The association between arsenic exposure from drinking water and cerebrovascular disease mortality in Taiwan

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The association between arsenic exposure from drinking water and cerebrovascular disease mortality in Taiwan Tain-Junn Cheng a,b,c,d, Der-Shin Ke b, How-Ran Guo a,e,f,g,* a

Department of Environmental and Occupational Health, Medical College, National Cheng Kung University, 138 Sheng Li Road, Tainan 704, Taiwan b Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan c Department of Occupational Medicine, Chi Mei Medical Center, Tainan, Taiwan d Department of Occupational Safety, College of Environment, Chia Nan University of Pharmacy and Science, Tainan, Taiwan e Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan f Sustainable Environment Research Center, National Cheng Kung University, Tainan, Taiwan g Center for Occupational and Environmental Health and Preventive Medicine, National Cheng Kung University, Tainan, Taiwan

article info

abstract

Article history:

Background: Chronic arsenic exposure is associated with a variety of diseases, including

Received 16 January 2010

cancer, peripheral vascular disease, and diabetes. However, its association with cerebro-

Received in revised form

vascular diseases (CVD) has not yet been resolved. The aim of this study is to explore this

20 April 2010

association in Taiwan using nation-wide data.

Accepted 21 May 2010

Materials and methods: We analyzed mortality data in Taiwan from 1971 to 2005 and choose

Available online 1 June 2010

two geographic areas with populations suffering from chronic exposure to arsenic in drinking water for study, the blackfoot disease endemic area (BFDEA) in the southwest and

Keywords:

Lan-Yang Basin (LYB) in the northeast parts of Taiwan. The Chia-Yi and Tainan Counties,

Cerebrovascular disease

which surround the BFDEA, and the nation of Taiwan as a whole were used as reference

Arsenic

populations. Direct standardized mortality rates and gender-specific indirect standardized

Blackfoot disease endemic area

mortality ratios (SMRs) were calculated for the four populations.

Mortality study

Results: The direct standardized mortality rate for CVD in Taiwan decreased from 2.46/103 person-year in 1971 to 0.63/103 person-year in 2005, and women had significantly lower mortality than men (SMR ¼ 0.80; p < 0.05). The CVD mortality rates of populations with chronic arsenic exposure were significantly higher than the reference populations (SMR ranging from 1.06 to 1.09 in men and 1.12 to 1.14 in women; p < 0.05). The BFDEA had higher CVD mortality rates than the LYB, with SMR ¼ 1.05 ( p < 0.05) in men and SMR ¼ 1.04 ( p ¼ 0.05) in women. Conclusion: In Taiwan, while CVD mortality decreased in both genders between 1971 and 2005, chronic arsenic exposure from drinking water was associated with increased risks of CVD. ª 2010 Elsevier Ltd. All rights reserved.

* Corresponding author at: Department of Environmental and Occupational Health, Medical College, National Cheng Kung University, 138 Sheng Li Road, 704 Tainan, Taiwan. Tel.: þ886 6 2353535x5802; fax: þ886 6 2752484. E-mail address: [email protected] (H.-R. Guo). 0043-1354/$ e see front matter ª 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.watres.2010.05.040

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1.

