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1 InTroduction The U.S. Environmental Protection Agency (EPA) is required under the Safe Drinking Water Act (SDWA) to establish the concentrations of contaminants permitted in public drinking-water supplies. There are two drinking-water contaminant concentrations that the statute requires EPA to set the maxi- mum contaminant level goal (MCkG) and the maximum contaminant level (MCL). The MCkG is a health goal to be based on the best available, peer- reviewed scientific data. It is to be set at a concentration at which no known or anticipated adverse health effects occur, allowing for adequate margins of safety. The MUG is not a regulatory requirement end might not tee attainable with current technology or analytical methods. The MCL, in contrast, is an enforceable standard. The MCL is required to be set as close to the MUG as is technologically feasible, taking cost into consideration. The EPA Of floe of Water is considering options for revising the cur- rent MCL of 50 ,ug/L for arsenic in drinking water. To incorporate the most recent scientific research into its decision, in April 2001, the Office of Water requested that the National Research Council (NRC) review the data pub- lished on the health effects of arsenic since the NRC's 1999 report, Arsenic in Drinking Water. The NRC was also asked to evaluate the arsenic risk as- sessment conducted by EPA for the proposed arsenic standard published in the January 22, 2001, Federal Register (EPA 2001a). 15 -

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6 ARSENIC IN DRINKING WA TER: 2001 UPDA TE SUMMARY OF THE NRC'S 1999 ARSENICINDRIN1[ING WATER REPORT ~ 1996, the NRC Subcommittee on Arsenic in Drinking Water was form- ed and charged with reviewing EPA's 1988 risk assessment for arsenic, re- viewing the scientific data relevant to an arsenic risk assessment, and identify- ing data gaps. The subcommittee did not provide a formal risk assessment or recommend anMCL. The subcommittee concluded, on the basis of epidem~o- logical studies in Taiwan, Chile, and Argentina, that "ingestion of arsenic in drinking water poses a hazard of cancer of the lung and bladder, in addition to cancer of the skin." The subcommittee further concluded, "No human studies of sufficient statistical power or scope have examined whether con- sumption of arsenic in drinking water at the current MCL (approximately 0.001 mg/kg (milligram per kilogram) body weight per day) results in an increased incidence of cancer or noncancer effects." Therefore, the subcom- mittee used the available epidemiological data and information on mode of action, uncertainty, and human susceptibility to extrapolate and estimate cancer risks at various concentrations of arsenic in drinking water. The sub- committee concluded that data Tom the area of southwestern Taiwan where arsenic is endemic provided the best data for dose-response assessment. Although data suggest an indirect mode of action, the subcommittee con- cluded that the data are insufficient to determine a threshold below which no effects are seen and are insufficient to depart from a linear extrapolation to zero. The subcommittee presented the risks using numerous models. Using the Poisson regression model, the lifetime risk for male bladder cancer at the MCL (50 micrograms per liter Dug/ is ~ to l.5 per 1,000, and the lifetime risk for all cancers combined could be on the order of ~ in 100.~ On the basis of its assessment, the subcommittee concluded that "the current EPA MCL for arsenic in drinking water of 50 ,ug/L does not achieve EPA's goal for public health protection and therefore requires downward revision as promptly as possible." 'Two of the 16 members of the previous subcommittee did not agree with the 1 in 100 estimate pending further analysis of the risk of lung cancer, as done for bladder cancer in Chapter 10 of the 1999 report.

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INTRODUCTION ~ 7 POLICY BACKGROUND In ~ 976, under the SDWA, EPA proposed an interim MCL of 50 ,ug/L for arsenic in drinking water as part of the National Interim Primary Drinking Water Standards; that standard was originally set in 1942 and would apply until EPA adopted a new MCL. In ~ 988, EPA conducted a risk assessment for arsenic in drinking water and, in ~ 996, requested that the NRC independently review the scientific database on the health effects of arsenic and evaluate the scientific validity of that risk assessment. Arsenic in Drinking Water MARC 1999) was published in response to that request. Summary of EPA's Actions Following the publication of that report, EPA published a proposed ar- senic MCL of 5 ,ug/L (EPA 2000a) in the FederaiRegister. That standard was based on the information in Arsenic in Drinking Water MARC ~ 999) and on epidemiological studies from southwestern Taiwan, Chile, and Argentina, some of which were remewed in the NRC report. EPA also reviewed data from an epidemiolog~cal study in Utah (Lewis et al. ~ 999) that was released after the NRC (1999) report. EPA concluded that "exposure to inorganic arsenic induces cancer in humans" and proposed a regulation on the basis of that effect. It further concluded that "tiin the absence of a known mode of actions, EPA has no basis for determining the shape of a sublinear dose- response curve for inorganic arsenic" (EPA 2000a) and, therefore, proposed using a linear type of a dose-response curve and setting an MUG of zero. On the basis of "national and international research, the bladder cancer risk analy- sis provided by the National Research Council (NRC) report issued by the National Academy of Sciences (NRC 1999), and the NRC's qualitative state- ments of overall risk of combined cancers," EPA evaluated the risk posed by arsenic in drinking water at 3 ~g/L, 5 PAL, ~ 0 ,ug/L, and 20 ,ug/L. According to EPA policy, an MCL is to be set "as close as feasible to the MC~G, based on available technology and taking costs to large systems into account" (EPA 2000a). EPA determined that 3 ~g/L is technologically feasible but that the costs associated with compliance for that concentration are notjustifiedby the benefits. Therefore, EPA proposed an MCL of 5 ~g/L but requested public comment on alternative MCEs of 3 PAL, 10 ~g/L, and 20 ~g/L. The effective date for compliance for small community water systems would be 5 years after the final rule issuance and 3 years for all other community water systems.

