Chronic Arsenic Exposure through Drinking Water and Risk of Type 2 Diabetes Mellitus: A study from Bangladesh

1.  Introduction

The contamination of groundwater with arsenic (As)is a big threat in various countries including Argentina, Australia, Bangladesh, Chile, China, Hungary, India, Mexico, Peru, Taiwan, and the United States of America exceeding the U.S. Environmental Protection Agency’s (EPA) maximum contaminant level (MCL) of 10 μg/L [1]. However, the worst case scenario has been reported in Bangladesh and West Bengal of India[2]. Approximately 56%of the tube wells (out of 34,000) throughout Bangladesh contain arsenic more than 10 μg/L and some 37% have greater than 50 μg/L [3]. It has been estimated that about 50 million people in Bangladesh are chronically exposed to arsenic through drinking water [4-6]. Public health problems related to chronic arsenic exposure through drinking water have been linked to increased risks of skin cancer [7] bladder, lung, and liver cancers [8,9] as well as cardiovascular diseases [10,11]. In addition, arsenic exposure has been suggested to be associated with development of diabetes mellitus as wel l [12]. A cohort study in Taiwan stated that a long-term exposure to arsenic is associated with diabetes mellitus in humans [13]. Similar findings have also been reported in the state of Coahuila, Mexico [14]. More recently, a cross-sectional study from National Health and Nutrition Examination Survey (NHANES) reported that the OR for diabetes was 3.6 (95% CI, 1.2-10.8) when they compared par­ticipants at the 80th percentile with those at the 20th percentile for urinary arsenic[15].As far as Bangladesh is concerned, a dose-response relationship between prevalence of diabetes mellitus and exposure to arsenic through drinking water was reported only in few studies[16,17].

Apart from arsenic exposure through drinking water, several studies reported occupational chronic arsenic exposure association with diabetes mellitus. For example, Swedish copper smelter workers revealed an increased risk of dying from diabetes mellitus with increasing arsenic exposure as compared to an unexposed control group [18]. In another study on Swedish art glass workers, the odds ratio of dying from diabetes mellitus was 1.8 for the exposed glass workers compared to unexposed ones [19]. Occupational exposure to arsenic was associated significantly with an increased level of glycosylated hemoglobin in Denmark [20] Other studies showed an increased morbidity and mortality of diabetic patients having exposed to arsenic at work when compared with general population or unexposed workers [18,19,21,22].

However, many studies opposed such association between chronic arsenic exposure and diabetes mellitus. For instance, no significant association was observed in a community-based studies in areas of low arsenic exposure in the USA [23,24].A study indicated no association between chronic arsenic exposure and diabetes, glycosuria, or blood HbA1c level in Bangladesh [25].Similarly, a couple of studies also reported no association of occupational arsenic exposures with increasing mortality of diabetes mellitus in arsenic-exposed workers than the general population [26-29].

This exploratory study further aimed at determining the possible association between chronic arsenic exposure and type 2 diabetes mellitus in Bangladesh taking into account demographic, social and medical risk factors.

2.   Methodology

This study was designed as a comparison of the prevalence of diabetes mellitus among subjects living in areas with and those without exposure to arsenic through drinking water. The total sample size was 300 including subjects exposed to arsenic (exposed subjects) and those not exposed to arsenic (unexposed subjects). Individuals aged 30 or more with skin manifestations such as keratosis, leucomelanosis and melanosis were defined as the exposed subjects in this study as skin lesions are a marker of pro­longed arsenic exposure. The skin lesions were confirmed by the physicians of local health centre. A total of 150 exposed subjects were randomly recruited from four village’s viz.Eruen, Madhaya Eruen, Rajapur and Nagrapa from Lacksam Upazila of Comilla district where groundwater is heavily contaminated with arsenic as reported from the national survey of Bangladesh Arsenic Mitigation Water Supply Project (BAMWSP). The arsenic concentration of artesian well water in these villages ranged from 0.07 to 1.4ppm with a mean concentration of 0.15 ppm. The standard for arsenic in drinking water set by the U.S. Environmental Protection Agency is 0.05 mg/L for Bangladesh [9].

A sum of 150unexposed subjects was arbitrarily recruited through door-to-door visit in a village Vespara, from Kaliganj Upazila of Jhenaidah district. The population of Jhenaidah was not known to be exposed to arsenic through drinking water according to the Water and Sewage Agency, Bangladesh. The unexposed subjects were recruited by matching age (≥30 years) and sex with the exposed subjects.

