Linköping University Medical Dissertation No 612

 

 

Nonmalignant Health Effects

of Arsenic Exposure.

 

av

Mahfuzar Rahman,

 

 

 

Akademisk Avhandling

som för avläggande av medicine doktorsexamen kommer att offentligt försvaras i Aulan, Administrationsbyggnaden, Hälsouniversitetet, Universitetsjukhuset,

tisdagen den 14 december 1999, kl 13 00.

 

 

Fakultetetopponent

Docent Per Gustavsson, Yrkes- och miljömedicin, Karolinska Institutet, Stockholm.

 

Abstract

This thesis comprises a series of studies concerning occupational and environmental exposure to arsenic and some novel chronic health effects of this element, namely diabetes mellitus and hypertension. Substantial prevalence of the well-known skin manifestations of arsenic ingestion was also found to occur as a result of environmental exposure through drinking water.

Two case-control studies on diabetes mellitus and occupational exposure to arsenic included individuals employed at a copper smelting industry (Paper I) and in art glassworks (Paper II) in Sweden. Although the number of smelter workers involved was small (12 cases and 31 controls), a significant exposure-response trend was obtained (p = 0.03). The assessment of arsenic exposure among 888 glass workers was less detailed, nonetheless it revealed an approximately doubled risk (MH-OR = 2.1; 95% confidence interval 1.2-3.7) for the workers with occupational titles that suggested exposure. Overall, the results of these studies provide evidence that occupational arsenic exposure may play a role in the development of diabetes mellitus. Four cross-sectional studies were carried out in Bangladesh, where a fairly large part of the population is exposed to inorganic arsenic in drinking water. In the first study (Paper III), the prevalence of diabetes mellitus among subjects with keratosis (n = 163) was compared with unexposed subjects (n = 854); keratosis was considered to be a definite sign of exposure. A dose-response relationship was found between categories of time-weighted arsenic exposure (mg/L in drinking water) and the prevalence of diabetes mellitus (p < 0.001), and the crude overall prevalence ratio amounted to 4.4. Despite the lack of detailed individual exposure data and information on potential confounders other than age, sex, and body mass index (BMI), the association seems strong enough to support a causal relationship, because the adjusted overall prevalence ratio was 5.9 (95% confidence interval 2.9-11.6).

One of the other studies performed in Bangladesh (Paper V; 1481 exposed individuals, 430 exhibiting keratosis) showed a somewhat higher prevalence rate of skin lesions in males (31%) than females (26%) due to chronic arsenic toxicity. The crude overall prevalence was 29% in the studied villages, and there was a distinct dose-response relationship between arsenic concentrations in drinking water and skin lesions (p < 0.01). A clear dose-response relationship was also observed (Paper VI) between arsenic exposure and glucosuria for subjects both with and without skin lesions (p < 0.01). The possibility of using the skin lesions for initial screening for glucosuria was considered. However, the appearance of dermatological signs of chronic arsenic toxicity proved to be a poor marker in this respect, because glucosuria also occurred in the absence of skin lesions.

A third Bangladeshi study (Paper IV) indicated a significantly increased risk of hypertension in connection with exposure to inorganic arsenic in drinking water (1481 exposed and 114 unexposed subjects). The overall crude prevalence ratio of hypertension amounted to 1.7, and the adjusted (for age, sex, and BMI) ratio was 1.9 (95% confidence interval 1.0-3.6). A significant trend in risk (p << 0.001) was observed between an approximate time-weighted mean exposure to arsenic, considered in milligrams per liter or milligram-years per liter, which strengthens the possibility of a causal association.

 

Key word: arsenic, case-control study, cross-sectional study, diabetes mellitus, drinking water, epidemiology, exposure, keratosis, public health, hypertension, risk factors.

