President's Cancer panel

Environmental Factors in Cancer: Water Contamination

December 4, 2008

Charleston, SC

Carcinogens in Drinking Water: The Epidemiologic Evidence

Kenneth P. Cantor, Ph.D, M.P.H.

Senior Investigator

Occupational and Environmental Epidemiology Branch

Division of Cancer Epidemiology and Genetics

National Cancer Institute

Drinking water in industrialized nations is generally of very high quality. However, growing evidence from laboratory investigations and epidemiologic studies suggests that some waterborne contaminants contribute to human cancer risk. This review summarizes the epidemiologic evidence for the major drinking water contaminants that are known or suspected carcinogens: inorganic arsenic, disinfection byproducts, and nitrate. In addition, some organic compounds from human commerce, radionuclides, some microbiologic agents, and asbestiform particles in water are suspected of causing human cancer. Further details on the epidemiologic evidence on cancer and these drinking water contaminants, including reference to specific studies, may be found elsewhere 1.

Water quality in the United States is regulated by the Environmental Protection Agency (EPA) under provisions of the Safe Drinking Water Act, first passed by Congress in 1974 and amended in 1986 and 1996 2. The law requires many actions to protect drinking water and its sources, including establishment of Maximum Contaminant Levels (MCL) for many substances. EPA standards apply to all U.S. public water supplies serving at least 25 persons. Of the 302 million persons in the U.S. population, 286 million (95%) receive their drinking water from 52,000 community water systems (2007 estimates)3. A relatively small number of large community water systems serve a large proportion of the population. The largest 400 systems serve 45% of the population and the largest 4,100 systems serve 82%, whereas 48,000 systems serve the remaining 18% . The proportion of the population served by public water supplies varies enormously across the United States. A majority of the population served by public water supplies (68%) uses water from surface waters (rivers, streams, reservoirs, etc.), with the remainder using ground water. The population not served by public water supplies (approximately 16 million persons) relies primarily on well water. EPA standards do not apply to these private sources of drinking water; however, many states have programs governing these sources.

Inorganic Arsenic

Background

The regulation of arsenic in drinking water is unique in that the scientific basis for the maximum contaminant level is anchored in human data on the carcinogenicity of arsenic, whereas allowable levels of most other water contaminants is primarily based on extrapolation of data from laboratory studies in animals. Carcinogenic effects of arsenic in drinking water have been found in studies in parts of the world with high-level exposures - greater than 100 micrograms per liter ( g/L). The most important research has come from populations in Southwest Taiwan, northern Chile, Mexico, Argentina, and Inner Mongolia in China. Currently, the most widespread exposure to high levels occurs in Bangladesh and West Bengal, where millions are recently exposed, and evidence of cancer is beginning to emerge. In the United States, exposure to these very high levels is rare. However, private wells in areas of California, Nevada, Alaska, Michigan, New England, New Mexico, Utah, and a few other states have revealed high exposures. While most arsenic contamination of water is from natural sources, human activities such as past use of arsenical pesticides, as well as the mining and processing of ores, contributes to waterborne inorganic arsenic in some places. In the U.S., the maximum contaminant level (MCL) for arsenic in drinking water in public water systems is 10 g/L 4-6. The reduction from the former MCL of 50 g/L in 2001 affected U.S. water systems serving approximately 13 million people. The World Health Organization similarly recommends 10 g/L. In addition to cancer, inorganic arsenic has been linked to a wide range of non-neoplastic outcomes, including cutaneous, gastrointestinal, vascular, endocrine, respiratory, and adverse reproductive and developmental effects.

Epidemiologic studies

In 2004, the International Agency for Research on Cancer (IARC) reviewed the human and laboratory evidence, and classified ingested arsenic as a human carcinogen for skin, lung, and bladder cancers 7. Additional evidence also suggests kidney cancer.

Formal observation that ingested arsenic causes cancer dates to 1887, when an astute clinician reported an unusual number of skin cancers among patients that he had treated with arsenicals, commonly used as pharmacologic agents. Since then, hundreds of clinical observations noting a wide variety of cancers have been reported, and epidemiologic studies have quantified the risk.