One exposed subject and two unexposed subjects with family history of hypertension were excluded from the study. Three exposed subjects and one unexposed subject denied taking part in the study. A semi-structured questionnaire was used to obtain information on socioeconomic, demographic characteristics, history of arsenic contaminated water consumption, height, weight, alcohol intake, cigarette smoking, physical activities, as well as personal, family history of hypertension and diabetes. The arsenic content of tube well water was taken from the report of BAMWSP survey. Type 2 diabetes was screened by a Glucometer. Diagnosis of DM was defined using the diagnostic criteria (FBG >6.1mmol/L) from the WHO guidelines.

3.   Statistics

The data were stratified according to age (30-44, 45-59, and >60 years), sex, and Body Mass Index (BMI). The BMI categories were <19, 19-22, and >22. Mantel-Haenszel weighted prevalence ratios (MH-PR) with 95 percent confidence intervals were calculated to determine the association of chronic arsenic exposure with type 2 diabetes mellitus. All the potential confounders were adjusted during the analysis. 

4.   Ethics

The study was approved by Khulna University, Khulna, Bangladesh as part of the graduation study. The study was performed following the Declaration of Helsinki principles and informed consent was given by all study participants before taking part in the survey.

5.  Results

This study was carried out in areas of high arsenic contamination in drinking water and compared with areas not containing arsenic in drinking water. The mean age of the exposed subjects was 45.5 years and unexposed subjects 45.7years. The number of male and female accounted for 26% and 74% respectively in the exposed subjects. The corresponding figures for male and female in the unexposed subjects were 30% and 70% respectively. The major occupations were housewife (74%) and farmer (12%)in the exposed subjects. In the unexposed subjects, the main occupations were also housewife (69%) and farmer (12%). In the exposed subjects, the age of most of the participants (53%) ranged from 30 to 44 years. While the corresponding figure for this age group in the unexposed subjects accounted for 51%. Participants aged between 45 and 60 years were stood at 35%and 37% in the exposed and unexposed subjects respectively. Among the exposed subjects, 74% had no formal education while the corresponding figure was 70% in the unexposed subjects. The comparison of socio-demographic characteristics between the exposed subjects and unexposed subjects are presented in (Table 1).

The exposed subjects had lower BMI compared to the unexposed subjects (Table 1). The history of alcohol intake, cigarette smoking, physical activities, as well as personal and family history of hypertension and diabetes in the family of the exposed subjects was comparable to those in the unexposed subjects (Table 1)

Diabetes mellitus was diagnosed in 13 individuals among the exposed subjects and in four persons among the subjects not exposed to arsenic through drinking water. The crude prevalence ratio for diabetes mellitus was3.5 (95%CI, 1.1-10.9) stating that the probability for developing diabetes mellitus for subjects exposed to arsenic contaminated drinking water is 3.5 times higher than those not exposed to arsenic through drinking water (Table 2).In order to find out a precise association between chronic arsenic exposure and diabetes mellitus, the effects of potential confounding factors viz. Age, Sex and BMI were adjusted. After adjusting for age (Table 3), the Mantel-Haenszel weighted prevalence ratio (MH-PR) was 3.5 (95% CI: 1.1-11.1, p=0.031). With adjustment for sex, MH-PR was 3.7 (95%CI: 1.1-11.8, p=0.029) (Table 4). When adjusted for BMI, MH-PR increased to 4.4 (95% CI: 1.1 - 17.2) p=0.032 (Table 5).

6.   Discussion

The results of this study support the association between chronic arsenic exposure and diabetes mellitus, as observed by other investigations [12,13,16,18,19].Exposure to inorganic arsenic, as indicated by animal and in vitro model systems, can potentially increase the risk of developing diabetes through its implications on the inhibition of insulin-dependent glu­cose uptake [30], insulin signaling [31], impairment of insulin secretion, transcription in pancre­atic beta cells [32] and modification of the expression of genes involved in insulin resistance [33]. However, the concentrations of arsenic in most of these experiments are high, and the resulting effects may not be pertinent to populations chronically exposed to arsenic in the environment.

