Low-dose Arsenic: In Search of a Risk Threshold

Charles W. Schmidt

Disclosures

Environ Health Perspect. 2014;122(5) 

In This Article

A Historical View

That arsenic can be lethal has been known since antiquity. But lethal doses of arsenic are difficult to quantify, and they depend on solubility, valence states, and other factors. The Agency for Toxic Substances and Disease Registry suggests that the minimal lethal exposure in humans ranges from 1 to 3 ppm, with death resulting from cardiovascular collapse and hypovolemic shock.[8]

Researchers didn't perceive arsenic as an environmental health threat until studies in Taiwan, and later in Chile, linked levels in groundwater with skin cancers such as squamous cell carcinoma (which is rarely fatal) and a condition called black foot disease (which affects blood vessels, leading to gangrene). Villagers were exposed to the arsenic beginning in the early twentieth century after artesian wells were drilled throughout southwestern Taiwan to avoid saltwater intrusion from shallower wells.[9] The U.S. Public Health Service aimed to protect against the arsenic-related skin problems seen in Taiwan when it set a 50-ppb standard for arsenic in drinking water in 1942, which was then adopted by the EPA in 1975.[10]

The levels deemed "low" in early environmental health research on arsenic were much higher than what's considered low today. Studies from Taiwan up to the 1980s described groundwater levels of up to 300 ppb as low, of up to 600 ppb as moderate, and values beyond that as high.[10,11] These delineations were based on a view that consuming arsenic in groundwater, while harmful, wasn't fatal in the long run.

Two pivotal studies led researchers to reconsider that point. Chien-Jen Chen, who was then a teaching assistant at the National Taiwan University College of Medicine, and colleagues showed that arsenic could, in fact, boost risks for fatal malignancies at groundwater concentrations far less than 600 ppb. Published in 1985, the first study reported statistically significant associations between chronic exposure to artesian well water in Southwestern Taiwan and elevated mortality from cancers of the lung, bladder, and other internal organs.[12,13] And in their follow-up study, Chen and colleagues reported that this relationship was dose-dependent—i.e., that cancer rates grew with higher arsenic exposure—and that mortality rates were especially high in areas where blackfoot disease also was endemic.[11]

Joseph Graziano, a professor of environmental health sciences and pharmacology at Columbia University, says Chen's data had far-reaching consequences that scientists are still grappling with today. Without evidence to the contrary, the EPA defaulted to what is still a standard regulatory assumption: namely that any exposure to a carcinogen, no matter how small, increases cancer risk to some degree. Therefore, the National Research Council (NRC) now describes arsenic levels beyond 150 ppb as high, between 150 ppb and 50 ppb as moderate, and below 50 ppb as low.[14]

But linear assumptions drive considerable risk even at low exposures. Extrapolating from high-dose human data, the NRC predicted in 1999 that the 50-ppb water standard could induce cancer in as many as 1 in 100 people.[15]

By that time, the EPA had already been engaged in technical review on arsenic for years. The agency ultimately evaluated more than 300 studies and drew on expert opinions from the NRC, the National Drinking Water Council, and its own Science Advisory Board (SAB) before it finally dropped the standard from 50 to 10 ppb in 2001[16]—a level the NRC estimated might lead to a cancer risk of approximately 1 in 300 for people exposed over a lifetime.[17] According to Craig Steinmaus, an associate adjunct professor in epidemiology at the University of California, Berkeley, School of Public Health, the EPA by necessity had to factor cost and technical feasiblity as well as health into the 10-ppb drinking water standard.

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