Biomarkers of metal toxicity in population studies: research potential and interpretation issues.

Biomarkers of effects are molecular tools that can serve to identify changes or effects occurring in the organism because of exposure to a given toxicant or stressor. The potential of biomarkers of effects in epidemiology resides mainly in their greater sensitivity and specificity as compared with more traditional endpoints. Noninvasiveness and objectivity are also important features of effect biomarkers that allow minimizing of the risks of participation and response biases in population studies. Since effect biomarkers are not specific for a given metal, they should always be used in combination with biomarkers or tests of exposure. Dose-response/effect relationships emerging between effect and exposure biomarkers should be carefully analyzed in order to avoid confounding by sampling conditions, subjects' characteristics or lifestyle, or else recent changes in exposure levels. It is also important to exclude the possibility of secondary associations, as well as to make sure that metal exposure is the cause of the effect and not the opposite (reverse causality). Assessing the health significance of associations between effect biomarkers and metal exposure is a delicate task, which necessarily implies some personal judgment. Factors to consider in this exercise include the magnitude and type of adverse effect, the possibility of some reversal, the strength of associations, and the type and size of populations at risk.