Trace elements as paradigms of developmental neurotoxicants: Lead, methylmercury and arsenic.

Trace elements have contributed unique insights into developmental neurotoxicity and serve as paradigms for such adverse effects. Many trace elements are retained in the body for long periods and can be easily measured to assess exposure by inexpensive analytical methods that became available several decades ago so that past and cumulated exposures could be easily characterized through analysis of biological samples, e.g. blood and urine. The first compelling evidence resulted from unfortunate poisoning events that allowed scrutiny of long-term outcomes of acute exposures that occurred during early development. Pursuant to this documentation, prospective studies of children's cohorts that applied sensitive neurobehavioral methods supported the notion that the brain is uniquely vulnerable to toxic damage during early development. Lead, methylmercury, and arsenic thereby serve as paradigm neurotoxicants that provide a reference for other substances that may have similar adverse effects. Less evidence is available on manganese, fluoride, and cadmium, but experience from the former trace elements suggest that, with time, adverse effects are likely to be documented at exposures previously thought to be low and safe.

Methylmercury and brain development: imprecision and underestimation of developmental neurotoxicity in humans.

Methylmercury is now recognized as an important developmental neurotoxicant, though this insight developed slowly over many decades. Developmental neurotoxicity was first reported in a Swedish case report in 1952, and from a serious outbreak in Minamata, Japan, a few years later. Whereas the infant suffered congenital poisoning, the mother was barely harmed, thus reflecting a unique vulnerability of the developing nervous system. Nonetheless, exposure limits for this environmental chemical were based solely on adult toxicity until 50 years after the first report on developmental neurotoxicity. Even current evidence is affected by uncertainty, most importantly by imprecision of the exposure assessment in epidemiological studies. Detailed calculations suggest that the relative imprecision may be as much as 50%, or greater, thereby substantially biasing the results toward the null. In addition, as methylmercury exposure usually originates from fish and seafood that also contains essential nutrients, so-called negative confounding may occur. Thus, the beneficial effects of the nutrients may appear to dampen the toxicity, unless proper adjustment is included in the analysis to reveal the true extent of adverse effects. These problems delayed the recognition of low-level methylmercury neurotoxicity. However, such problems are not unique, and many other industrial compounds are thought to cause developmental neurotoxicity, mostly with less epidemiological support than methylmercury. The experience obtained with methylmercury should therefore be taken into account when evaluating the evidence for other substances suspected of being neurotoxic.