Introduction

Arsenic is a naturally occurring element in the earth’s crust that can be emitted into ground water. Coal mining and smelting release arsenic, and herbicides, pesticides, and fungicides also contain it (ATSDR 2007). Arsenic-containing water is the major source of arsenic exposure for many people and is associated with diabetes, hepatitis, cancer, and cardiovascular disease in Argentina (Hopenhayn-Rich et al., 1996), Hungary (Varsanyi et al., 1991), Chile (Ferreccio et al., 2000; Rencher et al., 1977), Bangladesh (Rahman et al., 1998; Smith et al., 2000), the United States (Meliker et al., 2007; Lewis et al., 1999), and Taiwan (Guo et al., 1997). Acute arsenic intoxication from medicines and from occupational exposures may cause gastrointestinal symptoms, neuropathy (Morgan and Abernathy, 2001), and encephalopathy (Landrigm, 1992; ASTDR, 2007). Uranium miners, copper smelters, and gold mine and refinery workers with chronic exposure to inorganic arsenic are at increased risk for deaths from lung cancer (Toma´sek et al., 1994; Kusiak et al., 1993; Axelson et al., 1978; and Simonato et al., 1994), and population-based studies have also shown that chronic exposure to arsenic is associated with cancers of the pancreas, colon, liver, skin, larynx, kidney, and bladder, as well as with lymphoma (Chen et al., 1985; Rencher et al., 1977; Yeh, 1973; Tseng et al., 1968; Smith et al., 1998; Tsuda et al., 1995; and Tsai et al., 1999). Residents of an area on the southwestern coast of Taiwan, where chronic arsenic intoxication is common due to the high arsenic contents in ground water, are also at risk for an occlusive peripheral artery disease which manifests as blackfoot disease (BFD) (Tseng et al., 1968), and this area is called BFD endemic area (BFDEA). In this area, Wang et al. (2003) found a higher prevalence of cardiovascular diseases. In addition, occupational studies of copper smelters have demonstrated an increased risk of cardiovascular diseases in association with exposure to arsenic (Axelson et al., 1978). While Wu et al. (1989) observed doseeresponse relationships between chronic arsenic exposure and peripheral and cardiovascular diseases in the BFDEA in Taiwan, such a relationship was not found for CVD. However, increased prevalence of CVD was observed in the Lan-Yang Basin (LYB) (Chiou et al., 1997), another area of Taiwan where the underground water is contaminated with arsenic. Furthermore, an ecologic standardized mortality ratio analysis showed that exposure to low-to-moderate levels of arsenic in drinking water was associated with increased mortality rates for CVD in both men and women (Meliker et al., 2007). As previous studies reported inconsistent results regarding the association between chronic arsenic exposure and CVD, we conducted a study in Taiwan with an aim to clarify this issue.

2.

register deaths in a timely manner, and therefore the registry of death is comprehensive. The cause of death is coded according to the 9th Edition of the International Classification of Disease (ICD-9). In this study, we identified the number of CVD deaths (ICD-9 codes from 431 to 439) from 1971 to 2005. We limit the study to people over 35 years of age, because deaths in younger people might not involve chronic and acquired health effects of arsenic exposure. Residents of the BFDEA, which includes the Bu-Dai and Yi-Chu Townships in the Chia-Yi County and Bei-Men, Hsueh-Chia, and Yen-Shui Townships in the Tainan County (Tseng et al., 1968), and those of the LYB, which includes the Chiao-Hsi, Chuang-Wei, Wu-Chieh, and Tung-Shan Townships (Chiou et al., 1997) in the Yi-Lan County, comprised the two populations with chronic arsenic exposure. These populations were compared to two reference populations, the national population and the population of the Chia-Yi and Tainan Counties combined (CNC). The geographic locations of areas included in this study are shown in Fig. 1. A survey showed that the arsenic levels of water from artesian wells in the BFDEA ranged from 0.01 to 1.80 ppm (similar to mg/L), with a mean of 0.50 ppm, and about a half of the samples were between 0.40 and 0.70 ppm (Kuo, 1968). A survey measured arsenic levels of well water in nine villages surrounding the BFDEA and found the levels ranging from 0.001 to 0.017 ppm only (Yeh, 1963). In the LYB, a study found

Materials and methods

We used the data from the death registry system in Taiwan, which is maintained by the Department of Interior, Executive Yuan. The Taiwanese government requires residents to

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Fig. 1 e Location of studied area in Taiwan.

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that arsenic levels in the ground water ranged from undetectable (<0.00015 mg/L) to 3.59 mg/L (Chiou et al., 2001). Stratifying the populations by gender and age at intervals of 5 years, we calculated the crude mortality rate of CVD for each calendar year. We also calculated the direct standardized mortality rates using the population of Taiwan in mid-1988 as the standard population. Furthermore, we calculated genderspecific indirect standardized mortality ratios (SMRs) for the four populations. In constructing the figures, because the numbers of deaths in the areas with arsenic exposure were relatively small in each year, we calculated the 3-year moving average of the SMR and the 35-year cumulative sum to minimize the instability. We analyzed the data using Version 9.1.2 of the SAS software and performed all statistical test at the two-tailed significance level of 0.05.

3.

