Arsenic Exposure and Cardiovascular Disease: A Systematic Review of the Epidemiologic Evidence

Abstract

Arsenic exposure is a likely cause of blackfoot disease and a potential risk factor for atherosclerosis. The authors performed a systematic review of the epidemiologic evidence on the association between arsenic and cardiovascular outcomes. The search period was January 1966 through April 2005. Thirteen studies conducted in general populations (eight in high-arsenic areas in Taiwan, five in other countries) and 16 studies conducted in occupational populations were identified. Exposure was assessed ecologically in most studies. In Taiwan, relative risks comparing the highest arsenic exposure category with the lowest ranged from 1.59 to 4.90 for coronary disease, from 1.19 to 2.69 for stroke, and from 1.66 to 4.28 for peripheral arterial disease. In other general populations, relative risks ranged from 0.84 to 1.54 for coronary disease, from 0.69 to 1.53 for stroke, and from 0.61 to 1.58 for peripheral arterial disease. In occupational populations, relative risks ranged from 0.40 to 2.14 for coronary disease mortality and from 0.30 to 1.33 for stroke mortality. Methodologic limitations, however, limited interpretation of the moderate-to-strong associations between high arsenic exposure and cardiovascular outcomes in Taiwan. In other populations or in occupational settings, the evidence was inconclusive. Because of the high prevalence of arsenic exposure, carefully performed studies of arsenic and cardiovascular outcomes should be a research priority.

Full text

Review
Arsenic Exposure and Cardiovascular Disease: A Systematic Review of the
Epidemiologic Evidence
Ana Navas-Acien
1,2,3
, A. Richey Sharrett
1
, Ellen K. Silbergeld
4
, Brian S. Schwartz
1,4
,
Keeve E. Nachman
3,5
, Thomas A. Burke
3,5
, and Eliseo Guallar
1,2,3
1
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
2
Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD.
3
Johns Hopkins Center for Excellence in Environmental Public Health Tracking, Bloomberg School of Public Health, Johns
Hopkins University, Baltimore, MD.
4
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
5
Department of Health Policy and Management, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
Received for publication May 13, 2005; accepted for publication July 8, 2005.
Arsenic exposure is a likely cause of blackfoot disease and a potential risk factor for atherosclerosis. The authors
performed a systematic review of the epidemiologic evidence on the association between arsenic and cardiovas-
cular outcomes. The search period was January 1966 through April 2005. Thirteen studies conducted in general
populations (eight in high-arsenic areas in Taiwan, five in other countries) and 16 studies conducted in occupa-
tional populations were identified. Exposure was assessed ecologically in most studies. In Taiwan, relative risks
comparing the highest arsenic exposure category with the lowest ranged from 1.59 to 4.90 for coronary disease,
from 1.19 to 2.69 for stroke, and from 1.66 to 4.28 for peripheral arterial disease. In other general populations,
relative risks ranged from 0.84 to 1.54 for coronary disease, from 0.69 to 1.53 for stroke, and from 0.61 to 1.58 for
peripheral arterial disease. In occupational populations, relative risks ranged from 0.40 to 2.14 for coronary disease
mortality and from 0.30 to 1.33 for stroke mortality. Methodologic limitations, however, limited interpretation of the
moderate-to-strong associations between high arsenic exposure and cardiovascular outcomes in Taiwan. In other
populations or in occupational settings, the evidence was inconclusive. Because of the high prevalence of arsenic
exposure, carefully performed studies of arsenic and cardiovascular outcomes should be a research priority.
arsenic; arteriosclerosis; cardiovascular diseases; review [publication type]
Abbreviation: CI, confidence interval.
INTRODUCTION
Cardiovascular disease is the leading cause of mortality
worldwide (1). Atherosclerosis is the most common patho-
logic process underlying cardiovascular disease, and it often
manifests clinically as coronary disease, stroke, or periph-
eral arterial disease. Environmental toxicants have been
suggested to play a role in atherogenesis (2). In particular,
long-term exposure to arsenic, a documented poison and
carcinogen, has been implicated as a risk factor for cardio-
vascular disease (3, 4).
Arsenic is likely to cause blackfoot disease, a severe form
of peripheral arterial disease in southwestern Taiwan that is
characterized by thromboangiitis obliterans, severe arterio-
sclerosis, and high arsenic levels in the arterial wall (3, 5–7).
While epidemiologic studies conducted in Taiwan support
a role for high chronic arsenic exposure in atherosclerosis
(8, 9), data on other populations are scarce and results are
Correspondence to Dr. Ana Navas-Acien, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 2024
East Monument Street, Suite 2-636, Baltimore, MD 21205-2223 (e-mail: anavas@jhsph.edu).
1037 Am J Epidemiol 2005;162:1037–1049
American Journal of Epidemiology
Copyright ª2005 by the Johns Hopkins Bloomberg School of Public Health
All rights reserved; printed in U.S.A.
Vol. 162, No. 11
DOI: 10.1093/aje/kwi330
Advance Access publication November 3, 2005

inconclusive (8, 9). Because of the limited quantity and
quality of the epidemiologic evidence, the US Environmen-
tal Protection Agency considered cardiovascular outcomes
only qualitatively in risk analyses to establish the maximum
contaminant level of arsenic in drinking water (10). To our
knowledge, no systematic reviews or meta-analyses have
summarized the evidence on the relation between arsenic
and cardiovascular disease.
Our objective was to perform a systematic review and
a meta-analysis of the epidemiologic evidence on the asso-
ciation of arsenic with cardiovascular disease. Because of
the substantial heterogeneity in and methodologic limita-
tions of the available evidence, we present a qualitative sys-
tematic review without quantitative pooling of study results.
