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1
Introduction

THE U.S. Environmental Protection Agency (EPA) Office of Water is reviewing the interim maximum contaminant level (MCL) for arsenic in drinking water and is considering lowering the current level of 50 micrograms per liter (µg/L). The Safe Drinking Water Act (SDWA) Amendments of 1996 (PL 104-182) require that EPA propose a standard for arsenic by January 2000, and promulgate a final standard by January 2001. To meet those requirements, EPA's Office of Water requested that the National Research Council (NRC) review the arsenic toxicity data base and evaluate the scientific validity of EPA's 1988 risk assessment for arsenic in drinking water.

In response to EPA's request, the NRC assigned the project to the Committee on Toxicology (COT), which convened the Subcommittee on Arsenic in Drinking Water. Members of the subcommittee selected to serve have expertise in toxicology, pharmacology, pathology, chemistry, nutrition, medicine, epidemiology, risk assessment, and biostatistics. The specific tasks of the subcommittee were as follows: (1) review EPA's characterization of existing human health risks from ingestion of different compounds of arsenic found in drinking water and food and identify areas of major uncertainty in that characterization; (2) review the quantitative and qualitative evidence of human cancer and noncancer health effects from exposure to various forms of arsenic in drinking water and identify how that information would be relevant to a reassessment of human health risks from arsenic in drinking water; (3) review the data on the toxicokinetics, metabolism, and mechanism or mode of action of arsenic to ascertain how those data could assist in assessing human health risks from arsenic exposures; and (4) identify priorities for research to fill data gaps.

In this report, the subcommittee identifies the evidence that it considers relevant for determining the cancer risks to humans from exposure to arsenic and what inferences can be drawn from the evidence, including low-dose



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Page 10 1 Introduction THE U.S. Environmental Protection Agency (EPA) Office of Water is reviewing the interim maximum contaminant level (MCL) for arsenic in drinking water and is considering lowering the current level of 50 micrograms per liter (µg/L). The Safe Drinking Water Act (SDWA) Amendments of 1996 (PL 104-182) require that EPA propose a standard for arsenic by January 2000, and promulgate a final standard by January 2001. To meet those requirements, EPA's Office of Water requested that the National Research Council (NRC) review the arsenic toxicity data base and evaluate the scientific validity of EPA's 1988 risk assessment for arsenic in drinking water. In response to EPA's request, the NRC assigned the project to the Committee on Toxicology (COT), which convened the Subcommittee on Arsenic in Drinking Water. Members of the subcommittee selected to serve have expertise in toxicology, pharmacology, pathology, chemistry, nutrition, medicine, epidemiology, risk assessment, and biostatistics. The specific tasks of the subcommittee were as follows: (1) review EPA's characterization of existing human health risks from ingestion of different compounds of arsenic found in drinking water and food and identify areas of major uncertainty in that characterization; (2) review the quantitative and qualitative evidence of human cancer and noncancer health effects from exposure to various forms of arsenic in drinking water and identify how that information would be relevant to a reassessment of human health risks from arsenic in drinking water; (3) review the data on the toxicokinetics, metabolism, and mechanism or mode of action of arsenic to ascertain how those data could assist in assessing human health risks from arsenic exposures; and (4) identify priorities for research to fill data gaps. In this report, the subcommittee identifies the evidence that it considers relevant for determining the cancer risks to humans from exposure to arsenic and what inferences can be drawn from the evidence, including low-dose

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Page 11 extrapolation. The report also contains the subcommittee's review and critique of epidemiological studies on skin and internal cancers and other health effects in Taiwanese populations and in other studies in which exposure to arsenic in drinking water has been documented in other parts of the world. Although EPA's Office of Water considers inorganic arsenic the form of concern in drinking water, the subcommittee decided to evaluate whether organic arsenic compounds in drinking water also contribute substantially to health risks. The report contains the subcommittee's review of data on the metabolism, toxicokinetics, and mechanism of action of arsenic in humans and animals and evaluation of the implications of those data for estimating exposure-response relationships below the range of detectable responses in human epidemiological studies. The subcommittee also evaluates the implications of its findings for risks that might be associated with exposure to varying concentrations of arsenic in drinking water and states its assumptions about arsenic intake from food. The remainder of this chapter is divided into three sections. The first provides a brief background of the current MCL for arsenic, the second outlines the scientific controversies associated with the arsenic MCL, and the third describes the organization of this report. Background The current MCL of 50 µg/L has been the standard for arsenic in drinking water in the United States since 1942. In response to the 1974 SDWA, EPA adopted 50 µg/L as the interim standard for total arsenic in drinking water in 1975. Although the SDWA Amendments of 1986 required EPA to finalize its maximum contaminant level goal (MCLG) and enforceable MCL for arsenic by 1989, EPA has not yet finalized the MCLG or MCL for arsenic in part because of the scientific uncertainties and controversies associated with the chronic toxicity of arsenic. The SDWA Amendments of 1996 required EPA to develop an arsenic research strategy within 180 days of enactment of the amendments. The EPA (1996a,b) strategy was reviewed by its Board of Scientific Counselors (EPA 1997), which encouraged EPA to propose an MCL by the year 2000 that ''balances current scientific information on health risks with costs and other risk management factors," and then "establish a more definitive MCL by the year 2010, or earlier if feasible, based on results available from long-term studies."

