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 .