. 2014 Jun 2;13:44. doi: 10.1186/1476-069X-13-44

Table 2.

Summary results from ecological studies reporting on arsenic exposure and the risk of bladder cancer

Study [reference] (Table from original publication)	Study locale	Outcome	Exposure¹[comments]	ICD²	Outcome measure	Cases	Risk estimate (95% CI)
Chen et al. 1985³[24]	84 villages from 4 neighbouring townships on SW coast, Taiwan	Mortality 1968-82	Median arsenic content of artesian well and (range): 780 μg˙•L^-1 (350–1,140); in shallow well: 40 (0.0–300). Period of samples collection not reported.	ICD 188	SMR_male	167	11.0 (9.33–12.7)
Chen et al. 1985³[24]		Mortality 1968-82		ICD 188	SMR_female	165	20.1 (17.0–23.2)
			[Comparison of mortality rate in Blackfoot disease-endemic areas (BFD) with those of the general population.]
*Chen et al. 1988⁴[26] (Table One)	BFD endemic area, Taiwan	Mortality 1973-86	Arsenic well water concentration (μg˙•L^-1). Period of samples collection not reported.	ICD9 188
			General population		ASMR_male
			< 300			–	3.1
			300-590			–	15.7
			≥ 600			–	37.8
						–	89.1
			General population		ASMR_female
			< 300			–	1.4
			300-590			–	16.7
			≥ 600			–	35.1
			[Comparison of mortality rate in BFD with those of the general population.]			–	91.5
*Wu et al. 1989⁵[27] (Table Three)	BFD endemic area, Taiwan (42 villages)	Mortality 1973-86	Arsenic well water concentration (μg˙•L^-1) based on well water samples collected between 1964–66.	ICD8 188
			< 300		ASMR_male	23	22.6
			300–590			36	61.0
			≥ 600			26	92.7
			< 300		ASMR_female	30	25.6
			300–590			36	57.0
			≥ 600			30	111.3
Chen and Wang 1990⁶[28] (Table Four)	314 precincts & townships in Taiwan, including 4 from BFD endemic area	Mortality 1972-83	Average arsenic levels in water samples of all 314 geographical units. 73.9% had < 5% of wells with > 50 μg˙•L^-1 ; 14.7% had 5-14%; 11.5% had ≥ 15%. Well water samples collected between 1974–76.	ICD 188
			All precincts & townships		ASMR_male	–	3.9 (0.5)
			All precincts & townships		ASMR_female	–	4.2 (0.5)
			Southwestern townships		ASMR_male	–	3.7 (0.7)
					ASMR_female	–	4.5 (0.7)
Chiang et al. 1993⁷[29] (Table Two)	BFD endemic area in Taiwan and 2 neighbouring areas	Incidence 1981-85	Exposure not evaluated, but based on Chen et al. 1985, the median arsenic content of artesian well in this area was 780 μg˙•L^-1 (350 – 1,140); that of shallow well was 40 μg˙•L^-1 (0.0 – 300). Period of samples collection not reported.	N/A	Endemic area
					IR_{_both_sex}	140	23.5
					IR_male	81	26.1
					IR_female	59	21.1
			[Comparison of incidence rate in BFD with those of neighbouring areas and Taiwan as a whole.]		Neighbouring Endemic area
					IR_{_both_sex}	13	4.45
					IR_male	7	4.65
					IR_female	6	4.28
					All Taiwan
					IR_{_both_sex}	2,135	2.29
					IR_male	1,608	3.31
					IR_female	527	1.17
Hopenhayn-Rich et al. 1996⁸[35] (Table Three)	26 counties in Cordoba, Argentina	Mortality 1986-91	Arsenic drinking water concentration ranging from 100 to 2,000 μg˙•L^-1.	ICD9 188
*Hopenhayn-Rich et al. 1998 [36] (Tables Three, Four)			Low			113	0.80 (0.66–0.96)
			Medium		SMR_male	116	1.28 (1.05–1.53)
			High (178 μg˙•L^-1 on average)			131	2.14 (1.78–2.53)
			Low			39	1.21 (0.85–1.64)
			Medium		SMR_female	29	1.39 (0.93–1.99)
			High (178 μg˙•L^-1 on average)			27	1.82 (1.19–2.64)
			[Arsenic measurements from a variety of sources, including official reports of water analyses from the 1930, 2 scientific sampling studies and a water survey.]
Guo et al. 1997⁹[37] (Table Two)	243 townships in Taiwan	Incidence 1980-87	Arsenic well water concentration ranging from < 50 to > 640 μg˙•L-¹.	ICD 188	RD_male	–	0.57 (0.07)
Guo et al. 1997⁹[37] (Table Two)	243 townships in Taiwan	Incidence 1980-87	Estimate presented measured at > 640 μg˙•L^-1.	ICD 188	RD_female	–	0.33 (0.04)
			[Arsenic measurements from a National survey of 83,656 wells in 243 townships, collected mostly between 1974–76.]
Rivara et al.1997 [38] (Table Four)	Chile	Mortality 1950-92	Annual average arsenic concentration in drinking water for Antofagasta (Region II of Chile) ranging between 40 to 860 μg˙•L^-1. Data from historical records from 1950–1992.	ICD 188	RR	–	10.2 (8.6–12.2)
			[Comparison of mortality rate in Region II (exposed populations) vs Region VIII (control populations.]
Smith et al. 1998 [39]	Chile	Mortality 1989-93	Region II of Northern Chile with population weighted average arsenic concentration in drinking water up to 569 μg˙•L^-1 compared with the rest of Chile; exposure generally < 10 μg˙•L^-1.	N/A	SMR_male	93	6.0 (4.8–7.4)
Smith et al. 1998 [39]	Chile	Mortality 1989-93		N/A	SMR_female	64	8.2 (6.3–10.5)
			[Arsenic measurements from 1950–94.]
Hinwood et al. 1999 [88] (Table Two)	22 areas in Victoria, Australia	Incidence 1982-91	Median water arsenic concentration ranging 13 μg˙•L^-1 to 1,077 μg˙•L^-1.	ICD 188, 189.1-189.3	SIR	303	0.94 (0.84–1.06)
			[Selected areas were those where samples with soil and/or water arsenic concentration were generally in excess of 10 μg˙•L^-1. Period for samples collection is not available.]