METHODS
Search strategy and study selection
We searched MEDLINE and TOXNET for epidemiologic
studies investigating the relation of arsenic with cardiovas-
cular disease by using free text and the following Medical
Subject Headings: arsenic, arsenite, arsenate, arsenicals,
atherosclerosis, cardiovascular disease, myocardial infarc-
tion, stroke, peripheral vascular disease, peripheral arterial
disease, and mortality. The search period was January 1966
through April 2005. There were no language restrictions. In
addition, we manually reviewed the reference lists from
relevant original research and review articles, as well as
the investigators’ files.
We aimed to identify all studies assessing the relation
between arsenic exposure determined using environmen-
tal measures (drinking water or airborne arsenic levels),
biomarkers, or indirect measures (job titles or living in
arseniasis-endemic areas) and clinical cardiovascular dis-
ease outcomes (including coronary disease, stroke, and
peripheral arterial disease). Our exclusion criteria were:
1) publications containing no original research (reviews,
editorials, nonresearch letters); 2) studies not carried out
in humans (experimental studies); 3) case reports and case
series; 4) studies lacking a clinical cardiovascular outcome
(e.g., a study of subclinical atherosclerosis (11)); and
5) studies lacking data on arsenic exposure during adulthood
(e.g., persons who had lived within 4 km of a smelter during
childhood (12)) or studies of arsenic compounds for which
human exposure is uncommon (e.g., lewisite (13)). Four
case-control studies were excluded because cases and con-
trols were selected on the basis of prior history of arsenic
exposure (14–17). We also excluded a cohort of patients
who had taken Fowler’s solution (potassium arsenite) be-
tween 1945 and 1969 in Lancashire, England (18).
When several papers had been published on the same pop-
ulation, the publication with the longest follow-up period
was selected; when follow-up periods were equivalent, we
Distinct references identified (n = 1,217)
Medline search: 1,024
Toxnet (not in Medline): 156
Hand search: 37
Studies in general populations (n = 13)*
Coronary heart disease: 7
Stroke: 5
Peripheral arterial disease: 7
Cardiovascular disease: 1
Studies in occupational populations (n = 16)*
Coronary heart disease: 11
Stroke: 11
Peripheral arterial disease: 1
Cardiovascular disease: 5
References excluded (n = 1,162):
No original data
No human research
Case series, case reports
No clinical cardiovascular outcome
No data on arsenic exposure during adulthood
Lewisite or Fowler’s solution
Distinct references (n = 55)
General populations: 20
Occupational populations: 35
References excluded (n = 26):
Multiple publications from same population: 22
Cases and controls based on prior exposure: 4
FIGURE 1. Selection process used in a systematic review of studies on the relation between arsenic and cardiovascular disease, 1966–2005.
(*Categories under the main headings do not total 13 and 16, respectively, because a single study may have included more than one
cardiovascular disease outcome.)
1038 Navas-Acien et al.
Am J Epidemiol 2005;162:1037–1049

selected the study with the largest number of cases, the study
using internal comparisons, or the most recent publication.
Figure 1 summarizes the study selection process.
In nonoccupational populations, arsenic exposure occurs
mainly through drinking water, while in occupational set-
tings, exposure usually occurs via inhalation. In addition to
differences in the route of exposure, occupational studies
usually also differ methodologically from nonoccupational
studies. For this reason, we separated the analyses of studies
conducted in general populations from those of studies con-
ducted in occupational cohorts.
Data abstraction
Two investigators independently abstracted data from the
articles that met the selection criteria. They resolved dis-
crepancies by consensus. The following fatal and nonfatal
cardiovascular outcomes were defined a priori: coronary
disease (myocardial infarction and ischemic heart disease);
stroke (cerebrovascular disease, ischemic and hemorrhagic
stroke); and peripheral arterial disease (lower-extremity pe-
ripheral arterial disease, diseases of peripheral arteries, and
blackfoot disease). We also included five occupational stud-
ies (19–23) and one general population study (24) that
reported only total cardiovascular disease mortality.
To assess study quality, we adapted the criteria used by
Longnecker et al. (25) for observational studies (figure 2).
Statistical analysis
Measures of association (odds ratios, prevalence ratios,
standardized mortality ratios, relative risks, relative hazards,
comparisons of means) and their standard errors were ab-
stracted or were derived using data reported in the publica-
tions (26). Adjustment did not substantially modify the
conclusions of individual studies. In the studies by Lin
and Yang (27) and Ruiz-Navarro et al. (28), we used the
linear discriminant function method to estimate relative
risks from mean arsenic levels in cases and noncases (26).
In the studies by Varsanyi et al. (24), Engel and Smith (29),
Lewis et al. (30), and Xuan et al. (31), we estimated the
within-cohort relative risks by comparing standardized
mortality ratios in the highest category of exposure with those
in the lowest.
Because drinking water arsenic levels were much higher
in studies carried out in Taiwan than in other studies, we
present data from Taiwan separately from data from other
countries. For descriptive purposes, we report the range of
relative risk estimates and the unweighted median values.
For studies carried out in general populations (5, 14, 29, 30,
32–37) or occupational populations (38, 39) with published
results for at least three exposure categories, we graphically
present the dose-response trend in relative terms. A dose-
response meta-analysis was considered inappropriate be-
cause of the heterogeneity in and methodologic limitations
of the available studies.
FIGURE 2. Quality criteria applied and evaluation of the design and data analysis used in epidemiologic studies on the relation between arsenic
and cardiovascular disease, 1966–2005. For reference numbers, see reference list in text.
