Safe Water? Pharmacology Researchers Define Arsenic Dangers

In the 1944 film, Arsenic and Old Lace, audiences snickered when a pair of sweet old ladies used the poison to kill off lonely old men. Today, as the cause of one of the world's biggest water-related environmental health issues, arsenic is no joking matter. With no taste and no smell, it could be considered the perfect stealth killer. Which is why Donald Kirkpatrick, a third-year doctoral student in the department of pharmacology and toxicology, spends most of his days in the laboratory looking under a microscope for something that might indicate the level, in parts per billion, at which arsenic becomes dangerous to humans.

An environmental toxicant, arsenic occurs naturally in underground rocks and soil. It is often brought closer to the earth's surface, however, via industrial processes. Epidemiological studies have linked chronic inorganic arsenic exposure in humans with the development of skin, lung and bladder cancer as well as neurological and cardiovascular problems. Arsenic contamination is of particular concern in Arizona because the primary source of water in many parts of the state is from underground wells. Arsenic is naturally occurring in some well waters, and present in many ground water sources as a result of mining.

In May the United States Environmental Protection Agency proposed to change the drinking water standard for arsenic from 50 ppb to 5 ppb, a change that would remove many wells in Phoenix and Tucson from service, and one that would cost the state millions of dollars in remediation costs.

"The evidence is clear at 50 ppb there were risks," Kirkpatrick says. "But it is impossible to know right now the differences in effects between 10 ppb and 5 ppb. So the question really is, at what level does arsenic become a human carcinogen in the drinking water?"

Other kinds of environmental toxins include dioxins and trichloroethylene (TCE). "But with arsenic there's no known minimum level at which one can assume it's safe," Kirkpatrick says. His research hopes to change that.

To do so, he's reduced a complex issue down to something small and relatively more manageable - cells. "When arsenic goes in to a particular cell in a particular part of the body, what kinds of changes happen? Well, we know that some of these changes affect proteins, RNA, DNA. The changes in single cells will then cause changes in an organ and how it functions."

Kirkpatrick's research aims to understand what changes take place biologically when an organism is exposed to arsenic. To determine the effects of contamination, Kirkpatrick examined the cell biology of rabbit kidney slices bathed in an arsenic solution. The kidney, he explains, is the organ responsible for the excretion of arsenic, and therefore shows the highest exposures.

Kirkpatrick hypothesized that arsenic was affecting certain processes within cells and that those processes could be identified by understanding the changes within specific proteins. His study focused on a protein called ubiquitin, one of the most highly conserved proteins and one that is present in every cell of every organism. Ubiquitin acts as a mediator in degrading other proteins. Kirkpatrick believed that as arsenic bound to certain proteins, it would change the shape of the protein, rendering it unable to perform its job and stimulating ubiquitin to act. Therefore, a high number of activated ubiquitins within the kidney sample would indicate that the protein pathway had been altered by the presence of arsenic. Effects of that ubiquitin protein binding would be an early signal of human health effects.

As predicted, Kirkpatrick did discover a high number of activated ubiquitins within the samples, and thus confirmed that a low level of arsenic was affecting degradation of specific proteins. Though his search is not complete, by understanding precisely what is happening within the cell, he hopes to be able to pinpoint a human biomarker to indicate at exactly what level (in ppb) arsenic becomes dangerous for humans.

Kirkpatrick says in the long run, he hopes his research can include investigations of exposed human populations. This past summer he attended the Fourth International Conference on Arsenic Health Effects in San Diego. "At the conference, people came from all over the world. There I was sitting in the room with people [from India] saying, 'We have to address this, people in my [country] are dying.'"

The funding for Kirkpatrick's study came from by the Superfund Basic Research Program, a federally funded basic research program administered by the Division of Extramural Research and Training at the National Institute of Environmental Health Sciences, in coordination with the U.S. Environmental Protection Agency. The program serves 20 to 30 students throughout ten research programs in five colleges and 13 departments at the UA. Primary contaminants under investigation are trichloro-ethelyne (TCE) and arsenic. Among the issues students are researching are the ways of lowering levels of arsenic in water, how arsenic moves in the environment (in water and in copper mining tailings piles), strategies for environmental toxin clean up, and human susceptibility to contaminants.

Working under the direction of Jay Gandolfi, Kirkpatrick says that the research interests him because of its many implications. "For me the project is interesting because it's so multifaceted. On one hand it's the basic science. We're trying to figure out what arsenic does to the body. What does it change, why, and how much? If that basic scientific information can translate into something that will have an impact on human health, on methods of detection, and on policy related to safe drinking levels, then I've done my job."