© 1996 American Heart Association, Inc.
Articles |
Dose-Response Relationship Between Ischemic Heart Disease Mortality and Long-term Arsenic Exposure
From the Institute of Epidemiology, College of Public Health (C.-J.C., H.-Y.C., M.-H.C., L.-J.L.) and the Department of Internal Medicine, College of Medicine (T.-Y.T.), National Taiwan University, Taipei.
Correspondence to Chien-Jen Chen, ScD, Institute of Epidemiology, College of Public Health, National Taiwan University, No. 1 Jen-Ai Rd Section 1, Taipei 10018, Taiwan.
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Abstract |
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Abstract The cardiovascular effects of inorganic arsenic have been documented, but the dose-response relationship between ischemic heart disease (ISHD) and long-term arsenic exposure remains to be elucidated. Mortality rates from ISHD among residents in 60 villages of the area in Taiwan with endemic arseniasis from 1973 through 1986 were analyzed to examine their association with arsenic concentration in drinking water. Based on 1 355 915 person-years and 217 ISHD deaths, the cumulative ISHD mortalities from birth to age 79 years were 3.4%, 3.5%, 4.7%, and 6.6%, respectively, for residents who lived in villages in which the median arsenic concentrations in drinking water were <0.1, 0.1 to 0.34, 0.35 to 0.59, and
0.6 mg/L. A cohort of 263
patients affected with blackfoot disease (BFD), a unique
arsenic-related peripheral vascular disease, and 2293
non-BFD residents in the endemic area of arseniasis were recruited and
followed up for an average period of 5.0 years. There was a monotonous
biological gradient relationship between cumulative arsenic exposure
through drinking artesian well water and ISHD mortality. The relative
risks were 2.5, 4.0, and 6.5, respectively, for those who had a
cumulative arsenic exposure of 0.1 to 9.9, 10.0 to 19.9, and 20.0
mg/L-years compared with those without the arsenic exposure after
adjustment for age, sex, cigarette smoking, body mass index, serum
cholesterol and triglyceride levels, and
disease status for hypertension and diabetes through
proportional-hazards regression analysis. BFD patients were
found to have a significantly higher ISHD mortality than non-BFD
residents, showing a multivariate-adjusted relative
risk of 2.5 (95% CI, 1.1 to 5.4).
Key Words: arsenic • blackfoot disease • ischemic heart disease
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Introduction |
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Arsenic is a widely distributed element present in various compounds throughout the earth's crust. It is transported in the environment mainly by water. Humans are exposed to inorganic and organic arsenic through medicinal, environmental, and occupational sources.1 Inorganic arsenic has been used for the treatment of leukemia, psoriasis, and chronic bronchial asthma. Both inorganic and organic arsenic are present in various amounts in food. However, inorganic forms of arsenic are much more toxic than the organic forms. Cigarette smokers may be exposed to arsenic in tobacco, but the chemical form of arsenic in the smoke remains unclear. Workers in industries of smelting copper and gold ores, producing and applying arsenic-containing pigments, dyes, and pesticides, manufacturing glass and various pharmaceutical substances, and chimney sweeping may have a high exposure to arsenic. However, for the general population, the main exposure to inorganic arsenic is through ingestion of high-arsenic drinking water.2 The safety level of arsenic in drinking water set by the US Environmental Protection Agency was 0.05 mg/L. In the United States, it has been estimated that more than 350 000 people may be supplied with water containing >0.05 mg/L arsenic and more than 2.5 million people with levels >0.025 mg/L.3
Long-term exposure to inorganic arsenic has toxic effects on the cardiovascular system. Arsenic has been documented as the major risk factor of BFD, a unique peripheral vascular disease that frequently ends with dry gangrene and spontaneous amputation of affected extremities.4 5 The disease is endemic on the southwest coast of Taiwan, where residents have used high-arsenic artesian well water for drinking and cooking for decades. The pathological changes of BFD are compatible with arteriosclerosis obliterans (70%) and thromboangiitis obliterans (30%) that developed from severe underlying systemic arteriosclerosis.6 An increased risk of peripheral vascular disease associated with environmental exposure to inorganic arsenic through drinking water has also been observed in Chile and Mexico.7 8 Peripheral vascular lesions have been described in Moselle vintners chronically exposed to arsenic through contaminated wine,9 and copper smelter workers were reported to have an altered blood vessel function and Raynaud's phenomenon.10