The first quantitative epidemiologic studies of cancer used an ecologic approach (that is, a comparison of the geographic distribution of drinking water arsenic with the distribution of cancer rates). These studies were conducted in areas of chronic arsenicism and highly contaminated water supplies, including Taiwan, Argentina, and Chile. Most studies relied on mortality statistics, permitting assessment of arsenic effects for a variety of outcomes. These ecologic studies had no information on individual exposures to arsenic and little information on potential confounding factors. More recent efforts have included cohort and case-control studies with individual estimates of exposure and outcome, and, in many instances, information on several potential confounding factors.

In southwest coastal Taiwan, villages switched from surface to ground water (artesian wells) for drinking in the 1920s, to improve the bacteriologic quality of drinking water. Unexpectedly, the newly tapped aquifers were contaminated with arsenic. The first quantitative studies to assess excess cancer and other adverse effects were conducted in this region. Dose-response gradients in age-
standardized sex-specific mortality in Taiwanese villages were observed for cancers of the liver, lung, skin, bladder, and kidney in both sexes, and prostate among men. Studies of cancer mortality were also conducted in Cordoba Province, Argentina and Region II in northern Chile, where large populations have been exposed to high levels. Consistent with the Taiwanese studies, excess mortality in these South American studies was found for skin, lung, bladder, and kidney cancers. It is noteworthy that cancer mortality in Region II of Chile was still elevated 20 years after arsenic levels in drinking water started to decrease. The strong and consistent findings of arsenic's carcinogenicity from ecologic studies have been confirmed by cohort and case-control investigations that collected individual information on disease and exposure.

Direct observation of cancer risk at lower levels of exposure has been more challenging to investigate. To date, studies conducted among populations at these lower levels have not been informative due to several limitations, and risk at low levels has been estimated by extrapolation from the high-exposure studies. More precise estimates of risk in the lower part of the exposure range await completion of much larger studies that include rigorous exposure assessment, and collection of information on an individual level to permit control for confounding by other risk factors.

Biomarkers of exposure and susceptibility

Levels of inorganic and methylated forms of arsenic in the urine provide a quantitative measure of recent exposure, and serve as a marker of biotransformation to methylated metabolites. Variations in individual susceptibility to the carcinogenic effects of ingested arsenic is the focus of an increasing number of studies. Genetic susceptibility to the toxic effects of arsenic is suggested by variations in arsenic metabolism within and among populations, specifically by looking at individual differences in arsenic methylation capacity. These differences are detected primarily by variability in the concentrations of arsenic metabolites in urine. As we gain a better understanding of the metabolic pathways involved, analysis of polymorphisms in relevant DNA sequences are under investigation. Inadequate nutrition or low levels of micronutrients, such as vitamins B-2, B-6, B-12, and folic acid, may increase individual susceptibility to arsenic-induced cancers by influencing methylation capacity. The molecular mechanisms by which arsenic promotes cancer also has been studied by comparing tumor DNA from arsenic-exposed and unexposed individuals.

Summary and recommendations for future research

Epidemiologic studies provide unequivocal evidence that arsenic in drinking water is a human carcinogen, causing skin, lung, bladder, and possibly kidney cancer in highly exposed populations. To date, risk at much lower exposures, around the Maximum Contaminant Level (10 g/L) has been estimated by extrapolation from high-exposure studies. The carcinogenicity of arsenic at low levels of exposure is being investigated in a large collaborative case-control study in northern New England, under the leadership of the National Cancer Institute. Another promising area for future research involve studies that explore the mechanism(s) of arsenic carcinogenesis, which are poorly understood at present.

Disinfection Byproducts

Background

Disinfection of drinking water is one of the great successes in the annals of public health. A profound reduction of morbidity and mortality due to disinfection of drinking water with chlorine is well documented. It may therefore come as a surprise that this major public health benefit may be partially offset by moderate increases in cancer risk due to long-term exposure to chemicals unintentionally created when chlorine reacts with organic material common in untreated waters. Hundreds of disinfection byproducts (DBP) have been identified, with chloroform, other trihalomethanes (THM), and haloacetic acids the most commonly found. A large number of other compounds in the mixture have also been identified. Among the relatively small number of chemicals found in DBP mixtures that have been tested for carcinogenicity in rodent bioassays, some are positive. The overall mixture and some mixture components are mutagenic in in-vitro testing systems, also suggesting carcinogenicity.

