental_fillings_facts_full.pdf".

—James H. Berry, associate publisher

	FOOTNOTES

Dr. Martins is a neurologist and the director, Laboratorio de Estudios de Linguagem, Faculty of Medicine, University of Lisbon, Portugal.

Dr. Castro-Caldas is a professor, Department of Neurology, Faculty of Medicine, University of Lisbon, Portugal.

Dr. Bernardo is an associate professor and the chairperson, Department of Preventive Dentistry, Faculty of Dental Medicine, University of Lisbon, Portugal.

Mr. Luis is an assistant professor, Dental Hygiene Program, Faculty of Dental Medicine, University of Lisbon, Portugal.

Ms. Amaral is a patient care coordinator, Faculty of Dental Medicine, University of Lisbon, Portugal.

Dr. Leitão is a cathedratical professor, Institute of Health Sciences, Portuguese Catholic University, Lisbon, Portugal.

Dr. Martin is an associate professor, Department of Oral Medicine, School of Dentistry, University of Washington, UW Health Sciences Building, 1958 Pacific Northeast, Room B316, Seattle, Wash. 98195–6370, e-mail "mickeym{at}u.washington.edu". Address reprint requests to Dr. Martin.

Dr. Townes is a professor emeritus, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.

Ms. Rosenbaum is a psychometrist supervisor, Neuropsychology Laboratory, University of Washington, Seattle.

Dr. Woods is a research professor, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle.

Dr. DeRouen is the executive associate dean for academic affairs and research, School of Dentistry, and a professor, Department of Dental Public Health Sciences, School of Dentistry, University of Washington, Seattle.

This project was funded by the National Institute of Dental and Craniofacial Research Cooperative Agreement grant U01 DE11894. Additional funding was provided by Center grant P30ES07033 and by Superfund Program Project grant P42ES04696 to the University of Washington from the National Institute of Environmental Health Sciences.

Clarification: In a 2006 review, the Office of Human Research Protection of the U.S. Department of Health and Human Services said that the University of Washington institutional review board (IRB) should have required more discussion of the risk associated with both dental materials being studied in the consent forms that were approved at the beginning of the study in 1996 (P.J. McNeilly, PhD, Office for Human Research Protections, U.S. Department of Health and Human Services, written communication, Dec. 13, 2006). The University of Washington’s response was that its IRB exercised due diligence at the time in concluding that the consent form satisfied federal requirements for procedures that were standard of care and in routine use, but that it would implement a new IRB process for explicitly addressing risks associated with all procedures for future studies comparing two or more standard-of-care protocols (J.M. Cheek, PhD, Office of Research, University of Washington, written communication, March 8, 2007).

The authors wish to acknowledge the assistance of Peter Slade, PhD, of Expert Data Analysis for Doctors & Others, West Kirby, Wirral, England, and Tessa Rue, MS, of the University of Washington, Seattle, with the statistical analyses.

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