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Lifetime risk of urothelial carcinoma and lung cancer in the arseniasis-endemic area of Northeastern Taiwan
Journal of Asian Earth Sciences 77 (2013) 332–337
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Lifetime risk of urothelial carcinoma and lung cancer in the arseniasis-endemic area of Northeastern Taiwan Tse-Yen Yang a,b, Ling-I Hsu b, Hui-Chi Chen b, Hung-Yi Chiou c, Yu-Mei Hsueh c, Meei-Maan Wu c,d, Chi-Ling Chen e, Yuan-Hung Wang f,g, Ya-Tang Liao b,h, Chien-Jen Chen a,b,i,⇑ a
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Genomics Research Center, Academia Sinica, Taipei, Taiwan School of Public Health, Taipei Medical University, Taipei, Taiwan d Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan e Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan f Division of Urology, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan g Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan h Management Office for Health Data, China Medical University and Hospital, Taichung, Taiwan i Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Available online 4 April 2013 Keywords: Arsenic Urothelial carcinoma Lung cancer Lifetime risk Cigarette smoking
a b s t r a c t Arsenic in drinking water has been shown to increase the risk of urothelial carcinoma and lung cancer. However, the lifetime risk of developing urothelial carcinoma and lung cancer caused by exposure to arsenic in drinking water has not been reported. This study aimed to assess the lifetime risk of urothelial carcinoma and lung cancer caused by arsenic exposure from drinking water and cigarette smoking habit for residents living in the arseniasis-endemic area in Northeastern Taiwan. We recruited 8086 residents in 1991–1994 and monitored them for their newly developed types of cancers, identified by computerized linkage with the national cancer registry profile. There were 37 newly diagnosed urothelial carcinoma cases and 223 new lung cancer cases during the follow-up period (until 2007). The lifetime (35– 85 years old) cumulative risk of developing urothelial carcinoma from an arsenic concentration in the drinking water of <10, 10–99, and 100+ lg/L was 0.29%, 1.07% and 3.43%, respectively. The corresponding probabilities were 7.42%, 8.99% and 17.09% for the lifetime risk of developing lung cancer. Cigarette smoking was associated with an increased risk of urothelial carcinoma and lung cancer, showing the hazard ratio (95% confidence interval) of 2.48 (1.27–4.82) and 3.44 (2.00–5.90) after adjusting for the arsenic concentration in drinking water. After adjusting for cigarette smoking, the hazard ratio (95% confidence interval) of developing urothelial carcinoma caused by the arsenic concentration in drinking water of <10, 10–99 and 100+ lg/L was 1.0 (the reference group), 2.18 (0.59–8.01), and 8.71 (2.49–30.48), respectively. The corresponding figures were 1.0 (the reference group), 1.14 (0.80–1.61), 1.84 (1.28–2.65) for lung cancer. Synergistic effects on the development of urothelial carcinoma and lung cancer existed between the arsenic exposure level and cigarette smoking. It is suggested that people who have had a high exposure to arsenic in drinking water should stop smoking cigarettes to lower their lifetime risk of urothelial carcinoma and lung cancer. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction An increased risk of urinary tract cancer (specifically urothelial carcinoma) and lung cancer has been well documented to be associated with the arsenic concentration in drinking water in ecological studies (Chen et al., 1985, 1988; Chen and Wang, 1990; Wu et al., 1989), a case-control study (Chen et al., 1986) and cohort ⇑ Corresponding author. Address: Genomic Research Center, Academia Sinica, No. 128, Section 2, Academia Rd., Nankang, Taipei 11529, Taiwan. Tel.: +886 2 2789 9402; fax: +886 2 2788 2043 E-mail address: [email protected] (C.-J. Chen). 1367-9120/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jseaes.2013.03.023
studies (Chiou et al., 1995, 2001; Chen et al., 2004, 2010a, 2010b) in Taiwan. Arsenic has been classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC, 2004a). The U.S. Environmental Protection Agency lowered the maximum allowable contamination level of arsenic in drinking water from 50 to 10 lg/L (Carlson-Lynch et al., 1994) based on the cancer mortality in the arseniasis-endemic area in Southwestern Taiwan (Chen et al., 1992; Morales et al., 2000). A high arsenic concentration in drinking water is widespread in several countries, such as Argentina (Pou et al., 2011; Steinmaus et al., 2006), Bangladesh (Chen and Ahsan, 2004), Chile (Smith et al., 1998; Fraser, 2012), India (Guha Mazumder, 2008), and
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Table 1 Incidence rate and adjusted relative risk of urothelial carcinoma by the arsenic concentration in drinking water, cumulative arsenic exposure and cigarette smoking habit at enrollment. No. of participantsa
No. of cancer cases
Person-years of follow-up
Incidence rate (per 100,000 person-years)
Adjusted relative riskb,e
Adjusted relative riskb,e
Cigarette smoking habit No 4797 Yesc,e 3275
14 23
60,640 38,542
23.09 59.68
1.00 (referent) 2.48 (1.27–4.82)⁄
1.00 (referent) 2.35 (1.20–4.60)⁄
Arsenic concentration (lg/L)d <10 2285 10–99 2997 100+ 1594
3 9 17
28,254 36,754 19,341
10.62 24.49 87.90
1.00 (referent) 2.18 (0.59–8.01) 8.71 (2.49–30.48)⁄⁄⁄
(Not included)
arsenic exposure (lg/L y)d 2757 4 2968 11 1154 16
34,257 36,438 13,691
11.68 30.19 116.86
(Not included)
1.00 (referent) 2.46 (0.78–7.72) 9.36 (3.03–28.92)⁄⁄⁄
Cumulative <500 500–4999 5000+ a b c d e
One participant without birthdate and 13 participants had urothelial carcinoma before enrollment. Relative risk estimated using the Mantel-Cox method. Relative risk adjusted for arsenic concentration in drinking water or cumulative arsenic exposure. Relative risk adjusted for cigarette smoking habit. ⁄ p < 0.05, ⁄⁄p < 0.01, ⁄⁄⁄p < 0.001.
Fig. 1. Lifetime cumulative risk of urothelial carcinoma by the arsenic concentration in drinking well water (left) and cumulative arsenic exposure (right).
Taiwan (Morales et al., 2000; Chiou et al., 2001). Several studies in Argentina (Hopenhayn-Rich et al., 1998) and Chile (Smith et al., 1998; Ferreccio et al., 2000) have also found significant associations between arsenic in drinking water and a risk of urinary cancer and lung cancer. However, the lifetime cumulative risk of developing urothelial carcinoma and lung cancer has never been assessed previously. The synergistic effect of cigarette smoking and exposure to arsenic in drinking water on the development of lung cancer has recently been documented (Chen et al., 2004). However, the synergistic effect on urothelial carcinoma remains to be elucidated. The specific aims of this study included (1) an estimation of the lifetime cumulative risk of urothelial carcinoma and lung cancer caused by arsenic exposure levels, and (2) the assessment of the synergistic effect of cigarette smoking and exposure to arsenic in drinking water on the development of urothelial carcinoma and lung cancer.
2. Materials and methods 2.1. Study cohort The study cohort was recruited from residents living in four townships of the Lanyang Basin located in Northeastern Taiwan.
