Background:

Evidence linking arsenic in drinking water to digestive tract cancers is limited. We evaluated the association between arsenic levels in groundwater and gallbladder cancer risk in a case–control study (2019–2021) of long-term residents (≥10years) in two arsenic-impacted and high gallbladder cancer risk states of India—Assam and Bihar.

Methods:

We recruited men and women aged 30 to 69 years from hospitals (73.4% women), with newly diagnosed, biopsy-confirmed gallbladder cancer (N = 214) and unrelated controls frequency-matched for 5-year age, sex, and state (N = 166). Long-term residential history, lifestyle factors, family history, socio-demographics, and physical measurements were collected. Average-weighted arsenic concentration (AwAC) was extrapolated from district-level groundwater monitoring data (2017–2018) and residential history. We evaluated gallbladder cancer risk for tertiles of AwAC (μg/L) in multivariable logistic regression models adjusted for important confounders [Range: 0–448.39; median (interquartile range), T1–0.45 (0.0–1.19); T2–3.75 (2.83–7.38); T3–17.6 (12.34–20.54)].

Results:

We observed a dose–response increase in gallbladder cancer risk based on AwAC tertiles [OR = 2.00 (95% confidence interval, 1.05–3.79) and 2.43 (1.30–4.54); Ptrend = 0.007]. Participants in the highest AwAC tertile consumed more tubewell water (67.7% vs. 27.9%) and reported more sediments (37.9% vs. 18.7%) with unsatisfactory color, odor, and taste (49.2% vs. 25.0%) than those in the lowest tertile.

Conclusions:

These findings suggest chronic arsenic exposure in drinking water at low-moderate levels may be a potential risk factor for gallbladder cancer.

Impact:

Risk factors for gallbladder cancer, a lethal digestive tract cancer, are not fully understood. Data from arsenic-endemic regions of India, with a high incidence of gallbladder cancer, may offer unique insights. Tackling ‘arsenic pollution’ may help reduce the burden of several health outcomes.

Arsenic and inorganic arsenic compounds is a Group-1 carcinogen (1). Exposure to high levels in the drinking water, food, ambient air, or occupational exposure (e.g., mining, glass manufacturing, metal smelting, farming) is associated with an increased risk of specific cancers, with strong evidence for skin, urinary bladder, and lung cancers, and suggestive for kidney, liver, breast, and prostate cancers (2–6). High levels of arsenic in the groundwater arising from geogenic and anthropogenic activities, is an endemic public health concern in certain regions of South America (Argentina, Chile, Mexico, Bolivia, Uruguay), Asia (Bangladesh, China, Taiwan, India, Japan, Pakistan, Nepal, Myanmar) as well as certain parts of the US (Arizona, Pennsylvania, Colorado, Nevada, California), Canada, and Eastern Europe (5, 7).

Long-term exposure to arsenic can yield varying signs and symptoms of toxicity depending on the population and geographic region, due to interacting factors such as social determinants and lifestyle factors, genetic susceptibility, and differences in arsenic metabolism in the body (5, 8). While World Health Organization's current recommended limit of arsenic in drinking water is 10 μg/L, comprehensive evaluations of in vitro, in vivo, and human evidence indicate a threshold level of arsenic for these cancers to be around 100 μg/L, ranging between 50 and 150 μg/L (3, 9, 10).

Arsenic from drinking water is absorbed through the digestive tract, metabolized in the liver, and accumulates in the gallbladder, before getting excreted in urine and (partly) in bile (8, 11). It is hypothesized that less toxic metabolites of arsenic, such as the pentavalent and di-methylated forms, are excreted through urine, while toxic forms of mono-methylated and trioxides are excreted through bile by accumulating in the gallbladder (8). Evidence for the association of arsenic in drinking water and digestive tract cancers is limited (6, 12, 13).

Gallbladder cancers are rare and lethal, disproportionately affecting women in certain parts of Asia, South America, and Eastern Europe (14, 15), and India accounts for nearly a fifth of the global gallbladder cancer burden (15). Since 1998, population-based cancer registries in India have recorded some of the highest incidence rates in the world (16, 17)—6 of the top 10—with Northeast, East, and North India recording 3 to 7 times higher incidence than the rest of the country [e.g., age-standardized rate (ASR) per 100,000 women (2012–2016): 8.6–17.1 vs. 0.7–4.1 in South India]. In the Northeast, the state of Assam records the highest incidence in the country (ASR/100,000: 17.1–8.0 and 8.8–5.2 in women and men, respectively), whereby the rates in women are comparable with breast cancer and higher than cervical cancer, the leading cancer sites among women in India [e.g., ASR per 100,000 women (2012–2016): 8.6–17.1 for gallbladder cancer; 4.9–14.5 for cervix and 12.8–27.1 for breast cancer; ref. 14]. Opportunities for early detection, curative treatment and a complete assessment of risk factors for primary prevention are sparse (16–18), and there is limited evidence for an association between arsenic with gallbladder cancer (19–22). Ecological evidence from 52 countries indicates preliminary ecological correlations of arsenic levels in groundwater with gallbladder cancer incidence in arsenic endemic regions of India, Taiwan, and the USA (8).

Published literature to date include biological specimen estimations in Japan and India (19, 22), a hospital-based registry study on the ecological association of gallbladder cancer incidence with soil levels of arsenic in India (20), a Mendelian Randomization study of non-endemic European populations (21) and a serum metal analysis in China (23), that suggest gallbladder cancer risk may be associated with arsenic levels (19, 20, 22) but not all (21, 23). In India, regions of high arsenic contamination mirror areas with high gallbladder cancer incidence rates. The states of West Bengal, Punjab, Bihar, Assam, and Uttar Pradesh comprise one third of the arsenic-contaminated regions in the country, with 9% to 36% of the area in these regions potentially affecting 20% to 30% of the population at-risk, and these regions also record some of the highest incidence rates of gallbladder cancer in the country (14). In Bihar and Uttar Pradesh, for example, levels as high as 1,000 μg/L and >20,000 μg/L (respectively) have been recorded from groundwater spatial monitoring in 2019 (24).

We evaluated the association between arsenic exposure from drinking water and the risk of gallbladder cancer using a hospital-based case–control study among residents of Assam and Bihar, the two most arsenic-impacted states of India next to West Bengal and Punjab (24). Arsenic exposure was estimated using long-term residential history along with groundwater monitoring data for arsenic levels in drinking water.