Disinfection byproducts are generally elevated in water systems that use treated surface water sources, where chloroform and related compounds can range up to several hundred parts per billion (ppb) if they are not carefully controlled. Levels in treated ground water sources are typically below 15 or 20 ppb. Many epidemiologic studies have taken advantage of this characteristic, using "water source" (surface or ground) as a surrogate for high or low DBP exposure. Trihalomethanes (THM) generally track with other chemicals in the DBP mixture, and THM levels also have been used as a surrogate measure in epidemiologic studies, as well as an indicator chemical for regulatory purposes. The current EPA maximum contaminant level (MCL) permitted in the United States is 80 ppb total THM as an annual average, with requirements for the timing and location of sampling within water distribution systems 8. Maximum allowable levels for some other mixture components have also been established. Results from epidemiologic studies have been important in formulating these regulations. The primary route of exposure for the low molecular weight compounds such as the THM is inhalation and dermal absorption during bathing, showering, and swimming in chlorinated pools. Exposure to the higher molecular weight compounds is primarily through consumption.

Epidemiologic studies of disinfection byproducts and cancer

Epidemiologic evaluation of cancer risk and chlorination byproducts began with ecologic (geographic comparison) studies shortly after THM were detected in drinking water in 1974. Age-
adjusted, site-, sex-, and race specific incidence or mortality rates for regions such as U.S. counties were used as study outcome measures, and characteristics (chlorinated vs non-chlorinated, surface vs ground, THM level, or estimated mutagenicity) of the predominant regional drinking water source as the exposure. Cancers of the bladder, colon, and rectum were the most commonly observed cancer sites linked with DBP. These studies did not use individual information, had limited data on other risk factors, lacked detail on historical exposure levels, and were unable to account for the effects of migration on cancer rates. Subsequent cohort and case-control studies using individual-level measures of effect and exposure were largely able to address these limitations.

Bladder cancer has received the greatest attention, with data from three cohorts, six case-
control studies, and a pooled analysis. Elevated risk was found with long-term exposure to DBP in all but one study. In each case-control study, a long-term profile (from 35 years to lifetime) of water type and/or estimates of THM concentration or water mutagenicity served as the exposure index, and risk estimates were adjusted for age, sex (if applicable), smoking, and other potential confounders. Long-
term exposure estimates were developed by gathering a lifetime residential history from study participants (with type of water source (public or private) at each place), and merging these data with independently gathered historical data from water utilities in the study region. A pooled analysis of data from six published and unpublished case-control studies of bladder cancer showed an association with long term (a 40-year window) THM exposure among men, but not women 9. Among men, the relative risk estimate increased to 1.43 (95% confidence interval, 1.2-1.7) for a long-term average level of >50 ppb (p(trend) <0.001).

Current work from our group at NCI suggests that individuals with both long-term high exposures to DBP, and common genetic variants in selected enzymes that metabolize chemicals in the mixture, are at especially elevated risk of bladder cancer. Results from the few studies of colon and rectal cancer are mixed, possibly due to differences in methodology or regional water quality. Information from studies of other cancers, in which exposures were estimated for several decades before diagnosis, are more limited. Findings from at least one study of renal cell carcinoma and another of glioma provide a limited suggestion of elevated risk for these cancers.

Summary and recommendations for future research

Mounting evidence suggests an association of bladder cancer with long-term exposure to DBP in drinking water, a complex and variable mixture that contains many compounds that are carcinogenic and mutagenic in laboratory tests. Data for colon and rectal cancer from two well-conducted case-
control studies with long-term estimates of exposure are conflicting. For all cancer sites other than perhaps bladder cancer, there is need for additional work. The growing database indicates that where elevated risk exists, it is likely related to long term exposures, requiring that exposure assessment accounts for at least 35 years of experience prior to cancer diagnosis. Where associations have been observed, relative risks are modest (in the range 1.3-2.6). However, substantial numbers of people are exposed, and modest relative risks can translate to large attributable risks, suggesting important public health implications.

Nitrate

At the October 21st Indianapolis meeting of this Panel, my NCI colleague, Dr. Mary Ward, reviewed nitrate in drinking water, included as one of several presentations on environmental exposures related to agricultural practices. Here we include some brief comments on this important drinking water contaminant. Dr. Ward's white paper on nitrate and the implications of exposure on human cancer risk has been included in the background information for this meeting. Please see her paper for more details on exposure, mechanisms of action, epidemiologic studies on nitrate and cancer, and the cancer sites of greatest concern10.