Arsenic and Cardiovascular Disease 1039
Am J Epidemiol 2005;162:1037–1049

TABLE 1. Studies of arsenic exposure and cardiovascular outcomes in general populations
Location and
study (authors,
year, and
ref. no.)
Design Population %
men
Age
range
(years)
Arsenic
assessment
Comparison
(exposed vs.
reference)
Endpoint
ascertainment
Outcome(s)
studied
No. of
cases
No. of
noncases
Relative
risk
95%
confidence
interval
Factors
adjusted
for
Taiwan
Lin and Yang,
1988 (27)
Case-control HAA*NR*NR Urine
(hydride
AAS*)
75th
percentile
vs. 25th
percentile
NR BFD*
prevalence
20 20 1.66 0.78, 3.51 Age, sex
Chen et al.,
1988 (36)
Case-control HAA 49 <50–60 Years of
well-water
consumption
30 years vs.
0 years
Clinical
examination
BFD
prevalence
241 759 3.47 2.20, 5.48 Age, sex,
diet, family
history of
BFD
Tseng et al.,
1996 (5)
Cross-sectional HAA 45 Mean ¼53 CEI*,yfrom
village
drinking
water
20 mg/liter-
year vs.
0 mg/liter-
year
Ankle-
brachial
blood
pressure
index
PAD*
prevalence
69 513 4.28 1.26, 14.5 Age, sex,
smoking,
BMI,*lipids,
hypertension,
DM*
Chen et al.,
1996 (32)
Cohort (internal
comparisons)
HAA 52 4070 CEI from
village
drinking
water
20 mg/liter-
year vs.
0 mg/liter-
year
Death
certificate
CHD*
mortality
39 2,517 4.90 1.36, 17.7 Age, sex,
smoking,
BFD, BMI,
lipids,
hypertension,
DM
Chiou et al.,
1997 (34)
Cross-sectional HAA 50 4070 CEI from
village
drinking
water
5 mg/liter-
year vs.
<0.1
mg/liter-
year
Self-report þ
medical
records
Stroke
prevalence
139 7,963 2.69 1.35, 5.38 Age, sex,
smoking,
alcohol,
hypertension,
DM
Wu et al.,
1989 (35);
Tsai et al.,
1999 (40)
Cohort
(external
comparisons)
HAA 35 All ages Village
drinking
water level
HAA vs.
general
population
Death
certificate
CHD
mortality
728
deaths
1.59 1.32, 1.93 Age, sex
Stroke
mortality
2,638
deaths
1.19 1.10, 1.29
PAD
mortality
175
deaths
2.88 1.88, 4.42
Wang and
Chang,
2001 (6)
Case-control HAA 67 Mean ¼63 Arterial
tissue
(AAS)
75th percentile
vs. 25th
percentile
Surgery BFD
prevalence
31 30 2.40 2.00, 2.89 (Crude)
Tseng et al.,
2003 (33)
Cross-sectional HAA 44 30–60 CEI from
village
drinking
water
15 mg/liter-
year vs.
0 mg/liter-
year
Electrocardio-
gram
CHD
prevalence
78 384 3.60 1.11, 11.7 Age, sex,
smoking,
BMI, lipids,
hypertension,
DM
Other countries
Varsanyi
et al., 1991
(24)
Cohort
(external
comparisons)
12 villages
(Hungary)
49 All ages Village
drinking
water level
>50 lg/liter vs.
<40 lg/liter
Death
certificate
Cardiovascular
disease
mortality
NR NR Men: 1.19 Age
Women:
0.82
Engel and
Smith, 1994
(29)
Cohort
(external
comparisons)
30 counties
(United
States)
43 065 County
drinking
water level
>20 lg/liter
vs. 5–10
lg/liter
Death
certificate
CHD
mortality
63,831 ~1.7 million 0.84 0.76, 0.93 Age, sex
Stroke
mortality
20,963 ~1.7 million 0.91 0.74. 1.10
PAD
mortality
7,203 ~1.7 million 1.58 1.34, 1.88
1040 Navas-Acien et al.
Am J Epidemiol 2005;162:1037–1049

STUDIES IN GENERAL POPULATIONS
Study characteristics
Thirteen studies conducted in general populations (figure 1
and table 1) met our inclusion criteria. Eight studies were
from Taiwan, three were from the United States, one was
from Hungary, and one was from Spain. Of the cohort stud-
ies, two studies used internal comparisons (30, 32) and three
used external comparisons (24, 29, 40). The remaining stud-
ies used cross-sectional (5, 33, 34, 37) or case-control (6, 27,
28, 36) designs. Studies ascertaining coronary disease used
death certificates (29, 30, 32, 40), electrocardiographic cri-
teria (33), and self-reported bypass surgery, angina, or heart
attack (37). In one study, the diagnostic criteria for myocar-
dial infarction were not specified (28). Studies ascertaining
stroke used death certificates (29, 30, 40), self-reported
stroke followed by review of medical records (34), or self-
reported stroke exclusively (37). Studies ascertaining periph-
eral arterial disease used criteria for blackfoot disease (6, 27,
36), death certificates (29, 30, 40), or the ankle-brachial
blood pressure index (5). One study ascertained total cardio-
vascular disease mortality (24).
Arsenic exposure was assigned on the basis of drinking
water levels in most general population studies. Four studies
from Taiwan (5, 32–34) and one study from the United
States (30) created a cumulative arsenic exposure index
(mg/liter-year) by multiplying the number of years of living
in a specific village/area by the average arsenic level in
drinking water in that village/area (usually measured at
a single point in time). Other studies conducted in Taiwan
assigned exposure on the basis of residence in an area with
high arsenic levels in water (40) or number of years of
drinking artesian well water (36). Three studies used village
(24), county (29), or individual (37) drinking water arsenic
levels. Only three studies used biomarkers of exposure: Two
of them measured total urinary arsenic (27, 28) and the third
measured arsenic in arterial tissue (6).