Study participants’ identification and recruitment

This is a multicenter case–control hospital-based study conducted in 2019–2021 in the states of Assam and Bihar in Northeast and Eastern India, respectively (Supplementary Fig. 1). The eligibility criteria for all participants were age 30 to 69 years (at diagnosis for gallbladder cancer cases and at registration for matched controls) and residence in the study regions for at least 10 years. Cases were patients with newly diagnosed, biopsy-confirmed gallbladder cancer (International Classification of Disease-Oncology code C23) with a date of diagnosis from January 1, 2019, through March 31, 2021. For cases, men and women with any prior treatment for gallbladder cancer or history of another primary cancer were excluded from the study. For cancer-free controls, men and women with any prior history and/or treatment for gallbladder cancer or history of another primary cancer or any gallbladder disease including gallstones and gallbladder polyps were excluded from the study. Pregnant and lactating women as well as participants with cognitive problems, who cannot complete a questionnaire or recall residential history, were excluded from the study.

Cases were recruited from two large cancer centers located in the study regions (Bhubaneshwar Borooah Cancer Institute, Guwahati, Assam and Mahavir Cancer Sansthan and Research Center, Patna, Bihar). Cases had a date of diagnosis less than 6 months from the date of registration with any stage of disease and could not have started any treatment before recruitment into the study.

Controls were recruited from the nearest large specialty centers for ophthalmology (Sri Sankaradeva Nethralaya in Guwahati, Assam) or orthopedics (Akshat Seva Sadan Multispecialty Hospital, Patna, Bihar) that catered to the same catchment regions of the cases and within 6 months of the cases’ diagnosis. Due to COVID-related shutdowns, the protocol was adapted to include control participants in Assam who were cancer-free attendants of other patients unrelated to study participants and were attending outpatient departments for diseases other than gallbladder and related gastrointestinal sites at Bhubaneshwar Borooah Cancer Institute. All controls were frequency matched to cases in 5-year age groups (30–34, 35–39,… 65–69 years), sex, and region of residence (Assam or Bihar). We recruited consecutive eligible and consenting participants (N = 380; 214 cases and 166 controls) across the participating institutes. The overall response rate was 82% for cases and 86.4% for controls.

Our objectives were achieved by selecting hospital-based controls whose disease status was independent of environmental risk factors (e.g., orthopedic, and ophthalmic outpatient wards) as well as by selecting both cases and controls from locations with varied (high or low or medium) environmental exposures within the study sites (Supplementary Fig. 1).

Further, we excluded participants with prior history of any gallbladder disease from our control group for the following reasons: (i) to avoid overmatching of cases and controls by known and unknown common risk factors (14, 22); (ii) to exclude potential causal intermediates (e.g., gallstones) that may fall within the spectrum gallbladder cancers (16, 25, 26).

We obtained written informed consent from all study participants. Information sheets in the local language were given to the participants, and their signatures were obtained in the consent forms. Ethics committee approval was obtained from all participating institutions, which included the coordinating center Public Health Foundation of India (TRC IEC-389/18), as well as from study hospitals (BBCI-TMC/Misc-119/MEC/231/2019; 09/RMRI/EC/2019; SSN/IEC/JAN/2019/29), and the procedures followed were in accordance with the ethical standards of the committee with recognized ethical guidelines of Declaration of Helsinki. Strict COVID control protocol as approved by the ethical committee was followed during COVID pandemic.

Long-term residential history assessment

Self-reported long-term residential history from birth or early childhood was collected using structured interviewer-administered questionnaires. Information on (i) village/town/city, (ii) tehsil/taluk/revenue block or circle/sub-district, (iii) district and state, (iv) PIN code (similar to zip code in the US), and (v) duration of stay (in years) at a particular residential location were collected. Information on out-of-state addresses and the respective duration of stay were also collected.

All our study participants had lived in Assam and/or Bihar for at least 10 years (range: 15–70 years). Our study participants were permanent residents of the states of Assam and Bihar with 95.5% living in these regions for over 3 decades of life [median (interquartile range, IQR), 50 years (42–60 years)]. Very few participants (n = 23) reported residing in places outside of these states for a median (IQR) period of 9 years (2–15 years). Over half of the participants (52.1%) had at least 2 addresses but less than 5% had 3 addresses within Bihar/Assam. A fifth of participants (20.5%) resided in at least 2 different districts and 3 participants reported addresses in 3 different districts. The district-level information was incomplete for 1 participant thus, the final analyses included n = 379 participants.

Average-weighted arsenic concentration estimation (Supplementary Table 1)

Groundwater monitoring in India is undertaken by the Ministry of Jal Shakti through National Rural Drinking Water Programme and the Central Ground Water Board. Samples are collected once to several times a year from their network of wells across India and reported as annual data. The arsenic concentrations are measured from groundwater-sourced drinking water samples collected from tubewells and analyzed using ultraviolet-visible spectrophotometry and atomic absorption spectrophotometry. In India, while first reports of groundwater contamination of arsenic were between 1976 and 1983, regional estimations began in early 2000. Eleventh 5-year plan document of India (2007–2012) recognized the importance of surveillance and monitoring of water quality and set-up high quality testing laboratories with qualified manpower, equipment, and chemicals. More detailed and accurate information across several districts and blocks of the country are available from 2015 and the 2017–2018 period provided complete data coverage over the study area.

We calculated average-weighted arsenic concentration (AwAC) by extrapolating district-level groundwater monitoring data (2017–2018) and long-term residential history. Groundwater monitoring data from central groundwater board for the states of Assam and Bihar included samples from 192,694 wells from across 71 districts and the data on arsenic levels averaged per district varied between zero and 448.39 μg/L (Supplementary Figs. 2 and 3). Average weighted arsenic concentration in μg/L was estimated by ∑Ci Ti / ∑Ti where Ci denoted the district average of groundwater arsenic concentration and Ti denoted the duration of residence in the ith district respectively (27). The exposure measure AwAC (μg/L) ranged between zero and 448.39 μg/L and categorized into tertiles [median (IQR): T1–0.45 (0.0–1.19) μg/L; T2–3.75 (2.83–7.38) μg/L; T3–17.6 (12.34–20.54) μg/L; Supplementary Figs. 2 and 3].

Other exposure measures (Supplementary Table 1)

‘Maximum average arsenic concentration’ (MxAC) was estimated as the highest median level of average arsenic concentration in ground water (μg/L) at any point in long-term residence and ‘cumulative maximum average arsenic concentration’ (CMxAC) was estimated on the basis of the highest median level of average arsenic concentration in ground water at any point in long-term residence multiplied by the duration of residence at that level (μg/L*years). In a subset of participants who had block-level address data, block-level AwAC, MxAC, and CMxAC were estimated. Close to half of our participants had complete tehsil/block level information (n = 184) for all their self-reported addresses; 66.3% remained in one tehsil/block, 33.1% in 2 tehsils/blocks and one participant shifted locations across 3 tehsils/blocks. The groundwater monitoring data included samples from 783 blocks for these states and the data on arsenic levels averaged per block varied between zero and 662.0 μg/L (Supplementary Table S2).

