Detection of excess arsenic-related cancer risks. (Correspondence).

Morales et al. (1) reanalyzed data from a study in an arseniasis-endemic area of Taiwan (2-5). Cancer risks for low-level waterborne arsenic exposures were estimated using a variety of statistical models with and without a comparison population. Morales et al. (1) concluded that although the shape of the exposure-response curve is uncertain at low levels of arsenic exposure, over a lifetime, one out of every 100-300 people who consume drinking water containing 0.050 mg/L arsenic may suffer an arsenic-related cancer (lung, bladder, or liver cancer) death. Smith et al. (6) predicted similar levels of arsenic risk.

Morales et al. (1) noted that despite the considerable uncertainties in the underlying data, the risks are "sobering." However, they also concluded that the low concentrations of waterborne arsenic in the United States make it unlikely that such risks would be detected by epidemiologic studies (1), although they presented no calculations to support this conclusion. In reviewing the results of Lewis et al. (7) in the Millard County, Utah, study, the U.S. Environmental Protection Agency made a similar statement to the National Research Council Subcommittee to Update the 1999 Arsenic Report (8), although without listing their assumptions or showing a power calculation.

In the Millard County, Utah, study, Lewis et al. (7) followed a cohort of 4,058 individuals exposed to waterborne arsenic at levels of 0.014-0.166 mg/L. Expected death rates were calculated using Utah death rates for the same periods. No elevated death rates from bladder, lung, or liver cancers were observed for those who died through November 1996, and death rates were not higher in people with the highest levels of drinking water arsenic. In fact, for bladder and lung cancers, two cancer sites thought to have the strongest association with arsenic exposure, the authors observed 39 deaths when 63.5 were expected (p < 0.05). These findings are not consistent with the postulated excess risk for lung and bladder cancers, nor do they support the concerns that epidemiologic studies in the United States are not sufficiently powerful to detect the postulated arsenic-related health risks.

One of the problems in interpreting claims that studies in the United States lack the power to detect expected health risks is that these claims are made without presenting the assumptions and power calculations. Authors may assume that compliance with the 1946 drinking water arsenic standard for interstate carrier water systems of 0.050 mg/L (9) is complete and that no populations consume water above that level. This is unfortunately not correct. Several scientists have claimed that arsenic health effects studies cannot be conducted in the United States because of high rates of migration; however, critics do not generally consider the assumed latency of the effect. For example, if the latency is 20-30 years, as might be expected if arsenic is a primary cause of cancer, the effect of migration is likely to be large. Alternatively, if only exposures that occur late in life are important and the latency is 10-15 years, as might be expected if arsenic is a late-stage promoter of cancer (10-12), the effect of latency might be small. Older people have lower rates of migration than younger people.

Our goal in this letter was to estimate the sample size required to test the arsenic risk predicted by Morales et al. (1) in the United States. According to the National Cancer Institute Surveillance, Epidemiology, and End Results Program (13), the average lifetime risk of dying from lung cancer for males and females in the United States is approximately 6.2%, whereas the average lifetime risk of dying from bladder cancer is approximately 0.46%. We made the following assumptions for two hypothetical studies--one with a population exposed to 0.100 mg/L and one with a population exposed to 0.050 mg/L:

* The added lifetime risk of death is 1 in 100 from consuming 0.050 mg/L and 1 in 50 from consuming 0.100 mg/L arsenic in drinking water.

* The arsenic-related cancer death risks are equally divided between added bladder and lung cancer death risks.

* We assume that there is an equal number of people in the cohort at background arsenic levels (0.050 mg/L) and at the high waterborne arsenic concentration (0.100 mg/L).

We calculated sample sizes for a cohort study using a published computer program for power and sample size calculation (14). Based on the above lifetime risks of death from bladder and lung cancer, a power of 0.80, and a p-value of 0.05, we calculated the sample sizes presented in Table 1. The sample sizes were estimated based on relative risks presented by Morales et al. (1).

The sample sizes presented in Table 1 are based on an assumed lifetime cancer death risk for the general population. Lewis et al. (7), in their Utah study, included a cohort of presumed nonsmokers. Whether or not arsenic health risks are higher for smokers (15) is an important consideration when designing a study. The required sample size is smaller if the added risks are the same for smokers and nonsmokers, and the study could be restricted to nonsmokers, as was generally the case for Lewis et al.'s Utah cohort (7). Alternatively, if a study of smokers is required (15), the background risk of cancers is much higher and the required sample size is much larger.