Quality assessment
Most of the 13 general population studies failed to fulfill
important quality criteria (figure 2). Only four studies car-
ried out in general populations assessed arsenic exposure at
the individual level, and only three studies used biomarkers.
Thus, arsenic exposure in most of these studies was based on
geographic or other grouped or ecologic measurements.
Furthermore, only two studies used standard criteria to di-
agnose cardiovascular disease, and only six studies had in-
formation on established cardiovascular disease risk factors.
For cohort studies, losses to follow-up were clearly in-
dependent of exposure in only two studies, and in no study
was the intensity of the search for disease clearly indepen-
dent of exposure status. For case-control and cross-sectional
studies, data were collected in a similar manner in all study
participants, with interviewers blinded to the case or expo-
sure status of the participants in only three studies. Because
of the lack of objective criteria, in only two studies was it
possible to be certain that noncases would have been clas-
sified as cases if they had developed the disease. Finally,
Ruiz-Navarro
et al., 1998
(28)
Case-control Hospital-
based
(Spain)
39 NR Urinary
levels
75th
percentile
vs. 25th
percentile
NR Myocardial
infarction
prevalence
29 49 0.97 0.50, 1.89 (Crude)
Lewis et al.,
1999 (30)
Cohort
(internal
comparisons)
Mormons
(United
States)
52 >1 CEI from
community
drinking
water
5 mg/liter-
year vs.
<1 mg/liter-
year
Death
certificate
CHD
mortality
411 3,647 0.86 0.68, 1.10 Age, sex
Stroke
mortality
176 3,882 0.69 0.47, 0.99
PAD
mortality
47 4,011 0.61 0.28, 1.31
Zierold et al.,
2004 (37)
Cross-sectional Survey
participants
with private
wells (United
States)
NR Mean ¼62 Subject
drinking
water level
>10 lg/liter
vs. <2
lg/liter
Self-report CHD
prevalence
128 1,057 1.54 0.90, 2.68 Age, sex,
smoking,
BMI
Stroke
prevalence
31 1,154 1.53 0.60, 4.07
*HAA, high-arsenic area; NR, not reported; AAS, atomic absorption spectrometry; BFD, blackfoot disease; CEI, cumulative exposure index; PAD, peripheral arterial disease; BMI, body mass index; DM, diabetes
mellitus; CHD, coronary heart disease.
yCumulative exposure index ¼Rarsenic level in drinking water 3time of exposure (i¼specific village).
Arsenic and Cardiovascular Disease 1041
Am J Epidemiol 2005;162:1037–1049

none of the case-control studies were based on incident
cases of disease.
Relative risk estimates
The relative risk estimates comparing the highest cate-
gory of exposure with the lowest in each individual study for
different cardiovascular outcomes are shown in table 1. Rel-
ative risks were higher in studies conducted in Taiwan than
in studies conducted in other countries. In Taiwan, relative
risks ranged from 1.59 to 4.90 (median, 3.60) for coronary
disease, from 1.19 to 2.69 (median, 1.94) for stroke, and
from 1.66 to 4.28 (median, 2.40) for peripheral arterial dis-
ease. In studies conducted outside of Taiwan, the ranges of
relative risk estimates for coronary disease, stroke, and pe-
ripheral arterial disease were 0.84–1.54 (median, 0.92),
0.69–1.53 (median, 0.91), and 0.61–1.58 (median, 1.10),
respectively.
Figure 3 presents the relative risk estimates for studies
reporting results for three or more categories of arsenic
exposure. The risks of coronary disease, stroke, and periph-
eral arterial disease generally increased with increasing ex-
posure in studies from Taiwan (32–35). Risk trends in
studies from the United States were inconsistent.
STUDIES IN OCCUPATIONAL POPULATIONS
Study characteristics
Sixteen studies carried out in occupational populations
(figure 1 and table 2) met our inclusion criteria. The studies
were conducted in copper smelters in the United States (39,
41), Japan (42), and Sweden (38); in mines and refineries in
Japan (43), China (31), France (20), and the United King-
dom (44); in a power plant in the Czech Republic (23); in
pesticide/insecticide industries in the United States (22, 45,
46); in a factory handling inorganic arsenic in the United
Kingdom (19); and in the glass industry in Sweden (21) and
Italy (47). In the mine/refinery study carried out in Japan
(43), residents were also included because of evidence
that arsenic contamination of soil, ambient air, and water
had existed for at least 28 years. Similarly, the study by
Nakadaira et al. (48) included mostly residents living close
to a dye factory that had contaminated drinking water for 5
years (1954–1959) with arsenic levels of 3,000 lg/liter (48).
All occupational studies reported only mortality data. The
studies used death certificates to identify coronary and
stroke deaths (11 studies), peripheral arterial disease deaths
(one study), and overall cardiovascular disease mortality
(five studies). Most occupational studies used external com-
parisons to derive standardized mortality ratios; the ex-
ceptions were one proportional mortality study (19), one
case-control study (21), and four cohort studies with internal
comparisons (31, 38, 39, 45). Exposure was ascertained
mostly on the basis of job titles. Two studies assigned ex-
posure on the basis of receipt of compensation for arsenic
poisoning (43) and residence in a village with water con-
taminated by an industrial source (48). Several studies mea-
sured arsenic in urine or air to confirm exposure, but this
information was not linked to cardiovascular outcomes (20,
22, 41, 45, 46). Only three studies created a cumulative
exposure index (mg/m
3
-year) for each worker (31, 38, 39).