Covariates data collection

Structured interviewer-administered questionnaire data and anthropometric measurements were collected on important factors that may act as confounders, mediators, and effect modifiers. Data on the source of primary drinking water (tubewells/borewells, handpump, piped/bottled water/surface water, dugwells), the use of any purification methods before consumption (e.g., filtration, boiling, chlorination, reverse osmosis/Aquaguard, solar disinfection), daily water intake (in liters) and water quality (presence of sediments, transparency, color, taste, and smell) were collected from all participants. Data on demographic and socioeconomic characteristics included age, marital status, religion, education, and occupation including long-term occupational history from the first employment of self, spouse, and parents. Additional information included lifestyle factors such as tobacco, alcohol, betel quid use, diet, and physical activity, family history of gall stones, gallbladder cancer and other malignancies, personal history of gallstones for cases, medical history including history of past typhoid infection, and reproductive history including ages at menarche, first pregnancy and menopause, total number of pregnancies and children, breast feeding duration, and use of oral contraceptive pills for women participants. Information on diet was collected using a validated semi-quantitative food-frequency questionnaire adapted for regional dietary patterns (28). A nutrient database, developed by the Aravind Eye Hospital, Madurai, India (29, 30), was used to calculate the macro and micro-nutrient content of each recipe using Indian food composition tables (Gopalan C, 1971; ref. 31). The United States Department of Agriculture nutrient database (Release No. 14) or McCance and Widdowson's Composition of Foods were used when nutrient values were unavailable from the Indian food composition tables. Data on types and amounts of physical activity during occupational, recreational, household and commuting time periods was collected using the previously validated Global Physical Activity Questionnaire (32). Weight was measured to the nearest 0.1 kg with a digital balance (TANITA-H S 302), and standing height was measured to the nearest 1 mm with a plastic portable stadiometer (SECA 213). Measurements were taken twice and the average of two values was used in the analysis. Each participant's weight and height were used to calculate body mass index (BMI), expressed as kg/m2. Waist circumference was measured using a non-stretch measuring tape.

Statistical analysis

All data were presented as means (SD) or medians (IQR) for continuous variables or as percentages for categorical variables. Bivariate comparisons of cases and controls with respect to drinking water variables, socio-demographic, lifestyle factors, family and medical histories, reproductive and anthropometric factors were carried out using χ2 test for differences in proportions, t test for differences in means and Wilcoxon Rank-Sum test for differences in medians. We used multivariable logistic regression analysis adjusted for a priori selected confounders and matching variables to test the association of estimated long-term arsenic exposure for gallbladder cancer risk. We reported OR with 95% confidence interval (CI). The covariates in fully adjusted models included age (years), sex (men/women), states (Assam/Bihar), education (no formal/formal education), monthly household income (Indian Rupees <10,000; ≥10,000), tobacco and betel quid use (ever/never), alcohol use (ever/never), passive smoke at home (yes/no), physical activity moderate to vigorous at work and leisure (yes/no), daily consumption of energy kcal/day and fruits and vegetables in g/day as tertiles and waist circumference (cm) in tertiles.

The study population consisted of 214 gallbladder cancer cases and 166 controls (Table 1). Controls were frequency-matched by age, sex, and states. While there were no differences in proportion between cases and controls by sex or region; on an average, cases were older in age (mean SD: 52.1 ± 9.7 years) than the controls (mean SD: 49.5 ± 12.1 years). About three-fourths of our cases (73.8%) and controls (72.9%) were women. In our study population, gallbladder cancer patients were less formally educated (57.3% vs. 36.1%), more involved in manual jobs (30.4% vs. 23%) and physically more active (29.4% vs. 19.4%) compared with controls. Cases consumed fewer fruits and vegetables each day [median (IQR): 281.9 g/day (205.8, 433.5) vs. 365.3 g/day (279.7, 493.6) in controls], reported more prior typhoid infections and had lower waist circumference and BMI than controls at the time of recruitment. Among women participants, parity was higher for cases than controls [total live births: median (IQR): 4.0 (3.0, 5.0) vs. 3.0 (2.0, 4.0)]. Over 40% of cases reported the history of gallstones in the past. Most cases (82.7%) were diagnosed at advanced stages (stages 3 or 4).

Table 1.

Characteristics of study participants.