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Page 12 Scientific Controversies The scientific controversies surrounding the current MCL for arsenic primarily involve the carcinogenic potency of arsenic, which has been evaluated by several EPA or EPA-sponsored groups over the past 20 years, and to a lesser extent whether arsenic might be an essential nutrient. In 1968, Tseng and co-workers reported an association of arsenic in drinking water and skin cancer in a Taiwanese population. Based on those data, in 1984, EPA's Office of Research and Development estimated the potency of arsenic as a skin carcinogen in its health assessment document (HAD) for arsenic. The upper-bound estimate of potency suggested that the risk of skin cancer for individuals consuming 2 L of water with arsenic at 50 µg/L would be 2% (or 2/100). In 1988, EPA's Risk Assessment Forum published a special report reviewing the carcinogenicity of arsenic and the data suggesting that it might be an essential nutrient in birds and mammals. Using the same Taiwanese data, the forum estimated the risk of skin cancer associated with drinking 2 L of water containing arsenic at 50 µg/L on a daily basis over a lifetime to be 0.25% (or 2.5/1,000). Using the same risk-assessment assumptions to lower the estimated risk to 1/10,000, which is the upper bound of what EPA typically considers to be an "acceptable" risk, the forum concluded that the concentration of arsenic in drinking water would need to be lowered to 2 µg/L. In 1989, EPA's Scientific Advisory Board (SAB) recommended that the agency revise its arsenic risk assessment to consider possible detoxification mechanisms that might substantially reduce cancer risks at low exposure levels (EPA 1989). SAB also concluded that available data are inadequate to conclude that arsenic is an essential nutrient for humans. Over the past two decades, there have been repeated calls by EPA (1988, 1991, 1992, 1996b), the NRC (1977, 1980, 1983, 1986), the Agency for Toxic Substances and Disease Registry (ATSDR 1993), and interest groups, such as the American Water Works Association Research Foundation (AWWARF 1995), for additional research on the health effects of exposure to arsenic. In 1983, the NRC Committee on Drinking Water and Health concluded in Volume 5 of its report that (1) "epidemiological studies on U.S. populations have failed to confirm the association between arsenic in drinking water and the incidence of cancer observed in Taiwan"; (2) 50 µg/L provides "a sufficient margin of safety," but that "further experimental research and epidemiological evaluations of the association of elevated levels of arsenic in drinking water and skin cancer be undertaken"; and (3) in the absence of new data, arsenic should be presumed an "essential'' nutrient for humans on the basis of mammalian animal studies. In Volume 6, published in 1986, the committee stated that EPA should consider metabolism and pharmacokinetics in assessing the risks of carcinogenic substances in drinking water. Although epidemiological and experimental research