Arsenic trioxide was the main chemical form of arsenic ex-
posure in at least three studies (39, 41, 43), and it was also
mentioned among other arsenicals in a fourth study (46).
Quality assessment
The occupational studies did not fulfill most of the pre-
specified quality criteria (figure 2). With the exception of
four studies (31, 38, 39, 49), the reported effect estimates
were based on age-adjusted standardized mortality ratios
1 10 100 1,000 1 10 100 1,000 1 10 100 1,000
Relative increase in arsenic concentration with respect to baseline category
Relative risk estimate
Coronary disease Stroke Peripheral arterial disease
0.6
1.0
2.0
3.0
4.0
5.0
0.6
1.0
2.0
3.0
4.0
5.0
0.6
1.0
2.0
3.0
4.0
5.0
FIGURE 3. Dose-response relations between arsenic exposure in drinking water and cardiovascular disease outcomes in general population
studies. The thick lines represent studies conducted in Taiwan (nWu et al., 1989 (35); dChen et al., 1996 (32); :Tseng et al., 2003 (33); þ
3Chiou
et al., 1997 (34); )Chen et al., 1988 (36); Tseng et al., 1996 (5)). The thin lines represent studies conducted in the United States (4Engel and
Smith, 1994 (29); sLewis et al., 1999 (3); kZierold et al., 2004 (37)). The reference categories were as follows: Wu et al., 1989 (35): <300 lg/liter;
Chen et al., 1996 (32), Tseng et al., 2003 (33), and Tseng et al., 1996 (5): 0 mg/liter-year; Chiou et al., 1997 (34): <0.1 mg/liter-year; Chen et al.,
1988 (36): 0 years of well-water consumption; Engel and Smith, 1994 (29): 5–10 lg/liter; Lewis et al., 1999 (30): <1 mg/liter-year; Zierold et al.,
2004 (37): <2lg/liter.
1042 Navas-Acien et al.
Am J Epidemiol 2005;162:1037–1049

comparing the study sample with the general population.
None of the studies adjusted for cardiovascular disease risk
factors or other exposures. Only one study adjusted for the
‘‘healthy worker’’ survivor effect (39).
Relative risk estimates
Findings in the occupational studies were heterogeneous,
with increased, decreased, and null relative risks (table 2).
The relative risk estimates ranged from 0.40 to 2.14 (me-
dian, 0.83) for coronary disease and from 0.30 to 1.33 (me-
dian, 0.76) for stroke. Studies in the three copper smelters
with a large number of cases (38, 39, 41) showed an in-
creased relative risk for coronary disease, although the con-
fidence intervals overlapped the null value. The study by
Hertz-Picciotto et al. (39) also reported mortality data for
peripheral arterial disease. The crude relative risk of periph-
eral arterial disease mortality for workers exposed to 20
mg/m
3
-year compared with workers exposed to less than
2 mg/m
3
-year was 3.46 (95 percent confidence interval
(CI): 0.77, 15.5) (39).
The dose-response relation for coronary disease by cumu-
lative airborne arsenic exposure was available in two studies
(38, 39) (figure 4). Coronary disease mortality tended to in-
crease with increasing cumulative exposure to arsenic, par-
ticularly after adjustment for the healthy worker survivor
effect in the study by Hertz-Picciotto et al. (39). No clear
trends were observed for stroke.
One study controlled for the healthy worker survivor
effect by introducing a 20-year lag and adjusting for em-
ployment status in each year of follow-up (39). The relative
risk of coronary disease mortality comparing copper smelter
workers with ambient air cumulative exposure of 20
mg/m
3
-year with those with exposure of less than 0.75
mg/m
3
-year was 1.3 (95 percent CI: 0.87, 2.1) before adjust-
ment for the healthy worker survivor effect and 1.5 (95
percent CI: 0.95, 2.5) after adjustment. After adjustment,
the trend of increasing coronary disease mortality risk
with increasing arsenic exposure was statistically significant
(ptrend ¼0.003; figure 4). The corresponding relative risks
for stroke mortality were 0.45 (95 percent CI: 0.18, 1.1)
before adjustment and 0.67 (95 percent CI: 0.23, 1.9) after
adjustment, with no consistent trend with increasing arsenic
exposure.
DISCUSSION
Summary of findings
This systematic review revealed common limitations in
the epidemiologic literature on arsenic and cardiovascular
outcomes, including the use of indirect indicators of expo-
sure rather than direct measurements, the uncertain compa-
rability between exposed and unexposed participants, and
the use of nonstandardized outcome definitions. These lim-
itations added uncertainty to the association of high chronic
arsenic exposure in drinking water with peripheral arterial
disease and other cardiovascular outcomes identified in
Taiwan. Moreover, in populations outside of Taiwan or in
occupational populations, the epidemiologic evidence on
the association between low-to-moderate arsenic concen-
trations and cardiovascular outcomes was inconclusive be-
cause of methodologic limitations.
General population studies
Taiwan. The association between arsenic in drinking
water in southwestern Taiwan and blackfoot disease is prob-
ably causal (3, 7). This association is most evident at very high
cumulative doses of arsenic, typically above 10 mg/liter-year
(equivalent, for instance, to continuous exposure to 500
lg/liter of arsenic in drinking water for 20 years). A causal
role of arsenic in peripheral arterial disease and angiitis is
also supported by early reports from outside of Taiwan.