CharacteristicsControl (N = 166)Case (N = 244)Pa
Age (years), mean (SD) 49.5 (12.1) 52.1 (9.7) 0.019 
Sex 
 Men 45 (27.1%) 56 (26.2%) 0.84 
 Women 121 (72.9%) 158 (73.8%)  
Region 
 Assam 109 (65.7%) 133 (62.1%) 0.48 
 Bihar 57 (34.3%) 81 (37.9%)  
Education 
 No formal education 60 (36.1%) 122 (57.3%) <0.001 
 School education 106 (63.9%) 91 (42.7%)  
Occupation 
 Unemployed 112 (67.9%) 143 (66.8%) 0.014 
 Manualb 38 (23.0%) 65 (30.4%)  
 Nonmanual 15 (9.1%) 6 (2.8%)  
Monthly household income, Indian rupees 
 <10,000 115 (69.3%) 167 (78.0%) 0.053 
 ≥10,000 51 (30.7%) 47 (22.0%)  
Tobacco/betel quid 
 Never 79 (47.9%) 90 (42.1%) 0.26 
 Everc 86 (52.1%) 124 (57.9%)  
Alcohol 
 Never 148 (89.7%) 194 (90.7%) 0.76 
 Everc 17 (10.3%) 20 (9.3%)  
Passive smoke at home 38 (22.9%) 58 (27.1%) 0.35 
Moderate-vigorous physical activity (in work & leisure) 32 (19.4%) 63 (29.4%) 0.025 
Daily energy consumption (kcal/day) median (IQR) 3066.2 (2501.3–3901.2) 2839.7 (2237.4–3873.2) 0.13 
Daily fruits-vegetables consumption (g/day) median (IQR) 365.3 (279.7–493.6) 281.9 (205.8–433.5) <0.001 
Household mustard oil consumption (liter/month) median (IQR) 3.0 (2.0–4.0) 3.0 (2.0–4.0) 0.69 
Nonvegetarian diet 147 (89.1%) 184 (86.0%) 0.37 
Drinking water source 
 Tubewell/Borewell 86 (52.4%) 113 (54.1%) 0.017 
 Piped/Bottled water 36 (22.0%) 26 (12.4%)  
 Handpump 27 (16.5%) 56 (26.8%)  
 Dugwell/Surface 15 (9.1%) 14 (6.7%)  
 Water purification before consumption 38 (29.5%) 49 (41.2%) 0.005 
 Daily water intake in L (median, IQR) 0.9 (0.5–3.1) 0.8 (0.6–3.1) 0.54 
 Presence of sediments in drinking water) 38 (22.9%) 73 (34.1%) 0.017 
 Unsatisfactory water quality 59 (35.5%) 93 (43.5%) 0.12 
Family history of cancer 18 (10.9%) 17 (7.9%) 0.32 
Family history of gallstones 12 (10.0%) 11 (9.9%) 0.98 
Waist circumference, cm, median (IQR) 84.1 (80.1–89.1) 81.4 (74.6–87.5) 0.007 
BMI, kg/m2, mean (SD) 23.4 (3.6) 21.0 (10.9) 0.008 
Parity among women, median (IQR) 3.0 (2.0–4.0) 4.0 (3.0–5.0) <0.001 
Oestrogen exposure in years, median (IQR) 30.0 (24.0–32.5) 30.0 (27.0–33.0) 0.27 
History of typhoid infection 1 (0.6%) 12 (5.6%) 0.020 
History of gallstones (only among cases) — 88 (41.1%) NA 
Stage at diagnosis for cases 
 Stage-3 — 32 (14.9%) NA 
 Stage-4  145 (67.8%)  
CharacteristicsControl (N = 166)Case (N = 244)Pa
Age (years), mean (SD) 49.5 (12.1) 52.1 (9.7) 0.019 
Sex 
 Men 45 (27.1%) 56 (26.2%) 0.84 
 Women 121 (72.9%) 158 (73.8%)  
Region 
 Assam 109 (65.7%) 133 (62.1%) 0.48 
 Bihar 57 (34.3%) 81 (37.9%)  
Education 
 No formal education 60 (36.1%) 122 (57.3%) <0.001 
 School education 106 (63.9%) 91 (42.7%)  
Occupation 
 Unemployed 112 (67.9%) 143 (66.8%) 0.014 
 Manualb 38 (23.0%) 65 (30.4%)  
 Nonmanual 15 (9.1%) 6 (2.8%)  
Monthly household income, Indian rupees 
 <10,000 115 (69.3%) 167 (78.0%) 0.053 
 ≥10,000 51 (30.7%) 47 (22.0%)  
Tobacco/betel quid 
 Never 79 (47.9%) 90 (42.1%) 0.26 
 Everc 86 (52.1%) 124 (57.9%)  
Alcohol 
 Never 148 (89.7%) 194 (90.7%) 0.76 
 Everc 17 (10.3%) 20 (9.3%)  
Passive smoke at home 38 (22.9%) 58 (27.1%) 0.35 
Moderate-vigorous physical activity (in work & leisure) 32 (19.4%) 63 (29.4%) 0.025 
Daily energy consumption (kcal/day) median (IQR) 3066.2 (2501.3–3901.2) 2839.7 (2237.4–3873.2) 0.13 
Daily fruits-vegetables consumption (g/day) median (IQR) 365.3 (279.7–493.6) 281.9 (205.8–433.5) <0.001 
Household mustard oil consumption (liter/month) median (IQR) 3.0 (2.0–4.0) 3.0 (2.0–4.0) 0.69 
Nonvegetarian diet 147 (89.1%) 184 (86.0%) 0.37 
Drinking water source 
 Tubewell/Borewell 86 (52.4%) 113 (54.1%) 0.017 
 Piped/Bottled water 36 (22.0%) 26 (12.4%)  
 Handpump 27 (16.5%) 56 (26.8%)  
 Dugwell/Surface 15 (9.1%) 14 (6.7%)  
 Water purification before consumption 38 (29.5%) 49 (41.2%) 0.005 
 Daily water intake in L (median, IQR) 0.9 (0.5–3.1) 0.8 (0.6–3.1) 0.54 
 Presence of sediments in drinking water) 38 (22.9%) 73 (34.1%) 0.017 
 Unsatisfactory water quality 59 (35.5%) 93 (43.5%) 0.12 
Family history of cancer 18 (10.9%) 17 (7.9%) 0.32 
Family history of gallstones 12 (10.0%) 11 (9.9%) 0.98 
Waist circumference, cm, median (IQR) 84.1 (80.1–89.1) 81.4 (74.6–87.5) 0.007 
BMI, kg/m2, mean (SD) 23.4 (3.6) 21.0 (10.9) 0.008 
Parity among women, median (IQR) 3.0 (2.0–4.0) 4.0 (3.0–5.0) <0.001 
Oestrogen exposure in years, median (IQR) 30.0 (24.0–32.5) 30.0 (27.0–33.0) 0.27 
History of typhoid infection 1 (0.6%) 12 (5.6%) 0.020 
History of gallstones (only among cases) — 88 (41.1%) NA 
Stage at diagnosis for cases 
 Stage-3 — 32 (14.9%) NA 
 Stage-4  145 (67.8%)  

aDifferences in mean by t test; differences in proportion by χ2 test; differences in median by Wilcoxon Rank-Sum test.

bUnskilled/semiskilled/skilled manual work.

cCurrent or former.

Average arsenic concentrations were estimated for each study participant based on long-term residential history and groundwater monitoring data (2017–2018) for the respective regions at district-level (N = 379; Supplementary Table S1). At the district level, AwAC ranged from 0 to 448.39 μg/L [median (IQR): T1–0.45 (0.0–1.19) μg/L; T2–3.75 (2.83–7.38) μg/L; T3–17.6 (12.34–20.54) μg/L] and the median duration of residence was 50 years (IQR: 40–60 years). Over a third of participants (35.1%) were exposed to levels above 10 μg/L for a median duration of 44 years (IQR: 30.5–57.5; range: 9 to 69 years). Less than a 10% of participants were exposed to maximum level of 50 μg/L or above for a median duration of 36 years (IQR: 19–48; range: 9 to 64 years). A similar pattern of estimated average arsenic concentrations was observed at the block-level in a subset of study participants (n = 184; Supplementary Table S2) and the distribution of AwAC and MxAC at the block-level and district-level were similar (Supplementary Fig. 4).

