Arseniasis-endemic Areas Research Articles

Chromosomal aberrations in arsenic-exposed human populations: a review with special reference to a comprehensive study in West Bengal, India

For centuries arsenic has played an important role in science, technology, and medicine. Arsenic for its environmental pervasiveness has gained unexpected entrance to the human body through food, water and air, thereby posing a great threat to public health due to its toxic effect and carcinogenicity. Thus, in modern scenario arsenic is synonymous with “toxic” and is documented as a paradoxical human carcinogen, although its mechanism of induction of neoplasia remains elusive. To assess the risk from environmental and occupational exposure of arsenic, in vivo cytogenetic assays have been conducted in arseniasis-endemic areas of the world using chromosomal aberrations (CA) and sister chromatid exchanges (SCE) as biomarkers in peripheral blood lymphocytes. The primary aim of this report is to critically review and update the existing in vivo cytogenetic studies performed on arsenic-exposed populations around the world and compare the results on CA and SCE from our own study, conducted in arsenic-endemic villages of North 24 Parganas (district) of West Bengal, India from 1999 to 2003. Based on a structured questionnaire, 165 symptomatic (having arsenic induced skin lesions) subjects were selected as the exposed cases consuming water having a mean arsenic content of 214.96 µg/l. For comparison 155 age-sex matched control subjects from an unaffected district (Midnapur) of West Bengal were recruited. Similar to other arsenic exposed populations our population also showed a significant difference (P < 0.01) in the frequencies of CA and SCE between the cases and control group. Presence of substantial chromosome damage in lymphocytes in the exposed population predicts an increased future carcinogenic risk by this metalloid.

Prevalence of non-insulin-dependent diabetes mellitus and related vascular diseases in southwestern arseniasis-endemic and nonendemic areas in Taiwan.

There is evidence indicating that ingestion of arsenic may predispose the development of diabetes mellitus in arsenic-endemic areas in Taiwan. However, the prevalence of diabetes and related vascular diseases in the entire southwestern arseniasis-endemic and nonendemic areas remains to be elucidated. We used the National Health Insurance Database for 1999-2000 to derive the prevalence of non-insulin-dependent diabetes and related vascular diseases by age and sex among residents in southwestern arseniasis-endemic and nonendemic areas in Taiwan. The study included 66,667 residents living in endemic areas and 639,667 in nonendemic areas, all greater than or equal to 25 years of age. The status of diabetes and vascular diseases was ascertained through disease diagnosis and treatment prescription included in the reimbursement claims of clinics and hospitals. The prevalence of non-insulin-dependent diabetes, age- and gender-adjusted to the general population in Taiwan, was 7.5% (95% confidence interval, 7.4-7.7%) in the arseniasis-endemic areas and 3.5% (3.5-3.6%) in the nonendemic areas. Among both diabetics and nondiabetics, higher prevalence of microvascular and macrovascular diseases was observed in arseniasis-endemic than in the nonendemic areas. Age- and gender-adjusted prevalence of microvascular disease in endemic and nonendemic areas was 20.0% and 6.0%, respectively, for diabetics, and 8.6% and 1.0%, respectively, for nondiabetics. The corresponding prevalence of macrovascular disease was 25.3% and 13.7% for diabetics, and 12.3% and 5.5% for nondiabetics. Arsenic has been suggested to increase the risk of non-insulin-dependent diabetes mellitus and its related micro- and macrovascular diseases.

Arsenic in drinking water and adverse pregnancy outcome in an arseniasis-endemic area in northeastern Taiwan

The well water in Lanyang Basin, which is located in the northeastern portion of Taiwan island, was found to have high levels of arsenic ranging from undetectable levels (<0.15 ppb) to 3.59 ppm. We performed a study to compare the risk of adverse pregnancy outcomes (preterm delivery and birthweight) between an area with historic high well water arsenic levels (arsenic-exposed area (AE)) and a comparison area with no historic evidence of arsenic water contamination (non-arsenic-exposed area (NAE)). The mean birth weight in the AEs and NAEs were 3132.6 and 3162.6 g, respectively. Babies born in AEs were on average 30 g lighter than those born in NAEs. AEs had a higher rate of preterm delivery than NAEs (3.74% vs 3.43%). The results of this study suggest that, after adjustment for potential confounders, arsenic exposure from drinking well water was associated, although not significantly, with the risk of preterm delivery, with an odds ratio of 1.10 (0.91–1.33). The estimated reduction in birth weight was 29.05 g (95% CI=13.55–44.55). The findings from this investigation provide evidence for a potential role for arsenic exposure through drinking water in increasing the risk of low birthweight.

C-Src-dependent Activation of the Epidermal Growth Factor Receptor and Mitogen-activated Protein Kinase Pathway by Arsenic: ROLE IN CARCINOGENESIS

Environmental or occupational exposure to arsenic is associated with a greatly increased risk of skin, urinary bladder, and respiratory tract cancers in arseniasis-endemic areas throughout the world. Arsenic shares many properties of tumor promoters by affecting specific cell signal transduction pathways responsible for cell proliferation. The activation of the epidermal growth factor receptor (EGFR)-extracellular signal-regulated protein kinase (ERK) pathway is important in mediating gene expression related to regulation of cellular growth. In the current studies, we demonstrate that arsenic activates EGFR and ERK in a human uroepithelial cell line. The EGFR phosphorylation by arsenic is ligand-independent and does not involve the major autophosphorylation site Tyr(1173). c-Src activity is also induced by arsenic and is a prerequisite for the EGFR and ERK activation. Consistent with these in vitro observations, exposure of mice to arsenic in drinking water, which has been found previously to be associated with AP-1 activation and epithelial proliferation, induces EGFR and ERK activation in the urinary bladder. This response is also accompanied with an increase in c-Src levels interacting with EGFR. These findings represent a potential pathway for mediating arsenic-induced phenotypic changes in the uroepithelium.

