arsenic is a known carcinogen , and increasing evidence also suggests a possible role of chronic arsenic exposure in the development of chronic diseases , including cardiovascular diseases .
cardiovascular diseases associated with high levels of arsenic in the drinking water include atherosclerosis , hypertension , cerebrovascular diseases , ischemic heart diseases , and peripheral vascular disease [ 3 , 4 ] .
the possible role of chronic arsenic exposure in the development of hypertension has been previously reported from taiwan , bangladesh , and the united states [ 57 ] .
these studies reported that individuals drinking arsenic - contaminated water for a long period of time might be at higher risk of developing hypertension compared to those unexposed to arsenic , and the effects were dose dependent .
hypertension is one of the major risk factors for cardiovascular diseases   and is considered a major public health problem worldwide .
a total of 972 million adults were reported to have hypertension in 2000 and that number is estimated to increase by 60% , to a total of 1.56 billion , by the year 2025 .
, only a few cross - sectional and cohort studies have investigated the association between hypertension and chronic arsenic exposure .
therefore , it is important from the public health perspective to explore the role of chronic arsenic exposure in development and prevention of hypertension . in this study , we conducted a meta - analysis that included all relevant cross - sectional and cohort studies of chronic arsenic exposure and hypertension .
the meta - analysis provides greater precision in estimating risk especially when data are scarce and inconclusive .
our analysis includes a careful assessment of the possible effects of study quality as well as other biases on the meta - analysis results .
the research question was defined as  is there any association between chronic arsenic exposure and hypertension ?  this question was then broken down to cover specific search terms such as  hypertension ,   chronic arsenic exposure ,   arsenite ,  
the search was first carried out in ovid medline and google scholar in september 2009 , without limitation on the time of publication .
we also replicated the search in embase and pubmed , but no additional references were identified through these databases .
the search was last updated in february 2012 to locate new studies published after the initial search .
the references cited in the collected list of articles were also hand - searched for additional relevant studies .
the included studies ( 1 ) were observational studies , that is , cross - sectional , case control or cohort studies , of chronic arsenic exposure through drinking water and hypertension , ( 2 ) reported a relative risk ( rr ) or odds ratio ( or ) , or such parameters could be estimated from the published data , and ( 3 ) measured arsenic , using a laboratory technique .
two investigators ( t. a. and r. e. y. ) screened the initial list of articles to identify articles that were irrelevant and , therefore , discarded from the list . to facilitate faster screening ,
articles were first judged on the basis of their titles , where obviously irrelevant articles were discarded .
the abstracts of the remaining articles were then read by three investigators ( t. a. , b. r. , and a. h. m. ) to ensure that the main subject of the study was related to arsenic exposure and hypertension .
articles whose abstracts showed that the study was not relevant to the objective of the meta - analysis were discarded .
after the screening , information for the articles was extracted and a quality evaluation was done .
the data items extracted from each study were general information : first author 's name and affiliation , year of publication , country , and region in which the study was conducted ; study design : population , number and sources of study participants , and type of study ; exposure and outcome measurement : analytical methods for measuring arsenic , speciation of arsenic , duration of arsenic exposure , relevant information on individual level of exposure assessment , and measurement of hypertension ; analysis : covariates for adjustment in multivariate models , adjusted and unadjusted or stratified effect estimates ( i.e. , rr and or ) and 95% confidence intervals ( cis ) . if a study did not report cis , the standard error and the resulting ci from the p value were estimated , where possible . for cross - sectional studies
, ors were extracted as the estimate of the effect of arsenic exposure . for cohort studies ,
quality assessment was facilitated through the use of a standardised questionnaire which was developed specifically for this study .
the questionnaire was a comprehensive scoring instrument based on critical appraisal principles and understanding of the methodological issues of population selection , measurement of arsenic exposure and outcome , adjustment for potential confounders , and appropriateness of analysis .
each criterion was given weighted scores to evaluate the quality of the studies in comparison to each other , with key factors being given specific scores .
although the scoring in itself can be subjective , it enables comparisons among the studies .
three independent readers ( t. a. , r. e. y. , and a. f. ) scored each of the studies and were blinded to the others ' assessments . any significant disagreement between the readers was resolved through discussion . for minor differences ,
the maximum score value that could be assigned to each study was 100 , and this score summarised the overall quality of the study .
the score was the weighted sum of four major domains of quality : selection issues ( score weight 20% ) , measurement issues ( of exposure and outcome , score weight 50% ) , adjustment of confounding factors ( score weight 20% ) and analysis ( score weight 10% ) .
the analysis section was given the least weight because if the other three sections were of good quality but the analysis was not carried out properly , the data could often be reanalyzed .
two scoring systems were developed , one for cross - sectional studies and one for prospective studies .
to assess the interrater reliability of the study quality scores , reliability and reproducibility were analyzed by computing intraclass correlation coefficients ( iccs ) for absolute agreement between raters on each quality domain along with the overall score . to conduct the meta - analysis ,
ors were extracted from cohort studies and used to estimate the effects , with the exception of one cohort study where the rr was used instead . for studies where several measures of association were reported ,
associations which related hypertension to amount of arsenic intake , or to arsenic intake combined with duration of exposure , were considered .