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~ ~ ARSENIC IN DRINKING WA TER: 2001 UPDA TE After the publication of the proposed rule, Morales et al. (2000) published a study in which a risk assessment for mortality from several internal cancers was presented. That risk assessment was based on reanalyses ofthe data from southwestern Taiwan (Chen et al. 1985~. Risk estimates were calculated for mortality from lung, bladder, and liver cancers, as well as combined cancer deaths, using 10 different statistical models. Those models included linear, logarithmic and square-root models, calculated with and without a Taiwanese comparison population. EPA was considering those analyses in the finalrule- making and, therefore, published a Notice of Data Availability in the Federal Register (EPA 2000b) summarizing and further analyzing the information from Morales et al. (2000~. On December 12,2000, the EPA Science Advisory Board (SAB) issued a report on the proposed drinking-water regulation (EPA 2000c). In its major- ity report, the SAB commented on the scientific basis of EPA's health risk assessment and on the economic and engineering aspects of the final rule. Exposure assessment fortheU.S. population, costs, benefits, control technolo- gies, and policy issues discussed by the SAB go beyond the charge to this subcommittee and wall not be discussed here. The SAB also discussed the differential sensitivity of children to arsenic but could not reach consensus on whether children have an increased sensitivity to arsenic. A minority report was written on that issue. In general, the SAB agreed with the analyses cony ducted by the NRC Subcommittee on Arsenic in Drinking Water ARC ~ 999), which formed part of the basis for EPA's proposed regulation. It did not agree, however, with EPA's interpretation ofthe NRC report, stating that EPA "may have taken the modeling activity in the NRC report as prescriptive." T h e S A B a ~ s o s t a t e ~ t h a t E P A ~ i ~ n o t a ~ e q u a t e ~ y a ~ ~ r e s s t h e N ~ C s u b c o m m i t - tee' s cautions about such factors as nutrition and exposure measures that were to be considered when using the Taiwanese data for assessing risk in the U.S. population. The SAB also concluded "that the comparison populations [used in some analyses] were not appropriate control groups for the study area" in the Taiwanese study, and, therefore, dose-response models that did not use the comparison population are more appropriate. The SAB did not believe, how- ever, that "resolution of all these factors can nor must be accomplished before EPA promulgates a final arsenic rule." The SAB agreed that the "available data do not yet meet EPA's new criteria for departing from linear extrapola- tion of cancer risk." In response to public comment and the SAB report, on January 22, 2001, EPA issued a pending standard of 10 ,ug/L (EPA 2001a). To support this