Results

The population, cerebrovascular deaths, and crude mortality rate (per 1000 person-year) over the 35-year study period are illustrated in Tables 1e4. In general, the mortality rate increased with age, and men had higher rates than women. The direct standardized mortality rate of CVD in Taiwan declined steadily from 2.46/103 person-year (1.39/103 person-year in men and 1.06/103 person-year in women) in 1971 to 0.63/103 person-year (0.38/103 person-year in men and 0.25/103 person-year in women) in 2005. A trend of decreasing direct standardized mortality rate of CVD in both genders was also observed in the other three areas in the study period (CNC: 2.13 to 0.67/103 person-year with 1.21 to 0.42/103 person-year in men and 0.91 to 0.25/103 person-year in women; BFDEA: 2.13 to 0.75/103 person-year with 1.19 to 0.53/103 person-year in men and 0.95 to 0.22/103 person-year in women; LYB: 2.15 to 0.71/103 person-year with 1.29 to 0.45/103 person-year in men and 0.87 to 0.26/103 person-year in women). We evaluated the differences between men and women further by comparing the SMRs over the 35-year period in each

of the four populations and found that women generally had lower CVD mortality than men. To evaluate the association between arsenic exposure from drinking water and CVD, we compared the 35-year cumulative SMRs of CVD in the arsenic exposed populations to those in the reference populations in each gender. In both genders, the SMR of CVD was higher in the two populations with arsenic exposure (BFDEA and LYB) (Table 5). When the two exposed populations were compared, we found the BFDEA had higher risks, with SMR of 1.05 (95% confidence interval [CI]: 1.01e1.10, p < 0.05) in men and SMR of 1.04 in women (95% CI: 1.00e1.09, p ¼ 0.05).

4.

Discussion

The results of our study suggest that arsenic exposure from drinking water may increase the risk of CVD. Previous epidemiologic studies in Taiwan reported inconsistent results. Wu et al. (1989) conducted a study covering 42 villages of the BFDEA and observed significant doseeresponse relationships between the arsenic levels in well water and mortality of peripheral vascular diseases and cardiovascular diseases during 1973e1986, but such a relationship was not found for CVD. However, Wang et al. (2003) compared 66,667 residents of this area to 639,667 residents of nonendemic areas of arsenic intoxication and observed higher prevalence of CVD (prevalence odds ratio ¼ 3.22, 95% CI: 2.99e3.47). As in our study, Tsai et al., (1999) used two reference populations (the Chia-Yi and Tainan Counties as the local reference and Taiwan population as the national reference) to calculate the SMRs for BFDEA during the period from 1971 to 1994. They found higher CVD in both genders using either reference. In the LYB, Chiou et al. (1997) conducted a study of 8102 residents and determined the status of CVD through home-visit personal interviews and review of hospital medical records. They observed a significant doseeresponse relationship between arsenic levels in well water and prevalence of CVD. The current study is the second that covers the LYB and the first that includes both areas of endemic arsenic intoxication

Table 1 e The population, cerebrovascular deaths, and crude rate (per 1000 person-year) from 1971 to 2005 in the blackfoot disease endemic area. Age

Male

Female

Population

Deaths

Mortality

Population

Deaths

Mortality

35e39 40e44 45e49 50e54 55e59 60e64 65e69 70e74 75e79 80e84 85þ

81,330 133,770 128,455 118,051 109,618 96,876 76,328 52,648 30,362 14,421 6335

19 68 74 121 193 308 387 373 385 260 141

0.23 0.51 0.58 1.02 1.76 3.18 5.07 7.08 12.68 18.03 22.26

25,722 73096 80,996 113266 101,564 99,729 85,541 62,179 39,251 20,548 10,827

7 22 46 91 142 208 357 425 436 334 249

0.27 0.30 0.57 0.80 1.40 2.09 4.17 6.84 11.11 16.25 23.00

Total

848,194

2329

2.75

712,719

2317

3.25

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Table 2 e The population, cerebrovascular deaths, and crude mortality rates (per 1000 person-year) in the studied areas from 1971 to 2005 in the Lan-Yang Basin. Age