*Tsai et al. 1999 [41] (Tables Two, Three)	4 townships from BFD endemic area in SW coast, Taiwan	Mortality 1971-94	Median arsenic content of artesian well: 780 μg˙•L^-1 (range: 350–1,140). Period of samples collection not reported. Authors state that artesian wells were no longer used by the mid-1970s.	ICD9 188	SMR_local-male	312	8.92 (7.96–9.96)
					SMR_{national-male}	312	10.5 (9.37–11.7)
			[Comparison of mortality in BFD endemic area with that of a local reference population (Chiayi-Tainan county) and that of Taiwan as a whole.]		SMR_local-female	295	14.1 (12.51–15.8)
					SMR_{national-female}	295	17.8 (5.70–19.8)
*Lamm et al. 2004¹⁰[89] (Table One)	133 counties in 26 states, USA	Mortality 1950-79	Arsenic groundwater water concentration (μg˙•L^-1). Period of samples collection not reported.	N/A		Counties
			3.0–3.9		SMR_{white_male}	53	0.95 (0.89–1.01)
			4.0–4.9		SMR_{white_male}	22	0.95 (0.88–1.02)
			5.0–7.4		SMR_{white_male}	28	0.97 (0.85–1.12)
			7.5–9.9		SMR_{white_male}	14	0.89 (0.75–1.06)
			10.0–19.9		SMR_{white_male}	11	0.90 (0.78–1.04)
			20.0–49.9		SMR_{white_male}	3	0.80 (0.54–1.17)
			50.0–59.9		SMR_{white_male}	2	0.73 (0.41–1.27)
			[Median arsenic concentration ranged between 3–60 (μg˙•L^-1), with 65% of the counties and 82% of the population in the range of 3–5 (μg˙•L^-1).]
Marshall et al. 2007 [50] (Table Three)	Chile	Mortality 1950-2000	Northern Chile (Region II) with population weighted average arsenic concentration in drinking water up to 569 μg˙•L^-1 vs Region V which is otherwise similar to Region II but not exposed to arsenic. Between 1958–1970, arsenic concentration in water supply of Antofagasta and nearby Mejillones (Region II) averaged 870 μg˙•L^-1 and declined in the 1970s when water treatment plants were installed.	ICD 188
					RR_{male-1971–73}	9	1.71 (0.80–3.69)
					RR_{male-1974–75}	9	5.95 (2.22–16.0)
					RR_{male-1977–79}	17	2.10 (1.19–3.72)
					RR_{male-1980–82}	35	5.04 (3.13–8.10)
					RR_{male-1983–85}	41	5.77 (3.66–9.09)
					RR_{male-1986–88}	47	6.10 (3.97–9.39)
					RR_{male-1989–91}	52	4.73 (3.23–6.94)
					RR_{male-1992–94}	62	4.95 (3.47–7.06)
					RR_{male-1995–97}	56	4.43 (3.07–6.38)
					RR_{male-1998–2000}	58	4.27 (2.98–6.11)
					RR_{female-1971–73}	7	3.45 (1.34–8.91)
					RR_{female-1974–75}	4	3.09 (0.90–10.6)
					RR_{female-1977–79}	10	5.39 (2.24–13.0)
					RR_{female-1980–82}	22	9.10 (4.59–18.1)
					RR_{female-1983–85}	22	8.41 (4.30–16.4)
					RR_{female-1986–88}	37	7.28 (4.44–12.0)
					RR_{female-1989–91}	35	6.61 (4.02–10.9)
					RR_{female-1992–94}	42	13.8 (7.74–24.5)
					RR_{female-1995–97}	44	7.60 (4.78–12.1)
					RR_{female-1998–2000}	50	9.16 (5.76–14.5)
*†Meliker et al. 2007 [90] (Table Two)	6 counties, Southeastern Michigan, USA	Mortality 1979-97	Population weighted median arsenic concentration in water of 7.58 μg˙•L^-1. Data from 9,251 well water samples collected between 1983–2002.	ICD9 188	SMR_male	348	0.94 (0.82–1.08)
					SMR_female	171	0.98 (0.80–1.19)
*†Pou et al. 2011¹²[63] (Table Two)	26 counties in province of Cordoba, Argentina	Mortality 1986-2006	Arsenic drinking water concentration ( μg˙•L^-1). Period of samples collection not reported.	ICD10 C67
			Low (0–40)		SMR_male	–	3.14 (2.9–3.4)
			Medium (40–320)			–	4.0 (3.6–4.5)
			High (320–1,800)			–	4.7 (4.1–5.4)
			Low (0–40)		SMR_female	–	1.0 (reference)
			Medium (40–320)			–	0.94 (0.84–1.1)
			High (320–1,800) [Arsenic measurements from many surveys, one dating 50 years prior to study publication but with arsenic levels showing high degree of consistency with a more recent survey with no exact date detailed.]			–	1.2 (1.04–1.4)
*†Su et al. 2011 [64] (Table Two)	BFD endemic area, Taiwan	Mortality 1979-2003	Median arsenic content of artesian well: 780 μg˙•L-1 (range: 350–1,140). [Period of samples collection not reported. Artesian wells in the region were dug in the 1920s but no longer used by mid-1970s. Results show a comparison of mortality in BFD endemic area with that of Taiwan.]	ICD9 188	SMR	785	5.3 (4.9–5.6)
†Aballay et al. 2012¹¹[62] (Table Two)	123 districts in province of Cordoba, Argentina	Incidence 2004	Arsenic water samples from 3 aquifers: (1) Rjojan plain (concentration ranged 0–40 μg˙•L^-1 - 23 wells), (2) Pampean mountains (0–320 μg˙•L^-1- 114 wells) and (3) Chaco-Pampean plain (0–1,800 μg˙•L^-1 - 301 wells). In 80 wells, arsenic was undetected.	N/A	RR_male	–	13.8 (6.80–28.0)
					RR_female	–	12.7 (2.51–63.9)
†Fernández et al. 2012 [55]	Antofagasta, Chile	Mortality 1983-2009	Arsenic drinking water concentration ranging 800–900 μg˙•L^-1. [Arsenic levels based on the last 60 years and obtained from the local tap water company in Antofagasta. Results compares mortality rate in Antofagasta with the rest of Chile.]	ICD10 C67	RR_male	–	5.3 (4.8–5.8)
†Fernández et al. 2012 [55]	Antofagasta, Chile	Mortality 1983-2009		ICD10 C67	RR_female	–	7.8 (7.0–8.7)
					RR_{both_sex}	–	6.1 (5.7–6.6)

