Superfund Research Program
Arsenic as an Endocrine Disrupter
Understanding the mechanistic basis for human health effects of heavy metals is critical for evaluating the impact of these exposures on the U.S. population, and is relevant to setting exposure standards. For example, is there a threshold dose, a linear dose-response or some other dose-response relationship for these endpoints? Do combinations of these metals have additive, synergistic, antagonistic, or entirely unpredictable biological effects? Can these effects be blocked with other agents?
The researchers are working at doses of these metals that are highly relevant to U.S. exposures. For example, the doses of arsenic being used fall roughly between the current arsenic drinking water standard of 50 ppm and the proposed new standard of 2 ppm. Thus, these mechanistic studies are relevant to understanding the overall human health impact of exposure to these metals and setting standards for exposure.
This project's scientists have most recently shown that the heavy metals, chromium and arsenic, which are human carcinogens, each have significant, but different, effects on critical cellular targets which regulate gene expression. These effects are metal-, dose-, time- and tissue type-specific, and appear to involve direct effects on both the genes themselves and on the proteins which regulate their expression. In a model system, the scientists have narrowed down the apparent targets for these effects to several small regions within their promoter control region of the affected genes, and to a small number of critical protein factors which regulate their expression through these sites. Further studies will be aimed at understanding precisely how chromium and arsenic affect gene expression through these targets, and the relevance of these effects to the cancer process and possibly other disease processes. These pathways may contribute to the overall carcinogenic and other biological effects of these metals.