Both environmental and occupational exposures to inorganic arsenic have been related to an increased mortality from cardiovascular diseases. A significant excess mortality from cardiovascular disease has been found among copper smelter workers,11 12 chimney sweeps,13 14 and glass blowers15 who were exposed to arsenic in the workplace. Environmental exposures to inorganic arsenic through drinking water were associated with an increased mortality from cardiovascular disease among residents in Taiwan, Chile, and Japan.16 17 18 The studies on arsenic-induced cardiovascular disease were either occupational cohort studies or ecological correlation studies. The former may be subject to biases resulting from the healthy worker effect, which may underestimate the arsenic-related risk due to the fact that the severely ill are ordinarily excluded from employment, and multiple exposure to various chemicals, and the latter may have the problem of ecological fallacy. In addition, no examination of the biological gradient of arsenic-induced cardiovascular disease has ever been reported. We report here two studies, an ecological correlation study and a prospective cohort study, that were carried out to evaluate the dose-response relationship between long-term exposure to ingested inorganic arsenic and mortality from ISHD among residents of the endemic area of chronic arseniasis in Taiwan.
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Methods |
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Ecological Correlation Study
The mortality rates from ISHD among residents who lived in 60 villages of six BFD-endemic townships, including Peimen, Hsuechia, Putai, Ichu, Yensui, and Hsiaying, were analyzed to examine its association with the arsenic concentration in drinking water. The study area was located on the rising southwest coast of Taiwan. Because of the high salinity in water from shallow wells (<10 m deep), residents living in the area had used water from artesian wells for drinking and cooking since 1910. The artesian wells were
100 m deep and had a much
lower content of salt. In this confined study area of 30x40 km, water
from artesian wells was reported to have a much higher level of
inorganic arsenic than that from shallow wells.19 Most
residents in the study area were engaged in farming, fishery, and salt
production. They shared similar socioeconomic status, living
environments, lifestyles, dietary patterns, and health service
facilities. The major difference in environmental exposure among
residents in the study area appears to be the level of arsenic in
drinking water, ranging from 0.01 to 1.75 mg/L. In other words, such a
circumstance provides a unique natural experiment for the evaluation of
health hazards induced by ingested arsenic. In Taiwan, any events of birth, death, marriage and divorce, education, employment, and migration are mandatorily registered in the household registration offices. These registered records are double-checked annually through home-visit interviews by registration officers. Data for demographic and vital statistics derived from the household registration offices are quite complete and accurate in Taiwan. For the analysis of mortality from ISHD among residents in the study area, all death certificates of those who died during the period from 1973 through 1986 and person-years under observation for the same period were obtained from local household registration offices of the study townships. All death certificates were reviewed and coded according to the eighth revision of the ICD. There were 217 deaths with ISHD as the underlying cause (ICD 410 to 414). Person-years were calculated by summing up the midyear population reported annually by household registration offices during the study period. The person-years derived from these mandatorily registered and annually updated household records were considered much more accurate than those estimated from census data. A total of 1 355 915 person-years were under observation in the study area from 1973 through 1986.
To examine the association between arsenic concentration in drinking
water and mortality from ISHD, the 60 study villages were stratified
into four groups according to their median arsenic level in well water,
ie, <0.10, 0.10 to 0.34, 0.35 to 0.59, and 0.60 mg/L, on the basis
of the data reported previously.20 In total, there were
21, 17, 14, and 8 villages, respectively, in the four groups with an
arsenic level from the lowest to the highest. The person-years
under observation during the study period were 485 076, 413 185,
297 619, and 160 035, respectively, for these four study groups.