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INTRODUCTION ]9 revised proposed standard, EPA reviewed the available data and quantitatively estimated risks using the epidem~ological data from southwestern Taiwan (Chen et al. 1988, 1992; Wu et al. 1989) because, despite limitations, "the Taiwan epidemiological studies provide the basis for assessing potential risk from Tower concentrations of inorganic arsenic in drinking water, without having to adjust for cross-species toxicity interpretation." In its ruling, EPA discussed the implications for extrapolating from the observed range of ar- senic concentrations in the Taiwanese population to the risk in the U.S. popu- lation of (~) arsenic in food alluvia cooking, (2) uncertainty in exposure from the grouping of individuals with respect to exposure, (3) nutritional aspects of the Taiwanese population, and (4) a study in Utah, which did not find any excess bladder or lung cancer risk after exposure was taken into account. "tT]he best available science provides no alternative to use of a linear dose- response process for arsenic because a specific mode (or modes) of action has not been identified"; therefore, EPA used a Poisson model, with concentration entered as a linear term to estimate the dose that results in a I% increased risk (i.e., 1% benchmark dose; BMDo~), and extrapolated from that point using a linear extrapolation. That analysis follows the EPA draft carcinogen risk assessment guidelines (EPA 1996~. On the basis of that assumption and estimates of water intake, EPA calculated cancer risks at various MCL op- tions. Those risks were calculated for bladder and lung cancer combined. As described in the proposed rule (EPA 2000a), when estimating a risk at a given MCI option, EPA assumed that water-treatment facilities will treat water to achieve a concentration that is 80/O of the MCL and, therefore, calculates risks based on 80% of the MCL. EPA made that assumption because "water systems tend to treat below the MCL level in order to provide a margin of safety" (EPA 2000a). For example, when estimating population risks at an MCL of 10 ,ug/L, the actual average exposure after water treatment would be ,ug/L`. Therefore, the estimated risks presented by EPA at an MCL of 10 g/L are the risks calculated for a drinking-water concentration of ~ ~g/L. Such an adjustment to account for the difference between the MCL and the actual drinking-water concentrations was not done in the risk estimates of the previous NBC subcommittee. In addition, the NRC (1999) risk estimates are for mate bladder cancer alone, not combined cancers as presented by EPA, and estimates calculated with and without a comparison population (i.e., background data) are presented in the NRC report (1999~. Given those risks, what is known or not known about arsenic's mode-of-action, cost-benefit analyses, and policy considerations, EPA set an MUG of 0 ~g/L and an MCL

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20 ARSENIC IN DRINKING WA TER: 2001 UPDA TE of 10 Age. Further details on the models and parameters used by EPA to determine their risk estimates are presented in Chapter 5. On March 23, 200 I, EPA published a notice that delays the effective date of the arsenic rule pending further study (EPA 200 Ib). EPA's Of fice of Water requested that the NRC update its 1999 report as part of the further study. CHARGE TO TTIE SUBCOMMITTEE In response to EPA's request, the NRC assigned the project to the Com- mittee on Toxicology (COT), which convened the Subcommittee to Update the 1999 Arsenic in Drinking Water Report. Members selected to serve on this subcommittee have expertise in toxicology, epidemiology, cellular and molecular toxicology, biostatistics and modeling, risk assessment, uncertainty analyses, medicine, and public health. Five members of this subcommittee also served on the earlier Subcommittee on Arsenic in Drinking Water. This subcommittee is charged with the task of preparing a report updating the scientific analyses, uncertainties, findings, and recommendations of the Ar- senic in Drinking Water report (NRC ~ 999) on the basis of several new stud- ies and analyses published since the 1999 report was released. Specifically, the charge to the subcommittee was to review relevant toxicological and health-effects studies published and relevant data developed since the 1999 NRC report, including the toxicological risk-related analyses performed by EPA in support of its regulatory decision-making for arsenic in drinking wafer. The subcommittee addressed only scientific topics relevant to toxicological risk and health effects of arsenic; it did not address questions of economics, cost-benefit assessment, control technology, or regulatory decision-making. The subcommittee performed the following tasks in response to the charge: It determined whether data from the ~ 988, ~ 989, and ~ 992 Taiwanese studies remain the best data for dose-response assessment and risk estimation. It assessed whether the EPA analysis appropnately incorporates popu- lation differences, including diet, when extrapolating from the Taiwanese study population to the U.S. population. It evaluated whether the dose-response analysis conducted by EPA, as well as any available analyses of more recent data, is adequate for estimat- ing an effective dose for a 1% response (EDo~.

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INTRODUCTION 2] It determined whether EPA's analysis appropriately considers and characterizes the available data on the mode of action of arsenic and the infor- mation on dose-response and uncertainties, when assessing the public-health impacts. It determined whether EPA's risk estimates at 3, 5, ~ 0, and 20 ,ug/L are consistent with available scientific information, including information from new studies. This subcommittee was not asked to assess and did not assess U.S. popu- lation exposures. Therefore, it did not estimate the benefits or potential lives saved in the United States at each possible regulatory level. Consistent with the makeup ofthe subcommittee, it has addressed the scientific issues related to the hazards from arsenic in Winking water and has avoided commenting or making recommendations on risk-management or policy decisions to the extent possible. To that end, the subcommittee has not recommended an MCL, which, by definition, requires policy considerations that include evalua- tion of risk-management options and cost-benefit analyses that are beyond the scope ofthis subcommittee. If a particular analysis conducted by the subcom- m~ttee has policy or risk-management decisions inherent in it, the subcommit- tee presents the analysis as an example and indicates which parameter values are derived from policy decisions. It should also be noted that the subcommittee is charged with updating Arsenic in Drinking Water MARC ~ 999) and not with reviewing it. Therefore, the subcommittee has taken that report as a starting point and has evaluated the information published since the release of that report. ORGANIZATION OF THIS REPORT Subsequent to the release of Arsenic in Drinking Water MARC 1999), numerous new studies and analyses have been published on the health effects of arsenic and related data, including epidemiological studies on cancer and noncancer effects, toxicokinetic and mode-of-action studies, and reports on arsenic risk assessments. The remainder of the report is organized into five chapters that review those areas. To provide context for the update, each chapter includes a brief summary of the information from the 1999 report. Chapter 2 discusses recent data on the health effects of arsenic in humans. Chapter 3 presents information published since the 1999 report on the toxico-

