Arsenic Epidemiology and Drinking Water Standards

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Science  21 Jun 2002:
Vol. 296, Issue 5576, pp. 2145-2146
DOI: 10.1126/science.1072896

In the United States, setting the maximum contaminant level (MCL) that regulates the concentration of arsenic [HN1] in public water supplies has been an extraordinarily protracted process (see the first table, below). Recently, the MCL was lowered to 10 μg/liter, from the 50 μg/liter standard established in 1942. However, as early as 1962 the USPHS advised that water concentrations should not exceed 10 μg/liter when “more suitable supplies are or can be made available” (1). In 1986, Congress directed the U.S. Environmental Protection Agency (EPA) to revise the standard by 1989, but it failed to do so (2). Not until January 2001, in one of the last acts of the Clinton administration, was the announcement of a new U.S. standard of 10 μg/liter made by the EPA (3). Two months later, the Bush administration delayed adoption of the standard, citing concerns about the science supporting the rule and its estimated cost (2). Nevertheless, in October 2001, under pressure from Congress and following a pivotal report by the National Research Council (NRC) (4), the EPA adopted the 10 μg/liter standard [HN2] (2) (see the table, below). We will consider how the regulatory process might interpret and respond more effectively to results from epidemiological studies.

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Arsenic was one of the first chemicals recognized as a cause of cancer. As early as 1879, the high rates of lung cancer in miners in Saxony were attributed in part to inhaled arsenic (5). A few years later, skin cancers were reported in patients treated with medicine containing arsenic (6, 7). Evidence that arsenic in drinking water could cause skin cancer came much later, in the 1930s, from Argentina (8), and subsequently from many other countries (9), including a large population in Taiwan (10).

In the 1960s, evidence emerged in Argentina that arsenic in drinking water might cause internal cancers, particularly of the lung and urinary tract (11, 12). Startling results from Taiwan, appearing in 1985, showed increased mortality from several cancers, especially lung, bladder, and kidney cancers (13). Bladder cancer mortality rates for those with more than 600 μg/liter of arsenic in their water were more than 30 to 60 times the rates in the unexposed population (14). Such high cancer rates were unprecedented for any water contaminant. By 1992, the combination of evidence from Taiwan and elsewhere was sufficient to conclude that ingested inorganic arsenic was likely to cause several internal cancers [HN3] (15). At the same time, a risk assessment estimated the combined cancer mortality risk to be as high as 1 in 100 for people drinking water containing 50 μg/liter of arsenic (16). The epidemiological associations found in Taiwan (14, 1721) have since been confirmed by studies in Japan (22, 23), Argentina (24, 25), and Chile (26, 27). Two reports of the NRC (4, 28) affirmed that cancer risks might be of the order of 1 in 100 for 50 μg/liter. This estimated cancer risk is more than 100 times greater than that for any other drinking water contaminant with an MCL (see the table, below).

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With such high estimated risks, why did it take so long to reduce the arsenic drinking water standard? One problem was that most drinking water standards have been based on experimental animal studies with little, if any, evidence from studies of people. The absence of a good animal model for arsenic-induced cancer may have impeded its regulation (29). Major uncertainties have been tolerated in extrapolating from rodents to humans for other purported carcinogens, whereas the relatively minor uncertainties in epidemiological studies of arsenic exposure were not considered acceptable (30).

Uncertainties in epidemiological studies [HN4] include confounding of the exposure with some other disease cause. For example, smoking is the major cause of lung cancer in most populations. If arsenic-exposed populations smoked heavily, they would have higher rates of lung cancer than other populations. Smoking is not an important confounding factor in this situation, where relative risks are much higher for arsenic in drinking water (31). Similarly, diet can have relatively minor effects on the incidence of human cancers, and bladder cancer risks might be increased about 1.5-fold with diets poor in fruits and vegetables (32). Yet poor diet was invoked as a reason for uncertainty in the cancer risks estimated from Taiwan, where arsenic exposure was linked to 30- to 60-fold increases in bladder cancer risk (28, 33, 34).

