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Arsenic: The Jury is Still Out

DMS research is providing clues to the health effects of arsenic exposure through drinking water. In March the US Environmental Protection Agency (EPA) announced it was rescinding a former recommendation to lower the allowable amount of arsenic in public drinking water supplies, pending a review of the economic impact of lower levels.The EPA also said it would review the science underlying the recommended level.The issue has particular resonance in New Hampshire, which sits on streaks of arsenic-laden bedrock. That arsenic gets into drinking water throughout the state.

The announcement came shortly after publication of a study by Dartmouth Medical School investigators reporting on what may be a unique mechanism for how chronic exposure to low levels of arsenic increases the risk of certain diseases.

Arsenic at high doses has been known as the poison of choice since ancient times. More recently it has become evident that decades of exposure to very low doses of arsenic -- such as levels found in drinking water in areas of the United States and Northern New England -- substantially increase the risk of vascular disease, diabetes and several cancers. Until now, little was known about how arsenic might contribute to these diseases.

Using cultured animal cells, a team led by Joshua Hamilton, PhD, associate professor of pharmacology and toxicology, found that exposure to very concentrations of arsenic disrupts the function of the receptor for glucocorticoid, a steroid hormone that regulates a wide range of biological processes. Arsenic, a metal, appears to suppress the ability of this critical receptor to to its normal hormone signal. Chemicals such as pesticides that disrupt steroid hormone receptor signaling are called endocrine disrupters. Metals have not previously been shown to act as endocrine disrupters and arsenic appears to act through a unique mechanism.

"This is unlikely to be the only mechanism underlying diseases associated with low-level arsenic exposure, but we suspect it will be an important contributor," says Hamilton, also director of Dartmouth's Toxic Metals Research Program and the Center for Environmental Health Sciences at Dartmouth.The work is described in the March issue of the journal Environmental Health Perspectives. Co-authors are former graduate student Ronald Kaltreider (winner of the 2000 DMS Strohbehn Medal for research), undergraduate student Alisa Davis (recipient of national Goldwater and Beckman scholarships) and Research Assistant Jean Lariviere.

Glucocorticoids, steroid hormones in the same class as estrogen, progesterone and testosterone, are chemical messengers secreted by glands into the bloodstream to help regulate the body's functions. Acting through their receptor, glucocorticoids help regulate embryo development, stress, blood glucose levels, blood vessel function, and lung and skin development,and may also play a key role in suppressing cancer.

Unlike other endocrine disrupting chemicals which are thought to bind to a steroid receptor and either mimic the normal hormone to activate the receptor inappropriately, or block the ability of the normal hormone to activate the receptor, arsenic appears to act in a third way. In the presence of arsenic, the activated receptor is unable to stimulate the correct cascade of signals that usually results from hormone binding, particularly the ability to turn on certain hormone-responsive genes. Blocking the actions of the glucocorticoid receptor by arsenic in this unique way could explain, at least in part, many of the health effects observed in arsenic-exposed human populations.

In another arsenic study, published in the March issue of the American Journal of Epidemiology, Margaret Karagas, PhD, associate professor of community and family medicine, and colleagues report preliminary results of a New Hampshire case-control study of arsenic and skin cancer.The findings suggests a dose-response relationship between squamous cell carcinoma and high drinking water arsenic levels, but the researchers caution that a larger study is needed to be sure these results are predictive.

To measure arsenic, the investigators verified that toenail arsenic concentrations correlate well with concentrations of arsenic in water, indicating a useful biomarker of exposure.Their work is among the first to provide information on individual exposure to arsenic and risk of cancer in a geographically defined US population. Non-melanoma skin cancer, considered the most frequently occurring cancer in the US, is increasing, so detection of even small increases in the relative risk of skin cancers in relation to arsenic exposure could have a major impact on the scope of these malignancies.

Back to DMS Digest for March/April 2001