 

 

The thesis is based on the following papers

I. Rahman M, Axelson O. Diabetes mellitus and arsenic exposure: a second look at case control data from a Swedish copper smelter. Occup Environ Med 1995; 52: 773-4. Abstract available:

II. Rahman M, Wingren G, Axelson O. Diabetes mellitus among Swedish art glass workers—an effect of arsenic exposure? Scand J Work Environ Health 1996; 22: 146-9.Abstract available:

III. Rahman M, Tondel M, Ahmad SA, Axelson O. Diabetes mellitus associated with arsenic exposure in Bangladesh. Am J Epidemiol 1998; 148: 189-203.Abstract available:

IV. Rahman M, Tondel M, Chowdhury IA, Faruquee MH, Ahmad SA, Axelson O. Hypertension and arsenic exposure in Bangladesh. Hypertension 1999; 33: 74-8.Abstract available:

 

V. Tondel M, Rahman M, Magnuson A, Chowdhury IA, Faruquee MH, Ahmad SA. The relationship of arsenic levels in drinking water and the prevalence rate of skin lesions in Bangladesh. Environ Health Perspect 1999: 107: 727-729.Abstract available:

 

VI. Rahman M, Tondel M, Chowdhury IA, Axelson O. Relation between arsenic exposure, skin lesions and glucosuria. Occup Environ Med 1999: 56: 277-281.Abstract available:

 

 

Division of Occupational and Environmental Medicine,

Department of Health and Environment, Faculty of Health Sciences, Linköping University,

S-581 85 Linköping, Sweden

 

ISBN 91-7219-567-3                                                 ISSN 0345-0082

 

Environ Health Perspect 1999 Sep;107(9):727-729

The Relationship of Arsenic Levels in Drinking Water and the Prevalence Rate of Skin Lesions in Bangladesh.

Tondel M, Rahman M, Magnuson A, Chowdhury IA, Faruquee MH, Ahmad SA

Division of Occupational and Environmental Medicine, Department of Health and Environment, Faculty of Health Sciences, Linkoping University, Linkoping, Sweden.

[Record supplied by publisher]

To determine the relationship of arsenic-associated skin lesions and degree of arsenic exposure, a cross-sectional study was conducted in Bangladesh, where a large part of the population is exposed through drinking water. Four villages in Bangladesh were identified as mainly dependent on wells contaminated with arsenic. We interviewed and examined 1,481 subjects [Greater/equal to] 30 years of age in these villages. A total of 430 subjects had skin lesions (keratosis, hyperpigmentation, or hypopigmentation). Individual exposure assessment could only be estimated by present levels and in terms of a dose index, i.e., arsenic levels divided by individual body weight. Arsenic water concentrations ranged from 10 to 2,040 mug/L, and the crude overall prevalence rate for skin lesions was 29/100. After age adjustment to the world population the prevalence rate was 30.1/100 and 26.5/100 for males and females, respectively. There was a significant trend for the prevalence rate both in relation to exposure levels and to dose index (p < 0.05), regardless of sex. This study shows a higher prevalence rate of arsenic skin lesions in males than females, with clear dose-response relationship. The overall high prevalence rate in the studied villages is an

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Occup Environ Med 1999 Apr;56(4):277-81

Relations between exposure to arsenic, skin lesions, and glucosuria.

Rahman M, Tondel M, Chowdhury IA, Axelson O

Department of Health and Environment, Faculty of Health Sciences, Linkoping University, Sweden.