Another reason for delay involved extensive discussion concerning whether or not there is a threshold for arsenic exposure, below which it would not cause cancer (3538). Supporters of the threshold hypothesis postulated that, for inorganic arsenic to exert a carcinogenic effect, it would have to exceed the level of exposure at which most of the absorbed inorganic arsenic is methylated and presumably detoxified. However, numerous studies on arsenic methylation [HN5] in exposed and unexposed populations have provided substantial evidence that a threshold for arsenic methylation does not exist (35, 3944). More recent data suggest that methylation of inorganic arsenic may actually increase its carcinogenic potential (4, 45, 46). Furthermore, studies on human cell cultures have demonstrated genotoxic effects at concentrations of arsenic potentially attainable in human tissue after ingestion of water containing 50 μg/liter or less (4). To compound the uncertainties, complex statistical models were used to extrapolate the Taiwanese arsenic data to low exposure levels, producing a wide range of risk estimates (3, 47). Little attention was given to the small margin of safety between 500 μg/liter, causing about 1 in 10 people to die from cancer, and 50 μg/liter, for which risks could be 1 in 100 (28). Epidemiology can be used to demonstrate causation of disease in human populations, but it has sensitivity limitations. It would be extremely difficult to prove that consuming water containing 50 μg/liter of arsenic would cause 1 in 100 individuals to die from cancer.

In conclusion, when there is such direct human epidemiological evidence that a substance causes cancer, we should focus on margins of safety, avoiding extensive statistical manipulations of data and excessive debate about potential uncertainties. Prudent public health decisions should not wait until there is proof of serious cancer risks at low exposure.

HyperNotes Related Resources on the World Wide Web

General Hypernotes

This issue of Science has a related Enhanced Policy Forum by D. K. Nordstrom titled “Worldwide occurrences of arsenic in ground water.”

Dictionaries and Glossaries

The xrefer Web site offers searchable scientific and other dictionaries.

A Water Science Glossary of Terms is provided by the USGS Water Science for Schools Web site.

A National Water-Quality Assessment Glossary is provided by the U.S. Geological Survey (USGS).

A Glossary of Epidemiological Terms is provided by the EXCITE (Excellence in Curriculum Integration through Teaching Epidemiology) project of the Centers for Disease Control and Prevention (CDC).

A dictionary of epidemiology is maintained by J. Swinton.

A multilingual glossary of environmental terms is provided by the European Environment Agency.

Web Collections, References, and Resource Lists

The Google Directory provides links to Internet resources on environmental health and epidemiology.

The National Council for Science and the Environment provides the National Library of the Environment, a resource page with reports and Internet links.

The Center for Environmental Health Sciences at Dartmouth provides links to Internet resources related to environmental health sciences. A collection of epidemiology and public health links are included.

The WWW Virtual Library of Epidemiology is maintained by the Department of Epidemiology and Biostatistics, University of California, San Francisco.

The library of the Karolinska Institutet, Stockholm, provides links to Internet resources on epidemiology and biostatistics.

Epimonitor.net provides links to epidemiology Internet resources as well as news summaries.

MedLine Plus provides links to arsenic information resources.

Online Texts and Lecture Notes

Chronic Arsenic Poisoning: History, Study and Remediation is an Arsenic Project Web resource provided by R. Wilson, Department of Physics, Harvard University. A collection of Internet links are included.

The Toxic Metals Research Program, Dartmouth College, offers a metals primer with a presentation on arsenic and a history of arsenic. A collection of Internet links related to toxic metals is also provided.

The Ground Water and Drinking Water Division of the U.S. Environmental Protection Agency (EPA) provides information about the drinking water standards program.

The National Water-Quality Assessment Program of the Water Resources Division of the U.S. Geological Survey (USGS) provides a resource page on arsenic in ground water of the United States.

J. Moore, Department of Geology, University of Montana, offers lecture notes for an environmental geochemistry course.

S. Kardia, Department of Epidemiology, University of Michigan, offers lecture notes for an epidemiology course.

Lecture notes for the Supercourse on Epidemiology, the Internet, and Global Health are made available by the Department of Family and Preventive Medicine, University of Utah.

