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National Research Council (US) Subcommittee to Update the 1999 Arsenic in Drinking Water Report. Arsenic in Drinking Water: 2001 Update. Washington (DC): National Academies Press (US); 2001.

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Arsenic in Drinking Water: 2001 Update.

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6Hazard Assessment

After completing a hazard identification and dose-response assessment, it is important to place the conclusions of the assessment in the context of similar analyses and in the context of a real-world situation to ensure that the risk estimates are reasonable in view of available information. Therefore, this chapter will summarize the findings of the subcommittee, compare the results of the subcommittee's dose-response assessment with those of the previous NRC (1999) subcommittee and EPA (2001), and, finally, examine whether the estimated risks are plausible when considered in the context of the U.S. population.

FINDINGS OF THE SUBCOMMITTEE

There is increasing evidence that chronic exposure to arsenic in drinking water may be associated with an increased risk of hypertension and diabetes. The existing studies from Taiwan and Bangladesh, discussed in Chapter 2, have observed substantial increases in the risk of these medical conditions at levels of arsenic exposure that are within one to two orders of magnitude of the lower levels of current regulatory concern in the United States. Pending further research that characterizes the dose-response relationship for these end points, the magnitude of possible risk that exists at low levels is nonquantifiable. Nevertheless, because these end points are common causes of morbidity and mortality, even small increases in relative risk at low dose could be of considerable public-health importance. This potential impact should be qualitatively considered in the risk-assessment process.

A sound and sufficient database exists on the carcinogenic effects of arsenic in humans. The main end points for a quantitative risk assessment following exposure to arsenic in drinking water are lung and bladder cancers. The human data from southwestern Taiwan used by EPA in its risk assessment remain the most appropriate for determining quantitative risk estimates. Human data from more recent studies provide additional information for use in the risk assessment. Based on some of these studies, the subcommittee recommends using an external comparison population when analyzing the earlier studies from southwestern Taiwan, rather than comparing high- and low-exposure groups within the exposed population, because of concerns regarding probable exposure misclassification in the low-exposure villages within the data set and because of new data from southwestern Taiwan that suggest that confounding is unlikely. The data on the mode of action of arsenic do not indicate what form of extrapolation should be used below the exposure range of human data. The observed data should be modeled using a biologically plausible model form that best fits the data to determine a 1% effective dose (ED01). The subcommittee used an additive Poisson model with a linear term in dose for the southwestern Taiwan cancer data. The dose-response relationship should be extrapolated linearly from the ED01 to zero. Because the human data include exposures to arsenic concentrations relatively close to some U.S. exposures, the distance of extrapolation is very small—less than 1 order of magnitude.

The subcommittee calculated ED01s based on the southwestern Taiwanese data (Chen et al. 1985, 1992; Wu et al. 1989), the Chilean data (Ferreccio et al. 2000), and the northeastern Taiwanese data (Chiou et al. 2001). It calculated cancer risk estimates for the southwestern Taiwanese data (Chen et al. 1985, 1992; Wu et al. 1989), and the Chilean data (Ferreccio et al. 2000) discussed below. Cancer risks were not estimated for northeastern Taiwan (Chiou et al. 2001) because of instability of the model calculated with the small number of cases in that study.

COMPARISONS OF RESULTS OF DOSE-RESPONSE ASSESSMENTS

Estimates of Effective Dose for a 1% Response: ED01

Doses of an agent associated with the onset of a defined rate of observable response in a study population (often termed ED01 when referring to a response rate of 1%) can be useful in several key respects in risk assessment. The ED01 can be used as a point of departure for extrapolation to lower doses (typically to the origin) when insufficient data exist to characterize the shape of the dose-response curve in a region. They can also be used to assess a margin of exposure (MOE) between a dose with observed adverse effects and the level of exposure that exists in the general population. A MOE is calculated by dividing the dose associated with a defined level of response, such as a 1% (ED01) or 10% (ED10) response in animal or epidemiological studies, by the actual or projected human exposures (EPA 1996) —deciding which level of response to use (e.g., 1% or 10%) is a policy choice that depends, in part, on the size and quality of the epidemiological or animal data sets available. Therefore, the smaller the MOE is for a given population, the closer the population exposures are to exposures shown to have an adverse effect. The MOE can provide risk managers with information about the extent of apparent protection for the population. The MOE approach is complementary to more traditional approaches for determining a safe level of exposure, each approach providing different information to the risk managers (Presidential/Congressional Commission on Risk Assessment and Risk Management 1997a,b). Because the human epidemiological data set for arsenic encompasses exposure levels close to those for which the subcommittee calculated ED01s, the subcommittee elected to present its ED01s rather than ED10s used in EPA's margin-of-exposure analyses.