pooled ors were estimated by comparing the highest exposure category to the lowest one combined for males and females .
the meta - analysis included checking for heterogeneity of the ors , checking for influential studies , checking for asymmetry and publication biases , and checking for relationships between the log of effect measures and the article 's quality scores .
effect estimates ( ors ) were pooled using dersimonian and laird 's inverse - variance - weighted random effects method .
heterogeneity was measured using the i - statistic , which describes the proportion of total variation in study estimates that is due to heterogeneity .
the influence of each study on the pooled effect measure was examined by repeating the meta - analysis while omitting each study one by one .
a random effect metaregression was conducted using the logs of the effect measures ( or ) as the outcome variable and the study quality score as the explanatory variable to assess the possible impact of study quality on the effect measures .
these random effect models were fitted with two additive variance components : within study variance and between study residuals [ 16 , 17 ] .
the database search yielded 85 articles , 10 of which investigated the association between chronic arsenic exposure and hypertension .
two of these articles were excluded from the meta - analysis because the full texts were not available .
thus , the final meta - analysis comprised eight studies : seven analytical cross - sectional studies and one prospective cohort study .
of these eight studies , two reported arsenic concentration only as exposure , two reported arsenic concentration and duration of drinking arsenic - contaminated water as a combined exposure value , and three reported arsenic concentration and arsenic concentration and duration of exposure separately .  
the average total scores and average per criterion scores for quality assessment are summarized in table 2 .
the one cohort study scored better in the domains of selection and outcome compared to the other seven cross - sectional studies .
the cohort study had a selection score of 18.7 ( of 20 possible ) , while the cross - sectional studies averaged 15.8 .
the cohort had an outcome score of 16 ( of 20 possible ) , while the 7 cross - sectional studies averaged 14.7 .
in particular , the study by zierold et al .   scored low in this domain ( 1.3 ) due to missing details in the report .
the 7 cross - sectional studies scored higher in the exposure ( cross - sectional = 24.3 , cohort = 20 , of 30 possible ) and confounders ( cross - sectional = 18.6 , cohort = 10 , of 20 possible ) domains . the analysis ( cohort = 9.3 , cross - sectional = 10 , of 10 possible ) domain scores were similar ; but , overall , the cross - sectional studies ( total score = 84.1 ) scored higher than the cohort study ( total score = 74 ) .
good interobserver agreement on the total quality scores was verified by the intraclass correlation coefficient ( icc ) .
the highest agreement was seen among scores for the exposure ( icc = 0.87 95% ci :  .56.98 ) and outcome ( icc = 0.96 95% ci : 0.641.00 ) domains , and the lowest for the analysis ( icc = 0.001 95% ci : 0.240.78 ) domain .
the low icc , however , was due to one rater 's disagreement on one study , but there was perfect agreement among the raters on the rest of the studies .
other domains showed moderate agreement : the icc for confounders was 0.59 ( 95% ci : 0.190.90 ) while that for selection was 0.66 ( 95% ci : 0.010.93 ) .
the eight selected studies were scored based on criteria that were specifically developed to assess their quality .
the cohort study by wang et al .   scored a total of 74 points , having scored well on selection and exposure but not on confounder criteria .
the seven cross - sectional studies had an average score of 84.1 ( range = 61 to 93.3 ) .
overall , the cross - sectional studies scored higher than the prospective cohort study for the confounders and exposure criteria but scored lower for the selection and outcome criteria .
the studies differed in the adjustment of potential confounders , such as age , sex , and body mass index , as well .
the pooled or of studies using arsenic concentration as the exposure measure was 1.9 ( 95% ci : 1.23.0 ) , while the pooled estimate for or of studies using arsenic concentration and duration including biomarker as the exposure was 1.4 ( 95% ci : 0.952.0 ) .
< 0.001 ) , while , for the concentration and duration studies , i was 80% ( p
the meta - analysis results are presented with forest plots in figure 1 . in the forest plots , the point estimate for one study is represented by the centre of each rectangle .
the size of the rectangle is relative to the weight of the point estimate when the results are pooled .
the length of the horizontal line through the rectangle represents the 95% confidence interval of the point estimate .
the pooled estimate is represented by the diamond on the lower portion of the plot . the vertical axis through the diamond represents the point estimate , and the horizontal end corners are the upper and lower 95% confidence boundaries .
the results of the influence analysis showed that no single study exerted a disproportionate influence on the pooled estimate for either arsenic concentration or arsenic concentration and duration ( figure 2 ) .
investigation of the publication bias showed some evidence of positive results for the concentration and duration studies .
the egger 's test p value for arsenic concentration studies was 1.00 , while the egger 's test p value for the concentration and duration studies was 0.004 .
the funnel plot shows possible bias only for concentration and duration studies ( figure 3 ) . using the scores from the quality assessment ,
a metaregression was performed to verify the dependency of the outcome measure on the quality scores .
