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11
Risk Characterization

In its Statement of Task to the subcommittee, EPA requested guidance regarding ''the adequacy of the current EPA maximum contaminant levels (MCLs) and ambient-water-quality-criteria (AWQC) values for protecting human health in the context of stated EPA policy. . . . " EPA's stated policy in setting MCLs for known human carcinogens has the "goal of ensuring that the maximum risk at the MCL falls within the 10-4 to 10-6 range that the agency considers protective of the public health, therefore achieving the overall purpose of the SDWA (Safe Drinking Water Act)" (EPA 1992). EPA has not requested, nor has the subcommittee endeavored to provide, a formal risk assessment for arsenic in drinking water. However, the subcommittee believes it can provide EPA with an up-to-date summary appraisal of two key elements of the risk-assessment process—hazard identification and dose response—that qualitatively, if not quantitatively, address the protective nature of the current MCL.

As the subcommittee discussed in detail elsewhere in this report, there is sufficient evidence from human epidemiological studies in Taiwan, Chile, and Argentina to conclude that ingestion of arsenic in drinking water poses a hazard of cancer of the lung and bladder, in addition to cancer of the skin. Overt noncancer effects of chronic arsenic ingestion have been detected at arsenic doses on the order of 0.01 mg/kg per day and higher. Of the noncancer effects, cutaneous manifestations of exposure have been studied most widely. No human studies of sufficient statistical power or scope have examined whether consumption of arsenic in drinking water at the current MCL (approximately 0.001 mg/kg per day) results in an increased incidence of cancer or noncancer effects. Therefore, a characterization of the risk that exists at the current MCL must rely on extrapolation by using observed



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Page 299 11 Risk Characterization In its Statement of Task to the subcommittee, EPA requested guidance regarding ''the adequacy of the current EPA maximum contaminant levels (MCLs) and ambient-water-quality-criteria (AWQC) values for protecting human health in the context of stated EPA policy. . . . " EPA's stated policy in setting MCLs for known human carcinogens has the "goal of ensuring that the maximum risk at the MCL falls within the 10-4 to 10-6 range that the agency considers protective of the public health, therefore achieving the overall purpose of the SDWA (Safe Drinking Water Act)" (EPA 1992). EPA has not requested, nor has the subcommittee endeavored to provide, a formal risk assessment for arsenic in drinking water. However, the subcommittee believes it can provide EPA with an up-to-date summary appraisal of two key elements of the risk-assessment process—hazard identification and dose response—that qualitatively, if not quantitatively, address the protective nature of the current MCL. As the subcommittee discussed in detail elsewhere in this report, there is sufficient evidence from human epidemiological studies in Taiwan, Chile, and Argentina to conclude that ingestion of arsenic in drinking water poses a hazard of cancer of the lung and bladder, in addition to cancer of the skin. Overt noncancer effects of chronic arsenic ingestion have been detected at arsenic doses on the order of 0.01 mg/kg per day and higher. Of the noncancer effects, cutaneous manifestations of exposure have been studied most widely. No human studies of sufficient statistical power or scope have examined whether consumption of arsenic in drinking water at the current MCL (approximately 0.001 mg/kg per day) results in an increased incidence of cancer or noncancer effects. Therefore, a characterization of the risk that exists at the current MCL must rely on extrapolation by using observed

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Page 300 epidemiological findings, experimental data on mode-of-action-related end points, and available information regarding the anticipated variability in human susceptibility. At present, studies from the arsenic endemic area of Taiwan continue to provide the best available empirical human data for use in assessing the dose-response relationship for arsenic-induced cancer. The current state of knowledge is insufficient to reliably apply a biologically based model to those data. In accordance with EPA's "Proposed Guidelines for Carcinogen Risk Assessment" (EPA 1996), the subcommittee reviewed modes of action based on markers of tumor response and on available data that can determine the shape of the dose-response curve in the range of extrapolation. As discussed in Chapter 7, the several modes of action that are considered most plausible would lead to a dose-response curve that exhibits sublinear characteristics at some undetermined region in the low-dose range. Nonetheless, in the context of its task, the subcommittee considered the magnitude of the likely cancer risks within the range of human exposure at approximately the current MCL. In vitro studies of the genotoxic effect of submicromolar concentrations of arsenite on human and animal cells and one study of bladder-cell micronuclei in humans with arsenic concentrations of 57 to 137 µg/L in urine indicate that perturbations in cellular function related to plausible modes of carcinogenesis might be operating at arsenic exposure concentrations associated with the current MCL. The subcommittee believes that those data and the confidence with which they can be linked to arsenic-induced neoplasia are insufficient to determine the shape of the dose-response curve between the point of departure and the current MCL. The subcommittee also finds that existing scientific knowledge regarding the pattern of arsenic metabolism and disposition across this dose range does not establish mechanisms that mitigate neoplastic effects. In light of all the uncertainties on mode of action, the current evidence does not meet EPA's stated criteria (EPA 1996) for departure from the default assumption of linearity in this range of extrapolation. In Chapters 2 and 10, the subcommittee reviewed the strengths and limitations of the Taiwanese data. Chapter 10 also discussed the implications of applying different statistical models to the Taiwanese internal-cancer data for the purpose of characterizing cancer risk at the current MCL in the United States. With respect to EPA's 1988 risk assessment for arsenic-induced skin cancer in which the multistage Weibull model was used, a sensitivity analysis, within the limits of the available data, suggests that misclassification arising from the ecological-study design and the grouping of exposures would likely have only a modest impact on EPA's risk estimates. Sensitivity analyses applied to male bladder-cancer risk estimated by the multistage Weibull model had a greater impact on results. However, a more stable and reliable fit was provided by Poisson regression models that characterized the log relative risk

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Page 301 as a linear function of exposure and a quadratic function of age. For male bladder cancer, a straight-line extrapolation from the 1 % point of departure (LED1) yielded a risk at the MCL of 1 to 1.5 per 1,000. Considering the data on bladder and lung cancer in both sexes noted in the studies in Chapter 4, a similar approach for all cancers could easily result in a combined cancer risk on the order of 1 in 100. It is also instructive to note that daily arsenic ingestion at the MCL, approximately 100 µg in adults, provides a margin of exposure less than 10. As discussed in Chapter 8, the subcommittee recognizes that human susceptibility to the adverse effects of chronic arsenic exposure is likely to vary based on genetics, sex, and other possible factors. Some factors, such as poor nutrition and arsenic intake from food, might affect assessment of risk in Taiwan or extrapolation of results in the United States. Upon assessing the available evidence, it is the subcommittee's consensus that the current EPA MCL for arsenic in drinking water of 50 µg/L does not achieve EPA's goal for public health protection and therefore requires downward revision as promptly as possible. References 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).  1992. Drinking water; national primary drinking water regulations-synthetic organic chemicals and inorganic chemicals; national primary drinking water regulations implementation. Fed. Regist. 57(138):31797. EPA (U.S. Environmental Protection Agency). 1996. Proposed guidelines for carcinogen risk assessment. Notice.  Fed. Regist. 61(79):1795918011.