Male

Female

Population

Deaths

Mortality

Population

Deaths

Mortality

35e39 40e44 45e49 50e54 55e59 60e64 65e69 70e74 75e79 80e84 85þ

122,232 100,595 134,524 121,352 102,032 96,780 77,329 54,349 32,170 14,894 6035

28 36 70 122 164 276 363 407 387 230 134

0.23 0.36 0.52 1.01 1.61 2.85 4.69 7.49 12.03 15.44 22.20

22,915 73,957 62,676 95,382 79,150 81,224 69,900 53,001 35,317 19,970 11,034

7 26 29 74 92 173 250 374 367 341 271

0.31 0.35 0.46 0.78 1.16 2.13 3.58 7.06 10.39 17.08 24.56

Total

862,292

2217

2.57

604,526

2004

3.31

in Taiwan, and our findings are in line with most previous studies. We believe that the main reason why the first study in the BFDEA (Wu et al., 1989) failed to observe a significant increase in CVD mortality associated with arsenic exposure in drinking water was that the study period was the shortest (14 years) among the mortality studies in this area, which led to the smallest study power. Our findings are also supported by studies in other countries. Meliker et al. (2007) conducted a study in Michigan, U.S.A. with a population-weighted mean arsenic level of 0.01100 mg/L and a population-weighted median of 0.00758 mg/L and observed an increase in CVD mortality in both men (SMR ¼ 1.19, 99% CI: 1.14e1.25) and women (SMR ¼ 1.19, 99% CI: 1.15e1.23). A study in Spain (Medrano et al., 2010) evaluated the association of municipal drinking water arsenic concentrations during the period 1998e2002 with mortality during the period 1999e2003 and observed an SMR of 1.04 for CVD associated with arsenic levels >0.010 mg/L in drinking water. Compared to municipalities with arsenic levels <0.001 mg/L, adjusted CVD mortality rates were increased by 0.3% (95% CI: 4.1e4.9%) in municipalities with arsenic levels between 0.001 and 0.010 mg/L and 2.6% (95% CI: 2.0e7.5%) municipalities with arsenic levels >0.010 mg/L.

In addition to exposure from drinking water, some studies have evaluated the effect of arsenic in the air on CVD. Wall (1980) analyzed mortality data for 3919 male workers of a copper smelter in northeast Sweden and found an elevated risk of 60e70% for CVD. Ja¨rup et al. (1989) followed a cohort of 3916 male Swedish smelter workers and estimated cumulative arsenic exposure for each worker. While they observed a positive doseeresponse relationship between cumulative arsenic exposure and lung cancer mortality with an overall SMR of 3.72 (95% CI: 3.04e4.50), such a doseeresponse relationship was not found for CVD or ischemic heart disease. Hertz-Picciotto et al. (2000) conducted a study of 2802 smelter workers in Washington, U.S.A. and found no excess of CVD mortality associated with arsenic exposure while excess cardiovascular mortality was observed. A study on Japan found no effect of arsenic on CVD mortality while a significant effect was observed for lung cancer. (Yoshikawa et al., 2008) A study on 2422 male workers employed three or more years in the smelter or mill observed found limited evidence of increasing CVD mortality with increasing duration and cumulative arsenic exposure (Marsh et al., 2009). In summary, these studies do not support that arsenic exposure from air may cause CVD.

Table 3 e The population, cerebrovascular deaths, and crude mortality rates (per 1000 person-year) from 1971 to 2005 in the Chia-Yi and Tainan Counties. Age

Male

Female

Population

Deaths

Mortality

Population

Deaths

Mortality

35e39 40e44 45e49 50e54 55e59 60e64 65e69 70e74 75e79 80e84 85þ

3,141,440 2,865,406 2,512,322 2,141,155 1,792,650 1,556,464 1,247,309 898,215 538,900 251,972 111,568

417 808 1348 2137 3145 4521 5894 6273 5716 3641 2194

0.13 0.28 0.54 1.00 1.75 2.90 4.73 6.98 10.61 14.45 19.67

2,900,354 2,637,581 2,305,543 1,969,914 1,662,453 1,465,617 1,205,879 895,913 586,666 320,971 177,494

174 350 684 1141 1734 2634 4210 5485 6044 4797 3640

0.06 0.13 0.30 0.58 1.04 1.80 3.49 6.12 10.30 14.95 20.51

Total

17,057,401

36094

2.12

16,128,385

30893

1.92

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Table 4 e The population, cerebrovascular deaths, and crude mortality rate (per 1000 person-year) from 1971 to 2005 in Taiwan. Age

Male

Female

Population

Deaths

Mortality

Population

Deaths

Mortality

35e39 40e44 45e49 50e54 55e59 60e64 65e69 70e74 75e79 80e84 85þ

25,303,360 22,624,894 19,715,316 16583884 13,558,917 11,452,148 9,092,834 6,623,428 4,001,999 1,861,061 847,937

3298 6365 10,601 16,113 23,525 33,190 41,895 45,322 39,226 24,721 14,532

0.13 0.28 0.54 0.97 1.74 2.90 4.61 6.84 9.80 13.28 17.14

24,400,251 21,414,793 18,083,127 14,720,629 11,756,241 9,907,815 7,903,254 5,819,979 3,823,685 2,078,032 1,201,682