of all the scoring criteria , the quality of exposure measurement and total quality was significantly associated with the outcome measure . for one unit increase in the score from the exposure domain ,
the or decreased by 6% ( p = 0.004 , 95% ci : 2.1%10.7% ) .
in the studies included in the meta - analysis , arsenic exposure was measured by different studies in different ways .
even when two studies used the same units of measurement , they may still have differed in categorization and definition of subjects being exposed to arsenic .
however , the definition of  exposure  differs from one study to another , since there is no agreement on how to express the duration of exposure or what quantities of arsenic constitute an exposure .
this problem results from the fact that external validation of the methods used to determine exposure in studies is still problematic .
in addition , while methods for detection of exposure to high levels of arsenic have been well characterized , measurement of arsenic exposure at low concentrations is still not very reliable .
have followed the who protocol for the measurement of blood pressure and have used the criteria of diastolic blood pressure > 95  mm  hg or systolic blood pressure > 160  mm  hg to define hypertension , while huang et al .
specified hypertension as diastolic > 90  mm  hg or systolic > 140  mm  hg . in the study by jones et al . , they followed diastolic blood pressure > 90  mm  hg or systolic blood pressure > 140  mm  hg to define hypertension
. overall , this meta - analysis suggests that chronic arsenic exposure is likely to be associated with hypertension .
the pooled or of arsenic concentration studies is 1.9 ( 95% ci : 1.23.0 ) and that for arsenic concentration and duration studies is 1.4 ( 95% ci:.952.0 ) .
investigation of publication bias showed some evidence of positive results for concentration and duration studies .
the egger 's test p value for arsenic concentration studies was 0.828 , while the p value for concentration and duration studies was 0.04 .
chen et al .   obtained similar results in their 2007 review of arsenic , diabetes , and hypertension .
this paper included only four studies regarding arsenic exposure and hypertension and did not include a meta - analysis . in our meta - analysis , seven good quality studies were included that related arsenic exposure to hypertension using proper statistical analysis , with control groups ( table 1 ) . as opposed to the report of chen et al . , which only presented the results of their reviewed papers , the meta - analysis conducted here attempted to pool the reported ors , tested for heterogeneity , and conducted a meta - regression .
to the best of our knowledge , this is the first meta - analysis that has explored the association between hypertension and chronic arsenic exposure .
one of the major limitations of this meta - analysis is the limited number of studies examining the association between hypertension and chronic arsenic exposure .
these studies were also heterogeneous as reflected by the high values of the i statistics .
the adverse effects of arsenic on blood vessels have been demonstrated in previous studies which reported that constant exposure of rats and rabbits to arsenite caused a considerable increase in peripheral vascular resistance .
the eight studies evaluated in this paper have shown how varied the impact of arsenic on hypertension , depending on factors such as sex , age , body - mass index , diabetes , and triglyceride levels of the subject population . however , an increased risk for hypertension among arsenic exposed participants has not been consistently observed .
for instance , dastgiri et al .   reported a significant difference both for systolic and diastolic blood pressures between exposed and unexposed subjects , while khan et al .  
inconsistent findings may be due to differences in measurement criteria both for exposure and outcome variables , or due to bias caused by limited consideration of potential confounders . due to these inconsistencies , the increased prevalence of hypertension for a population that is exposed to high arsenic levels can not yet be established .
. however , the small number of studies and limitations in study quality pose challenges to establishing causation between arsenic exposure and hypertension .
nevertheless , since a larger proportion of the rural bangladeshi population drink arsenic contaminated water and the risk of hypertension is increasing among the general population , even a small association may lead to a large number of cases and a large population attributable risk .
 
 background . there is inconclusive evidence from cross - sectional and cohort studies that arsenic 
 exposure is a risk factor involved in the development of hypertension . methods . a database search , using several keywords , was conducted to identify relevant studies . 
 separate odds ratio estimates for arsenic exposure with concentration only and arsenic exposure with duration , including biomarker , were extracted from studies that met all inclusion criteria . the extracted odds ratios ( or ) comparing the highest exposure categories with the lowest in each study 
 were pooled using the random effects methods of meta - analysis . 
 heterogeneity of odds ratios in the included studies were analyzed using i2 statistics . 
 results . 
 eight studies were analyzed . using the exposure as arsenic concentration in the drinking water , 
 the or estimate was 1.9 ( 95% ci : 1.23.0 ) , with the i2 = 92% , while using the exposure as concentration and duration , the or estimate was 1.4 ( 95% ci : 0.952.0 ) with the i2 = 80% . 
 meta - regression was done and the quality of exposure measurement was found to be significantly associated with the effect measure . for a one unit increase in the score from exposure assessment , the odds ratio decreased by 6% . 
 no publication bias was evident . 
 the only major weaknesses of this study were heterogeneity across studies and small sample size . 
 conclusions . 
 the study findings provide limited evidence for a relationship between arsenic and hypertension . in summary , 
 the relationship between arsenic exposure and hypertension is still inconclusive and needs further validation through prospective cohort studies . 
1. Introduction
2. Materials and Methods
3. Statistical Analysis
4. Results
5. Risk Estimate and Meta-Analysis
6. Discussion
7. Conclusions and Recommendations