Nevertheless, the epide­miologic literature suggests that diabetes is an adverse outcome associated with prolonged exposure to high levels of arsenic (>500 μg/L) in drinking water [17] among patients with skin lesions, a marker of pro­longed exposure, the OR for diabetes in associ­ation with 500-1,000 μg/L and >1,000 μg/L was 2.2 and 2.6 respectively [17]. In a cohort study in southwestern Taiwan, the OR of diabetes was 2.1 comparing individuals with cumulative arsenic exposure >17,000 μg/L-years to those with <17,000 μg/L-years [13].

On the other hand, the relation between inorganic arsenic exposure and diabetes mellitus has been reported yet to be inconclusive particularly at low to moderate levels of exposure to arsenic [34].  Even no evidence of an association was found in a study in Bangladesh where 90% of study population was exposed to well water arsenic (<300 μg/L) when comparing the highest level of exposure (176-864 μg/L; mean, 291.2 μg/L) with the lowest (0.1-8 μg/L; mean, 2.4 μg/L) [25].

Occupational studies have also been inconclusive. While in the studies at a copper smelter [18] and an art glass industry [19]in Sweden, an association between occupational arsenic exposure and diabetes has been reported, no relation has been observed in a US copper smelter [26]and in a UK tin smelter [35].The experimental and epidemiologic evidence suggest that the adverse effects on diabetes may be dose specific and limited to population with prolonged exposure to very high levels of arsenic exposure.

One of the main problems of published epidemiological studies is related to measurement errors. In several studies, only glycosuria [16,17] or statistical records [36-39] were used as a diagnosis of the disease. Only a couple of studies used glucose measurement after an oral glucose tolerance test [12,13] but in one of them the comparison group was not studied concurrently with the exposed group [13]. In our study, glucose measurement after an oral glucose tolerance test was used to diagnose diabetes as advised by WHO.

Deficiencies of trace elements such as copper and zinc have been suggested to play a role in the pathogenesis of diabetes mellitus [40]; administration of cadmium has been shown also to cause hyperglycemia [41]. Arsenic has been reported to interact with these chemicals. Arsenic exposure can lead to a significant increase in renal copper excretion and can potentiate the effects of cadmium when arsenic and cadmium are used together [42]. Arsenic may also compete with zinc in metal-binding proteins that display vicinal dithiols contained in zinc fingers of DNA binding and repair proteins. This competitive binding causes conformational change and altered biological function in proteins [43]. Due to financial restrictions in this explorational study, no other trace elements could be studied in the drinking water which is a limitation of this study.

In this study, all subjects were recruited from rural villages of almost similar occupation, socioeconomic status, and lifestyle. Therefore, these variables were reasonably similar between exposed and unexposed subjects and it was, therefore, unlikely to influence glycosuria either in the presence or absence of skin lesions.  The subjects unexposed to arsenic had higher BMI than those exposed to As. This might indicate that a low body mass may be ascribed to the effect of arsenic exposure for long time.

Availability of data on environmental exposure to arsenic is a great strength of our study. Unlike previous studies [15,23,24] this study popu­lation was well described with detailed data on the duration, source, and form of expo­sure. This study also considered social and clinical risk factors as well as other risk factors like alcohol intake, cigarette smoking, physical activities, plus personal and family history of hypertension and diabetes.

7.  Conclusions

This exploratory study suggests a possibility of association of chronic arsenic intake with type 2 diabetes mellitus. As such we recommend an organized large-scale study to address this public health issue.  In such a study, one may consider measuring other trace elements like Cadmium, Zinc and Copper in the drinking water.

8.  Acknowledgements

We would like to express our sincere gratitude to the study population for their active participation in the study. We are also grateful to the local health centers for their cooperation.

Variables	Exposed group (n=150)		Non-exposed group (n=150)
	No	(%)	No	(%)
Age (years)
30-44	80	53.3	76	50.7
45-60	53	35.3	56	37.3
>60	17	11.3	18	12
Sex
Male	39	26	45	30
Female	111	74	105	70
Occupation
Cultivator	18	12	17	11.3
Day labor	5	3.3	11	7.3
House wife	111	74	103	68.7
Business	7	4.7	15	10
Service	6	4	2	1.3
*Others	3	0.21	2	1.3
Education
No formal Education	111	74	105	70
Primary School	21	14	17	11.3
High School	12	8	21	14
SSC	5	3.3	4	2.7
HSC	1	0.7	3	2
Religion
Islam	147	98	52	34.7
Hinduism	3	2	98	65.3
Marital Status
Married	134	89.3	130	86.7
Widowed	14	9.3	20	13.3
Divorced	1	0.7	0
Never Married	1	0.7	0
Body Mass Index (BMI)
<19	90	60	33	22
19-22	36	24	51	34
>22	24	16	66	44
Physical Activities
Light	40	26.6	38	25.3
Moderate	79	52.6	73	48.6
Vigorous	31	20.6	39	20
Alcohol Intake	0	0	0	0
Cigarette Smoking	17	11.3	14	9.3
*Others=Rickshaw puller, Union Member, Tuition

