Children's Amalgam Trial (CAT) is a randomised trial to determine the impact of amalgam restorations and mercury on children's neuropsychological function. Bellinger et al.  conducted a study on 534 New England children, aged 6-10 years for 5 years. Each subject required at least two posterior restorations. Participants were randomized to receive either amalgam or composite restoration at baseline and at subsequent visits. Primary endpoints were the changes in IQ over a 5-year period. Secondary endpoints included measures of other neuropsychological assessments and renal functioning. During the five-year period of follow-up, the investigators performed multiple assessments on IQ, urinary albumin, and memory index. No statistically significant differences were reported in neuropsychological or renal effects observed in the children who had amalgam restorations compared to those with composite restorations.
Another study concluded that the neuropsychological functions of children receiving amalgam restorations were no different from those with composite restorations. In the Children's Amalgam Trial, a dose-effect study of amalgam exposure and neuropsychological functions was evaluated. A dose-effect study was conducted on a group of children who had significant unmet dental requirements. There was no significant association between neuropsychological outcomes and mercury exposure. They concluded that amalgam use did not appear to have any discernible negative neuropsychological effects on children.  The relation between amalgam and the psychosocial status of children was also assessed as a part of the New England Children's Amalgam Trial (NECAT). Psychosocial outcomes were assessed for the two groups of kids. The study was conducted using a "Child Behaviour Checklist", completed by parents, and the children's own reports. It concluded that adverse psychosocial effects were not associated with amalgam placement in the five-year period. 
Kingman et al. Kingman et al.  investigated correlations between amalgam exposure and neurological functions. No significant associations between amalgam exposure and clinical neurological signs of abnormal tremor, coordination, gait, strength, sensation or muscle stretch reflexes or for any level of peripheral neuropathy in the subjects have been observed. The continuous vibrotactile response was significantly associated with amalgam exposure. The study reported that this association was a subclinical finding that was not associated with symptoms, clinically evident signs of neuropathy or any functional impairment.
One of the secondary outcomes in the Children's Amalgam Trial was renal function. Investigators evaluated changes in markers for glomerular, tubular, and urinary Mercury levels. They found no significant differences between the treatment groups and no significant effects related to the number of dental amalgam restorations on the markers. Children in both treatment groups experienced micro albuminuria, but the prevalence was higher in amalgam group. They concluded that this increase may have been random but it should be evaluated further.  The other safety trial was conducted in Lisbon, Portugal in which a randomized controlled clinical trial carried out in 507 children 8- to 10-years old at baseline. They were evaluated for several years thereafter to determine if any health changes occurred following restorations with amalgam or composites. On carrying out annual standardized tests of memory, attention, physical coordination, and velocity of nerve conduction, the scientists did not detect a pattern of decline in the test scores of individual children who received amalgam restorations. The scientists found that composite was associated with a higher need for treatment in the children who received it. This suggests that amalgam is a good option to restore teeth. Investigators conducted annual clinical neurologic examinations in order to evaluate the neurological and neurobehavioral effects. The authors concluded that amalgam exposure had no adverse neurological outcomes. 
The 7 years of longitudinal data provide extensive evidence about relative safety of amalgam in dental treatment. Substantial amalgam exposure did lead to creatinine adjusted urinary mercury levels that were higher in the amalgam group. Children with amalgam restorations had slightly elevated levels of mercury in their urine, measuring on average 1.5 mg/L of urine for the first two years and levelling off to 1.0 mg/L or less thereafter. These values are within the normal background range of 0-4mg/L for a person who is not exposed to any industrial sources or mercury. The longitudinal studies of the use amalgams in children have not shown any adverse effects to neuropsychological or renal functions within a 5-year period. It was reported that urinary mercury concentrations were highly correlated with both the number of amalgam restorations and the time since placement in children. The finding suggested that there may be sex-related differences in mercury excretion. They found that females have significant increase in the rate of mercury excreted in urine than males. Thus, this association might confer a lower mercury toxicity risks in females.  Dunn et al.  evaluated scalp, hair, and urine mercury content of children collected over the 5-year period, mean hair mercury level was 0.3-0.4 mg/g and mean urinary mercury level was 0.7-0.9 mg/g creatinine. The authors reported that use of chewing gum in the presence of amalgam restoration was a predictor of higher urinary mercury levels. The data suggested that gum chewing in the presence amalgam restorations could reduce amalgam-associated Mercury exposure.