From the 1930s to the 1950s, peripheral arterial disease
and amputations were described among German vintners
exposed to inorganic arsenic through the application of ar-
senical pesticides and intake of arsenic-contaminated wine
(3, 49–52), including pathology reports of a combination of
endangiitis and atheromatosis (52). In addition, long-term
arsenic inhalation in occupational settings was associated
with the Raynaud phenomenon (53, 54), an intermittent
form of vasculitis characterized by digital paleness and
low finger blood pressure on cooling that also occurs in
thromboangiitis obliterans. Similarly, persons exposed to
high levels of arsenic in drinking water (up to 1,790 lg/liter)
in Inner Mongolia, China, showed an improved vascular
response to cold stress 13 months after an intervention pro-
viding lower-arsenic drinking water (37 lg/liter).
To our knowledge, the pathologic characteristics of cor-
onary disease and stroke associated with high arsenic expo-
sure in southwestern Taiwan have not been described in the
accessible literature. In Antofagasta, Chile, researchers who
conducted histopathologic studies of children and young
adults exposed to high levels of arsenic in drinking water
(~600 lg/liter (55)) described fibrous intimal thickening of
small and medium-sized arteries (56–58). Some of these
children had electrocardiographic signs of myocardial in-
farction before death (57). In Taiwan, a dose-response pat-
tern has also been reported associating arsenic exposure
with carotid plaques and intima-media thickness, which
are subclinical markers of atherosclerosis (11).
While high arsenic exposure in Taiwan may relate to car-
diovascular disease, the magnitude of the associations is
uncertain. The use of average drinking water levels and the
lack of individual measures of arsenic make it possible to
systematically underestimate exposure due to other sources
in these areas, such as contaminated food and cooking water
(8). In addition, other methodologic limitations may have
a substantial impact on the magnitude of the associations.
Because arsenic exposure was assessed at the village level,
this ecologic association could be related to unmeasured
confounders.
Other factors may limit the generalizability of the Taiwan
findings even to high-arsenic areas. Exposure to high arsenic
levels in drinking water in Taiwan occurred over a long
period of time. Moreover, there may be differences in arse-
nic species to which populations were exposed (59), in other
coexposures (7, 59), in socioeconomic development, or in
dietary deficiencies (such as carotenoids, selenium, or zinc
Arsenic and Cardiovascular Disease 1043
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TABLE 2. Studies of arsenic exposure and cardiovascular disease mortality in occupational populations
Study (authors,
year, and
ref. no.)
Country
Design
(type of
comparison)
Occupational
population
%
men
Age range
(years)
Arsenic
assessment
(compound(s))
Comparison
(exposed vs.
reference)
Mortality
outcome(s)
studied
No. of
cases
Duration
of follow-
up
(years)
Age-
adjusted
relative
risk
95%
confidence
interval
Bradford
Hill and
Faning,
1948 (19)
United
Kingdom
Proportional
mortality
Factory with
inorganic
arsenic
100 >20 at
death
Job title
(inorganic
arsenic)
Workers
vs. other
workers
CVD*393 33 0.73 0.45, 1.19y
Tokudome
and
Kuratsune,
1976 (42)
Japan Cohort
(external)
Copper
smelter,
Ooita
100 42–76 at
death
Job title (NS*) Workers vs.
general
population
CHD*7 22 0.47 0.22, 0.99
Stroke 26 0.76 0.52, 1.12
Mabuchi
et al.,
1980 (46)
United
States
Cohort
(external)
Pesticide
manufacturer,
Maryland
75 <20–40
at time
of hiring
Job title (lead
arsenate,
arsenic
trioxide,
sodium
arsenite)
Workers vs.
general
population
CHD 76 31 0.90 0.72, 1.13
Stroke 15 1.33 0.80, 2.21
Bencko
et al.,
1980 (23)
Czech
Republic
Proportional
mortality
Coal-
burning
power
plant
100 30–80 at
death
Job title (NS) Workers vs.
other
workers
CVD 101 18 0.88 0.58, 1.33y
Wingren
and
Axelson,
1987 (21)
Sweden Case-control Glass
industry
area
100 45–75 at
death
Job title (NS) Workers vs.
general
population
CVD 2,029 32 1.20 1.10, 1.40
Sobel et al.,
1988 (22)
United
States
Cohort
(external)
Insecticide
manufacturer,
Michigan
100 NR*Job title (lead
arsenate,
calcium
arsenate,
magnesium
arsenate,
copper
acetoarsenite)
Workers vs.
general
population
CVD 96 8 0.80 0.65, 0.98
Jarup et al.,
1989 (38)
Sweden Cohort
(internal)
Copper
smelter,
Ronskar
100 <20–80
at death
CEI*,z(lg/m
3
-
year) with air
monitoring
and employee
work history
(NS)
>100 mg/m
3
-
year vs.
<0.25 mg/
m
3
-year
CHD 437 39 1.12 0.72, 1.74
Stroke 123 0.64 0.24, 1.71
Tsuda et al.,
1990 (43)
Japan Cohort
(external)
Mine/refinery,
Toruku
(workers/
residents)
50 Mean ¼61 Compensated
for arsenic
poisoning
(arsenic
trioxide)
Workers vs.
general
population
CHD 7 17 2.14 1.00, 4.37
Stroke 8 0.77 0.36, 1.53
Xuan et al.,
1993 (31)
China Cohort
(internal)
Tin mine 86 Mean ¼19
at time
of hiring
CEI (mg/m
3
-
year) with air
monitoring
(NS)
>75th
percentile
vs. <25th
percentile
CHD 47 11 0.40 0.17, 0.92
Stroke 302 0.30 0.15, 0.61
Simonato et al.,
1994 (20)
France Cohort
(external)
Gold mine/
refinery
100 NR Job title (NS) Workers vs.
general
population
CVD 43 32 0.54 0.39, 0.73
Tollestrup
et al.,
1995 (45)
United
States
Cohort
(internal)
Orchard
workers
66 8–55 at
time of
hiring
Job title (lead
arsenate)
Workers vs.
general
population
CHD NR 45 1.27 0.72, 2.23
Stroke NR; total
N¼1,097
0.82 0.31, 2.12
1044 Navas-Acien et al.
Am J Epidemiol 2005;162:1037–1049

(27, 60)) that may interact with arsenic. Differences among
populations in the prevalence of functional polymorphisms
in genes related to arsenic metabolism may also play a role
(61–65).