General Reports and Articles

Epidemiology for the Uniniated by D. Coggon, G. Rose, and D. Barker is made available on the Web by the BMJ (British Medical Journal) Web site.

Arsenic and Old Laws: A Scientific and Public Health Analysis of Arsenic Occurrence in Drinking Water, Its Health Effects, and EPA's Outdated Arsenic Tap Water Standard is a 2000 report published by the Natural Resources Defense Council.

The National Academy Press makes available the National Research Council (NRC) reports Arsenic in Drinking Water (1999) and Arsenic in Drinking Water: 2001 Update.

The United Nations Synthesis Report on Arsenic in Drinking Water is made available by the Water and Sanitation Division of the World Health Organization (WHO).

The June 2001 issue of Scientific American had an article by M. Alpert titled “A touch of poison” with a sidebar titled “The mysterious carcinogen arsenic.”

Numbered Hypernotes

1. Arsenic. The Visual Elements Periodic Table, provided by the Chemical Societies Network, offers information about arsenic. Arsenic was a Chemical of the Week selection by B. Shakhashiri, Department of Chemistry, University of Wisconsin. The INCHEM Web site from the International Program on Chemical Safety (IPCS) provides information on arsenic. The U.S. Agency for Toxic Substances and Disease Registry provides a fact sheet on arsenic.

2. New U.S. standard for arsenic in drinking water. The EPA Office of Ground Water and Drinking Water offers presentations on drinking water standards and setting standards and a resource page about standards for arsenic in drinking water. The EPA issued an 11 November 2001 press release titled “EPA announces arsenic standard for drinking water of 10 parts per billion.” The Office of Ground Water and Drinking Water provides a fact sheet on the arsenic drinking water standard, the arsenic rule as published in the 22 January 2001 Federal Register, a guide on the implementation of the new rule, and other relevant documents and links. A Congressional Research Service report by M. Tiemann titled “Arsenic in drinking water: Recent regulatory developments and issues” is made available by the National Library for the Environment.

3. Health effects of arsenic. R. Wilson's Arsenic Project Web site offers a presentation on effects of arsenic on human health. The U.S. Agency for Toxic Substances and Disease Registry provides a toxicological profile for arsenic. The IPCS INCHEM Web site makes available a 1987 summary on the carcinogenicity of arsenic and arsenic compounds from the International Agency for Research on Cancer. The 1999 NRC report Arsenic in Drinking Water has a chapter on the health effects of arsenic and a chapter on the mechanisms of toxicity; the 2001 update report includes a chapter on human health effects. The United Nations Synthesis Report on Arsenic in Drinking Water has a section on health effects including cancer. The 8 January 2002 issue of the Canadian Medical Association Journal had an article by E. Weir titled “Arsenic and drinking water.” The August 1998 issue of the International Journal of Epidemiology had an article (full text available in PDF format) by C. Hopenhayn-Rich, M. Biggs, and A. Smith titled “Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba, Argentina” (25).

4. Epidemiological studies. Epidemiology is defined in xrefer's Macmillan Encyclopedia. An introduction to epidemiology is provided by the CDC's EXCITE Web site. Kimball's Biology Pages offers a presentation on epidemiology. The Extension Toxicology Network offers an information brief on epidemiology. Epidemiology for Journalists is a tutorial provided by FACSNET; a discussion of confounding factors is included. Arsenic in Drinking Water: 2001 Update includes a chapter on variability and uncertainty in risk assessment. The National Academy Press makes available volume 1 (1991) and volume 2 (1997) of Environmental Epidemiology.

5. Methylation is defined in xrefer's Dictionary of Science. A discussion of methylation is included in the chapter on the disposition of inorganic arsenic of the 1999 NRC report Arsenic in Drinking Water. J. Moore offers lecture notes on biomethylation for an environmental geochemistry course.

6. A. H. Smith, P. A. Lopipero, M. N. Bates, and C. M. Steinmaus are in the School of Public Health, University of California, Berkeley. A. H. Smith directs the Arsenic Health Effects Research Program.

References and Notes

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