The element arsenic is an environmental contaminant found in soil, air, food, and water. Chronic exposure to high levels of inorganic arsenic (iAs) is associated with numerous adverse effects, such as skin lesions, vascular diseases, cancers, reproductive toxicity, and neurological effects. Cancers of the skin and other internal organs, including the lungs, liver, bladder, and kidneys, are associated with iAs exposure. In some areas of the world, such as Bangladesh, India, China, Chile, Argentina, and Mexico, there are high levels of iAs at > 100 ppb in their drinking water[1–3]. According to the literature, bladder and kidney cancer mortality resulting from arsenic exposure has a long latency, with increased risks not manifesting until 40 years after exposure to arsenic. The International Agency for Research on Cancer (IARC), based on compelling evidences, indicate that arsenic increases the risk of urinary bladder cancer. Studies have demonstrated that the association between exposure to iAs in drinking water and bladder cancer is detectable only after exposure to iAs concentrations exceeding 100 µg/L. A prospective cohort study in northeastern Taiwan reported that the multivariate-adjusted relative risk of urinary tract cancer was statistically significant for residents who drank well water containing arsenic at levels > 100 µg/L[4, 5]. Results from different geographical areas have indicated a threshold for the association between iAs exposure at concentrations of 100 µg/L or higher and bladder cancer[6–8]. An increase in cancer mortality among cohorts exposed to extremely high levels at beyond 500 ppb of arsenic has been reported in Japan and Chile [9, 10]. The risks related to exposure to arsenic in the 10–100 µg/L range remain unclear[11, 12]. In studies on lower arsenic exposure conducted in the United States, no increase in bladder cancer incidence was found in populations consuming drinking water containing iAs at concentrations lower than 100 µg/L[12–14]. Multiple epidemiological studies have supported that exposure to low concentrations of iAs may not increase the risk of bladder cancer[8, 15].
On the other hand, a study demonstrated an association between low-to-moderate levels of arsenic in drinking water and bladder cancer risk in New England. In addition, a review article characterizing the risks in populations exposed to low concentrations of arsenic identified a potential association between bladder cancer risk and exposure to arsenic at concentrations of less than 100 µg/L in drinking water. An ecological study demonstrated that a low concentration arsenic may be associated with lung and bladder cancers. However, evidence in the form of individual data with dose-response relationship remains lacking.
Most previous epidemiological reports have focused on the relationship between arsenic exposure and bladder cancer, whereas only a few studies have addressed the relationship between arsenic exposure and upper urinary tract urothelial carcinoma (UUT-UC). Furthermore, a clear association between arsenic exposure and higher UUT-UC mortality rates has not been reported[19–22]. In a study in Chile, exposure to arsenic was reportedly related to a critical need for UUT-UC health care and to high mortality rates, even after arsenic levels in drinking water had been controlled for 25 years. An unusually high incidence of UUT-UC has been reported in southwestern and northeastern Taiwan[4, 24]. For renal pelvis and ureter cancers, the adjusted odds ratios (ORs) based on average intakes of arsenic at the high concentrations of < 400, 400–1,000, and > 1,000 µg/day (median water concentrations of 60, 300, and 860 µg/L) were 1.00, 5.71 (95% confidence interval [CI]: 1.65, 19.82), and 11.09 (95% CI: 3.60, 34.16; Ptrend < 0.001), respectively. Although the IARC has indicated that the evidence that ingested arsenic causes lung, bladder, and skin cancer is sufficient, a similar statement has not been made for kidney cancer or other UUT-UC because “no studies have reported dose–response relationships on the basis of individual exposure data.” However, a study presented a latency pattern of increased mortality from kidney cancer among young adults exposed to arsenic and indicated that early life exposure may result in markedly higher kidney cancer mortality. Therefore, investigations of the association between iAs exposure and UUT-UC under low-to-moderate exposure necessitates a relatively long period of observation.
Methylation is the central issue concerning inorganic arsenic carcinogenesis in humans. Studies have suggested that a higher ratio of methylarsonic acid (MMA) to dimethylarsinic acid (DMA) in urine is associated with an increased risk of developing bladder cancer[27, 28]. Studies have demonstrated that the risk of developing skin and bladder cancer increases with the percentage of methylated arsenic in urine[29, 30]. Furthermore, the overall risk of bladder (OR = 1.79; 95% CI: 1.42–2.26, n = 4 studies) and lung (OR = 2.44; 95% CI: 1.57–3.80, n = 2 studies) cancer increased significantly with the increase in %MMA without statistical heterogeneity. In addition, a Taiwanese study demonstrated that subjects with a lower methylation capacity were more likely to develop a dose–response relationship between iAs exposure below the low-to-moderate range and lung cancer. However, the effects of low-to-moderate arsenic exposure and its methylation on urothelial tract cancers occurrence are awaiting for investigations. Therefore, this study also aims to examine the moderating effects of iAs methylation capacity on the relationship between low-to-moderate iAs exposure and urothelial tract cancers.