Among residents >15 years old, the proportions of those engaged in
labor including farming, fishing, and salt production were
63%, 69%, 65%, and 70%, respectively, in the four study groups. The
corresponding proportions of those who had 
6 years of schooling were
65%, 62%, 59%, and 63%, respectively. The average monthly family
income ranged from US $350 to $400 in these four groups in 1980. In
other words, these four study groups had similar socioeconomic
conditions.
Age-specific mortality rates were first calculated for the four study groups with different arsenic concentrations in drinking water. Cumulative ISHD risks from birth to the age of 39, 49, 59, 69, and 79 years, respectively, were then derived for the four study groups separately according to standard life-table methods.21
Cohort Follow-up Study
In addition to the ecological correlation study described above,
a cohort follow-up study was also carried out to examine the
association between ISHD mortality and long-term arsenic exposure
at the individual level. The study cohort consisted of two separate
subcohorts, ie, a subcohort of BFD patients and matched community
control subjects and a subcohort of residents in villages where BFD was
hyperendemic. The first subcohort included a total of 1010 BFD patients
and matched healthy community control subjects who were selected from
four BFD-endemic townships, Peimen, Hsuechia, Putai, and Ichu, in 1985
and followed up for 8 years. These study subjects were recruited
for examination of multiple risk factors associated with BFD as
reported previously.5 Originally, 249 BFD patients and 759
control subjects were recruited and interviewed. Case patients and
control subjects were 1:3 frequency-matched on age (within 5-year
age categories), sex, and residential township. Eight BFD patients
whose recruitment interviews had been rated as unreliable were
reinterviewed. Six control subjects became affected with BFD during the
follow-up period, and two additional BFD patients were identified
and also recruited in this study. In other words, 257 BFD patients and
753 matched control subjects were included in this subcohort.
The second subcohort included a total of 1557 residents in the villages of Homei, Fuhsin, and Hsinming in Putai Township. Residents in these three villages had the highest BFD prevalence in Taiwan. The prevalence of BFD was reported to be 13.6% in Homei, 9.6% in Fuhsin, and 10.3% in Hsinming. The median arsenic concentration of the artesian well water was found to range from 0.7 to 0.93 mg/L in the early 1960s. A tap water supply system was implemented in the study villages at that time, but its coverage remained low until the early 1970s. Artesian well water was no longer used for drinking and cooking after the mid-1970s. Study subjects for this second subcohort were recruited from 1988 to 1989 for a community-based survey of multiple health hazards induced by ingested inorganic arsenic. Six subjects in this subcohort had been found in the recruitment health examination to be affected with BFD. Eleven subjects in this subcohort had also been included in the first subcohort. In total, the overall study cohort had 2556 subjects, including 263 BFD patients and 2293 non-BFD residents.
All study subjects in the cohort had been personally interviewed according to a structured questionnaire to obtain information on their sociodemographic characteristics; history of residential villages and water consumption; lifestyles, including cigarette smoking and alcohol drinking habits; history of dietary consumption frequency; and personal and familial history of cancer, hypertension, diabetes mellitus, and cardiovascular diseases at recruitment. Systolic and diastolic blood pressures, height, body weight, triceps skinfold thickness, and arm circumference were measured according to standardized protocols. Body mass index was derived by dividing weight in kilograms by the square of height in meters. Fasting blood was also collected from study subjects by use of vacuum syringes and disposable needles. Serum samples were centrifuged, separated into aliquots, and stored at -70°C until examination. Fasting blood glucose and serum levels of cholesterol and triglycerides were determined by autoanalyzer.