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Page 13 on arsenic toxicity has continued, studies have largely identified the same data gaps. Clearly, any reassessment of the potential health risks of arsenic in drinking water before the completion of the long-term studies proposed by EPA (or others) should focus on two developments over the past decade: (1) the epidemiological studies published during that time, and (2) data on arsenic metabolism and mechanisms of genotoxicity and carcinogenicity. Organization Of This Report The remainder of this report is organized in 11 chapters and two addendums. Chapter 2 provides an overview of EPA's current risk assessment for arsenic in drinking water (EPA 1988); it identifies the major areas of uncertainty in the assessment and raises questions that the subcommittee will address in the remaining chapters. Chapter 3 provides the background on analytical methods for measuring arsenic in water, food, urine, blood, hair, and nails needed to evaluate the epidemiological and experimental studies of arsenic toxicity. In Chapter 4, the subcommittee reviews the known cancer and noncancer health effects of oral exposures to arsenic and evaluates the reliability of exposure estimates of the most sensitive effects. Chapter 5 provides an overview of what is known about the disposition of arsenic in humans and nonhuman mammals and the implications of that information for estimating health effects associated with low-level exposures. In Chapter 6, the subcommittee evaluates various biomarkers as meaningful measures of the absorbed dose of inorganic arsenic. Several proposed mechanisms or modes of action by which ingestion of arsenic might cause skin cancer, other cancers, and other noncancer health effects are reviewed in Chapter 7. Chapter 8 presents a discussion on the factors that influence variation in human sensitivity to arsenic, including genetic and nutritional factors and interactions with other micronutrients and environmental exposures. Chapter 9 reviews the evidence for the essentiality of arsenic as a nutrient for animals and humans and its therapeutic uses. Chapter 10 describes statistical issues that are important for interpretation of epidemiological studies and for any reassessment of human health risks from arsenic exposure. Chapter 11 discusses the adequacy of the current EPA MCLs and ambient-water-quality-criteria values for protecting human health. It should be noted that, with the exception of the term sublinear, the definitions for the terms linear, point of departure, nonlinear, and margin of exposure used throughout this report are consistent with EPA proposed guidelines (EPA 1996c). The term sublinear is used in this report but is not defined in the EPA proposed guidelines. For sublinear responses, the risk per

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Page 14 unit dose increases with increasing dose. At exposures below the point of departure, the risk is lower when based on a sublinear curve rather than a linear curve. References ATSDR (Agency for Toxic Substances and Disease Registry). 1993. Toxicological Profile for Arsenic. Rep. TP-92.02. U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, Ga. AWWARF (American Water Works Association Research Foundation). 1995. Research Needs Report: Arsenic in Drinking Water. Draft Report. International Expert Workshop, T.D. Chinn, rapporteur; May 31-June 2, Ellicott City, Md. EPA (U.S. Environmental Protection Agency). 1984. Health Assessment Document for Inorganic Arsenic. Final Report. EPA 600/8-83/021F. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, Ohio. EPA (U.S. Environmental Protection Agency). 1988. Special Report on Ingested Inorganic Arsenic: Skin Cancer; Nutritional Essentiality. EPA 625/3-87/013. U.S. Environmental Protection Agency, Risk Assessment Forum, Washington, D.C. EPA (U.S. Environmental Protection Agency). 1989. Science Advisory Board's Review of the Arsenic Issues Relating to the Phase II Proposed Regulations from the Office of Drinking Water. EPA-SAB-EHC-89-038. U.S. Environmental Protection Agency, Science Advisory Board, Washington, D.C. EPA (U.S. Environmental Protection Agency). 1991. Arsenic Research Recommendations—Report of the Ad Hoc Arsenic Research Recommendation Workgroup. U.S. Environmental Protection Agency, Health Effects Research Laboratory, Research Triangle Park, N.C. EPA (U.S. Environmental Protection Agency). 1992. Review of Arsenic Research Recommendations—Review by the Drinking Water Committee of the Office of Research and Development's Arsenic Research Recommendations. EPA-SAB-DWC-92-018. U.S. Environmental Protection Agency, Science Advisory Board, Office of Drinking Water, Washington, D.C. EPA (U.S. Environmental Protection Agency). 1996a. Research Plan for Arsenic in Drinking Water: Board of Scientific Counselors (BOSC)

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Page 15 Review Draft. U.S. Environmental Protection Agency, Office of Research and Development, Washington, D.C. EPA (U.S. Environmental Protection Agency). 1996b. Workshop on Developing an Epidemiology Research Strategy for Arsenic in Drinking Water. U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Research Triangle Park, N.C. EPA (U.S. Environmental Protection Agency). 1996c. Proposed guidelines for carcinogen risk assessment. Notice. Fed. Regist. 61(79): 17959-18011. EPA (U.S. Environmental Protection Agency). 1997. Peer review of EPA's Research Plan for Arsenic in Drinking Water. Draft Report. Ad Hoc Subcommittee on Arsenic Research, Board of Scientific Counselors (BOSC), Office of Research and Development, Washington, D.C. NRC (National Research Council). 1977. Drinking Water and Health, Vol. 1. Washington, D.C.: National Academy Press. NRC (National Research Council). 1980. Drinking Water and Health, Vol. 3. Washington, D.C.: National Academy Press. NRC (National Research Council). 1983. Drinking Water and Health, Vol. 5. Washington, D.C.: National Academy Press. NRC (National Research Council). 1986. Drinking Water and Health, Vol. 6. Washington, D.C.: National Academy Press. Tseng, W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin, and S. Yeh. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl. Cancer Inst. 40:453-463.