Table 5–3 presents the ED01s estimated by the subcommittee (based on mortality or incidence data, depending on the study) for the Chilean data (Ferreccio et al. 2000), the northeastern Taiwanese data (Chiou et al. 2001), and the southwestern Taiwanese data (Chen et al. 1985, 1992; Wu et al. 1989). Those values were estimated using a number of statistical models to fit the data, including additive and multiplicative models using linear or logarithmic terms in dose. The ED01s were estimated using the published or calculated relative risk values and a modification of the BEIR IV (NRC 1988) formula, as described in Chapter 5. Despite the variability, it is evident that most of the ED01s are less than a factor of 10 higher than the current U.S. maximum contaminant level (MCL) of 50 µg/L.

The subcommittee determined ED01s (i.e., the dose at which there is a 1% response in the study population) for various studies using a number of statistical models. For example, the estimated ED01s from the Chilean study on lung cancer ranged from 5 to 27 µg/L, depending on the exposure data used.

The previous Subcommittee on Arsenic in Drinking Water estimated ED01s of 404 to 450 µg/L, depending on the model used, for arsenic and male bladder cancer mortality. Those values are approximately within the range of ED01s estimated by this subcommittee. However, because the ED01 values reported by the current and prior subcommittees were derived using different biostatistical approaches, they are not directly comparable. The ED01 values in NRC (1999) reflect a 1% increase relative to background cancer mortality in Taiwan, whereas the current subcommittee's approach, using a modification of the BEIR IV analysis (NRC 1988), reports ED01s based on a 1% increase relative to the background cancer mortality in the United States. This is an important difference because the background rates for lung and bladder cancer are substantially different between Taiwan and the United States. Background rates for lung cancer in the United States are approximately 3-and 2.3-fold higher than in Taiwan for females and males, respectively; and bladder cancer risks are approximately 1.4- and 3-fold higher in females and males, respectively, in the United States when compared to Taiwan.

Cancer Risk Estimates

The subcommittee presents the theoretical lifetime excess cancer risks for lung and bladder cancer incidence for the U.S. population (females and males calculated separately) at fixed arsenic concentrations in drinking water of 3, 5, 10, and 20 µg/L. Table 6–1 presents the maximum-likelihood estimates (MLEs) of the risk of bladder and lung cancer combined based on the data from southwestern Taiwan. Estimates calculated using the U.S. background cancer incidence data or Taiwanese background cancer incidence data are presented. The U.S. background cancer incidence data is taken from SEER (2001). The Taiwanese background cancer incidence data were estimated by multiplying the subcommittee's corresponding U.S. lifetime incidence rate (Tables 5–7 and 5–8) by the ratio of the Taiwanese annualized rate (You et al. 2001) to the U.S. annualized rate (Ferlay et al. 2001). The relatively small confidence limits around the MLE (+/− less than 12% of the MLE) reflect the relatively large sample size, and they are not indicative of the true uncertainty associated with the risk assessment discussed in Chapters 4 and 5. The MLEs of the lifetime excess risks for combined lung and bladder cancer incidence for females range from 9 per 10,000 from exposure to drinking water with arsenic at 3 µg/L to 60 per 10,000 from exposure to drinking water with arsenic at 20 µg/L. The corresponding risk estimates for males are 11 to 72 per 10,000. Those values are estimates of the combined lifetime excess risk of lung and bladder cancer (incidence) in a given population following lifetime exposure to arsenic in drinking water at the given concentration.

TABLE 6–1. Theoretical Maximum-Likelihood Estimates of Excess Lifetime Risk (Incidence per 10,000 people) of Lung Cancer and Bladder Cancer for U.S. Populations Exposed at Various Concentrations of Arsenic in Drinking Water.

TABLE 6–1

Theoretical Maximum-Likelihood Estimates of Excess Lifetime Risk (Incidence per 10,000 people) of Lung Cancer and Bladder Cancer for U.S. Populations Exposed at Various Concentrations of Arsenic in Drinking Water.

As presented in Chapter 5, the subcommittee used data from a study performed in northern Chile (Ferreccio et al. 2000) to estimate the theoretical lifetime excess risk of incident lung cancer in U.S. males and females at arsenic concentrations in drinking water of 3, 5, 10, and 20 µg/L. Using the peak period of arsenic exposure in Chile from 1958 to 1970 as a dose metric, the resulting estimates for excess lung cancer incidence in the United States were 3 to 4 times higher than the risks derived from the Taiwanese data. In contrast, when the dose metric used in the Chilean data was the average arsenic concentration in drinking water from 1930 to 1994, the corresponding risk estimates were an order of magnitude higher.