Over the past 50 years, humans have doubled the natural rate of nitrogen deposition onto land, largely through application of manufactured nitrogen fertilizers, but also through combustion of fossil fuels and replacement of natural vegetation with nitrogen-fixing crops. The bulk of nitrogen-containing compounds on the land surface is converted to nitrate, much of which winds up in ground water. The U.S. Geological Survey assessed available private well measurements in 1970-92 and found that 9% of samples exceeded the Maximum Contaminant Level (MCL) of 10 mg/L as nitrate-nitrogen (nitrate-N). A significant proportion of wells, particularly those less than 30 meters in depth in agricultural areas, exceed the MCL for nitrate. Almost all public water supplies have nitrate levels below the MCL. Thus, rural populations with private wells, especially shallow wells, have a much higher potential for exposure to elevated nitrate than consumers of public drinking water. As nitrogen fertilizers are increasingly used, so too is the nitrate contamination of aquifers used to supply drinking water increased. The U.S. Environmental Protection Agency (EPA) has established an MCL for nitrate in drinking water at 10 mg/L nitrate-N to protect against methemoglobinemia, to which infants are especially susceptible. The MCL is not based on risk of cancer or other health outcomes. Mechanistic studies of nitrate suggest the possibility that nitrate is a human carcinogen at levels of exposure lower than the MCL. However, the epidemiologic database is very limited and no conclusion on this question is possible at present. Clearly, we need to pursue research opportunities to address this important question.

Other waterborne exposures and cancer risk

Other waterborne exposures that may be linked with elevated cancer risk are briefly summarized in this final section. Further details on exposure, epidemiologic studies, regulations, and preventive measures may be found elsewhere 1.

Organic Chemicals from Human Commerce

Contamination of underground and surface waters with organic chemicals from industrial, agricultural, commercial, and domestic sources, as well as from hazardous waste disposal sites, is increasingly found. Epidemiologic assessment of the health impact of such drinking water contaminants is challenging, due to the difficulty in estimating the levels, the timing of the exposure and the specific chemicals involved, the relatively small populations typically exposed, and deciding which health endpoints, or intermediate biological markers, to examine. When health effects are observed, it is often not possible to sort out multiple exposures. Epidemiologic studies frequently involve exposure to poorly defined mixtures of chemicals, and where associations are observed, it may not be possible to link effects with exposure to specific chemicals.

County and local cancer mortality and incidence rates, calculated from routinely collected information, have been examined in places with hazardous waste sites, or with municipal water supplies with documented contamination. For example, in a nationwide survey, age-adjusted cancer mortality rates from 339 U.S. counties with 593 hazardous waste sites listed by EPA were compared with rates from 2,726 other counties. Significant associations were found for lung, bladder, stomach, colon, and rectal cancers in white males and females, esophageal cancer in white males, and breast cancer in white females. Another approach has been to focus on health conditions in the vicinity of hazardous waste sites, or other places where disposal of chemicals has measurably contaminated the groundwater. The best known of these are Love Canal, near Niagara Falls, New York and Woburn, Massachusetts. In Woburn, for example, a cluster of childhood leukemia was associated with multiple contaminants, including trichloroethylene, trichlorotrifluoroethane, and dichloroethylene in the community water supply. Continued health surveillance of potentially exposed populations in the vicinity of toxic waste disposal sites should be a high priority.

Radionuclides

Traces of natural and anthropogenic radioactivity are found in drinking water supplies throughout the U.S. Levels vary geographically with local soil and rock conditions and may be increased by industrial and other point discharges, such as radiopharmaceutical production and use, radionuclide and weapons production, and nuclear power generation. The principal naturally-occurring species include: Ra-226, Ra-228, U, Rn-222, Pb-210, Po-210, Th-230, and Th-232. Most of the population dose of alpha radiation derived from drinking water is from airborne radon released from water in dish and clothes washers, showers, baths, toilets, and cooking, drinking, and cleaning. The primary exposure is to the lungs from inhalation, as described by Dr. Lubin 11. In most cases, radon in water adds a relatively small increment to total radon in household air. Most epidemiologic investigations of cancer and radioactivity in drinking water are ecologic in design. Studies have been conducted in Florida, Maine, Iowa, and North Carolina showing weak associations with leukemia, and cancers of the lung, bladder, lung, and breast. Elevated risk of osteosarcoma has been linked with radium-226 in drinking water in studies from Iowa, Illinois, Wisconsin, Ontario, and New Jersey.

