Dental amalgam, which contains 50% mercury by weight, has been used for at least 150 years. because mercury is an acknowledged neurotoxin, concerns about the health effects of ex posure to this chemical are widespread. Consequently, many individuals have submitted to removal of amalgam dental fillings, an uncomfortable, expensive procedure that is not free of hazard. In this issue of JAMA, Bellinger and col- leagues1 and DeRouen and colleagues2 report the first 2 ran- domized controlled trials comparing the health effects in chil- dren treated with mercury amalgam fillings with those treated with a composite dental restorative material.

Mercury is a highly reactive metal that has widely recog- nized toxic properties at high dose, including parethesias, cerebellar ataxia, dysarthria, and constriction of the visual fields.3 The significance of lower-level asymptomatic expo- sures on brain function is less clear, and sound clinical stud- ies are needed to define this risk. Amalgam mercury enters the bloodstream, and a number of investigations suggest that this has toxic consequences. Mercury levels in expired air are correlated with the number of amalgam fillings.4 Den- tists and dental assistants have deficits in motor function and cognitive scores in relation to their number of fillings and to their urinary mercury excretion.5 Mercury also has been suggested as a risk factor for multiple sclerosis and Alz- heimer disease.6

Sensitivity to mercury toxicity may have a genetic basis. Echeverria et al7 recently reported that polymorphisms of coproporphyrinogen oxidase (CPOX4), the gene encoding urinary porphyrin excretion, altered the impact of mer- cury on cognitive and mood scores. Approximately 25% of the US population is polymorphic for this genotype.7 Al- though the literature is sparse, other molecular effects of mer- cury exposure also are receiving attention. For example, in an in vitro study, mercury has been shown to affect heat shock protein levels in human cells8and in an animal model, mer- cury inhibited the binding of guanosine triphosphate (GTP) to tubulin in the rodent brain.9

With the application of better epidemiological designs and more robust statistical methods to investigate toxicity, the usual consequence is uncovering effects at lower thresh- olds. The trajectory of discovery of the toxic effects of an- other metal, lead, has followed this path and may offer in- sight into the future path that mercury investigations may follow.

When childhood lead poisoning was first reported, it was believed to have only 2 outcomes: death or complete recov- ery with no sequelae. After long-term neurobehavioral defi- cits were found in survivors of lead poisoning, these effects were thought to occur only in children who had displayed signs of severe encephalopathy.10 In the 1970s, studies of elevated lead burden in children who had displayed no symp- toms revealed dose-dependent deficits in cognitive skills, attention, and behavioral control.11 In the 1960s, the de- fined toxic threshold for lead was 60 µg/dL (2.90 µmol/L); however, over the next 30 years, on the basis of newer stud- ies, this threshold was sequentially reduced to 10 µg/dL (0.48 µmol/L). A recent pooled analysis of 7 longitudinal cohort studies demonstrated that blood lead levels below 10 µg/dL (0.48 µmol/L) in children are associated with decrements in IQ scores.12 These findings are the consequence of larger sample sizes, more sensitive outcome measures, and better multivariate techniques. History is likely to repeat itself with other neurotoxins.

The 2 clinical trials reported in this issue of JAMA exam ine the neuropsychological and renal effects of dental amal- gam in children. In their study of 534 New England children aged 6 to 10 years, Bellinger et al1found that, at 5 years' follow-up, children randomly assigned to the amalgam group had higher mean mercury levels than those in the resin- based composite group, but there were no statistically significant differences between the groups in terms of 5-year change in full-scale IQ score, 4-year change in general memory index, or visual motor composite score, or uri- nary albumin levels. In the report by DeRouen et al,2 507 8- to 10-year-old children from Lisbon, Portugal, were ran- domly assigned to receive dental restorations using amalgam or resin composite. At 7 years of follow-up, children in the amalgam group had higher urinary mercury levels, but there were no statistically significant differences be-tween the groups' scores on neurobehavioral assessments results toward the null and thus underestimates the true effect of memory, attention/concentration, or motor/visuomotor size.

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