They had consumed well water since the 1940s until the public water supply system was implemented in early 1990s (Chiou et al., 1997, 2001). Overall, 8102 residents from 4586 households in 18 villages of the study area participated in the baseline home interview from 1991 to 1994. Because the national identification numbers were used for the computerized linkage with the national cancer registry profile, 16 participants with missing or incorrect numbers were excluded. In total, 8086 participants were included in this analysis. Information collected using the structured questionnaire included demographic characteristics, cigarette smoking status, and residential and well water consumption history. All participants signed written informed consents forms to participate in this study, which was approved by the Institutional Review Board of the College of Public Health, National Taiwan University. Data on the arsenic concentration in the drinking water for 6888 participants (85.1%) were determined using well water samples collected from study households. This data for the other 1198 residents (14.9%) were unavailable. The concentration of arsenic in the drinking water was determined using hydride generation combined with flame atomic absorption spectrophotometry, which had a detection limit of 0.15 lg/L. The arsenic concentrations in the water samples ranged from ‘‘undetectable’’ to higher 3000 lg/L. In addition to the arsenic concentration in drinking
c
d
Relative risk estimated using the Mantel-Cox method. Arsenic concentration <10 lg/L or cumulative arsenic exposure <500 lg/L * y without cigarette smoking habit as referent. One participant without birthdate and 13 participants had urothelial carcinoma before enrollment. ⁄ p < 0.05, ⁄⁄p < 0.01, ⁄⁄⁄p < 0.001. a
b
7820 641
5 5000+
63.94
4.95 (1.21– 20.17)⁄ (p for trend 0.0384)
513
11
5871
187.35
12.71 (3.34– 48.36)⁄⁄⁄ (p for interaction 0.0355)
1.00 (referent) 7.14 c(0.88– 58.07)⁄ 23.45 (3.02– 182.27)⁄⁄⁄ (p for trend < 0.0001) 0.48 (0.05–5.19) 4.13 (1.07–15.95)⁄ 7.69 55.28 13,000 14,471 1 8 1.00 (referent) 1100 0.91 (0.19–4.43) 1219 21,257 21,967
14.11 13.66
1.00 (referent) 4.19 (0.51–34.54) 16.50 (2.12– 128.61)⁄⁄⁄ (p for trend < 0.0001) 0.76 (0.06–9.68) 3.31 (0.64–17.14) 14.85 (2.80– 78.63)⁄⁄⁄ (p for interaction < 0.0001) 9.18 40.37 145.53 10,897 14,864 7558 1 6 11
Incidence rate (per 100,000 Adjusted relative person-years) riska,b,d Yes
1.00 (referent) 926 1.14 (0.20–6.66) 1253 4.64 (0.89– 650 24.23)⁄ (p for trend 0.0060) 11.52 13.7 50.92
Cumulative arsenic exposure (lg/L y)c <500 1657 3 500–4999 1749 3
One participant without an exact birthdate and 13 participants affected with urothelial carcinoma before enrollment were excluded in the analysis of the risk of urothelial carcinoma. As shown in Table 1, there were 37 newly diagnosed cases of urothelial carcinoma in 99,182 person-years of follow-up. The incidence rate per 100,000 person-years was 10.62, 24.49, and 87.90 for an arsenic concentration in the drinking water of <10, 10–99, and 100+ g/L, respectively. The corresponding lifetime (35–85 years old) cumulative risk (95% confidence interval) of developing urothelial carcinoma was 0.29% (0.07–1.17%), 1.07% (0.53–2.14%) and 3.43% (2.02–5.81%), as shown in Fig. 1. The corresponding relative risk (95% confidence interval) of developing urothelial carcinoma was 1.00 (the reference group), 2.18 (0.59–8.01), and 8.71 (2.49–
17,357 21,890 11,783
3.1. Risk of urothelial carcinoma from arsenic exposure levels and cigarette smoking
Arsenic concentration (lg/L)c <10 1359 2 10–99 1744 3 100+ 944 6
3. Results
Incidence rate (per 100,000 Adjusted No. of No. of Person-years of person-years) relative riska,b,d participants cancer cases follow-up
The person-years of the follow-up for each participant were calculated from the date of the questionnaire interview to the date of cancer diagnosis, death, or December 31, 2007, whichever came first. The arsenic concentration in drinking water was classified into three groups of <10, 10–99, and 100+ lg/L, and the cumulative arsenic exposure was categorized into three groups of <500, 500– 4999, and 5000+ lg/L-years. Because gender was not statistically associated with either urothelial carcinoma or lung cancer, only cigarette smoking and the arsenic exposure index were included in multiple regression analyses. The adjusted relative risk and 95% confidence interval (CI) of developing urothelial carcinoma or lung cancer for each risk factor were estimated using the Mantel-Cox method. Lifetime cumulative risk was calculated using a modified technique of survival analyses (Huang et al., 2011). All statistical analyses were performed with SAS statistical software, version 9.2 (SAS Institute, Inc., Cary, NC) and the Stata statistical software, version 11 (StataCorp LP, College Station, TX). The Nelson–Aalen cumulative hazard function was used to derive the lifetime cumulative risk plots.
No. of Person-years of cancer cases follow-up
2.3. Statistical analysis
No. of participants
Newly developed cases of urothelial carcinoma and lung cancer were identified through the computerized linkage with the national cancer registry profiles in Taiwan. Urothelial carcinomas were ascertained as cancer of the bladder (as indicated by the International Classification of Disease, 9th revision [ICD-9], codes 188), of the kidney (ICD-9 code 189.0), and of other urinary organs (ICD-9 code 189.1-189.9) with the histologic confirmation of urothelial carcinoma.
No
2.2. Ascertainment of newly developed urothelial carcinoma and lung cancer
Cigarette smoking
water, other indices of arsenic exposure from drinking water were derived: the total duration that well water was consumed, the age at which well water consumption started and stopped, whether well water was being consumed at the time of enrollment, and cumulative arsenic exposure. All of these exposure indices were derived from the questionnaire containing a detailed history of residential and well water consumption information. The cumulative arsenic exposure was calculated as the products of arsenic concentration in well water (lg/L) and the total years of well water consumption until recruitment. Detailed descriptions of the study areas and enrollment procedures have been described previously (Chen et al., 2010a,b; Chiou et al., 1997, 2001).
Adjusted relative riska,d
T.-Y. Yang et al. / Journal of Asian Earth Sciences 77 (2013) 332–337
Table 2 Incidence rate and relative risk of urothelial carcinoma by the combination of arsenic concentrations in drinking water/cumulative arsenic exposure and cigarette smoking habit at enrollment.
334
335
T.-Y. Yang et al. / Journal of Asian Earth Sciences 77 (2013) 332–337
Table 3 Incidence rate and adjusted relative risk of lung cancer by the arsenic concentration in drinking water, cumulative arsenic exposure and cigarette smoking habit at enrollment. No. of participantsa
No. of cancer cases
Person-years of followup
Incidence rate (per 100,000 personyears)
Adjusted relative riskb,e
Adjusted relative riskb,e
Cigarette smoking habit No 4797 Yesc,e 3274
71 152
60,620 38,428
117.12 395.54
1.00 (referent) 3.44 (2.00–5.90)⁄⁄⁄
1.00 (referent) 3.47 (2.01–5.97)⁄⁄⁄
Arsenic concentration (lg/L)d <10 2284 10–99 2994 100+ 1596
52 82 65
28,220 36,672 19,311
184.27 223.60 336.60
1.00 (referent) 1.14 (0.80–1.61) 1.84 (1.28–2.65)⁄⁄
(Not included)
arsenic exposure (lg/L y)d 2756 65 2965 79
34,215 36,370
189.98 217.21
(Not included)
1.00 (referent) 1.09 (0.79–1.52)
1153
13,650
395.62
Cumulative <500 500– 4999 5000+ a b c d e
54
1.85 (1.29–2.65)⁄⁄
One participant without birthdate and 14 participants had lung cancer before enrollment. Relative risk estimated using the Mantel-Cox method. Relative risk adjusted for arsenic concentration in drinking water or cumulative arsenic exposure. Relative risk adjusted for cigarette smoking habit. ⁄ p < 0.05, ⁄⁄p < 0.01, ⁄⁄⁄p < 0.001.
