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R E S E A R C HR E P O R T S

Arsenic and Cancer

Lead Researcher: Tom K. Hei

Tom K. Hei, associate professor of radiation oncology and public health, has shown for the first time that the heavy metal arsenic is a potent mutagen. His research, published in the July 1998 Proceedings of the National Academy of Science, helps solve a mystery about the carcinogenic mechanism of arsenic and may shed light on the toxic activity of other heavy metals.

Arsenic is a naturally occurring element in the Earth’s crust. All humans are exposed to at least low levels of it, usually in food, drinking water, and air. Higher exposures are commonly associated with copper smelting, pesticides, and chemical disposal sites. Cigarette smoke and fossil fuels also contain arsenic.

“Arsenic is ubiquitous in the environment, and high exposure is often related to industrial pollution,” says Dr. Hei. It has become an especially serious problem in Mexico, China, and Southeast Asia, where arsenic is used in the rapidly growing semiconductor industry. In Bangladesh, millions of people drink dangerous amounts of arsenic, which occurs naturally in the groundwater.

Arsenic has been known as a poison since ancient times, with high doses capable of causing death. Of more concern, however, is epidemiological evidence that long-term exposure to lower doses of arsenic causes cancers of the lung, skin, bladder, and liver. Because of its apparent carcinogenicity and high concentrations in Superfund pollution sites, the U.S. Environmental Protection Agency puts arsenic at the top of its list of hazardous chemicals.

Scientists have found it very difficult to study how arsenic might cause cancer. For unknown reasons, arsenic does not cause cancer in laboratory animals. Cell-culture studies have shown that arsenic can break chromosomes, stop cell division, and inhibit DNA repair, among other effects. However, cell mutation assays have generally come up negative. These results led to unconfirmed hypotheses that arsenic causes cancer by inducing DNA hypomethylation and abnormal gene expression.

Dr. Hei and his colleagues, Su X. Liu and Charles Waldren at Colorado State University, however, thought that arsenic most likely causes cancer by mutating DNA. They hypothesized that conventional mutation assays might not show much activity because arsenic induces large chromosomal losses, which would be deadly.

Cell mutation assays generally look for mutations in one or two specific genes. In many cases, genes crucial to survival of the cell exist close to the genes being monitored. Dr. Hei and his colleagues thought that when arsenic deletes the monitored gene, it might also delete crucial genes nearby, thus killing the cell. Dead cells are not included when mutants are counted.

To get around this problem, Dr. Hei and his colleagues used a hamster cell line containing a single copy of human chromosome 11. They exposed the cells to arsenic and monitored the mutation rate for two genes. One gene, HPRT, resides on the hamster X chromosome. Large DNA deletions around the HPRT gene often kill the cell. The other monitored gene, S1, resides on the human chromosome. The cells can survive even in the face of large deletions from that chromosome, since it is not required for survival of the hybrid cells. In addition, mutations to that chromosome can easily be detected because its genes code for antigens on the cell surface.

The researchers then measured the mutagenic properties of arsenic at these two locations. Arsenic appeared to have little mutagenic ability when researchers looked at HPRT. But when they looked at the S1 gene, arsenic was clearly mutagenic, with more mutations occurring at higher and longer exposures to arsenic.

In their experiment, the researchers also searched for the mechanism by which arsenic causes DNA mutations. They pretreated several cell cultures with dimethyl sulfoxide (DMSO), an effective scavenger of free radicals. Free radicals are highly reactive molecules that are known to damage DNA. Far fewer mutations occurred in the cells pretreated with DMSO, suggesting that arsenic causes mutations by triggering the formation of free radicals. In more recent experiments, Dr. Hei and his colleagues have shown that arsenic induces the production of free radicals and 8OHdG, a product of oxidatively damaged DNA, in the hybrid cells.

Pinning the arsenic-induced mutations on free radicals suggests that people chronically exposed to high levels of arsenic, such as people working with asbestos, could take antioxidants to reduce their chances of developing cancer.

Dr. Hei plans to extend the study to other heavy metals, such as nickel and cadmium, to see if they act in a manner similar to arsenic. He also is studying environmental pollutants, such as radon, that seem to interact with arsenic to boost carcinogenic activity to especially high levels in underground miners exposed to both chemicals at the same time.

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