The vital status of study subjects was followed up through the data linkage with household registration records and computerized national death certification file. As already mentioned, the household registration and death certification system in Taiwan keeps updated and complete information on the vital status and causes of death of all inhabitants. Inhabitants in Taiwan can easily be traced through these registration and certification systems. The household registration records of study subjects were reviewed by well-trained registration officers. Both vital status and date of death or migration were abstracted. Copies of death certificates were also obtained for subjects who died during the follow-up period. The national identification number, date of birth, and sex were used as the linking variables to double-check the vital status and causes of death of study subjects from the national death certification system. The vital status and causes of death for all subjects in the study cohort during the entire follow-up period from initial recruitment in 1985 to December 31, 1992, were thus verified.
To assess the association between the long-term arsenic exposure and the development of ISHD, Cox's proportional-hazards regression analyses were used to estimate multivariate-adjusted RR and its 95% CI. Detailed residential history, including villages and duration of residence, as well as history of water consumption, including water source and duration, were obtained from the questionnaire interview. These were used to derive the overall duration of consuming artesian well water. Arsenic levels in artesian well water of every village in which study subjects had lived were obtained from reports of previous studies carried out in the 1960s.20 The arsenic level in artesian well water in the study area has been reported to be stable in two surveys carried out by the Taiwan Provincial Institute of Environmental Sanitation.22
Some study subjects had moved from one village to another, and the
arsenic concentrations in artesian well water of these villages were
different. Since both the duration of drinking and arsenic level of
artesian well water may be associated with ISHD mortality, an index of
cumulative arsenic exposure from drinking artesian well water was
derived to reflect the overall exposure to arsenic for each study
subject. The cumulative arsenic exposure from drinking artesian well
water (in mg/L-years) was defined as the sum of products, derived
by multiplying the arsenic concentration in artesian well water (mg/L)
by the duration of consuming the artesian well water (years) during
consecutive periods of living in different villages. In other words, it
was derived by the formula 
(CixDi), where
Ci was the median arsenic concentration in artesian well
water of the village in which a given study subject lived during the
period i, and Di was the duration of drinking artesian well
water in the village during the period i. An index of average arsenic
concentration in drinking water was also derived by the formula
(CixDi)/(Di).
Both cumulative arsenic exposure from drinking artesian well water and average arsenic concentrations in drinking water were calculated only for those subjects who had complete information on arsenic exposure from drinking artesian well water throughout his or her lifetime. In other words, these two arsenic exposure indexes of a given subject were classified as unknown if the arsenic concentration of artesian well water in any village in which the subject had lived was not available. Some study subjects had moved into the study villages after they had lived for several years in other areas, and some others moved out to study or work for several years and then returned to the study area. Because the arsenic concentration in artesian well water was not always available in other areas, the average arsenic concentration in drinking water and cumulative arsenic exposure from drinking artesian well water could not be calculated for 796 study subjects (31%).
Because using the category of missing value for a categorical
variable may introduce bias,23 Cox's
proportional-hazards regression analyses both with and
without a missing-value category were carried out to estimate the
RR of developing ISHD and 95% CI for various indexes of long-term
arsenic exposure. Other risk factors for ischemic heart
disease, including age, sex, cigarette smoking habits, body mass index,
serum levels of cholesterol and triglycerides,
and disease status for hypertension and diabetes mellitus, were further
included in the regression models as independent variables to
calculate multivariate-adjusted RR and 95% CI for
arsenic exposure indexes. Tertiles of body mass index and serum levels
of cholesterol and triglycerides were used to
categorize study subjects into three almost equal groups in the
multivariate analyses. The cutoff points were
20 and 25 kg/m2 for body mass index, 200 and 230 mg/dL for
serum cholesterol level, and 90 and 140 mg/dL for serum
triglyceride level. Hypertension status was defined as a
systolic blood pressure of 160 mm Hg, a diastolic
blood pressure of 95 mm Hg, and/or a history of hypertension
regularly treated with antihypertensive drugs. Diabetes status was
defined by a fasting glucose level of 7.8 mmol/L and/or a history of
diabetes regularly treated with insulin or sulfonylurea agents.
