Cancer Risks Associated with Arsenic in Drinking Water

Environ Health Perspect 115:2-8 (2007). doi:10.1289/ehp.9927 available via http://dx.doi.org [Online 19 June 2007]

Referencing: Arsenic Cancer Risk Confounder in Southwest Taiwan Data Set

Arsenic in drinking water is a worldwide problem, and studies in southwest Taiwan (Chen et al. 1985, 1988; Tseng 1977; Tseng et al. 1968; Wu et al. 1989) have been the bases of many cancer risk assessments. In a recent reanalysis of the data, Lamm et al. (2006) found "township" a confounder. Specifically, of six townships, only three (2, 4, and 6) showed positive dose–response relationships with arsenic exposure, and three others (0, 3, and 5) demonstrated cancer risks independent of arsenic exposure. The authors speculated that the confounding was related to blackfoot disease (BFD), a peripheral vascular disease associated with arsenic ingestion (Ch'i and Blackwell 1968; Tseng 1977), but they did not know the identities of the individual townships.

On the basis of data collected in previous studies (Brown et al. 1997, 2000; Kuo 1968), townships 0, 2, 3, 4, 5, and 6 (Lamm et al. 2006; National Research Council 1999) can be identified as I-chu, Pu-tai, Hsieh-chia, Yen-shui, Pei-men, and Hsia-ying. With the highest prevalence of BFD in the country, I-chu, Pu-tai, Hsieh-chia, and Pei-men are generally referred as the "BFD-endemic area." Therefore, the "township factor" might be indeed related to BFD, because all three of the townships affected by this factor were in the endemic area. Pu-tai was the only BFD-endemic township not affected by the factor, and two of the five villages included in the analysis are in the northern part of the township, where the prevalence was low; this might be why it appeared to be a nonendemic township.

Lamm et al. (2006) further speculated that the township factor was a reflection of a selection bias because the water sampling was focused on villages with high BFD prevalence. Although the sampling was related to BFD cases, the chance of a bias occurring in the selection of villages by Wu et al. (1989) was small because they included almost all of the villages covered in the survey by Kuo (1968) in the six townships.

Lamm et al. (2006) claimed that their finding of a threshold-like model indicating no increase of bladder cancer with exposure levels < 150 µg/L was consistent with results from toxicologic studies and other epidemiologic data from the United States, Argentina, and northeastern Taiwan. Actually, it is also consistent with studies on bladder cancers covering the whole of Taiwan (Guo et al. 1997), southwest Taiwan only (Guo 1999; Guo and Tseng 2000), and another reanalysis of the same data (Morales et al. 2000; Stöhrer 2001). Furthermore, their results are consistent with studies on lung (Guo 2004) and skin (Guo et al. 1998, 2001) cancers. Whereas Lamm et al. (2006) stated that low-dose villages showed a negative dose–response curve for bladder and lung cancers, they reported a positive slope (1.275) in their Figure 2; this is likely to be an error. In previous studies, exposures between the detection limit (0.001 ppm) and 0.01 ppm had a significant negative effect on transitional cell cancer of the kidney and on skin cancer in both sexes; the negative effect on bladder cancer was also significant in women, but not in men (Guo et al. 1994, 1998).

Even if the dose–response relationship fits a threshold-like model, using the median arsenic level in each village as the exposure indicator might not generate accurate risk estimates because villages with similar median arsenic levels can have very different distributions of exposures. For example, villages 0-G and 3-5 had very close median arsenic levels, 0.030 and 0.032 ppm, respectively (Lamm et al. 2006); if there was a threshold at 0.150 ppm, as proposed by Lamm et al., one would expected an increased risk in village 0-G, where the residents had exposure levels up to 0.770 ppm, but not in village 3-5, where all residents were assigned the exposure level of 0.032 ppm. In fact, previous studies on urinary cancers in Taiwan suggested an inflection point > 0.32 ppm (Guo 1999; Guo et al. 1994, 1997). If 0.32 ppm is adopted as the cut-off, villages 0-G, 0-E, 0-I, and 3-Q would be placed in the "low-dose villages" group, although they should have increased risks because some of the residents had exposures above the threshold. These four villages were in the township group "0, 3, and 5," which Lamm et al. regarded as being affected by the township factor, but no villages in the other township group (townships 2, 4, and 6) had this problem. Therefore, misclassifications might also contribute to the township factor; a different choice of exposure indicator may help clarify the uncertainties.

The author declares he has no competing financial interests.

