Arsenic, variability, and risk.

Millions of people across the world consume arsenic daily in their drinking water. In some regions, such as parts of Bangladesh and Taiwan, the drinking water levels of this toxic metal have been associated with diseases such as anemia, vascular lesions, peripheral neuropathy, and cancers of the skin, bladder, kidney, prostate, liver, and lung. But these risks may vary considerably, even among populations that seem to have similar levels of arsenic exposure. According to Ellen Silbergeld, a professor of environmental health sciences at The John Hopkins University, such variations could reflect polymorphisms in genes such as those that code for methylase enzymes (which mediate the metabolism of arsenic), and these polymorphisms may determine both the incidence and severity of disease among individuals.

Silbergeld and her colleagues, reporting in the June 2003 issue of Environmental Research, analyzed data on the urinary distribution of arsenic and arsenic metabolites in three populations from Mexico, Chile, and Inner Mongolia. Earlier analysis by other researchers had revealed a substantial variability in levels of urinary arsenic and methylated metabolites. Silbergeld's reassessment of the data set revealed that the distribution of arsenic metabolites was consistent with the possibility of genetic differences in arsenic metabolism.

Christopher Loffredo, the Georgetown University cancer epidemiologist who spearheaded the reassessment, says the reported differences in arsenic-associated health risks among the populations his team surveyed may reflect, at least in part, the ethnic variation across the three groups. "This research eventually might help us identify subsets of the population that are at higher risk for developing arsenic-related cancers," he says.

But whether these population-based differences reflect genetic polymorphisms in arsenic-metabolizing enzymes remains an open question. The frequency of polymorphisms in several methylase genes is known to vary by ethnicity, and such polymorphisms could exert differential effects on arsenic metabolism. However, this study was not designed to demonstrate that relationship. Moreover, because the Chilean and Mongolian population samples were relatively small, the researchers acknowledge that larger studies are needed to verify the results. Finally, the analysis did not control for covariates such as water intake and diet, both of which may influence the distributions of urinary arsenic metabolites.

According to the National Research Council, it has been difficult to establish the magnitude of arsenic-related risks in human population studies when data are drawn from different countries. Improvements in cancer risk estimation may require an improved understanding of such factors as metabolism, as well as the role of metabolites in carcinogenicity and other toxic effects.

Silbergeld agrees. For a complete picture, she says, genotypic studies should be coupled with studies of phenotypic variation, such as those that measure biomarkers of arsenic metabolism.