Incidence of transitional cell carcinoma and arsenic in drinking water: a follow-up study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan.

A significant association between ingested arsenic and bladder cancer has been reported in an arseniasis-endemic area in southwestern Taiwan, where many households share only a few wells in their villages. In another arseniasis-endemic area in northeastern Taiwan, each household has its own well for obtaining drinking water. In 1991-1994, the authors examined risk of transitional cell carcinoma (TCC) in relation to ingested arsenic in a cohort of 8,102 residents in northeastern Taiwan. Estimation of each study subject's individual exposure to inorganic arsenic was based on the arsenic concentration in his or her own well water, which was determined by hydride generation combined with atomic absorption spectrometry. Information on duration of consumption of the well water was obtained through standardized questionnaire interviews. The occurrence of urinary tract cancers was ascertained by follow-up interview and by data linkage with community hospital records, the national death certification profile, and the cancer registry profile. Cox proportional hazards regression analysis was used to estimate multivariate-adjusted relative risks and 95% confidence intervals. There was a significantly increased incidence of urinary cancers for the study cohort compared with the general population in Taiwan (standardized incidence ratio = 2.05; 95% confidence interval (CI): 1.22, 3.24). A significant dose-response relation between risk of cancers of the urinary organs, especially TCC, and indices of arsenic exposure was observed after adjustment for age, sex, and cigarette smoking. The multivariate-adjusted relative risks of developing TCC were 1.9, 8.2, and 15.3 for arsenic concentrations of 10.1-50.0, 50.1-100, and >100 microg/liter, respectively, compared with the referent level of < or =10.0 microg/liter.

Chen and Chiou Respond to “Arsenic and Cancer of the Urinary Tract” by Cantor

Received for publication December 11, 2000, and accepted for publication December 19, 2000. Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan. Department of Public Health, College of Medicine, Taipei Medical University, Taipei, Taiwan. Reprint requests to Prof. Chien-Jen Chen, 1 Jen-Ai Road, Section 1, Taipei 10018, Taiwan (e-mail: cjchen@ha.mc.ntu.edu.tw). In his commentary (1) on our paper (2), Cantor has provided an excellent summary of the current state of knowledge on ingested arsenic and cancer risk. He has also highlighted a number of important issues regarding the epidemiologic study of risk of arsenic-induced cancers due to arsenic in drinking water. We shall briefly address several of his comments. As Cantor points out, there is an urgent need to reassess the maximum contamination level of arsenic in drinking water. Global environmental change, rapid population growth, and manmade pollution have led to a shortage of available surface water for drinking and cooking in many countries. In more and more areas, underground water is being used as the main source of water for daily consumption. Since arsenic is a ubiquitous element in the earth’s crust and is abundant in well water, arseniasis is becoming an emerging epidemic in several Asian countries (3). Epidemiologic studies on skin cancer carried out in southwestern Taiwan have long been used for risk assessment of arsenic in drinking water (4). Because the water of shallow wells in this arseniasis-endemic area had a high salt content, rather than microbial contamination as observed in Bangladesh and West Bengal, India, residents in the area had used high-arsenic artesian well water from the early 20th century to the 1970s. There was a striking difference in the arsenic levels of water obtained from shallow wells and artesian wells. Since vital statistics were collected at the village level and there were several wells in each village that were shared by villagers, the median arsenic level of water in the wells of a given village was used as the exposure information. In our earlier studies on arsenic and internal cancers (5, 6), we grouped arsenic levels in well water into three broad groups: <300, 300–599, and ≥600 μg/liter. In a reanalysis of cancer mortality using more refined exposure levels, we found that the current maximum contamination level of 50 μg/liter is associated with a substantial excess risk of cancer and is not sufficiently protective of public health (7, 8). However, the data from southwestern Taiwan had two limitations, as Cantor noted: 1) use of the median level of arsenic during the 1960s as the exposure dose and 2) use of mortality rather than incidence to estimate cancer risk. Our current study in northeastern Taiwan (2) provided better measurement of arsenic levels in individual households. Furthermore, we used incidence rather than mortality to assess the risk of transitional cell carcinoma. As Cantor mentioned, our conclusions were indeed based on the assumption that current or recent measures of arsenic in water from these wells could represent long term historical levels. We conducted retests of arsenic levels in the water of randomly sampled wells. The correlation for the repeated measurements was quite high. Although 2,199 (26 percent) of the study subjects had changed wells at some time prior to study enrollment, they had used their current wells for approximately 60 percent (standard deviation 21) of their life span. In other words, most of them had used their current wells for at least 10 years. There is indeed individual susceptibility to arsenic-induced health hazards. Undernourishment, liver dysfunction, poor arsenic methylation capability, and low serum levels of antioxidant vitamins have been found to increase the risk of arsenic-related vascular diseases and skin cancer (9–12). Genetic polymorphisms of glutathione S-transferases M1, T1, and P1 and several DNA repair enzymes were recently found to modify the risks of skin cancer and transitional cell carcinoma induced by arsenic (13–15). Both acquired and genetic susceptibility must be taken into consideration in assessment of the risk of arsenic. Inorganic arsenic is readily absorbed through ingestion and is widely distributed in the human body. It does not require metabolic activation to exert its effects. The health hazards of arsenic do not show any unique organotropism. In addition to various malignant neoplasms and circulatory diseases (16, 17), arsenic has been documented to induce diabetes mellitus and lens opacity (18, 19). Diseases other than cancer must be considered in setting the maximum contamination level of inorganic arsenic in drinking water.