A higher proportion of participants in the highest tertile of AwAC compared with the lowest tertile consumed tubewell/borewell water for drinking (67.7 vs. 27.7%) with purification (45.2 vs. 25.5%) and reported sediments in water (35.7% vs. 18.9%) and unsatisfactory water-quality (49.2 vs. 25.0%) but reported less daily water intake [median (IQR): 0.6 (0.5, 1.3) vs. 2.5 (0.8, 3.8); Table 2]. When comparing cases and controls, gallbladder cancer cases more often used tubewell/borewell/handpump water (80.9% vs. 68.9%), noted sediments (34.1% vs. 24.9%) and reported unsatisfactory quality in terms of color, odor, and taste (43.5% vs. 35.5%) than controls. The overall quantity of water intake in this study population ranged between 0.125 and 6.25 L/day, with no significant difference in daily intake between cases and controls (Table 1).

Table 2.

Characteristics of study participants by average arsenic concentration in groundwater.

Mean (±SD)/Median (IQR)/Number (%)Tertile-1Tertile-2Tertile-3
Number132121126Pa
Median level of average weighted arsenic concentration in ground water μg/L 0.45 (0.0–1.19) 3.75 (2.83–7.38) 17.6 (12.34–20.54)  
Range (min-max levels) of average weighted arsenic concentration in ground water μg/L 0.0–1.19 1.38–8.97 9.14–448.39  
Age (years), mean (±SD) 49.8 (11.4) 52.1 (10.1) 51.0 (11.0) 0.25 
Sex 
 Women 84 (63.6%) 93 (76.9%) 101 (80.2%) 0.006 
Study Region 
 Assam 50 (37.9%) 94 (77.7%) 98 (77.8%) <0.001 
 Bihar 82 (62.1%) 27 (22.3%) 28 (22.2%)  
Education 
 No formal education 60 (45.5%) 59 (48.8%) 62 (49.6%) 0.78 
 School education 72 (54.5%) 62 (51.2%) 63 (50.4%)  
Occupation 
 Unemployed 77 (58.3%) 89 (73.6%) 88 (70.4%) 0.026 
 Manualb 42 (31.8%) 29 (24.0%) 32 (25.6%)  
 Nonmanual/profess/business 13 (9.8%) 3 (2.5%) 5 (4.0%)  
Household income 
 <10,000/month 95 (72.0%) 90 (74.4%) 96 (76.2%) 0.74 
 ≥10,000/month 37 (28.0%) 31 (25.6%) 30 (23.8%)  
Ever tobacco-betel quid usec 50 (38.2%) 83 (68.6%) 77 (61.1%) <0.001 
Ever alcohol usec 7 (5.3%) 19 (15.7%) 11 (8.7%) 0.019 
Passive smoking at home (yes) 21 (15.9%) 35 (28.9%) 40 (31.7%) 0.008 
No moderate-vigorous physical activity 101 (77.1%) 87 (71.9%) 95 (75.4%) 0.63 
Energy consumption kcal/day 2761.1 (2129.6, 3865.5) 3106.8 (2589.6, 4036.2) 2913.7 (2327.6, 3605.9) 0.10 
Fruits-vegetables consumption g/day 293.5 (208.9, 417.2) 350.8 (252.5, 505.1) 316.5 (232.3, 467.0) 0.024 
Family history of cancer 9 (6.9%) 14 (11.6%) 12 (9.5%) 0.43 
Drinking water source 
 Tubewell/Borewell 37 (28.7%) 78 (65.5%) 84 (67.7%) <0.001 
 Piped/Bottled water 43 (33.3%) 12 (10.1%) 7 (5.6%)  
 Handpump 43 (33.3%) 18 (15.1%) 21 (16.9%)  
 Dugwell/Surface 6 (4.7%) 11 (9.2%) 12 (9.7%)  
Water purification before consumption (yes) 38 (29.5%) 49 (41.2%) 56 (45.2%) 0.028 
Daily water intake in L (median, IQR) 2.5 (0.8–3.8) 0.8 (0.5–1.9) 0.6 (0.5–1.3) <0.001 
Presence of sediments in drinking water 25 (18.9%) 41 (33.9%) 45 (35.7%) 0.005 
Unsatisfactory water qualityd 33 (25.0%) 57 (47.1%) 62 (49.2%) <0.001 
Mean (±SD)/Median (IQR)/Number (%)Tertile-1Tertile-2Tertile-3
Number132121126Pa
Median level of average weighted arsenic concentration in ground water μg/L 0.45 (0.0–1.19) 3.75 (2.83–7.38) 17.6 (12.34–20.54)  
Range (min-max levels) of average weighted arsenic concentration in ground water μg/L 0.0–1.19 1.38–8.97 9.14–448.39  
Age (years), mean (±SD) 49.8 (11.4) 52.1 (10.1) 51.0 (11.0) 0.25 
Sex 
 Women 84 (63.6%) 93 (76.9%) 101 (80.2%) 0.006 
Study Region 
 Assam 50 (37.9%) 94 (77.7%) 98 (77.8%) <0.001 
 Bihar 82 (62.1%) 27 (22.3%) 28 (22.2%)  
Education 
 No formal education 60 (45.5%) 59 (48.8%) 62 (49.6%) 0.78 
 School education 72 (54.5%) 62 (51.2%) 63 (50.4%)  
Occupation 
 Unemployed 77 (58.3%) 89 (73.6%) 88 (70.4%) 0.026 
 Manualb 42 (31.8%) 29 (24.0%) 32 (25.6%)  
 Nonmanual/profess/business 13 (9.8%) 3 (2.5%) 5 (4.0%)  
Household income 
 <10,000/month 95 (72.0%) 90 (74.4%) 96 (76.2%) 0.74 
 ≥10,000/month 37 (28.0%) 31 (25.6%) 30 (23.8%)  
Ever tobacco-betel quid usec 50 (38.2%) 83 (68.6%) 77 (61.1%) <0.001 
Ever alcohol usec 7 (5.3%) 19 (15.7%) 11 (8.7%) 0.019 
Passive smoking at home (yes) 21 (15.9%) 35 (28.9%) 40 (31.7%) 0.008 
No moderate-vigorous physical activity 101 (77.1%) 87 (71.9%) 95 (75.4%) 0.63 
Energy consumption kcal/day 2761.1 (2129.6, 3865.5) 3106.8 (2589.6, 4036.2) 2913.7 (2327.6, 3605.9) 0.10 
Fruits-vegetables consumption g/day 293.5 (208.9, 417.2) 350.8 (252.5, 505.1) 316.5 (232.3, 467.0) 0.024 
Family history of cancer 9 (6.9%) 14 (11.6%) 12 (9.5%) 0.43 
Drinking water source 
 Tubewell/Borewell 37 (28.7%) 78 (65.5%) 84 (67.7%) <0.001 
 Piped/Bottled water 43 (33.3%) 12 (10.1%) 7 (5.6%)  
 Handpump 43 (33.3%) 18 (15.1%) 21 (16.9%)  
 Dugwell/Surface 6 (4.7%) 11 (9.2%) 12 (9.7%)  
Water purification before consumption (yes) 38 (29.5%) 49 (41.2%) 56 (45.2%) 0.028 
Daily water intake in L (median, IQR) 2.5 (0.8–3.8) 0.8 (0.5–1.9) 0.6 (0.5–1.3) <0.001 
Presence of sediments in drinking water 25 (18.9%) 41 (33.9%) 45 (35.7%) 0.005 
Unsatisfactory water qualityd 33 (25.0%) 57 (47.1%) 62 (49.2%) <0.001 