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22 ARSENIC IN DRINKING WA TER: 2001 UPDA TE kinetics and possible mode of action of arsenic. Chapter 4 addresses vanabil- ity and uncertainty, which are to be considered when assessing the hazards of arsenic, arising Mom intenndiv~dual vanability, dietary and nutritional factors, exposure issues in epidemiology studies, and latency periods. Chapter 5 pro- v~des a discussion on the modeling approaches for quantitative evaluation of nsks. It includes analyses conducted by EPA in its proposed regulations and the comments of the EPA Science Advisory Board (SAB) as well as analyses conductedby this subcommittee. Chapter6 presents a summery ofthe subcom- mittee's findings, including lifetime cancer risk estimates associated with lifetime consumption of arsenic at different concentrations in Winking water. REFERENCES Chen, C.J., Y.C. Chuang, T.M. Lin, and H.Y. Wu. 1985. Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: High-arsenic artesian well water and cancers. Cancer Res. 45~11 Pt 2~:5895-5899. Chen, C.J., M. Wu, S.S. Lee, J.D. Wang, S.H. Cheng, and H.Y. Wu. 1988. Athero- genicity and carcinogenicity of high-arsenic artesian well water. Multiple risk factors and related malignant neoplasms of blackfoot disease. Arteriosclerosis 8(5):452-460. Chen, C.J., C.W. Chen, M.M. Wu, and T.L. Kuo. 1992. Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in dunking water. Br. J. Cancer 66~5~:888-892. EPA (U.S. EnvironmentalProtection Agency). 1996. Carcinogenic Risk Assess- mentGuidelines.Notice. Fed.Regist.61~79~:17960-18011. EPA (U.S. Environmental Protection Agency). 2000a. 40 CFR Parts 141 and 142. National Primary Drinking Water Regulations. Arsenic and Clarifications to Compliance and New Source Contaminants Monitoring. Notice of proposed rulemalcing. Fed. Regist. 65~121~:38887-38983. EPA (U.S. Environmental Protection Agency). 2000b. 40 CFR Parts 141 and 142. National Primary Drinking Water Regulations. Arsenic and Clarifications to Compliance end New Source Contaminants Monitoring. Notice of data availabil- ity. Fed. Regist. 65~204~:63027-63035. EPA (U.S. Environmental Protection Agency). 2000c. Arsenic Proposed Drinking Water Regulation: A Science Advisory Board Review of Certain Elements of the Proposal, A Report by the EPA Science Advisory Board. EPA-SAB-DWC-01- 001. Science Advisory Board, U.S. Environmental Protection Agency, Washing- ton, DC. [Online]. Available: http://www.epa.gov/sab/fiscalOl.hun . EPA (U.S. Environmental Protection Agency). 2001a. 40 CFR Parts 9,141 and 142. National Primary Dnnking Water Regulations. Arsenic and Clarifications to

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INTRODUCTION 23 Compliance end New Source Contaminants Monitoring. Final Rule. Fed. Regist. 66~14~: 6975-7066. EPA (U.S. Environmental Protection Agency). 2001b. 40 CFR Parts 9,141 and 142. National Prunary Drinking Water Regulations. Arsenic and Clarifications to Compliance and New Source Contaminants Monitoring. Final rule. Delay of effective date. Fed. Regist. 66~57~: 16134- 16135. Lewis, D.R., J.W. Southwick, R. Ouellet-Hellstrom, J. Rench, and R.L. Calderon. 1999. Drinking water arsenic in Utah: A cohort mortality study. Environ. Health Perspect. 107~5~:359-365. Morales, K.H., L. Ryan, T.L. Kuo, M.M. Wu, and C.J. Chen. 2000. Risk of internal cancers from arsenic in Mung water. Environ. Health Perspect. 108~7~:655- 661. N1