The previous Subcommittee on Arsenic in Drinking Water presented lifetime excess cancer risk estimates for bladder cancer mortality in males based on its analyses of the southwestern Taiwanese data (Chen et al. 1985, 1992; Wu et al. 1989). Some of those risk estimates are presented in Table 5–1. Those risks were estimated using an external comparison population and a multiplicative linear model. At an arsenic concentration of 50 µg/L of drinking water, the excess risk of bladder cancer mortality for males was estimated to be 10 to 15 per 10,000 (NRC 1999). Assuming linearity and dividing by 5, that corresponds to a mortality risk estimate of 2 to 3 per 10,000 at 10 µg/L. If the U.S. mortality rate for bladder cancer is 20% (SEER 2001), that corresponds to an estimated risk of bladder cancer incidence of 10–15 per 10,000. Using the southwestern Taiwanese data, this subcommittee's estimate for lifetime excess bladder cancer incidence in males in the United States at an arsenic concentration of 10 µg/L is 23 per 10,000 (see Table 6–1). Therefore, although some analytical approaches were different, the estimates for bladder cancer risk in males for arsenic at 10 µg/L of drinking water determined by the subcommittee in this report are generally consistent with those presented in the previous NRC report.

As discussed in Chapter 5, EPA did not present theoretical lifetime excess cancer risk estimates for arsenic in drinking water in its notices in the Federal Register (2000, 2001). The risk estimates it presents (EPA 2001) are adjusted for the occurrence of arsenic in U.S. drinking water; consideration of such an adjustment is beyond the charge to this subcommittee. It is not possible to directly compare the theoretical lifetime cancer risks estimated by this subcommittee with those presented by EPA. The different assumptions used by EPA (2001) and this subcommittee are presented in Table 6–2.

TABLE 6–2. Summary of Assumptions Used by EPA and the Subcommittee for Dose-Response Analyses and Their Impact on the EPA's Risk Estimates Relative to the Subcommittee's Risk Estimates.

TABLE 6–2

Summary of Assumptions Used by EPA and the Subcommittee for Dose-Response Analyses and Their Impact on the EPA's Risk Estimates Relative to the Subcommittee's Risk Estimates.

The subcommittee did, however, use a linear extrapolation from the ED01s estimated in the analysis on which EPA based its risk estimates (Morales et al. 2000) to estimate the theoretical lifetime excess bladder and lung cancer risks at 3, 5, 10, and 20 µg/L, presented in Table 5–2. Thus, the subcommittee compared its risk estimates with those estimates calculated from the published analyses (Morales et al. 2000) on which EPA based its risk estimates (Table 5–2). The subcommittee notes, however, that the estimates in Table 5–2 are not adjusted for water consumption or arsenic in food in the same manner as used by EPA, nor by this subcommittee in its analysis in Chapter 5. (The adjustments used by EPA for food and water consumption would decrease the risk estimates.) However, even without those adjustments, the risk estimates on which EPA based its analyses are lower than this subcommittee's estimates, regardless of whether the U.S. or Taiwanese background cancer rates are used to estimate the risks. Several factors contribute to that difference. Unlike the subcommittee's estimates, EPA's analyses were based on estimates that were calculated without using an external comparison population. The subcommittee also used a different statistical method than EPA to estimate lifetime cancer risks. The subcommittee has presented lifetime excess cancer risk estimates calculated using either the U.S. or the Taiwanese background rates; Morales et al. (2000) estimated the ED01s using Taiwanese background rates. The magnitude of the difference between the estimates can be seen in Table 6–1. In addition, the method the subcommittee used to adjust for arsenic in food and its assumptions regarding water intake in the U.S. and Taiwanese populations were different from those used by EPA in its analyses.

It should be noted that the subcommittee was split on whether using the U.S. background rates was preferable to using the Taiwanese background rates for estimating arsenic risks in the United States. Some members of the subcommittee felt strongly that using U.S. background rates was the preferred approach, while others felt that there was not sufficient justification to select one set of background rates over the other, and that both should be presented. Thus, the results from both approaches are presented in Table 6–1. The subcommittee agreed, however, that if there was a multiplicative interaction between a complex array of risk factors, including smoking, that establish the background rates, then using the U.S. background cancer incidence rates would be preferred over the Taiwanese background rates for estimating arsenic cancer risks in the U.S. population.