Microbiologic Agents

Viruses, bacteria, and protozoa are the principal microbes in drinking water that can be transmitted to man by ingestion and are generally not thought to be important as carcinogens. Their concentrations and sources vary greatly in different raw water sources, but the dramatic decreases and continued low incidence of waterborne infectious disease over the last 100 years underscore the effectiveness and importance of disinfection in maintaining acceptably low levels of these agents in finished water in most industrialized countries. A waterborne micro-organism, Schistosoma haematobium, has been associated with elevated bladder cancer rates in many tropical and subtropical regions where schistosomiasis is endemic. Helicobacter pylori infection is a risk factor for stomach cancer, gastric lymphoma, and possibly other cancers. In addition to low socio-economic status, poor hygiene, and crowded living conditions, drinking water contaminated with H. pylori has been identified as a risk factor for infection, as measured serologically or by other methods, in many settings.

Asbestiform Fibers

"Asbestos" is a vernacular term referring to a large group of "naturally occurring hydrated silicate minerals possessing fibrous morphology and commercial utility". For human carcinogenesis, the size, shape, and crystalline structure of these fibers is as important as concentration, and these characteristics are modified by physico-chemical processes in water or gastric fluid. Asbestos fibers reach drinking water through weathering from natural deposits such as serpentine, release from asbestos-cement pipes, and from processes associated with mining and production of various ores, with varying concentrations. The relatively few epidemiologic studies of populations served by water containing high concentrations of asbestos have not yielded conclusive results. However, epidemiologic and experimental research should continue, since airborne asbestos is a well-described carcinogen, asbestiform fibers have a wide distribution in drinking water supplies, and the available data cannot rule out adverse health effects.

Inorganic Solutes Other than Arsenic: Trace metals, hardness, magesium, and calcium

Other than arsenic, there has been relatively little study of trace metals in water and cancer risk. Metals such as beryllium, cadmium, and lead are present in U.S. drinking waters (usually under 100 g/L) and can increase or decrease during water treatment. The few existing studies of total water hardness, calcium, and magnesium are limited in that they examined mortality data, information on potential confounding factors other than age, sex, and urbanization were not available, and levels were estimated at the time of death, not during a presumably lengthy latent period. Since findings of dietary calcium have suggested lower risk for colorectal cancer, further study of protection associated with water hardness and magnesium and calcium levels is warranted.

References

1.	Cantor KP, Ward MH, Moore L, Lubin J. Water contaminants. In: Schottenfeld D, Fraumeni JF, Jr., editors. Cancer Epidemiology and Prevention, 3rd Edition. Oxford & New York: Oxford University Press; 2006. p. 382-404.

2.	U.S.Environmental Protection Agency, Office of Water. Understanding the Safe Drinking Water Act. EPA 816-F-04-030. 2004.

3.	US Environmental Protection Agency, Office of Water. Factoids: Drinking Water and Ground Water Statistics for 2007. EPA 816-K-07-004. 2007.

4.	Environmental Protection Agency. National Primary Drinking Water Regulations; Arsenic and clarifications to compliance and new source contaminants monitoring: 40 CFR Parts 9, 141, and 142. Federal Register 2001;66, No. 14:6975-7066.

5.	National Research Council: Subcommittee on Arsenic in Drinking Water. Arsenic in Drinking Water. Washington, DC: National Academy Press, 1999.

6.	National Research Council: Subcommittee to Update the 1999 Arsenic in Drinking Water Report. Arsenic in Drinking Water: 2001 Update. Washington, D.C.: National Academy Press, 2001.

7.	International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 84: Some Drinking-Water Disinfectants and Contaminants, including Arsenic. Lyon: IARC, 2004.

8.	Environmental Protection Agency. National Primary Drinking Water Regulations; Disinfectants and Disinfection Byproducts. Federal Register 1998;63, No. 241:69389-476.

9.	Villanueva CM, Cantor KP, Cordier S, Jaakkola JJ, King WD, Lynch CF et al. Disinfection byproducts and bladder cancer: a pooled analysis. Epidemiology. 2004;15:357-67.

10.	Ward, M. Too much of a good thing? Nitrate from nitrogen fertilizers and cancer: Presentation to the President's Cancer Panel. 10-21-2008. Indianapolis, Indiana.

11.	Lubin, J. H. Environmental Factors in Cancer: Radon. Presentation to the President's Cancer Panel. 12-4-2008. Charleston, SC.