Sixty children were studied to assess urinary mercury excretion and its relation to amalgam restoration and fish consumption. The urinary levels of mercury in children who had amalgams restored were significantly higher than those with non-amalgams. The urinary mercury levels in the amalgam group were well below levels that are known to cause adverse health effects. 
The Health Canada Assessment Of Mercury Exposure And Risks From Amalgam
The comparisons are difficult because mercury occurs in a variety of chemical forms that have different absorption rates, excretion rates, threshold effect levels and adverse effects. These comparisons can be difficult to make because there are many chemical forms of mercury that have different levels of absorption, excretion, threshold effects, and adverse effects.
Mark Richardson, a physician at the Medical Devices Bureau of Health Canada, authored a report entitled Assessment of Mercury Exposure & Risks From Dental Amalgam. It was released by Health Canada in November 1995. It was the first comprehensive risk assessment in Canada of mercury exposure from dental amalgam.
This study made an estimate of the exposure of the Canadian population to mercury from amalgam, food, and the environment. This study does not involve laboratory or clinical research. The study reviewed international literature regarding the effects of mercury on health and employed sophisticated computer modeling techniques to estimate mercury exposure. This calculated exposure was then used in standard risk assessment procedures to estimate a tolerable daily intake level (TDI) for mercury.
The report used a probabilistic model, together with a computer technique called Monte Carlo simulation, to estimate mercury exposure. Model calculated mercury exposures based on environmental sources such as soil, water, indoor and ambient air and food. The model was based on data regarding the correlation between fillings, mercury concentration in urine and air concentration.
The report, using this model, estimated that the daily average mercury exposure for Canadians who have amalgam filled teeth (the amount absorbed by their body) ranges between 3.3 ug and 9.4 ug in adults ages 20-59. The report estimated that the amount of mercury absorbed by adults 20-59 years old from all sources ranged between 0.8 and 3.4 micrograms.
The Monte Carlo simulations indicated that amalgam contributes about 50% of the daily mercury exposure of the average Canadian. The most important source of mercury is amalgam, which has the highest exposure rate compared with food, air indoors and outdoors, drinking water and soil.
Some studies have found evidence of slight sub-clinical impairment of cognitive functions, particularly short-term memory, in individuals exposed to fairly low mercury vapour levels. These effects are not easily detected, and the existing data do not allow the calculation of a no-effect threshold level. According to the report, mercury vapour concentrations likely to be generated by the average number dental amalgam fillings are 50-100 times lower than those levels that caused subclinical effects.
One of the most important aspects of the study was that it calculated a Tolerable Daily Intake (TDI) for mercury and related that TDI to the estimated mercury exposure from amalgam. This calculation was not done before for mercury vapour.
The TDI concept is used to set guidelines for limiting exposure to substances that are hazardous from either industrial or environmental sources. The TDI is the maximum level of exposure to a substance that people can endure over their entire lifetime.
A TDI calculation is usually based on observed adverse effects at high exposure levels, usually in industrial settings. In order to extrapolate from these observations a level where we are confident there won't be any harmful effects, it is necessary to make a few estimates and assumptions. Furthermore, accepted principles of risk assessment state that if there are uncertainties in the available data, safety factors must be applied in order to err on the side of caution.
Health Canada asked an international group of experts on risk assessment, toxicology and public health policies to review the study and provide comments about its conclusions and methodology before it was released. The peer reviewers were scientists from Canadian and US universities, research centres, and government regulatory agencies.
Peer reviewers agreed in general that the study's methodology was solid, but they expressed concern over the data available. Some reviewers were doubtful that a reliable numerical estimate for a TDI could be determined because of the number of assumptions which had to be made, and the lack of accurate data for many of the factors in the assessment model. Some reviewers doubted the ability of probabilistic estimation methods to compensate for a lack of accurate data.
Since several reviewers believed that the clinical study used in the first draft of the report was not suitable for this purpose, Dr. Richardson repeated his analysis using a different study by Fawer and co-workers. That study measured a central nervous system effect in men who were exposed to mercury vapour in a factory. This study measured a central nervous system effect in men exposed to mercury vapour. The forearm-tremor was classified as a subclinical effect, which means that it isn't considered an illness.