aDifferences in mean by t test; differences in proportion by χ2 test differences in median by Wilcoxon Rank-Sum test.

bUnskilled/semiskilled/skilled manual work.

cCurrent or former.

dNontransparent with abnormal color, smell & taste.

In multivariable analyses adjusted for age, sex, study region, education, occupation, use of tobacco, betel-nut products, alcohol, estimated energy intake, fruits-vegetables consumption, physical activity, exposure to passive smoke and waist circumference, participants with higher AwAC levels had an increased gallbladder cancer risk with successively higher risk in the second (2.00, 95% CI: 1.05–3.79) and third (2.43, 95% CI, 1.30–4.54) tertiles of AwAC compared with the lowest tertile (Ptrend for linearity = 0.007). These associations remained when we evaluated MxAC and CMxAC as exposure variables as well (Table 3). The findings were further confirmed with significant linear trend in a sub-set with block-level AwAC, MxAC and CMxAC estimations (Table 4).

Table 3.

Unadjusted and adjusted associations of arsenic concentration in groundwater at district level with gallbladder cancer risk (OR, 95% CI).

District levelAge, sex, and region adjustedFully adjusteda
AwACb Median level of weighted arsenic concentration in ground water μg/L N = 379 N = 366 
Tertile 1 (n = 132) 0.45 (0.0–1.19) Ref Ref 
Tertile 2 (n = 121) 3.75 (2.83–7.38) 1.85 (1.07–3.21) 2.00 (1.05–3.79) 
Tertile 3 (n = 126) 17.6 (12.34–20.54) 2.60 (1.49–4.53) 2.43 (1.30–4.54) 
Ptrend  0.001 0.007 
MxACc Median level of anytime maximum arsenic concentration in ground water μg/L N = 379 N = 366 
Tertile 1 (n = 131) 0.45 (0.0–1.95) Ref Ref 
Tertile 2 (n = 123) 7.38 (3.28–7.64) 2.22 (1.27–3.88) 2.42 (1.26–4.65) 
Tertile 3 (n = 125) 18.15 (12.87–25.35) 2.31 (1.33–4.01) 2.15 (1.15–4.02) 
Ptrend  0.004 0.024 
CMxACd Median level of cumulative maximum arsenic exposure dose μg/Lbyears N = 379 N = 366 
Tertile 1 (n = 127) 19.3 (0.0–39.22) Ref Ref 
Tertile 2 (n = 126) 191.93 (118.29–318.09) 1.33 (0.79–2.25) 1.40 (0.75–2.58) 
Tertile 3 (n = 126) 760.67 (577.87–1211.33) 2.04 (1.18–3.53) 2.08 (1.12–3.87) 
Ptrend  0.010 0.019 
District levelAge, sex, and region adjustedFully adjusteda
AwACb Median level of weighted arsenic concentration in ground water μg/L N = 379 N = 366 
Tertile 1 (n = 132) 0.45 (0.0–1.19) Ref Ref 
Tertile 2 (n = 121) 3.75 (2.83–7.38) 1.85 (1.07–3.21) 2.00 (1.05–3.79) 
Tertile 3 (n = 126) 17.6 (12.34–20.54) 2.60 (1.49–4.53) 2.43 (1.30–4.54) 
Ptrend  0.001 0.007 
MxACc Median level of anytime maximum arsenic concentration in ground water μg/L N = 379 N = 366 
Tertile 1 (n = 131) 0.45 (0.0–1.95) Ref Ref 
Tertile 2 (n = 123) 7.38 (3.28–7.64) 2.22 (1.27–3.88) 2.42 (1.26–4.65) 
Tertile 3 (n = 125) 18.15 (12.87–25.35) 2.31 (1.33–4.01) 2.15 (1.15–4.02) 
Ptrend  0.004 0.024 
CMxACd Median level of cumulative maximum arsenic exposure dose μg/Lbyears N = 379 N = 366 
Tertile 1 (n = 127) 19.3 (0.0–39.22) Ref Ref 
Tertile 2 (n = 126) 191.93 (118.29–318.09) 1.33 (0.79–2.25) 1.40 (0.75–2.58) 
Tertile 3 (n = 126) 760.67 (577.87–1211.33) 2.04 (1.18–3.53) 2.08 (1.12–3.87) 
Ptrend  0.010 0.019 

Ref, reference values.

aAge, sex, site, education, monthly household income, tobacco & betel quid use, alcohol, passive smoke at home, physical activity, fruits-vegetables, energy, waist.

bAwAC in μg/L = ∑Ci Ti / ∑Ti where Ci and Ti denote the district average of groundwater arsenic concentration and duration of residence in the ith district respectively (Chen and colleagues 2011; BMJ 2011;342:d2431).

cDistrict average maximum arsenic concentration of groundwater at any time of residence.

dDistrict average maximum arsenic concentration of groundwater at any time of residence multiplied by total duration of residence in that district.

Table 4.

Unadjusted and adjusted associations of arsenic concentration in groundwater at block-level with gallbladder cancer risk (OR, 95% CI).