In addition, small relative risks, such as those for lung cancer, are difficult to study because of the potential effects of uncontrolled confounding. Investigators who believe that U.S. populations cannot be studied may have reached that conclusion because they considered the combined risks of bladder and lung cancer. We would agree that a study of current lung cancer risks in the general population could be problematic for water arsenic exposures of [less than or equal to] 0.050 mg/L. However, at higher arsenic exposures a study might be feasible because the sample size would be considerably less.

As mentioned above, specific assumptions about the magnitude of migration are important because loss of cohort members through migration would require an increased sample size to offset the expected losses. It is also essential to clearly specify the goal of the epidemiologic study and the outcomes of interest. Studies to better understand, the underlying mechanisms for how arsenic causes or promotes the risk of cancer may require a different design than a study to validate or test the predicted increased health risks from waterborne arsenic exposure.

Floyd Frost
Lovelace Respiratory Research Institute
Albuquerque, New Mexico
E-mail: [e-mail]
Gunther Craun
G.F. Craun and Associates
Staunton, Virginia
Kenneth G. Brown
Kenneth Brown Inc.
Chapel Hill, North Carolina
Table 1. Sample sizes for each cohort.

                   RR
                 bladder   Sample   RR lung   Sample
Exposure level   cancer     size    cancer     size

0.050 mg/L        1.72      7,600    1.05     77,228
0.100 mg/L        3.17      1,371    1.16      8,051

RR, relative risk.

REFERENCES AND NOTES

(1.) Morales KH, Ryan L, Kuo T-L, Wu M-M, Chen C-J. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect 108:655-661 (2000).

(2.) Chen CJ, Kuo TL, Wu MM. Arsenic and cancers [Letter] Lancet 2:414-415 (1988).

(3.) Wu MM, Kuo TL, Hwang YH, Chen CJ. Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases Am J Epidemiol 130:1123-1132 (1989).

(4.) We MM, Kuo TL, Hwang YH, Chen CJ. Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular disease. Am J Epidemiol 130:1123-1132 (1989).

(5.) Chen CJ, Chen CW, Wu MM, Kuo TL. Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br J Cancer 66:888-892 (1992).

(6.) Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, Wood R, Kosnett MJ, Smith MT. Cancer risks from arsenic in drinking water. Environ Health Perspect 97:259-267 (1992).

(7.) Lewis DR, Southwick JW, Ouillet-Hellstrom R, Rench J, Calderon RL. Drinking water arsenic in Utah: a cohort mortality study. Environ Health Perspect 107:359-365 (1999).

(8.) National Research Council. Arsenic in Drinking Water. Washington, DC:National Academy Press, 1999.

(9.) U.S. PHS. Public Health Service Drinking Water Standards. U.S. Public Health Service Publication 956. Washington, DC:U.S. Government Printing Office, 1962.

(10.) Brown CC, Chu KC. Implications of the multistage theory of carcinogenesis applied to occupational arsenic exposure. J Natl Cancer Inst 70:455-463 (1983).

(11.) Basu A, Mahata J, Gupta S, Girl AK. Genetic toxicology of a paradoxical human carcinogen, arsenic: a review. Mutat Res 488:171-194 (2001).

(12.) Wang Z, Rossman TG. The carcinogenicity of arsenic. In: Toxicology of Metals (Chang LW, Magos L, Suzuki T, eds). Boca Raton, FL:CRC Press, 1996,221-229.

(13.) National Cancer Institute. SEER Cancer Statistics Review, 1973-1997. Available: http://www.seer.cancer.gov/ Publications/CSR1973_1997 [cited 30 November 2001].

(14.) Dupont WD, Plummer WD Jr. Power and sample size calculation. A review end computer program. Controlled Clinical Trials 11:116-128 (1990).

(15.) Hertz-Picciotto I. Interactions between arsenic and other exogenous exposures in relation to health outcomes. In: Arsenic Expsosure and Health Effects: Proceedings of the Fourth International Conference on Arsenic Exposure and Health Effects, July 18-22, 2000, San Diego, California (Chappell WR, Abernathy CO, Calderon RL, eds). Oxford:Elsevier Science, 2001.