PLAUSIBILITY OF CANCER RISK ESTIMATES

Upon completion of an assessment of the potential health effects of an environmental contaminant, it is wise to compare the results of the assessment with a real-world situation—that is, the adverse health effects observed among the people most exposed to the contaminant. The key factors triggering public-health concern regarding arsenic in drinking water have been the high incidences of different types of cancer in populations exposed to increased concentrations of arsenic in drinking water (greater than 100 µg/L) in Taiwan, Chile, and Argentina. The cancer with the highest increases in relative risk in these countries is cancer of the bladder.

It has been suggested that, if the risks of bladder cancer from arsenic in drinking water were indeed as high as estimated in this report (see Table 6–1), high cancer rates would have been anticipated in areas of the United States with increased concentrations of arsenic in groundwater, and these high rates would have readily attracted public-health attention. Some simple calculations demonstrate how risk estimates for low-level arsenic exposure in this report might be difficult to detect by observing geographical differences in cancer incidence or mortality. To illustrate that point, the subcommittee used its risk estimate of 45 per 10,000 for bladder cancer incidence in U.S. males (based on the Taiwanese data, U.S. cancer incidence data, and a ratio of 3 for water ingestion on a per-body-weight basis for the Taiwanese population compared with the U.S. population) exposed to arsenic at a concentration of 20 µg/L (Table 6–1). The lifetime risk of being diagnosed with bladder cancer in U.S. males is 3.42% for the period of 1996–1998 (or 342 per 10,000) (SEER 2001). An increased risk of 45 per 10,000 over a background risk of 342 cases in 10,000 males would be difficult to detect. In terms of bladder cancer mortality, if it is assumed that only about one in five bladder cancer cases in the United States results in death (the ratio of mortality to incidence is approximately 20% for U.S. males, SEER 2001), a lifetime excess risk for mortality from bladder cancer in U.S. males is about 9 in 10,000 following lifetime exposure to arsenic in drinking water at 20 µg/L. The subcommittee further explored how that risk contributes to overall U.S. mortality for bladder cancer. Lifetime mortality for bladder cancer in the United States for males is 0.72% (72 per 10,000) for the period of 1996–1998 (SEER 2001). That increase in mortality risk of 9 per 10,000 would be difficult to detect against that background rate of 72 per 10,000. Indeed, it would represent only about 13% of the total risk of bladder cancer mortality. Furthermore, the denominator of the risk estimate for arsenic assumes that all 10,000 individuals are at risk (e.g., all consume arsenic at 20 µg/L of their drinking water for a lifetime). Detection is further complicated by the variability in the actual exposure to arsenic in drinking water (not considered by this subcommittee), the unknown distribution of other risk factors (especially smoking), and the mobility of the U.S. population. However, if the risks for arsenic-related bladder cancer were higher than the estimate used in this example, then bladder cancer incidence and mortality at exposures of 20 µg/L would be proportionately higher and thus might be easier to detect in a population. Because background lung cancer mortality is almost 10-fold greater than bladder cancer, it would be even more difficult to demonstrate an association between low concentrations of arsenic in drinking water and lung cancer risk. Therefore, although the subcommittee's risk estimates are of public-health concern, they are not high enough to be easily detected in U.S. populations by comparing geographical differences in the rates of specific cancers with geographical differences in the concentrations of arsenic in drinking water.

In accordance with its charge, the subcommittee has not conducted an exposure assessment and subsequent risk characterization and risk assessment. The theoretical lifetime excess cancer risks estimated by the subcommittee and presented in this report, however, should be interpreted in a public-health context using an appropriate risk-management framework, such as that proposed by the Presidential/Congressional Commission on Risk Assessment and Risk Management (1997a,b).

SUMMARY AND CONCLUSIONS

  • The subcommittee's evaluation and analyses of the data from southwestern Taiwan indicate that the lifetime excess cancer risks in the United States for bladder and lung cancers combined at arsenic concentrations in drinking water between 3 and 20 µg/L (ppb) are estimated to be between 9 and 72 per 10,000 people based on U.S. background cancer incidence data. (The corresponding range based on Taiwanese background cancer incidence data is 4 to 24 per 10,000.) These estimates can be interpreted in light of EPA's stated goals for public-health protection (EPA 1992).
  • Depending on the dose metric used in the study, excess risk estimates for cancer in the United States derived from a recent investigation in Chile are either similar to or higher than risk estimates derived from the Taiwanese data.
  • Although these risk estimates are high, they would not be detected in U.S. populations by comparing geographical differences in the rates of specific cancers with geographical differences in the concentration of arsenic in drinking water.

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Copyright 2001 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK223673
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