Block level-subsetAge, sex, and region adjustedFully adjusteda
AwACb Median level of weighted arsenic concentration in ground water μg/L N = 184 N = 179 
Tertile 1 (n = 92) 0.0 (0.0–0.0) Ref Ref 
Tertile 2 (n = 31) 4.50 (2.0–6.47) 2.18 (0.89–5.32) 1.85 (0.64–5.35) 
Tertile 3 (n = 61) 16.95 (13.90–19.36) 2.36 (1.12–4.94) 2.63 (1.11–6.19) 
Ptrend  0.018 0.026 
MxACc Median level of anytime maximum arsenic concentration in ground water μg/L   
Tertile 1 (n = 92) 0.0 (0.0–0.0) Ref  
Tertile 2 (n = 31) 5.50 (2.0–10.0) 1.70 (0.71–4.06) 1.91 (0.67–5.41) 
Tertile 3 (n = 61) 18.80 (15.0–24.30) 2.74 (1.29–5.83) 2.63 (1.10–6.26) 
Ptrend  0.008 0.027 
CMxACd Median level of cumulative maximum arsenic exposure dose μg/Lbyears   
Tertile 1 (n = 92) 0.0 (0.0–0.0) Ref Ref 
Tertile 2 (n = 31) 175.5 (70.0–273.60) 2.68 (1.08–6.62) 2.40 (0.81–7.10) 
Tertile 3 (n = 61) 772.2 (528.90–1001.70) 2.10 (1.01–4.37) 2.32 (0.99–5.40) 
Ptrend  0.034 0.046 
Block level-subsetAge, sex, and region adjustedFully adjusteda
AwACb Median level of weighted arsenic concentration in ground water μg/L N = 184 N = 179 
Tertile 1 (n = 92) 0.0 (0.0–0.0) Ref Ref 
Tertile 2 (n = 31) 4.50 (2.0–6.47) 2.18 (0.89–5.32) 1.85 (0.64–5.35) 
Tertile 3 (n = 61) 16.95 (13.90–19.36) 2.36 (1.12–4.94) 2.63 (1.11–6.19) 
Ptrend  0.018 0.026 
MxACc Median level of anytime maximum arsenic concentration in ground water μg/L   
Tertile 1 (n = 92) 0.0 (0.0–0.0) Ref  
Tertile 2 (n = 31) 5.50 (2.0–10.0) 1.70 (0.71–4.06) 1.91 (0.67–5.41) 
Tertile 3 (n = 61) 18.80 (15.0–24.30) 2.74 (1.29–5.83) 2.63 (1.10–6.26) 
Ptrend  0.008 0.027 
CMxACd Median level of cumulative maximum arsenic exposure dose μg/Lbyears   
Tertile 1 (n = 92) 0.0 (0.0–0.0) Ref Ref 
Tertile 2 (n = 31) 175.5 (70.0–273.60) 2.68 (1.08–6.62) 2.40 (0.81–7.10) 
Tertile 3 (n = 61) 772.2 (528.90–1001.70) 2.10 (1.01–4.37) 2.32 (0.99–5.40) 
Ptrend  0.034 0.046 

Ref, reference values.

aAge, sex, site, education, monthly household income, tobacco & betel quid use, alcohol, passive smoke at home, physical activity, fruits-vegetables, energy, waist.

bAwAC in μg/L = ∑Ci Ti / ∑Ti where Ci and Ti denote the block average of groundwater arsenic concentration and duration of residence in the ith block respectively (Chen and colleagues 2011; BMJ 2011;342:d2431).

cBlock average maximum arsenic concentration of groundwater at any time of residence.

dBlock average maximum arsenic concentration of groundwater at any time of residence multiplied by total duration of residence in that block.

In this multicenter, hospital-based case–control study, chronic exposure to arsenic in drinking water was associated with an increased risk of gallbladder cancer in Assam and Bihar, India, after adjusting for important confounders. On the basis of estimates from long-term residential history and groundwater monitoring data, chronic exposure to arsenic concentrations averaging 1.38 to 8.97 μg/L in groundwater, yielded a 2-fold increased risk of gallbladder cancer, while higher arsenic levels (9.14–448.39 ug/L) yielded a 2.4 increased risk, with a significant linear dose–response trend (P = 0.007). These associations remained consistent with ‘MxAC’ and ‘CMxAC’ as exposure variables as well as in a sub-set with block-level exposure estimations. The median (IQR) duration of exposure at these levels was 50 years (40–60 years) and ranged between 16 to 70 years. Over a third of our participants were exposed to levels more than 10 μg/L, and a 6% were exposed to levels more than or equal to 50 μg/L.

Although there is limited epidemiologic evidence supporting an increased risk of gallbladder cancer due to arsenic exposure (8, 19–22), our findings for increased risk with chronic exposure to low-moderate levels of arsenic in drinking water are not in-line with the current evidence for a threshold level of arsenic for cancer risk (3). Recently an ecological study identified significant correlations between arsenic levels in groundwater of the regions and gallbladder cancer incidence rates among women in endemic regions of India and Taiwan, but a modest correlation in the USA, also possibly indicating a threshold effect (8). In India and Taiwan, the arsenic concentrations in groundwater are generally higher (up to >1,500 μg/L) than in the USA (up to >500 μg/L; ref. 7).

We hypothesize that long-term cumulative exposure of low-to-moderate levels of arsenic may be a risk factor for gallbladder cancer; this may also be true for other cancers in endemic regions. Emerging evidence suggests low levels of arsenic (10 μg/L) may be associated with up to a 40% increase in urinary bladder cancer risk (33) and 2-fold increase in melanoma and nonmelanoma skin cancers at levels as low as 1 to 2 μg/L (34). More recently, a systematic review in arsenic endemic and non-endemic regions (e.g., of North America and Europe) has shown significant increased risks of cardiovascular disease endpoints and hypertension (pooled relative risk: 1.2–1.9) due to arsenic in drinking water at levels 1 to 10 μg/L (35). Our results need to be interpreted in the context that different individuals and populations may exhibit different levels of toxicity (5). Interestingly, a recent comprehensive analysis of metals and metalloid species in China potentially reveals total arsenic in serum to be inversely associated with gallstones and gallbladder cancer with reduced risk at least up to 30% (23). The Mendelian Randomization approach in European populations explains this contradiction partly due to the differences in the ability to metabolize arsenic in these populations (21). Variation exists in the capacity to metabolize ingested arsenic, which may be partially explained by genetic factors. Increased inorganic arsenic and certain metabolites, such as monomethylarsonic acid, and decreased dimethylarsinic acid that are indicative of incomplete metabolism may explain the differences in arsenic toxicity in susceptible individuals, however the evidence to date is inconclusive with differences in European and Asian populations (21, 36).