References

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Brown KG, Kuo T-L, Guo H-R, Ryan LM, Abernathy CO. 2000. Sensitivity analysis of EPA's estimates of skin cancer risk from inorganic arsenic in drinking water. Hum Ecol Risk Assess 6:1055–1074.

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Cancer Risks Associated with Arsenic: Lamm et al. Respond

Environ Health Perspect 115:2-8 (2007). doi:10.1289/ehp.9927R available via http://dx.doi.org [Online 19 June 2007]

Figure 1. SMRs for bladder and lung cancer by median village well arsenic level for the 42 villages in the six townships in the southwest Taiwan study of Wu et al. (1989) with linear regression analysis by township. SMR = 100 is the level of no increased risk with southwest Taiwan as the reference population. Townships: 0, I-chu; 2, Pu-tai; 3, Hsieh-chia; 4, Yen-shui; 5, Pei-men; 6, Hsia-ying.

We thank Guo for his comments and additional information. As indicated by Guo in his letter, three of the six southwest Taiwan townships in in the internal cancer study of Wu et al. (1989) (townships 2, 4, and 6) show significant dose–response relationships for bladder and lung cancer standardized mortality ratios (SMRs) with respect to the median village well arsenic levels, whereas the other three townships (townships 0, 3, and 5) show high background rates for these cancers and no significant dose–response relationship with village arsenic level. Figure 1 demonstrates that the township-specific inverse linear regression lines for townships 2, 4, and 6 all meet the no increased risk level of SMR = 100 (inflection point) at arsenic exposure levels of approximately 125–150 µg/L, which is consistent with a threshold model. That is the same inflection point range seen for skin cancer prevalence in southwest Taiwan (Byrd et al. 1996) and in Inner Mongolia (Lamm et al., in press).

In contrast, the data for townships 0, 3, and 5 are indicative of high background bladder and lung cancer rates (SMRs > 250 at low arsenic levels) that are independent of the arsenic level. We inferred from these analyses the presence of a second (nonarsenic) carcinogenic factor and speculated that it might be related to the nonarsenic etiological factors for blackfoot disease, a condition uniquely reported for this area. On the basis of ongoing analyses, we are currently less inclined to believe that the "township" factor is related to blackfoot disease.

Guo inquires whether exposure heterogeneity within the villages has affected the accuracy of the risk estimates based on the village medians and suggests using alternative exposure indicators. We have examined this. The analytic fits to the models demonstrated in Figure 1 are quite similar whether the median or the mean is used as the summary exposure indicator for the villages; Table 1 shows the robustness of the arsenic concentration of the inflection point with the use of a variety of exposure indicators. The table demonstrates that the inflection point for this group of townships and its 95% confidence interval (CI) for these townships is also robust, based on 20 villages. The lower confidence limit of the inflection point is 40 µg/L arsenic.

Table 1.

In spite of the uncertainties in the exposure assessments, the analytic findings are quite robust. They best fit a nonlinear or threshold carcinogenic risk model for arsenic with an inflection point at 150 µg/L (Taiwan) with the presence of at least one additional confounding risk factor. Further analysis will follow the deciphering of the village code. However, interpretation should be cautious because the Wu et al. (1989) study contained data for only about one-third of the villages in the six-township area.

S.H.L. is a consultant in medical epidemiology and has clients (plaintiff and defendant) involved in arsenic issues before regulatory agencies and in litigation. The other authors declare they have no competing financial interests.

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Ch'i IC, Blackwell RQ. 1968. A controlled retrospective study of blackfoot disease, an endemic peripheral gangrene disease in Taiwan. Am J Epidemiol 88(1): 115–129.

Lamm SH, Engel A, Penn CA, Chen R, Feinleib M. 2006. Arsenic cancer risk confounder in southwest Taiwan data set. Environ Health Perspect 114:1077–1082; doi:10.1289/ehp.8704 [Online 13 January 2006].

Lamm SH, Luo ZD, Bo FB, Zhang GY, Zhang YM, Wilson R, et al. In press. An epidemiologic study of arsenic-related skin disorders and skin cancer and the consumption of arsenic-contaminated well waters in Huhhot, Inner Mongolia. Hum Ecol Risk Assess.

National Research Council. 1999. Addendum to Chapter 10. Table A10-1. Internal cancer data from arsenic-exposure studies conducted in Taiwan region endemic to blackfoot disease. In: Arsenic in Drinking Water. Washington, DC:National Academy Press, 308–309.

Tseng WP, Chu HM, How SW, Fong JM, Lin CS, Yeh S. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Natl Cancer Inst 40(3): 453–462.

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