Fig. 2. Lifetime cumulative risk of lung cancer by the arsenic concentration in drinking well water (left) and cumulative arsenic exposure (right).
30.48), after adjusting for cigarette smoking (Table 1). Cigarette smoking was also associated with an increased risk of urothelial carcinoma, showing a relative risk (95% confidence interval) of 2.48 (1.27–4.82), after adjusting for arsenic concentration in the drinking water. Table 1 also shows the urothelial carcinoma incidence rate using cumulative arsenic exposure. There was an increasing biological gradient of urothelial carcinoma risk with the cumulative arsenic exposure. The incidence rate per 100,000 person-years was 11.68, 30.19, and 116.86 for cumulative arsenic exposure levels of <500, 500–4999, and 5000+ lg/L-years, respectively. As shown in Fig. 1, the corresponding lifetime cumulative risk (95% confidence interval) of developing urothelial carcinoma was 0.33% (0.10–1.04%), 1.15% (0.62–2.14%) and 4.55% (2.68– 7.72%). The corresponding relative risk (95% confidence interval) of developing urothelial carcinoma was 1.00 (reference group), 2.46 (0.78–7.72), and 9.36 (3.03–28.92) after adjusting for cigarette smoking (Table 1). 3.2. Combinatory effects of arsenic exposure levels and cigarette smoking on urothelial carcinoma Table 2 shows the combinatory effects of the arsenic exposure levels and cigarette smoking on the development of urothelial car-
cinoma. Among both cigarette smokers and non-smokers, a significant dose–response relation to urothelial carcinoma risk was still observed for the arsenic concentration in the drinking water (p for trend 0.006 and <0.0001) and the cumulative arsenic exposure (p for trend 0.0384 and <0.0001). The highest risk of urothelial carcinoma was observed for the cigarette smokers who had the highest arsenic exposure levels. Compared to non-smokers who consumed drinking water with arsenic concentrations of <10 lg/L (reference group), smokers who consumed drinking water with an arsenic concentration of 100 + lg/L had an highly increased risk of developing urothelial carcinoma (relative risk, 14.85; 95% confidence interval, 2.80–78.63), as shown in Table 2. The corresponding relative risk (95% confidence interval) was 12.71 (3.34–48.36) for cigarette smokers with a cumulative arsenic exposure of 5000 + lg/Lyears compared to non-smokers with a cumulative arsenic exposure of <500 lg/L-years, as shown in Table 2. 3.3. Risk of lung cancer caused by arsenic exposure levels and cigarette smoking One participant without an exact birthdate and 14 participants affected with lung cancer before the enrollment were excluded in the analysis of the risk of lung cancer. As shown in Table 3, there
331.86 353.22
737.96
12,957 14,439
5827 43
c
d
Relative risk estimated using the Mantel–Cox method; Arsenic concentration <10 lg/L or cumulative arsenic exposure <500 lg/L * y without cigarette smoking habit as referent. One participant without birthdate and 14 participants had lung cancer before enrollment. ⁄ p < 0.05, ⁄⁄p < 0.01, ⁄⁄⁄p < 0.001. a
b
(p for trend 0.2050)
1.22 (0.60–2.50) 7823 640
11 5000+
140.62
513
43 51 1099 1217 1.00 (referent) 1.19 (0.68–2.07)
651 (p for trend 0.2308)
103.49 127.67 21,258 21,931 Cumulative arsenic exposure (lg/L y)c <500 1657 22 500–4999 1748 28
1.30 (0.67–2.56) 135.61 11,799 16 945 100+
2.88 (1.72–4.82)⁄⁄⁄ 1.00 (referent) 3.09 (1.87–5.09)⁄⁄⁄ 1.05 (0.70– 1.58) 6.31 (3.74– 2.17 (1.42– 10.65)⁄⁄⁄ 3.32)⁄⁄⁄ (p for trend (p for interaction < 0.0001) 0.0005)
652.28 7512
926 1251 1.00 (referent) 1.15 (0.64–2.08) 103.81 123.47 18 27 Arsenic concentration (lg/L)c <10 1358 10–99 1743
17,339 21,867
49
No. of No. of Person-years of participants cancer cases follow-up
34 55
Yes
Incidence rate (per 100,000 Adjusted relative person-years) riska,b,d
2.72 (1.53–4.83)⁄⁄ 1.00 (referent) 3.14 (1.85–5.33)⁄⁄⁄ 1.15 (0.75– 1.77) 6.04 (3.49– 2.14 (1.38– 10.48)⁄⁄⁄ 3.32)⁄⁄⁄ (p for (p for trend interaction < 0.0001) 0.0006) 312.48 371.49
3.4. Combinatory effects of arsenic exposure levels and cigarette smoking on lung cancer
No. of No. of Person-years of participants cancer cases follow-up
Incidence rate (per 100,000 Adjusted relative person-years) riska,b,d
were 223 newly diagnosed cases of lung cancer in 99,048 personyears of follow-up. The incidence rate per 100,000 person-years was 184.27, 223.60 and 336.60 for arsenic concentrations in drinking water of <10, 10–99, and 100 + lg/L, respectively. The corresponding lifetime (35–85 years old) cumulative risk (95% confidence interval) of developing lung cancer was 7.42% (5.51– 9.99%), 8.99% (7.04–11.49%), and 17.09% (12.76–22.89%), respectively, as shown in Fig. 2. The corresponding relative risk (95% confidence interval) of developing lung cancer was 1.00 (the reference group), 1.14 (0.80–1.61), and 1.84 (1.28–2.65), after adjusting for cigarette smoking. Cigarette smoking was also associated with an increased risk of lung cancer, showing a relative risk (95% confidence interval) of 3.44 (2.00–5.90) after adjusting for the arsenic concentration in the drinking water. Table 3 also shows the lung cancer incidence rate by cumulative arsenic exposure. There was an increasing biological gradient of lung cancer risk with the cumulative arsenic exposure. The incidence rate per 100,000 person-years was 189.98, 217.21, and 395.62 for cumulative arsenic exposure levels of <500, 500–4999, and 5000+ lg/L-years. As shown in Fig. 2, the corresponding lifetime cumulative risk (95% confidence interval) of developing lung cancer was 7.84% (6.00– 10.25%), 9.23% (7.15–11.91%), and 17.46% (12.78–23.85%). The corresponding relative risk (95% confidence interval) of developing lung cancer was 1.00 (reference group), 1.09 (0.79–1.52), and 1.85 (1.29–2.65) after adjusting for cigarette smoking (Table 3).
No
Cigarette smoking
Table 4 Incidence rate and relative risk of lung cancer by the combination of arsenic concentrations in drinking water/cumulative arsenic exposure and cigarette smoking habit at enrollment.