Various pathways by which arsenic could initiate gallbladder cancer by concentrating in bile include direct DNA toxicity, DNA damage secondary to oxidative stress, cytotoxicity, disruption of repair mechanism, epigenetic modifications and immunotoxicity and reduced cell death (3). Competitive substitution activities, such as replacing phosphates and selenium, also may further aid in promoting carcinogenesis (11), wherein reduction in selenium and zinc levels are reported in serum, bile, and tissue samples of patients with gallbladder cancer compared with healthy controls (37) or controls with gallstones (38), especially in Indian populations. The role of inorganic arsenic (trioxide form) in disruption of estrogen signaling and steroid metabolism is also documented (6).

This study is one of the few attempts using long-term residential history assessments in low- and middle-income countries, to aid in understanding cumulative exposures and gallbladder cancer outcomes. Chronic diseases such as cancer have a latent period of at least 5 to 10 years, and long- vs. short-term exposures may have different influences on various stages of disease. Long-term residential history and historical data on different levels of exposures over time may capture some of these variations better than cross-sectional assessments and even may have an advantage over the point estimate using biological samples. Residential history also helps us to identify the sources of exposure at the individual level. For example, our findings showed that a high proportion of participants in the highest tertile of estimated average arsenic concentrations were likely to have consumed tubewell or borewell water for drinking with sediments. They also reported unsatisfactory water quality and less daily water intake. Thus, this exercise yielded results but not without limitations that need to be addressed in future similar efforts. Nevertheless, the findings need to be interpreted with caution due to small sample size and potential residual confounding with unknown and unmeasured factors.

The major limitations included one-time arsenic levels based on 2017–2018 groundwater monitoring data and the lack of biochemical validation from the primary drinking water source of the individuals. While periodic arsenic monitoring estimations are limited globally, and more so in developing country settings, studies in the literature have employed this strategy for long-term arsenic estimations, suggesting these estimations although crude might remain valid (27, 39), specifically for long-term residents with minimal residential relocations. The primary predictors of regional arsenic concentrations in groundwater include geology, soil characteristics, topography, and physical characteristics of aquifers, as well as climate. Thus, large shifts in the levels indicating a changing pattern or distribution of high- or low-level regions may take a long period. We have evidence in literature documenting temporal stability of average arsenic levels for up to 5 to 10 years in drinking water source (40–42). Occurrences of high arsenic in groundwater have been reported by several previous studies from a decade back from the districts of Bihar and Assam in India. A recent all India study on groundwater arsenic distribution by machine learning geospatial modelling utilized data points between 2005 and 2020 with stable distribution of arsenic contamination in high-impact zones of India over this time (43). Notably, in Bihar region the ‘hot-spots’ or high contaminated districts remained the same during this period.

It is also important to highlight the limitations of our control selection. By excluding self-reported benign gallbladder diseases it was possible that our associations were overestimated due to less exposure among selected controls compared with general healthy population (44). Data on population-based prevalence of gallbladder diseases is limited, nevertheless an overall 6% is reported in high-risk regions of India wherein the prevalence is higher among symptomatic than asymptomatic individuals (7% vs. 3%; ref. 45). Notably, the prevalence of gallstones among women in these regions is reported to be higher at >10% (16, 25). Further, the control selection also has limited our ability to interpret risk factor associations across broad spectrum of disease. On the other hand, undetected gallbladder conditions in the control group could have led to underestimated associations. While this would have been a major concern for lifestyle risk factors, environmental factors might be less influenced.

The findings of our study suggest it is feasible to collect long-term residential history to estimate chronic arsenic exposure. Our findings provide preliminary but suggestive evidence for the association of arsenic in drinking water and gallbladder cancer risk—which is understudied to date in rigorous epidemiologic studies—and in regions where both exposure and outcome are of significant public health importance. This may identify a potential preventive strategy for gallbladder cancer, a cancer site for which the unique geographic distribution and modifiable risk factors for prevention are not fully understood. While the findings need to be confirmed, tackling ‘arsenic pollution’ regardless may help reduce the burden of many other associated health outcomes (46). Efforts to generate data integrating long-term residential history with potentially associated environmental exposures at the individual level, may contribute to etiologic research. Further, we investigated low-to-moderate levels of arsenic in drinking water in two arsenic affected states of India for residency durations of 15 to 70 years. It may also have broader public health implications, such as monitoring high-risk populations for early signs of arsenic poisoning.

K. Shridhar reports grants from Centre for Environmental Health, Public Health Foundation of India during the conduct of the study. D. Prabhakaran reports grants from NIH Fogarty International Center, National Institutes of Environmental Health Sciences, NCI outside the submitted work. P.K. Dhillon reports other support from Genentech, Roche outside the submitted work. No disclosures were reported by the other authors.

Funders had no role in study design, data collection, analysis, or publication of the manuscript.

K. Shridhar: Conceptualization, resources, formal analysis, supervision, funding acquisition, writing–original draft, project administration. M. Krishnatreya: Resources, supervision, project administration, writing–review and editing. S. Sarkar: Data curation, formal analysis, methodology, writing–review and editing. R. Kumar: Resources, supervision, project administration, writing–review and editing. D. Kondal: Formal analysis, writing–review and editing. S. Kuriakose: Data curation, writing–review and editing. V. RS: Data curation, writing–review and editing. A.K. Singh: Resources, project administration, writing–review and editing. A.C. Kataki: Resources, supervision, writing–review and editing. A. Ghosh: Resources, supervision, writing–review and editing. A. Mukherjee: Formal analysis, supervision, writing–review and editing. D. Prabhakaran: Resources, supervision, writing–review and editing. D. Mondal: Investigation, methodology, writing–review and editing. P. Prabhakaran: Conceptualization, resources, supervision, writing–review and editing. P.K. Dhillon: Conceptualization, supervision, methodology, writing–review and editing.

This study was funded by the Public Health Foundation of India's Centre for Environmental Health core funds to Dr. Krithiga Shridhar as part of her Research Development Grant Fellowship (2018–2021). The groundwater arsenic data utilized by authors in the study (A. Mukherjee, A. Ghosh, and S. Sarkar) were partly supported by the project of the Department of Science and Technology (DST), Government of India [vide no. DST/TMD-EWO/WTI/2K19/EWFH/2019/201 (G) & (C) Dated: 28.10.2020].

The authors thank Dr. Aastha Aggrawal, Dr. Ruby Gupta, and Kritika Anand of the Public Health Foundation of India, Gurugram, Haryana; Dr. Sumita Sarma Barthakur and Dr. Gayatri Bharali of Sri Sankaradeva Nethralaya, Guwahati, Assam for their support during study inception; and Banti Kalita and Prakriti Snehil of the Public Health Foundation of India, Gurugram, Haryana for meticulous data collection and management. We thank all study participants for their kind contribution.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

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