 

Table 1: Socio-demographic characteristics of participants: exposed and unexposed subjects to arsenic through drinking water (n=300).

Arsenic exposure	Diabetes
	Diabetic	Non-diabetic	Total
Exposed	13 (8.7%)	137 (91.3%)	150 (100%)
Not exposed	4 (2.7%)	146 (97.3%)	150 (100%)
Total	17 (5.7%)	283 (94.3%)	300 (100%)
Fisher's Exact Test	0.043
Mantel-Haenszel Common Odds Ratio	3.5
95% Confidence Interval	1.1-10.9

 

Table 2: Type 2 Diabetes in exposed and unexposed subjects to arsenic through drinking water (n=300).

 

Age	Arsenic exposure	Diabetic status
		Diabetic	Not diabetic	Total
30-44	Exposed	5 (6.2%)	75 (93.8%)	80 (100%)
	Not exposed	1 (1.3%)	75 (98.7%)	76 (100%)
Total		6 (3.8%)	150 (96.2%)	156 (100%)
45-60	Exposed	5 (9.4%)	48 (90.6%)	53 (100%)
	Not exposed	3 (5.4%)	53 (94.6%)	53 (100%)
Total		8 (7.3%)	101 (92.7%)	109 (100%)
>60	Exposed	3 (17.6%)	14 (82.4%)	17 (100%)
	Not exposed	0 (0%)	18 (100%)	18 (100%)
Total		3 (8.6%)	32 (91.4%)	35 (100%)
Mantel-Haenszel Common Odds Ratio           3.5
Exact Sig. (2-sided)                                       0 .031
95% Confidence Interval                              1.1-11.1

 

Table 3: According to age, type 2 diabetes mellitus in exposed and unexposed subjects to arsenic through drinking water (n=300).

 

Sex		Diabetic	Non-diabetic	Total
Male	Exposed	4 (10.3%)	35 (89.7%)	39 (100%)
	Not exposed	3 (6.7%)	42 (93.3%)	45 (100%)
Total		7 (8.3%)	77 (91.7%)	84 (100%)
Female	Exposed	9 (8.1%)	102 (91.9%)	111 (100%)
	Not exposed	1 (1.0%)	104 (99.0%)	105 (100%)
Total		10 (4.6%)	206 (95.4%)	216 (100%)
Mantel-Haenszel Common Odds Ratio        3.7
Exact Sig. (2-sided)                                     0.029
95% Confidence Interval                            1.1-11.8

 

Table 4: According to sex, type 2 diabetes mellitus in exposed and unexposed subjects to arsenic through drinking water (n=300).

 

BMI		Diabetic	Non-diabetic	Total
<19	Exposed	9 (10.0%)	81 (90.0%)	90 (100%)
	Not exposed	0 (0%)	33 (100%)	33 (100%)
Total		9 (7.3%)	114 (92.7%)	123 (100%)
19-22	Exposed	2 (5.6%)	34 (94.4%)	36 (100%)
	Not exposed	1 (2.0%)	50 (98.0%)	51 (100%)
Total		3 (3.4%)	84 (96.6%)	87 (100%)
>22	Exposed	2 (8.3%)	22 (91.7%)	24 (100%)
	Not exposed	3 (4.5%)	63 (95.5%)	66 (100%)
Total		5 (5.6%)	85 (94.4%)	90 (100%)
Mantel-Haenszel Common Odds Ratio                4.4
Exact Sig. (2-sided)                                            0.032
95% Confidence Interval                                   1.1-17.2

 

Table 5: According to BMI, type 2 diabetes mellitus in exposed and unexposed subjects to arsenic through drinking water (n=300).

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