Because BFD status is a marker for long-term arsenic exposure and may also be an indicator for individual susceptibility to arsenic-induced health hazards, two separate regression analyses with and without BFD status included as an independent variable were carried out. In the model assessing the relative ISHD risk associated with long-term arsenic exposure, the BFD status was not included so as to avoid the problem of overcontrol.24 In the model assessing the relative ISHD risk for BFD status as a susceptibility marker, the RRs for long-term arsenic exposure will be underestimated.
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Results |
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Ecological Correlation Study
As shown in the Figure
, there was a monotonous
increase in cumulative ISHD mortality with increasing median arsenic
concentration in well water. The older the subject, the greater the
difference in cumulative mortality from ISHD among different exposure
groups. The cumulative mortalities from ISHD from birth to 69
years old were 1.0%, 1.2%, 1.8%, and 2.2%, respectively, for
residents who lived in villages in which the median arsenic
concentrations in well water were <0.10, 0.10 to 0.34, 0.35 to 0.59,
and 0.60 mg/L. The corresponding figures for cumulative mortality
from ISHD from birth to 79 years old were 3.4%, 3.5%, 4.7%, and
6.6%, respectively.
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Cohort Follow-up Study
Table 1 shows subject numbers, follow-up
person-years, and ISHD deaths by age, sex, and BFD status. In
total, 1448 and 11 265 person-years were observed for 263 BFD
patients and 2293 non-BFD residents, respectively, showing an average
follow-up period of 5.5 and 4.9 years. During the follow-up
period, 16 BFD patients and 23 non-BFD residents died from ISHD. The
ISHD mortality was found to increase with age for both BFD patients and
non-BFD residents. BFD patients had a much higher ISHD mortality than
non-BFD residents, giving rate ratios of 29.5, 3.8, and 3.1,
respectively, for age groups of 40 to 54, 55 to 69, and 70 years. Men
had a much higher ISHD mortality than women, showing a sex ratio of 1.3
for BFD patients and 1.6 for non-BFD residents.
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The associations between various long-term arsenic exposure indexes
and ISHD mortality are shown in Table 2. After
adjustment for age and sex through Cox's proportional-hazards
regression analysis as shown in model 1 in Table 2, significant
associations with ISHD mortality were observed for three different
long-term arsenic exposure indexes. Moreover, there was a
monotonicity of RRs for the two more precise measures of long-term
arsenic exposure, the average arsenic concentration in drinking water
and the cumulative arsenic exposure from drinking artesian well water.
The RRs for the highest-exposure groups of the two indexes were as
much as five times greater than those for the unexposed groups. The
inclusion of the missing values as one category did not alter the
dose-specific RRs.
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There were consistent decreases in RRs for all three long-term arsenic exposure indexes after further adjustment for the BFD status, as shown in model 2, but significant dose-response relationships remained between ISHD mortality and average arsenic concentration in drinking water and cumulative arsenic exposure from drinking artesian well water. After adjustment for ISHD risk factors, including cigarette smoking, body mass index, serum levels of cholesterol and triglycerides, and disease status for hypertension and diabetes mellitus but not BFD status as shown in model 3, the biological gradient of ISHD risk was still observed for the two more precise indexes of long-term arsenic exposure through drinking artesian well water. In model 4, further including BFD status as an independent variable, the monotonicity of RRs remained, with slight decreases in their magnitude. The dose-specific RRs remained similar after the inclusion of the missing values as one category in models 2, 3, and 4.
Table 3 shows multivariate-adjusted
RRs for various independent variables included in models 3 and 4 of
Table 2
. As shown in model 3, there was a statistically significant
increase in risk of lethal ISHD with age. Men had a higher mortality
from ISHD than women, but the sex difference was not statistically
significant. No significant association with ISHD mortality was
observed for cigarette smoking, body mass index, serum
cholesterol and triglyceride levels, and
diabetes mellitus in this study cohort. Hypertensive subjects had a
significantly increased mortality from ISHD over nonhypertensive
subjects, showing an approximately twofold increased
multivariate-adjusted RR. There was a monotonous
increase in RRs for the cumulative arsenic exposure through drinking
artesian well water, showing a
multivariate-adjusted RR of 6.5 for the
highest-exposure group.