10,881 14,805
T.-Y. Yang et al. / Journal of Asian Earth Sciences 77 (2013) 332–337
Adjusted relative riska,d
336
Table 4 shows the combinatory effects of arsenic exposure levels and cigarette smoking on the development of lung cancer. Among both cigarette smoker and non-smokers, the significant dose–response relation to lung cancer risk was still observed for the arsenic concentration in the drinking water and the cumulative arsenic exposure. The highest risk of lung cancer was observed for cigarette smokers who had the highest arsenic exposure levels. Compared to non-smokers who consumed drinking water with arsenic concentrations of <10 lg/L (the reference group), smokers who consumed drinking water with an arsenic concentration of 100 + lg/L had a highly increased risk of developing lung cancer (relative risk, 6.04; 95% confidence interval, 3.49–10.48). The corresponding relative risk (95% confidence interval) was 6.31 (3.74–10.65) for cigarette smokers with a cumulative arsenic exposure of 5000 + lg/L-years compared to non-smokers with a cumulative arsenic exposure of <500 lg/L-years, as shown in Table 4.
4. Discussion Both arsenic and cigarette smoking have been documented as group 1 human carcinogens of lung and urinary tract cancer (IARC, 2004a,b). In this study, we found a significant biological gradient of urothelial carcinoma and lung cancer with increasing arsenic exposure levels, which is consistent with previous findings observed in Southwestern and Northeastern Taiwan, in Argentina, and in Chile (Chen et al., 1988, 2004, 2010a,b; Wu et al., 1989; Chiou et al., 1995; 2001; Ferreccio et al., 2000; Hopenhayn-Rich et al., 1998; Smith et al., 1998). However, the lifetime cumulative risk of arsenic-induced urothelial carcinoma and lung cancer has never been assessed. To the best of our knowledge, this was the first study that estimated the lifetime cumulative risk of urothelial carcinoma and lung cancer caused by the arsenic concentration in drinking water and the cumulative arsenic exposure. The cumulative risk of arsenic-induced lung cancer was much higher than that of arsenic-induced urothelial carcinoma.
T.-Y. Yang et al. / Journal of Asian Earth Sciences 77 (2013) 332–337
The synergistic interaction between cigarette smoking and arsenic in drinking water has been previously reported for lung cancer (Chen et al., 2004; Ferreccio et al., 2000). We found similar synergistic interactions for both urothelial carcinoma and lung cancer. For those who have been exposed to high-arsenic drinking water, it is recommended to avoid exposures to cigarette smoke. This study provides an accurate estimation of arsenic exposure for each person. Each household in the area of interest in Northeastern Taiwan had a tube well in its backyard, and house members were using the well water for drinking and cooking. The arsenic concentration in the drinking water and the cumulative arsenic exposure may have been estimated in Northeastern Taiwan more accurately for each participant than in Southwestern Taiwan, where all households in a village shared several wells, thereby making the arsenic exposure difficult to estimate. This study has limitations. First, data on the concentration of arsenic in the drinking water were unavailable for approximately 15% of the participants in our study, which resulted in a reduced number of study participants included in the analysis (consequently lowering the statistical power of the study). Nevertheless, we still found a significant dose–response relationship between arsenic exposure and cancer risk, as well as a significant synergistic interaction between cigarette smoking and arsenic exposure. Second, we did not actively examine the occurrences of newly developed cancer by using regular follow-up health examinations. Early-stage cancer cases may therefore have been missed in the computerized linkage with cancer registry profiles. Because the national cancer registry in Taiwan is almost complete, current, and accurate, the number of cancer cases missed in data linkage would likely be small. Furthermore, the missing cases would occur in various exposure groups non-differentially, which would result in the underestimation of the relative risk. However, we still found a significantly elevated relative risk of urothelial carcinoma and lung cancer associated with arsenic exposure and cigarette smoking. In other words, the relative risks were estimated in a conservative manner. 5. Conclusion In this large-scale long-term follow-up cohort study, we observed a significant dose–response relationship between arsenic exposure and the risk of urothelial carcinoma and lung cancer. We estimated the lifetime cumulative risk of urothelial carcinoma and lung cancer for various categories of exposure to arsenic in the drinking water. We documented the synergistic effects between cigarette smoking and arsenic exposure on the development of urothelial carcinoma and lung cancer. Acknowledgment Funding was supported by Grants (NSC100-2314-B-001-004MY3&NSC100-2314-B-001-006-MY3) from the National Science Council and Academia Sinica, Taipei, Taiwan. References Carlson-Lynch, H., Beck, B.D., Boardman, P.D., 1994. Arsenic risk assessment. Environmental Health Perspectives 102, 354–356.
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Chen, C.J., Chuang, Y.C., Lin, T.M., Wu, H.Y., 1985. Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: High-arsenic artesian well water and cancers. Cancer Research 45, 5895–5899. Chen, C.J., Chuang, Y.C., You, S.L., Lin, T.M., Wu, H.Y., 1986. A retrospective study on malignant neoplasms of bladder, lung and liver in blackfoot disease endemic area in Taiwan. British Journal of Cancer 53, 399–405. Chen, C.J., Kuo, T.L., Wu, M.M., 1988. Arsenic and cancers. Lancet 1, 414–415. Chen, C.J., Wang, C.J., 1990. Ecological correlation between arsenic level in well water and age-adjusted mortality from malignant neoplasms. Cancer Research 50, 5470–5474. Chen, C.J., Chen, C.W., Wu, M.M., Kuo, T.L., 1992. Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. British Journal of Cancer 66, 888–892. Chen, C.L., Hsu, L.I., Chiou, H.Y., Hsueh, Y.M., Chen, S.Y., Wu, M.M., Chen, C.J., 2004. Ingested arsenic, cigarette smoking and lung cancer risk: a follow-up study inarseniasis-endemic areas in Taiwan. Journal of the American Medical Association 292, 2984–2990. Chen, C.L., Chiou, H.Y., Hsu, L.I., Hsueh, Y.M., Wu, M.M., Chen, C.J., 2010a. Ingested arsenic, characteristics of well water consumption and risk of different histological types of lung cancer in northeastern Taiwan. Environmental Research 110, 455–462. Chen, C.L., Chiou, H.Y., Hsu, L.I., Hsueh, Y.M., Wu, M.M., Wang, Y.H., Chen, C.J., 2010b. Arsenic in drinking water and risk of urinary tract cancer: a follow-up study from northeastern Taiwan. Cancer Epidemiology, Biomarkers & Prevention 19, 101–110. Chen, Y., Ahsan, H., 2004. Cancer burden from arsenic in drinking water in Bangladesh. American Journal of Public Health 94, 741–744. Chiou, H.Y., Hsueh, Y.M., Liaw, K.F., Horng, S.F., Chiang, M.H., Pu, Y.S., Lin, J.S., Huang, C.H., Chen, C.J., 1995. Incidence of internal cancers and ingested inorganic arsenic: a seven-year follow-up study in Taiwan. Cancer Research 55, 1296– 1300. Chiou, H.Y., Huang, W.I., Su, C.L., Chang, S.F., Hsu, Y.H., Chen, C.J., 1997. Doseresponse relationship between prevalence of cerebrovascular disease and ingested inorganic arsenic. Stroke 28, 1717–1723. Chiou, H.Y., Chiou, S.T., Hsu, Y.H., Chou, Y.L., Tseng, C.H., Wei, M.L., Chen, C.J., 2001. Incidence of transitional cell carcinoma and arsenic in drinking water: a followup study of 8102 residents in an arseniasis-endemic area in northeastern Taiwan. American Journal of Epidemiology 153, 411–418. Ferreccio, C., González, C., Milosavjlevic, V., Marshall, G., Sancha, A.M., Smith, A.H., 2000. Lung cancer and arsenic concentrations in drinking water in Chile. Epidemiology 11, 673–679 (Erratum: Epidemiology, 12, 283). Fraser, B., 2012. Cancer cluster in Chile linked to arsenic contamination. Lancet 379, 603. Guha Mazumder, D.N., 2008. Chronic arsenic toxicity & human health. The Indian Journal of Medical Research 128, 436–447. Hopenhayn-Rich, C., Biggs, M.L., Smith, A.H., 1998. Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba, Argentina. International Journal of Epidemiology 27, 561–569. Huang, Y.T., Jen, C.L., Yang, H.I., Lee, M.H., Su, J., Lu, S.N., Iloeje, U.H., Chen, C.J., 2011. Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. Journal of Clinical Oncology 29, 3643–3650. IARC, 2004a. IARC Monographs on Evaluation of Carcinogenic Risks to Humans: Some Drinking-water Disinfectants and Contaminants, including Arsenic. vol. 84. International Agency for Research on Cancer, Lyon, pp. 1–512. IARC, 2004b. IARC Monographs on Evaluation of Carcinogenic Risks to Human: Tobacco Smoke and Involuntary Smoking. vol. 83. International Agency for Research on Cancer, Lyon, pp. 1–1438. Morales, K.H., Ryan, L., Kuo, T.L., Wu, M.M., Chen, C.J., 2000. Risk of internal cancers from arsenic in drinking water. Environmental Health Perspectives 108, 655– 661. Pou, S.A., Osella, A.R., Diaz Mdel, P., 2011. Bladder cancer mortality trends and patterns in Cordoba, Argentina (1986–2006). Cancer Causes & Control 22, 407– 415. Smith, A.H., Goycolea, M., Haque, R., Biggs, M.L., 1998. Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water. American Journal of Epidemiology 147, 660–669. Steinmaus, C., Bates, M.N., Yuan, Y., Kalman, D., Atallah, R., Rey, O.A., Biggs, M.L., Hopenhayn, C., Moore, L.E., Hoang, B.K., Smith, A.H., 2006. Arsenic methylation and bladder cancer risk in case-control studies in Argentina and the United States. Journal of Occupational and Environmental Medicine 48, 478–488. Wu, M.M., Kuo, T.L., Hwang, Y.H., Chen, C.J., 1989. Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases. American Journal of Epidemiology 130, 1123–1132.
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Journal of Asian Earth Sciences journal homepage: www.elsevier.com/locate/jseaes
Lifetime risk of urothelial carcinoma and lung cancer in the arseniasis-endemic area of Northeastern Taiwan Tse-Yen Yang a,b, Ling-I Hsu b, Hui-Chi Chen b, Hung-Yi Chiou c, Yu-Mei Hsueh c, Meei-Maan Wu c,d, Chi-Ling Chen e, Yuan-Hung Wang f,g, Ya-Tang Liao b,h, Chien-Jen Chen a,b,i,⇑ a
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Genomics Research Center, Academia Sinica, Taipei, Taiwan School of Public Health, Taipei Medical University, Taipei, Taiwan d Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan e Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan f Division of Urology, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan g Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan h Management Office for Health Data, China Medical University and Hospital, Taichung, Taiwan i Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Available online 4 April 2013 Keywords: Arsenic Urothelial carcinoma Lung cancer Lifetime risk Cigarette smoking
a b s t r a c t Arsenic in drinking water has been shown to increase the risk of urothelial carcinoma and lung cancer. However, the lifetime risk of developing urothelial carcinoma and lung cancer caused by exposure to arsenic in drinking water has not been reported. This study aimed to assess the lifetime risk of urothelial carcinoma and lung cancer caused by arsenic exposure from drinking water and cigarette smoking habit for residents living in the arseniasis-endemic area in Northeastern Taiwan. We recruited 8086 residents in 1991–1994 and monitored them for their newly developed types of cancers, identified by computerized linkage with the national cancer registry profile. There were 37 newly diagnosed urothelial carcinoma cases and 223 new lung cancer cases during the follow-up period (until 2007). The lifetime (35– 85 years old) cumulative risk of developing urothelial carcinoma from an arsenic concentration in the drinking water of <10, 10–99, and 100+ lg/L was 0.29%, 1.07% and 3.43%, respectively. The corresponding probabilities were 7.42%, 8.99% and 17.09% for the lifetime risk of developing lung cancer. Cigarette smoking was associated with an increased risk of urothelial carcinoma and lung cancer, showing the hazard ratio (95% confidence interval) of 2.48 (1.27–4.82) and 3.44 (2.00–5.90) after adjusting for the arsenic concentration in drinking water. After adjusting for cigarette smoking, the hazard ratio (95% confidence interval) of developing urothelial carcinoma caused by the arsenic concentration in drinking water of <10, 10–99 and 100+ lg/L was 1.0 (the reference group), 2.18 (0.59–8.01), and 8.71 (2.49–30.48), respectively. The corresponding figures were 1.0 (the reference group), 1.14 (0.80–1.61), 1.84 (1.28–2.65) for lung cancer. Synergistic effects on the development of urothelial carcinoma and lung cancer existed between the arsenic exposure level and cigarette smoking. It is suggested that people who have had a high exposure to arsenic in drinking water should stop smoking cigarettes to lower their lifetime risk of urothelial carcinoma and lung cancer. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction An increased risk of urinary tract cancer (specifically urothelial carcinoma) and lung cancer has been well documented to be associated with the arsenic concentration in drinking water in ecological studies (Chen et al., 1985, 1988; Chen and Wang, 1990; Wu et al., 1989), a case-control study (Chen et al., 1986) and cohort ⇑ Corresponding author. Address: Genomic Research Center, Academia Sinica, No. 128, Section 2, Academia Rd., Nankang, Taipei 11529, Taiwan. Tel.: +886 2 2789 9402; fax: +886 2 2788 2043 E-mail address: [email protected] (C.-J. Chen). 1367-9120/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jseaes.2013.03.023
studies (Chiou et al., 1995, 2001; Chen et al., 2004, 2010a, 2010b) in Taiwan. Arsenic has been classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC, 2004a). The U.S. Environmental Protection Agency lowered the maximum allowable contamination level of arsenic in drinking water from 50 to 10 lg/L (Carlson-Lynch et al., 1994) based on the cancer mortality in the arseniasis-endemic area in Southwestern Taiwan (Chen et al., 1992; Morales et al., 2000). A high arsenic concentration in drinking water is widespread in several countries, such as Argentina (Pou et al., 2011; Steinmaus et al., 2006), Bangladesh (Chen and Ahsan, 2004), Chile (Smith et al., 1998; Fraser, 2012), India (Guha Mazumder, 2008), and
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Table 1 Incidence rate and adjusted relative risk of urothelial carcinoma by the arsenic concentration in drinking water, cumulative arsenic exposure and cigarette smoking habit at enrollment. No. of participantsa
No. of cancer cases
Person-years of follow-up
Incidence rate (per 100,000 person-years)
Adjusted relative riskb,e
Adjusted relative riskb,e
Cigarette smoking habit No 4797 Yesc,e 3275
14 23
60,640 38,542
23.09 59.68
1.00 (referent) 2.48 (1.27–4.82)⁄
1.00 (referent) 2.35 (1.20–4.60)⁄
Arsenic concentration (lg/L)d <10 2285 10–99 2997 100+ 1594
3 9 17
28,254 36,754 19,341
10.62 24.49 87.90
1.00 (referent) 2.18 (0.59–8.01) 8.71 (2.49–30.48)⁄⁄⁄
(Not included)
arsenic exposure (lg/L y)d 2757 4 2968 11 1154 16
34,257 36,438 13,691
11.68 30.19 116.86
(Not included)
1.00 (referent) 2.46 (0.78–7.72) 9.36 (3.03–28.92)⁄⁄⁄
Cumulative <500 500–4999 5000+ a b c d e
One participant without birthdate and 13 participants had urothelial carcinoma before enrollment. Relative risk estimated using the Mantel-Cox method. Relative risk adjusted for arsenic concentration in drinking water or cumulative arsenic exposure. Relative risk adjusted for cigarette smoking habit. ⁄ p < 0.05, ⁄⁄p < 0.01, ⁄⁄⁄p < 0.001.
