LAUSR

Supplemental Digital Content is available in the text. Gallbladder cancer (GBC) is an aggressive malignancy, associated with dismal outcomes. Although several risk factors including age, sex, and gallstones have been postulated, epidemiologic determinants of the disease remain largely uncovered. Moreover, the implication of environmental toxicants as possible risk factors is increasingly suspected. Arsenic (As), an established human carcinogen, is a natural contaminant of groundwater and has a geographic distribution similar to GBC incidence. This, combined with As metabolites being partially excreted in bile, raised the hypothesis that As may represent a carcinogenic hazard for the gallbladder. We conducted an analysis of the association between As concentration in groundwater and incidence rates of GBC worldwide in 52 countries. The USA, India, and Taiwan were selected on the basis of availability and quality of data for further investigation at a county-level. Relationships between As levels and GBC incidence were assessed using multivariable linear regression analyses. Analyses revealed significant associations between high As concentrations in groundwater and increased GBC incidences. Among women, correlations were observed worldwide (Spearman = 0.31, P = 0.028), in Taiwan (Spearman = 0.57, P = 0.005) and in India (R2 = 0.23, P = 0.006). In men, a correlation was observed in India (R2 = 0.26, P = 0.009) and a modest correlation was identified in the USA (Spearman = 0.14, P = 0.026). These results provide some support to the hypothesis of an association between high exposures to As-contaminated water on GBC, which appeared more prominent in women. Further observational and molecular studies, conducted at the individual level, are required to confirm this association and decipher its nature.