Other countries. The cardiovascular effects of low
chronic arsenic exposure are unknown. Studies from Taiwan
are inadequate to address this question, because few subjects
were exposed to low or intermediate levels in drinking wa-
ter. Furthermore, studies from other populations with likely
lower exposures, including the United States, are scarce and
inconclusive (24, 28–30, 37).
Important common limitations include the uncertain
comparability of exposure groups in terms of cardiovascular
disease risk factors, socioeconomic development, and ac-
cess to care; the use of cross-sectional or case-control de-
signs based on prevalent cases; the lack of individual
exposure assessment; and the lack of standardized criteria
for diagnosing cardiovascular endpoints. The inconsistent
associations between arsenic and cardiovascular outcomes
in these studies cannot be interpreted as evidence of a lack
of effect of arsenic. Because of the methodologic limitations
of these studies, it is possible that even a substantial effect
could have been undetected. High-quality prospective stud-
ies evaluating the association between long-term arsenic
exposure and cardiovascular endpoints in populations with
a varied range of exposures should be a public health re-
search priority.
Occupational studies
The methodologic limitations of the occupational studies
reviewed precluded our reaching conclusions in favor of or
against an association. Most of these studies reported only
results from external comparisons. These comparisons are
of questionable validity, because workers are likely to have
substantially different cardiovascular risks than the general
population. The two studies that used internal comparisons
showed dose-response relations compatible with increased
coronary disease mortality with increasing airborne arsenic
concentrations (38, 39). Additional limitations include un-
certainties in exposure and outcome assessment, possible
changes in arsenic exposure in the workplace over time, lack
of information on concomitant exposures (such as metals in
copper smelters), and lack of information on established
cardiovascular disease risk factors. Finally, only one study
adjusted for the healthy worker survivor effect (39). After
adjustment, the association of arsenic with coronary disease
mortality was stronger and the increasing trend was statis-
tically significant. It is known that the healthy worker sur-
vivor effect attenuates the observed effect of arsenic on lung
cancer (66), and it is possible that not accounting for it
might have produced underestimation of the association
with coronary disease mortality in other studies (41, 67).
Possible mechanisms for arsenic-related
cardiovascular disease
The possibility that arsenic causes cardiovascular disease
is supported by several biologic mechanisms. Arsenic can
increase the production of reactive oxygen species like
Bartoli et al.,
1998 (47)
Italy Cohort
(external)
Glass
industry
100 <40–65
at death
Job title (NS) Workers vs.
general
population
CHD 53 35 0.67 0.53, 0.84
Stroke 41 0.77 0.58, 1.00
Lubin et al.,
2000 (41)
United
States
Cohort
(external)
Copper
smelter,
Montana
100 <10–30
at time
of hiring
Job title
(arsenic
trioxide)
Workers vs.
general
population
CHD 1,574 32 1.05 0.99, 1.10
Stroke 335 1.03 0.93, 1.15
Hertz-Picciotto
et al., 2000
(39)
United
States
Cohort
(internal)
Copper
smelter,
Tacoma,
Washington
100 NR CEI (lg/m
3
-
year) with air
monitoring
and employee
work history
(arsenic
trioxide)
>20 mg/m
3
-
year vs.
<0.75 mg/
m
3
-year
CHD 394 36 1.50 0.95, 2.50§
Stroke 91 0.67 0.23, 1.90§
Peripheral
arterial
disease
18 3.46 0.77, 15.5y
Nakadaira
et al., 2002
(48)
Japan Cohort
(external)
Dye factory
(residents)
45 Mean ¼30 Living in a
contaminated
village
(inorganic
arsenic)
Residents vs.
general
population
CHD 2 33 0.58 0.14, 2.31
Stroke 4 0.67 0.25, 1.78
Binks et al.,
2005 (44)
United
Kingdom
Cohort
(external)
Tin smelter 100 40–70 at
death
Job title (NS) Workers vs.
general
population
CHD 104 34 0.83 0.68, 1.01
Stroke 32 1.07 0.73, 1.51
*CVD, cardiovascular disease; NS, not specified; CHD, coronary heart disease; NR, not reported; CEI, cumulative exposure index.
yNot adjusted for age.
zCumulative exposure index ¼Rarsenic level in air 3time of exposure (i¼job title).
§ Adjusted for the healthy worker survivor effect.
Arsenic and Cardiovascular Disease 1045
Am J Epidemiol 2005;162:1037–1049

hydrogen peroxide (68, 69), hydroxyl radicals (70), and
others (68). Lipid peroxidation increased significantly after
6 months of arsenic feeding in mice (71). Persons exposed to
high arsenic in drinking water in Inner Mongolia had higher
levels of lipid peroxides (72), and in Taiwanese subjects,
blood arsenic was positively correlated with levels of super-
oxide radicals (73). The production of reactive oxygen
species has been implicated as the initial step in arsenic-
induced endothelial cell proliferation (68) and apoptosis
(69, 74), two mechanisms proposed for arsenic-related
atherosclerosis (73).