Because of uncertainties in the data, Dr. Richardson applied a safety factor of 100 to derive a proposed TDI for mercury vapour of about 1 ug/day for a 70 kg adult. His comparison of this TDI with the quantities of mercury absorbed daily by individuals with amalgam fillings indicated that four amalgam fillings should cause no observable adverse health effects in adults during a lifetime of exposure. Canadian adults who have an average of seven fillings may exceed this limit.
The meaning of this TDI has been widely misunderstood. Many people have assumed that it sets a maximum level above which illness will result. However, because of the conservative safety factor used, and the sub-clinical effect on which the calculation was based, exposures several times greater than the TDI would probably not produce any harmful effects.
Since this study was the first of its kind for dental amalgam and had generated a great deal of public interest, since some of the reviewers' concerns related to questions of judgment, and since the study had been extensively revised in response to the reviewers' suggestions, the Department decided to make the study available for public review and comment. The Department then decided to not rely on the calculated TDI for its safety recommendations. In Section 8, we discuss the reasons behind this decision.
The Health Canada Stakeholder Committee And Its Recommendations
In order to obtain views on all aspects of the amalgam question, the Medical Devices Bureau convened a committee representing the groups with major interests in the issue: provincial health ministries, the Canadian Dental Association, manufacturers of dental materials, academic researchers, dentists, environmental and patient advocacy groups, and individuals.
The committee was asked to review and comment on the Health Canada assessment report and to give advice on other aspects of the issue which they felt were important. The committee held two meetings. In the first session, Dr. Richardson answered all questions about the report and presented his research. At the second meeting, committee members made presentations on the amalgam issue and the assessment study.
The committee discussed the assessment study at some length. The comments made were often similar to the ones of peer reviewers. Many of the comments were similar to those made by peer reviewers.
New comments related to the suitability of the research paper by Fawer and coworkers as the basis for establishing a TDI for mercury vapour. The major criticisms of the Fawer study were that the sample size was small, the experiment provided no dose-response data, the hand tremors were subtle and difficult to measure, and the researchers did not know the previous exposure history of the subjects, which might have been a factor in the severity of the tremors. The comment was also made that other risk assessment agencies did not consider hand tremor to be an appropriate end point for measuring central nervous system changes in adults.
The committee adopted the following statement on the assessment report:
"The amalgam risk assessment was done in a careful and conscientious manner with methods generally appropriate for this type of risk assessment. However, given the poor quantifications of exposure in the key toxicological studies used, it is inappropriate to conclude that a TDI set using this approach represents a distinction between health and disease. In any further risk assessments (when sufficient data become available), the committee believes that significant adverse effects on the central nervous system (or other body systems) would be the appropriate end points."
Health Canada has accepted the position of Health Canada and decided to not include a TDI of mercury in amalgams as part of its position statement.
Eight other recommendations were also approved by the committee.
- The evidence does not exist to warrant the wholesale removal of amalgam fillings [passed unanimously].
- Medical and dental professionals should be aware that certain individuals are sensitive to amalgam, and they must also take into account their needs. The law passed 18-1 gives all individuals the right to choose the materials they want placed in their mouth.
- Some patients may have concerns that they have adverse systemic effects due to amalgam fillings. Although removal of existing amalgam fillings may, in some individuals, have positive effects, at this time substantial experimental evidence does not exist to confirm those positive effects. If you are considering this action, it is important to discuss with your dentist and doctor.
- There is evidence to suggest that individuals who suffer from these conditions are more susceptible to mercury than the rest of us. These concerns should guide the choice of materials used by dentists and doctors for patients with these conditions [as passed 12-6].
- The unanimous recommendation is that an informational package for the general public, as well as professionals, be developed to help them make informed decisions about their dental health, together with their healthcare providers.
- The public should be aware that it is the responsibility of the dentist to obtain and update a patient's health history. It is also the responsibility of patients to notify their dentist of any changes in their health status [passed unanimously].
- Dentists are to be encouraged to decrease the use of amalgam and other restorative materials through the use of diagnostic and preventive treatment strategies based on tooth structure preservation [passed 15-3].
- This committee recommends strongly that funds be allocated to research into the safety of dental amalgams or their alternatives. The funding of this research should be done jointly by the industry, dental professionals and government (passed on 13-5).
A report containing a summary of the discussion, the recommendations and dissenting opinions was prepared by the moderator of the meeting, Dr. D. Wayne Taylor of McMaster University on March 1, 1996. The committee's recommendations, as per its terms of reference, are not legally binding, but they have been carefully considered.
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