OBJECTIVES: Exposure to arsenic causes keratosis, hyperpigmentation, and hypopigmentation and seemingly also diabetes mellitus, at least in subjects with skin lesions. Here we evaluate the relations of arsenical skin lesions and glucosuria as a proxy for diabetes mellitus. METHODS: Through existing measurements of arsenic in drinking water in Bangladesh, wells with and without arsenic contamination were identified. Based on a questionnaire, 1595 subjects > or = 30 years of age were interviewed; 1481 had a history of drinking water contaminated with arsenic whereas 114 had not. Time weighted mean arsenic concentrations and mg-years/l of exposure to arsenic were estimated based on the history of consumption of well water and current arsenic concentrations. Urine samples from the study subjects were tested by means of a glucometric strip. People with positive tests were considered to be cases of glucosuria. RESULTS: A total of 430 (29%) of the exposed people were found to have skin lesions. Corresponding to drinking water with < 0.5, 0.5-1.0, and > 1.0 mg/l of arsenic, and with the 114 unexposed subjects as the reference, the prevalence ratios for glucosuria, as adjusted for age and sex, were 0.8, 1.4, and 1.4 for those without skin lesions, and 1.1, 2.2, and 2.6 for those with skin lesions. Taking exposure as < 1.0, 1.0-5.0, > 5.0-10.0 and > 10.0 mg-years/l of exposure to arsenic the prevalence ratios, similarly adjusted, were 0.4, 0.9, 1.2, and 1.7 for those without and 0.8, 1.7, 2.1, and 2.9 for those with skin lesions. All series of risk estimates were significant for trend, (p < 0.01). CONCLUSIONS: The results suggest that skin lesions and diabetes mellitus, as here indicated by glucosuria, are largely independent effects of exposure to arsenic although glucosuria had some tendency to be associated with skin lesions. Importantly, however, glucosuria (diabetes mellitus) may occur independently of skin lesions.

PMID: 10450246, UI: 99378740

 


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Hypertension 1999 Jan;33(1):74-8

Hypertension and arsenic exposure in Bangladesh.

Rahman M, Tondel M, Ahmad SA, Chowdhury IA, Faruquee MH, Axelson O

Department of Health & Environment, Faculty of Health Sciences, Linkoping University, Sweden.

-A prevalence comparison of hypertension among subjects with and those without arsenic exposure through drinking water was conducted in Bangladesh to confirm or refute an earlier observation of a relation in this respect. Wells with and without present arsenic contamination were identified, and we interviewed and examined 1595 subjects who were depending on drinking water from these wells for living, all >/=30 years of age. The interview was based on a questionnaire, and arsenic exposure was estimated from the history of well-water consumption and current arsenic levels. Of the 1595 subjects studied, 1481 had a history of arsenic-contaminated drinking water, whereas 114 had not. Time-weighted mean arsenic levels (in milligrams per liter) and milligram-years per liter of arsenic exposure were estimated for each subject. Exposure categories were assessed as <0.5 mg/L, 0.5 to 1.0 mg/L, and >1.0 mg/L and alternatively as <1.0 mg-y/L, 1.0 to 5.0 mg-y/L, >5.0 but </=10.0 mg-y/L, and >10.0 mg-y/L, respectively. Hypertension was defined as a systolic blood pressure of >/=140 mm Hg in combination with a diastolic blood pressure of >/=90 mm Hg. Corresponding to the exposure categories, and using "unexposed" as the reference, the prevalence ratios for hypertension adjusted for age, sex, and body mass index were 1.2, 2.2, 2.5 and 0.8, 1.5, 2.2, 3.0, in relation to arsenic exposure in milligrams per liter and milligram-years per liter, respectively. The indicated dose-response relationships were significant (P<<0.001) for both series of risk estimates. These results suggest that arsenic exposure may induce hypertension in humans.

PMID: 9931084, UI: 99130061

 


 

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Am J Epidemiol 1998 Jul 15;148(2):198-203

Diabetes mellitus associated with arsenic exposure in Bangladesh.

Rahman M, Tondel M, Ahmad SA, Axelson O

Department of Health and Environment, Faculty of Health Sciences, Linkoping University, Sweden.