Arsenic may also induce alterations in nitric oxide me-
tabolism and endothelial function (75, 76). Persons exposed
to high-arsenic drinking water in Inner Mongolia had de-
creased serum and urine concentrations of nitric oxide me-
tabolites (75, 76), and this association was reversed after an
intervention provided lower-arsenic drinking water (76). In
Mexican children from Regio
´n Lagunera, urinary arsenic
levels were inversely associated with nitric oxide production
in activated monocytes (77). In human endothelial cells,
arsenite at concentrations of 1–25 lMinhibited endothelial
nitric oxide synthase activity (78, 79), resulting in de-
creased cell growth. At concentrations below 1 lM, however,
arsenite up-regulated the expression of constitutive nitric
oxide synthase 3, and this mechanism was proposed as a
possible explanation for arsenic-induced cell growth and
angiogenesis (79).
In addition, inorganic arsenic up-regulates inflammatory
signals (80, 81), releases tumor necrosis factor afrom
mononuclear cells (81), and stimulates cyclooxygenase-2
expression (82). An inflammatory component was also re-
ported in studies exposing apolipoprotein E-deficient mice
to arsenite in drinking water at 10,000–20,000 lg/liter for
18–24 weeks (83, 84). At these very high doses, arsenic
accumulated in vessel walls, and plaques covering the intima
were increased in size in comparison with unexposed mice
(83, 84). Arsenic-treated mice had higher serum levels
of leukotriene E
4
and prostacyclin (prostaglandin I
2
) (84),
and in vitro, arsenic induced the expression of genes coding
inflammatory mediators, including interleukin-8 (83).
Arsenic may also induce atherosclerosis by enhancing
arterial thrombosis and platelet aggregation (85, 86). Fi-
nally, arsenic exposure has been related to diabetes (87–
89) and hypertension (90, 91), but these studies have often
had significant methodologic limitations, and their findings
have been inconsistent (37, 41).
While experimental studies suggest potential mecha-
nisms for arsenic atherogenicity, their relevance to low or
moderate arsenic exposures is uncertain, because these ex-
perimental studies were typically performed using high ar-
senic concentrations. Experimental studies using lower
concentrations of arsenic are needed to identify mechanistic
pathways for arsenic-induced atherosclerosis.
Quality of the evidence and limitations
Limitations in the assessment of exposure (often per-
formed in an ecologic manner) and cardiovascular out-
comes, the cross-sectional or retrospective nature of many
studies, and the lack of adjustment for potential confound-
ers, among other methodologic limitations, make it impos-
sible to establish firm conclusions regarding the effects of
arsenic on cardiovascular outcomes at concentrations lower
than those observed in Taiwan. Similar methodologic limi-
tations make it difficult to quantify the magnitude of the
association in Taiwan. Unfortunately, the evidence on the
association between arsenic and cardiovascular outcomes
that is available from other areas with high arsenic levels
in drinking water (in Chile, Argentina, Mexico, Bangladesh,
and Inner Mongolia) is limited to uncontrolled case reports
on cardiovascular endpoints (56, 58, 92), even though there
are case-control studies of arsenic and cancer from these
areas (93, 94). The lack of epidemiologic reports from these
populations could be related to publication bias, but it could
also reflect a lack of investigation.
Airborne arsenic (mg/m3-year)
Relative risk estimate
Coronary mortality Stroke mortality
Airborne arsenic (mg/m3-year)
0.15 0.5 5.0 50 150
0.5
1.0
2.0
0.15 0.5 5.0 50 150
0.5
1.0
2.0
FIGURE 4. Dose-response relations between cumulative arsenic exposure in ambient air and cardiovascular disease outcomes in occupational
studies. Cumulative airborne arsenic exposure ¼Rarsenic levels in ambient air
i
3time of exposure
i
(i¼job position, with different levels assigned
to each position in different periods). dHertz-Picciotto et al., 2000 (39); nJarup et al., 1989 (38).
1046 Navas-Acien et al.
Am J Epidemiol 2005;162:1037–1049

Conclusion
The evidence from Taiwan is consistent with a role for high
arsenic exposure in atherosclerosis, although the magnitude
of the association is uncertain because of the methodologic
limitations of the available studies. These cardiovascular ef-
fects, together with cancer, developmental and reproductive
effects, and skin lesions, provide strong support for wide-
spread efforts to reduce arsenic exposure (8). The cardio-
vascular effects of chronic low-dose exposure to arsenic are
unknown, and current epidemiologic studies are inadequate
to answer this question. It is becoming increasingly evident,
however, that low-level chronic exposure to environmental
pollutants may have important cardiovascular effects (2, 95–
99), and it is plausible that low-level arsenic exposure also
increases cardiovascular risk. Since low or moderate arsenic
exposure is widely prevalent, even a small effect of arsenic
on cardiovascular risk is potentially important. Carefully
planned prospective studies in populations exposed to a wide
range of arsenic levels, using individual biomarkers of ar-
senic exposure and standardized information on cardiovas-
cular disease risk factors and outcomes, is a public health
research priority.
ACKNOWLEDGMENTS
This work was supported by grant 1R01 ES012673 from
the National Institute of Environmental Health Sciences.
Drs. Ana Navas-Acien and Eliseo Guallar were supported
by the Johns Hopkins Center for Excellence in Environ-
mental Public Health Tracking. Dr. Eliseo Guallar was also
supported by grant 0230232N from the American Heart
Association.
Conflict of interest: none declared.
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