1488 2895 5506 8643 12,122 17,813 26,316 33,958 36,615 29,613 23,725

0.06 0.14 0.30 0.59 1.03 1.80 3.33 5.83 9.58 14.25 19.74

Total

131,665,778

258,788

1.97

12,110,9488

198,694

1.64

In our study, the CVD SMR of men in the BFDEA was significantly higher than that in the LYB ( p < 0.05), and the increase in women was with marginal significance ( p ¼ 0.05). A most likely major reason was that the arsenic levels in drinking water in the BFDEA were higher than those in the LYB. Nonetheless, other factors might also contribute to the difference. For example, the humic acids found in the ground water in the BFDEA may lead to occlusive peripheral arterial disease when combined with arsenic in an animal study (Lu, 1990). Many factors contribute to the development of CVD, including non-modifiable (age, family history, ethnicity, and race) and modifiable ones (hypertension, hyperlipidemia, smoking, physical inactivity, obesity, diet, and diabetes mellitus). The importance of these factors varies in developing and developed countries, and arsenic in drinking water may be relatively more important in developing countries with lower prevalence of risk factors related to unhealthy life styles such as hypertension, hyperlipidemia, obesity, and diabetes mellitus. In countries like Taiwan, approximate 75% of CVD may be attributed to conventional risk factors, and drinking water, sanitation, and hygiene might contribute to 1.7% of CVD mortality (Mackay and Mensah, 2004). To evaluate an unconventional and relative small contributory factor like arsenic in drinking water in Taiwan, a large sample size and a long duration are necessary. In comparison with previous studies in Taiwan, our study has the largest study population and the longest study period, and therefore the results should be more convincing than data from smaller studies.

Like most of the previous studies on this issue, our study used aggregated data instead of data on each individual and did not apply a biomarker to estimate the long-term cumulative arsenic exposure. Nonetheless, our findings are compatible with the study by Chiou et al., (1997) in the LYB, in which data on individual participants were analyzed. We found that women had lower CVD mortality in all the four study populations, which is consistent with a study from Brazil (Lotufo et al., 2007). However, it should be noted that studies in other countries found women with CVD events have poorer prognoses (Chong et al., 2006), receive less intensive medical evaluations (Smith et al., 2005) and fewer carotid endarterectomies or tissue plasminogen activator infusions (Ramani et al., 2000), and are older than men when admitted to the hospital (Reid et al., 2008). Whether women in Taiwan with CVD receive the same medical treatment as men, or whether other explanations exist for the lower CVD mortality of women needs to be clarified by further studies. In addition, further studies using data on each individual and applying biomarkers to estimate the long-term cumulative arsenic exposure should be conducted to confirm findings in this study.

5.

Conclusions

In Taiwan, while CVD mortality has steadily decreased in both men and women since 1971 till 2005, chronic arsenic exposure from drinking water was associated with increased risks of CVD. In general, women have lower CVD mortality than men.

Table 5 e The 35-years cumulative standardized mortality ratio (SMR) and associated 95% confidence interval (CI) in women and men in the blackfoot disease endemic area (BFDEA), Lan-Yang Basin (LYB), Chia-Yi and Tainan Counties combined (CNC), and whole Taiwan. Women

p

SMR (95% CI) BFDEA vs. Taiwan BFDEA vs. CNC LYB vs. Taiwan BFDEA vs. LYB *p < 0.05.

1.14 (1.09e1.19)* 1.12 (1.08e1.17)* 1.13 (1.08e1.13)* 1.04 (1.00e1.09)

Men

p

SMR (95% CI) < 0.05 < 0.05 < 0.05 0.05

1.09 1.05 1.06 1.05

(1.04e1.13)* (1.01e1.10)* (1.02e1.11)* (1.01e1.10)*

<0.05 <0.05 <0.05 <0.05

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Because CVD was the second leading cause of death during the period 1971e2005 accounting for tens of thousands of death each year and arsenic exposure from drinking water was prevalent in Taiwan, if arsenic can cause CVD, it may contribute a substantial number of deaths. Consequently, in endemic areas of arsenic exposure, minimizing arsenic exposure from drinking water might benefit the prevention and control of CVD, along with many other diseases that are often fatal such as cancer and cardiovascular disease.

Competing interests declaration None.

Acknowledgements Grant information: This study was supported in part by a grant from the Chi Mei Medical Center (grant No.:CMNCKU9813).

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