The objective of this study was to assess whether arsenic exposure is a risk factor for diabetes mellitus as indicated in a few earlier studies. Arsenic in drinking water is known to occur in western Bangladesh, and in 1996, two of the authors conducted a survey of the prevalence of diabetes mellitus among 163 subjects with keratosis taken as exposed to arsenic and 854 unexposed individuals. Diabetes mellitus was determined by history of symptoms, previously diagnosed diabetes, glucosuria, and blood sugar level after glucose intake. The crude prevalence ratio for diabetes mellitus among keratotic subjects exposed to arsenic was 4.4 (95% confidence interval 2.5-7.7) and increased to 5.2 (95% confidence interval 2.5-10.5) after adjustment for age, sex, and body mass index. On the basis of a few earlier measurements of arsenic concentrations in drinking water by the authorities in Bangladesh and another 20 new ad hoc analyses, approximate time-weighted exposure levels to arsenic in drinking water could be estimated for each subject. Three time-weighted average exposure categories were created, i.e., less than 0.5, 0.5-1.0, and more than 1.0 mg/liter. For the unexposed subjects, the corresponding prevalence ratios were 1.0, 2.6, 3.9, and 8.8, representing a significant trend in risk (p < 0.001). The result corroborates earlier studies and suggests that arsenic exposure is a risk factor for diabetes mellitus.

PMID: 9676702, UI: 98339324

 


 

Diabetes mellitus among Swedish art glass workers--an effect of arsenic exposure?

Rahman M, Wingren G, Axelson O

Department of Occupational and Environmental Medicine University Hospital, Linkoping, Sweden.

OBJECTIVES: The purpose of this study was to search for evidence of an association between occupational arsenic exposure and diabetes mellitus, as implied by the relation of this disease to arsenic in drinking water in a recent study from Taiwan. METHODS: A case-referent analysis on death records of 5498 individuals in the art glass producing part of southeastern Sweden was performed. Out of all the enrolled subjects, 888 were glass workers. According to occupational title, glassblowers, foundry workers, and unspecified workers were regarded as potentially exposed to arsenic. Persons with a diagnosis of diabetes mellitus either as an underlying or contributing cause of death were considered cases. Referents were decedents without any indication of cancer, cardiovascular disease, or diabetes. RESULTS: A slightly elevated risk [Mantel-Haenszel odds ratio (MH-OR) 1.2, 95% confidence interval (95% CI) 0.82-1.8] was found for diabetes mellitus among the glassworks employees, especially in combination with cardiovascular disease (MH-OR 1.4, 95% CI 0.81-2.3). For the glassblowers, other foundry workers and unspecified glassworkers probably exposed to arsenic, the M-H odds ratio was 1.4 (95% CI 0.92-2.2). Unspecified glass workers, who probably included persons with high exposure, carried the higher risk (MH-OR 1.8, 95% CI 1.1-2.8). CONCLUSIONS: The observations from this study provide limited support for the possibility that occupational arsenic exposure could play a role in the development of diabetes mellitus. Many other metallic compounds are also used in art glass production, however, and there is a possibility of confounding.

PMID: 8738894, UI: 96353374

 


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Occup Environ Med 1995 Nov;52(11):773-4

Diabetes mellitus and arsenic exposure: a second look at case-control data from a Swedish copper smelter.

Rahman M, Axelson O

Department of Occupational and Environmental Medicine, University Hospital, Linkoping, Sweden.

OBJECTIVES--To find out whether a newly found association between diabetes mellitus and arsenic in drinking water in Taiwan could be reproduced in copper smelters with arsenic exposure. METHODS--Extended analysis of a previous case-control study from 1978 was based on death records and objective exposure information from the company. The final analysis included only those employed at the smelter. Cases were 12 people with diabetes mellitus on the death certificate and those for whom there was clinical information on this disease. Controls were 31 people without cancer, cardiovascular and cerebrovascular disease as these disease categories had been associated with arsenic exposure in the original study and elsewhere. RESULTS--The odds ratios found for diabetes mellitus with increasing arsenic exposure categories were (reference level = 1), 2.0, 4.2, and 7.0, but the 95% confidence intervals included unity. Unstratified test for trend was weakly significant, P = 0.03. CONCLUSIONS--Although based on small numbers, the findings provide some support for the suggestion that arsenic exposure could sometimes play a part in the development of diabetes mellitus.

PMID: 8535499, UI: 96138268