Fig. 1. Lifetime cumulative risk of urothelial carcinoma by the arsenic concentration in drinking well water (left) and cumulative arsenic exposure (right).
Taiwan (Morales et al., 2000; Chiou et al., 2001). Several studies in Argentina (Hopenhayn-Rich et al., 1998) and Chile (Smith et al., 1998; Ferreccio et al., 2000) have also found significant associations between arsenic in drinking water and a risk of urinary cancer and lung cancer. However, the lifetime cumulative risk of developing urothelial carcinoma and lung cancer has never been assessed previously. The synergistic effect of cigarette smoking and exposure to arsenic in drinking water on the development of lung cancer has recently been documented (Chen et al., 2004). However, the synergistic effect on urothelial carcinoma remains to be elucidated. The specific aims of this study included (1) an estimation of the lifetime cumulative risk of urothelial carcinoma and lung cancer caused by arsenic exposure levels, and (2) the assessment of the synergistic effect of cigarette smoking and exposure to arsenic in drinking water on the development of urothelial carcinoma and lung cancer.
2. Materials and methods 2.1. Study cohort The study cohort was recruited from residents living in four townships of the Lanyang Basin located in Northeastern Taiwan.
They had consumed well water since the 1940s until the public water supply system was implemented in early 1990s (Chiou et al., 1997, 2001). Overall, 8102 residents from 4586 households in 18 villages of the study area participated in the baseline home interview from 1991 to 1994. Because the national identification numbers were used for the computerized linkage with the national cancer registry profile, 16 participants with missing or incorrect numbers were excluded. In total, 8086 participants were included in this analysis. Information collected using the structured questionnaire included demographic characteristics, cigarette smoking status, and residential and well water consumption history. All participants signed written informed consents forms to participate in this study, which was approved by the Institutional Review Board of the College of Public Health, National Taiwan University. Data on the arsenic concentration in the drinking water for 6888 participants (85.1%) were determined using well water samples collected from study households. This data for the other 1198 residents (14.9%) were unavailable. The concentration of arsenic in the drinking water was determined using hydride generation combined with flame atomic absorption spectrophotometry, which had a detection limit of 0.15 lg/L. The arsenic concentrations in the water samples ranged from ‘‘undetectable’’ to higher 3000 lg/L. In addition to the arsenic concentration in drinking
c
d
Relative risk estimated using the Mantel-Cox method. Arsenic concentration <10 lg/L or cumulative arsenic exposure <500 lg/L * y without cigarette smoking habit as referent. One participant without birthdate and 13 participants had urothelial carcinoma before enrollment. ⁄ p < 0.05, ⁄⁄p < 0.01, ⁄⁄⁄p < 0.001. a
b
7820 641
5 5000+
63.94
4.95 (1.21– 20.17)⁄ (p for trend 0.0384)
513
11
5871
187.35
12.71 (3.34– 48.36)⁄⁄⁄ (p for interaction 0.0355)
1.00 (referent) 7.14 c(0.88– 58.07)⁄ 23.45 (3.02– 182.27)⁄⁄⁄ (p for trend < 0.0001) 0.48 (0.05–5.19) 4.13 (1.07–15.95)⁄ 7.69 55.28 13,000 14,471 1 8 1.00 (referent) 1100 0.91 (0.19–4.43) 1219 21,257 21,967
14.11 13.66
1.00 (referent) 4.19 (0.51–34.54) 16.50 (2.12– 128.61)⁄⁄⁄ (p for trend < 0.0001) 0.76 (0.06–9.68) 3.31 (0.64–17.14) 14.85 (2.80– 78.63)⁄⁄⁄ (p for interaction < 0.0001) 9.18 40.37 145.53 10,897 14,864 7558 1 6 11
Incidence rate (per 100,000 Adjusted relative person-years) riska,b,d Yes
1.00 (referent) 926 1.14 (0.20–6.66) 1253 4.64 (0.89– 650 24.23)⁄ (p for trend 0.0060) 11.52 13.7 50.92
Cumulative arsenic exposure (lg/L y)c <500 1657 3 500–4999 1749 3
One participant without an exact birthdate and 13 participants affected with urothelial carcinoma before enrollment were excluded in the analysis of the risk of urothelial carcinoma. As shown in Table 1, there were 37 newly diagnosed cases of urothelial carcinoma in 99,182 person-years of follow-up. The incidence rate per 100,000 person-years was 10.62, 24.49, and 87.90 for an arsenic concentration in the drinking water of <10, 10–99, and 100+ g/L, respectively. The corresponding lifetime (35–85 years old) cumulative risk (95% confidence interval) of developing urothelial carcinoma was 0.29% (0.07–1.17%), 1.07% (0.53–2.14%) and 3.43% (2.02–5.81%), as shown in Fig. 1. The corresponding relative risk (95% confidence interval) of developing urothelial carcinoma was 1.00 (the reference group), 2.18 (0.59–8.01), and 8.71 (2.49–
17,357 21,890 11,783
3.1. Risk of urothelial carcinoma from arsenic exposure levels and cigarette smoking
Arsenic concentration (lg/L)c <10 1359 2 10–99 1744 3 100+ 944 6
3. Results
Incidence rate (per 100,000 Adjusted No. of No. of Person-years of person-years) relative riska,b,d participants cancer cases follow-up
The person-years of the follow-up for each participant were calculated from the date of the questionnaire interview to the date of cancer diagnosis, death, or December 31, 2007, whichever came first. The arsenic concentration in drinking water was classified into three groups of <10, 10–99, and 100+ lg/L, and the cumulative arsenic exposure was categorized into three groups of <500, 500– 4999, and 5000+ lg/L-years. Because gender was not statistically associated with either urothelial carcinoma or lung cancer, only cigarette smoking and the arsenic exposure index were included in multiple regression analyses. The adjusted relative risk and 95% confidence interval (CI) of developing urothelial carcinoma or lung cancer for each risk factor were estimated using the Mantel-Cox method. Lifetime cumulative risk was calculated using a modified technique of survival analyses (Huang et al., 2011). All statistical analyses were performed with SAS statistical software, version 9.2 (SAS Institute, Inc., Cary, NC) and the Stata statistical software, version 11 (StataCorp LP, College Station, TX). The Nelson–Aalen cumulative hazard function was used to derive the lifetime cumulative risk plots.