*Study included in meta-analyses.

†Recent study not included in the International Agency for Research on Cancer 2012 review (Monograph 100C [23]).

¹ All ecological studies assessed arsenic exposure at the group-level.

²ICD = International Classification for Disease for cancer site abstracted which included, bladder and urothelial/transitional cell carcinoma of the bladder or kidney. Transitional cell carcinoma of the renal pelvis often share the same etiology as bladder cancer, and as such, have been treated as bladder within the meta-analyses as recommended by IARC [23]. N/A = not available.

³SMR, standardized mortality ratio.

⁴Age-standardized mortality rates per 100,000 using the 1976 world population as standard population and based on 899,811 person-years.

⁵All age-standardized mortality rates shown are significant at p < 0.001 based on trend test.

⁶ Regression coefficient showing an increase in age-adjusted mortality per 100,000 persons-years for every 0.1 ppm increase in arsenic level, adjusting for indices of industrialization and urbanization. Standard errors are in brackets. Bladder cancer was significantly correlated with average arsenic level in water.

⁷Incidence rate per 100,000, adjusted for age.

⁸County is the unit of analysis.

⁹RD, rate difference (per 100,000 person-years) for one unit increase in the predictor and associated standard error for exposure > 640 μg˙•L^-1(SE). Results shown for transitional-cell carcinoma.

¹⁰Average annual age-adjusted (to U.S. 1970 standard population) death rates per 100,000 abstracted at the state level for each decade were used as standard rates to calculate county-specific SMRs.

¹¹Incidence rate ratio estimates with arsenic as continuous.

¹²Used lung cancer mortality rates as surrogate to smoking - may result in an overestimation of risk where smoking has declined; an underestimation of risk where smoking has increased; and an over-adjusted model as lung cancer is also associated with arsenic exposure.