No. of Person-years of cancer cases follow-up
2.3. Statistical analysis
No. of participants
Newly developed cases of urothelial carcinoma and lung cancer were identified through the computerized linkage with the national cancer registry profiles in Taiwan. Urothelial carcinomas were ascertained as cancer of the bladder (as indicated by the International Classification of Disease, 9th revision [ICD-9], codes 188), of the kidney (ICD-9 code 189.0), and of other urinary organs (ICD-9 code 189.1-189.9) with the histologic confirmation of urothelial carcinoma.
No
2.2. Ascertainment of newly developed urothelial carcinoma and lung cancer
Cigarette smoking
water, other indices of arsenic exposure from drinking water were derived: the total duration that well water was consumed, the age at which well water consumption started and stopped, whether well water was being consumed at the time of enrollment, and cumulative arsenic exposure. All of these exposure indices were derived from the questionnaire containing a detailed history of residential and well water consumption information. The cumulative arsenic exposure was calculated as the products of arsenic concentration in well water (lg/L) and the total years of well water consumption until recruitment. Detailed descriptions of the study areas and enrollment procedures have been described previously (Chen et al., 2010a,b; Chiou et al., 1997, 2001).
Adjusted relative riska,d
T.-Y. Yang et al. / Journal of Asian Earth Sciences 77 (2013) 332–337
Table 2 Incidence rate and relative risk of urothelial carcinoma by the combination of arsenic concentrations in drinking water/cumulative arsenic exposure and cigarette smoking habit at enrollment.
334
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T.-Y. Yang et al. / Journal of Asian Earth Sciences 77 (2013) 332–337
Table 3 Incidence rate and adjusted relative risk of lung cancer by the arsenic concentration in drinking water, cumulative arsenic exposure and cigarette smoking habit at enrollment. No. of participantsa
No. of cancer cases
Person-years of followup
Incidence rate (per 100,000 personyears)
Adjusted relative riskb,e
Adjusted relative riskb,e
Cigarette smoking habit No 4797 Yesc,e 3274
71 152
60,620 38,428
117.12 395.54
1.00 (referent) 3.44 (2.00–5.90)⁄⁄⁄
1.00 (referent) 3.47 (2.01–5.97)⁄⁄⁄
Arsenic concentration (lg/L)d <10 2284 10–99 2994 100+ 1596
52 82 65
28,220 36,672 19,311
184.27 223.60 336.60
1.00 (referent) 1.14 (0.80–1.61) 1.84 (1.28–2.65)⁄⁄
(Not included)
arsenic exposure (lg/L y)d 2756 65 2965 79
34,215 36,370
189.98 217.21
(Not included)
1.00 (referent) 1.09 (0.79–1.52)
1153
13,650
395.62
Cumulative <500 500– 4999 5000+ a b c d e
54
1.85 (1.29–2.65)⁄⁄
One participant without birthdate and 14 participants had lung cancer before enrollment. Relative risk estimated using the Mantel-Cox method. Relative risk adjusted for arsenic concentration in drinking water or cumulative arsenic exposure. Relative risk adjusted for cigarette smoking habit. ⁄ p < 0.05, ⁄⁄p < 0.01, ⁄⁄⁄p < 0.001.
Fig. 2. Lifetime cumulative risk of lung cancer by the arsenic concentration in drinking well water (left) and cumulative arsenic exposure (right).
30.48), after adjusting for cigarette smoking (Table 1). Cigarette smoking was also associated with an increased risk of urothelial carcinoma, showing a relative risk (95% confidence interval) of 2.48 (1.27–4.82), after adjusting for arsenic concentration in the drinking water. Table 1 also shows the urothelial carcinoma incidence rate using cumulative arsenic exposure. There was an increasing biological gradient of urothelial carcinoma risk with the cumulative arsenic exposure. The incidence rate per 100,000 person-years was 11.68, 30.19, and 116.86 for cumulative arsenic exposure levels of <500, 500–4999, and 5000+ lg/L-years, respectively. As shown in Fig. 1, the corresponding lifetime cumulative risk (95% confidence interval) of developing urothelial carcinoma was 0.33% (0.10–1.04%), 1.15% (0.62–2.14%) and 4.55% (2.68– 7.72%). The corresponding relative risk (95% confidence interval) of developing urothelial carcinoma was 1.00 (reference group), 2.46 (0.78–7.72), and 9.36 (3.03–28.92) after adjusting for cigarette smoking (Table 1). 3.2. Combinatory effects of arsenic exposure levels and cigarette smoking on urothelial carcinoma Table 2 shows the combinatory effects of the arsenic exposure levels and cigarette smoking on the development of urothelial car-
cinoma. Among both cigarette smokers and non-smokers, a significant dose–response relation to urothelial carcinoma risk was still observed for the arsenic concentration in the drinking water (p for trend 0.006 and <0.0001) and the cumulative arsenic exposure (p for trend 0.0384 and <0.0001). The highest risk of urothelial carcinoma was observed for the cigarette smokers who had the highest arsenic exposure levels. Compared to non-smokers who consumed drinking water with arsenic concentrations of <10 lg/L (reference group), smokers who consumed drinking water with an arsenic concentration of 100 + lg/L had an highly increased risk of developing urothelial carcinoma (relative risk, 14.85; 95% confidence interval, 2.80–78.63), as shown in Table 2. The corresponding relative risk (95% confidence interval) was 12.71 (3.34–48.36) for cigarette smokers with a cumulative arsenic exposure of 5000 + lg/Lyears compared to non-smokers with a cumulative arsenic exposure of <500 lg/L-years, as shown in Table 2. 3.3. Risk of lung cancer caused by arsenic exposure levels and cigarette smoking One participant without an exact birthdate and 14 participants affected with lung cancer before the enrollment were excluded in the analysis of the risk of lung cancer. As shown in Table 3, there
331.86 353.22
737.96
12,957 14,439
5827 43
c
d
Relative risk estimated using the Mantel–Cox method; Arsenic concentration <10 lg/L or cumulative arsenic exposure <500 lg/L * y without cigarette smoking habit as referent. One participant without birthdate and 14 participants had lung cancer before enrollment. ⁄ p < 0.05, ⁄⁄p < 0.01, ⁄⁄⁄p < 0.001. a
b
(p for trend 0.2050)
1.22 (0.60–2.50) 7823 640
11 5000+
140.62
513
43 51 1099 1217 1.00 (referent) 1.19 (0.68–2.07)
651 (p for trend 0.2308)
103.49 127.67 21,258 21,931 Cumulative arsenic exposure (lg/L y)c <500 1657 22 500–4999 1748 28
1.30 (0.67–2.56) 135.61 11,799 16 945 100+
2.88 (1.72–4.82)⁄⁄⁄ 1.00 (referent) 3.09 (1.87–5.09)⁄⁄⁄ 1.05 (0.70– 1.58) 6.31 (3.74– 2.17 (1.42– 10.65)⁄⁄⁄ 3.32)⁄⁄⁄ (p for trend (p for interaction < 0.0001) 0.0005)
652.28 7512
926 1251 1.00 (referent) 1.15 (0.64–2.08) 103.81 123.47 18 27 Arsenic concentration (lg/L)c <10 1358 10–99 1743
17,339 21,867
49
No. of No. of Person-years of participants cancer cases follow-up
34 55
Yes
Incidence rate (per 100,000 Adjusted relative person-years) riska,b,d
2.72 (1.53–4.83)⁄⁄ 1.00 (referent) 3.14 (1.85–5.33)⁄⁄⁄ 1.15 (0.75– 1.77) 6.04 (3.49– 2.14 (1.38– 10.48)⁄⁄⁄ 3.32)⁄⁄⁄ (p for (p for trend interaction < 0.0001) 0.0006) 312.48 371.49
3.4. Combinatory effects of arsenic exposure levels and cigarette smoking on lung cancer
No. of No. of Person-years of participants cancer cases follow-up
Incidence rate (per 100,000 Adjusted relative person-years) riska,b,d
were 223 newly diagnosed cases of lung cancer in 99,048 personyears of follow-up. The incidence rate per 100,000 person-years was 184.27, 223.60 and 336.60 for arsenic concentrations in drinking water of <10, 10–99, and 100 + lg/L, respectively. The corresponding lifetime (35–85 years old) cumulative risk (95% confidence interval) of developing lung cancer was 7.42% (5.51– 9.99%), 8.99% (7.04–11.49%), and 17.09% (12.76–22.89%), respectively, as shown in Fig. 2. The corresponding relative risk (95% confidence interval) of developing lung cancer was 1.00 (the reference group), 1.14 (0.80–1.61), and 1.84 (1.28–2.65), after adjusting for cigarette smoking. Cigarette smoking was also associated with an increased risk of lung cancer, showing a relative risk (95% confidence interval) of 3.44 (2.00–5.90) after adjusting for the arsenic concentration in the drinking water. Table 3 also shows the lung cancer incidence rate by cumulative arsenic exposure. There was an increasing biological gradient of lung cancer risk with the cumulative arsenic exposure. The incidence rate per 100,000 person-years was 189.98, 217.21, and 395.62 for cumulative arsenic exposure levels of <500, 500–4999, and 5000+ lg/L-years. As shown in Fig. 2, the corresponding lifetime cumulative risk (95% confidence interval) of developing lung cancer was 7.84% (6.00– 10.25%), 9.23% (7.15–11.91%), and 17.46% (12.78–23.85%). The corresponding relative risk (95% confidence interval) of developing lung cancer was 1.00 (reference group), 1.09 (0.79–1.52), and 1.85 (1.29–2.65) after adjusting for cigarette smoking (Table 3).
No
Cigarette smoking
Table 4 Incidence rate and relative risk of lung cancer by the combination of arsenic concentrations in drinking water/cumulative arsenic exposure and cigarette smoking habit at enrollment.
10,881 14,805
T.-Y. Yang et al. / Journal of Asian Earth Sciences 77 (2013) 332–337
Adjusted relative riska,d
336
Table 4 shows the combinatory effects of arsenic exposure levels and cigarette smoking on the development of lung cancer. Among both cigarette smoker and non-smokers, the significant dose–response relation to lung cancer risk was still observed for the arsenic concentration in the drinking water and the cumulative arsenic exposure. The highest risk of lung cancer was observed for cigarette smokers who had the highest arsenic exposure levels. Compared to non-smokers who consumed drinking water with arsenic concentrations of <10 lg/L (the reference group), smokers who consumed drinking water with an arsenic concentration of 100 + lg/L had a highly increased risk of developing lung cancer (relative risk, 6.04; 95% confidence interval, 3.49–10.48). The corresponding relative risk (95% confidence interval) was 6.31 (3.74–10.65) for cigarette smokers with a cumulative arsenic exposure of 5000 + lg/L-years compared to non-smokers with a cumulative arsenic exposure of <500 lg/L-years, as shown in Table 4.
4. Discussion Both arsenic and cigarette smoking have been documented as group 1 human carcinogens of lung and urinary tract cancer (IARC, 2004a,b). In this study, we found a significant biological gradient of urothelial carcinoma and lung cancer with increasing arsenic exposure levels, which is consistent with previous findings observed in Southwestern and Northeastern Taiwan, in Argentina, and in Chile (Chen et al., 1988, 2004, 2010a,b; Wu et al., 1989; Chiou et al., 1995; 2001; Ferreccio et al., 2000; Hopenhayn-Rich et al., 1998; Smith et al., 1998). However, the lifetime cumulative risk of arsenic-induced urothelial carcinoma and lung cancer has never been assessed. To the best of our knowledge, this was the first study that estimated the lifetime cumulative risk of urothelial carcinoma and lung cancer caused by the arsenic concentration in drinking water and the cumulative arsenic exposure. The cumulative risk of arsenic-induced lung cancer was much higher than that of arsenic-induced urothelial carcinoma.
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The synergistic interaction between cigarette smoking and arsenic in drinking water has been previously reported for lung cancer (Chen et al., 2004; Ferreccio et al., 2000). We found similar synergistic interactions for both urothelial carcinoma and lung cancer. For those who have been exposed to high-arsenic drinking water, it is recommended to avoid exposures to cigarette smoke. This study provides an accurate estimation of arsenic exposure for each person. Each household in the area of interest in Northeastern Taiwan had a tube well in its backyard, and house members were using the well water for drinking and cooking. The arsenic concentration in the drinking water and the cumulative arsenic exposure may have been estimated in Northeastern Taiwan more accurately for each participant than in Southwestern Taiwan, where all households in a village shared several wells, thereby making the arsenic exposure difficult to estimate. This study has limitations. First, data on the concentration of arsenic in the drinking water were unavailable for approximately 15% of the participants in our study, which resulted in a reduced number of study participants included in the analysis (consequently lowering the statistical power of the study). Nevertheless, we still found a significant dose–response relationship between arsenic exposure and cancer risk, as well as a significant synergistic interaction between cigarette smoking and arsenic exposure. Second, we did not actively examine the occurrences of newly developed cancer by using regular follow-up health examinations. Early-stage cancer cases may therefore have been missed in the computerized linkage with cancer registry profiles. Because the national cancer registry in Taiwan is almost complete, current, and accurate, the number of cancer cases missed in data linkage would likely be small. Furthermore, the missing cases would occur in various exposure groups non-differentially, which would result in the underestimation of the relative risk. However, we still found a significantly elevated relative risk of urothelial carcinoma and lung cancer associated with arsenic exposure and cigarette smoking. In other words, the relative risks were estimated in a conservative manner. 5. Conclusion In this large-scale long-term follow-up cohort study, we observed a significant dose–response relationship between arsenic exposure and the risk of urothelial carcinoma and lung cancer. We estimated the lifetime cumulative risk of urothelial carcinoma and lung cancer for various categories of exposure to arsenic in the drinking water. We documented the synergistic effects between cigarette smoking and arsenic exposure on the development of urothelial carcinoma and lung cancer. Acknowledgment Funding was supported by Grants (NSC100-2314-B-001-004MY3&NSC100-2314-B-001-006-MY3) from the National Science Council and Academia Sinica, Taipei, Taiwan. References Carlson-Lynch, H., Beck, B.D., Boardman, P.D., 1994. Arsenic risk assessment. Environmental Health Perspectives 102, 354–356.
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