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As shown in model 4, BFD patients were found to have a significantly higher ISHD mortality than non-BFD residents after adjustment for age, sex, cigarette smoking, serum levels of cholesterol and triglycerides, hypertension, diabetes mellitus, and cumulative arsenic exposure. The multivariate-adjusted RR was around 2.5 for BFD status.
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Discussion |
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In this study, we observed a significantly increased ISHD mortality among residents in the BFD-endemic area, a significantly higher ISHD mortality for BFD patients than for age-, sex-, and residence-matched control subjects, and a dose-response relation between ISHD mortality and long-term exposure to ingested inorganic arsenic. The association remained significant after further adjustment for other ISHD risk factors, including age, sex, cigarette smoking, serum levels of cholesterol and triglycerides, and disease status for hypertension, diabetes, and BFD. The finding in this study is consistent with those reported in previous studies11 12 13 14 15 16 17 18 that were subject to the limitations of ecological fallacy, healthy worker effect, poor quantification of arsenic exposure, and inadequate control of confounding factors.
As in most studies on ISHD, a significant association with lethal ISHD was observed for age and hypertension as well as for long-term exposure to ingested inorganic arsenic. But no significant associations were found for cigarette smoking, body mass index, serum levels of cholesterol and triglycerides, and diabetes mellitus. Our previous study also showed no association between cigarette smoking and BFD.5 It has been shown in the same study that residents who were undernourished, as reflected by a low consumption of vegetables, meat, eggs, and fish, were at a higher risk of developing BFD.5 Arsenic-related ISHD seems to be different from that related to obesity and hyperlipidemia.
However, some issues deserve discussion. Mortality rather than incidence of ISHD was used to assess the association between ingested inorganic arsenic and disease in this study. The mortality of a disease is a function of its incidence and fatality. If a disease is not completely lethal, ie, fatality is not 100%, the association between its incidence and exposure to a given risk factor will be underestimated by the association between its mortality and exposure. The relative ISHD risks observed for various indexes of long-term arsenic exposure in this study are considered to be underestimated under such a conservative circumstance.
Because arsenic levels in artesian well water of some areas other than
the BFD-endemic area were not available, the average and cumulative
arsenic exposure levels were unknown for 31% of study subjects. The
duration of consuming artesian well water, which was available for all
study subjects, was similar for subjects with the information on
arsenic exposure and those without it. Furthermore, the odds ratios for
those who had no information on average arsenic concentration in
drinking water or cumulative arsenic exposure from drinking artesian
well water were between the odds ratios for those who had the lowest
and highest exposures, as shown in Table 2. The unavailability of these
arsenic exposure data for some study subjects seems not to affect the
assessment of the association between exposure to arsenic and ISHD
risk. Unfortunately, no information on the amount of water consumed by
each study subject during different periods of his or her lifetime was
obtained in the study. It has to be assumed that the mean consumption
was similar across exposure groups. To adjust for the difference in
water consumption between men and women, the variable of sex was
included in the regression analyses. Separate analyses
for men and women showed similar dose-specific RRs with wider 95%
CIs because of the smaller sample size.
The numbers of study subjects in lower-exposure categories were not large enough to draw a definite conclusion on the existence of an exposure threshold for an effect. Since more than 98% of study subjects who had consumed artesian well water were exposed from immediately after birth, it is not possible to assess the effect of age of first exposure to arsenic on the development of ISHD.
Physical and chemical characteristics of drinking water, such as pH values and levels of arsenic, sodium, calcium, magnesium, manganese, iron, mercury, chromium, lead, nitrous and nitric nitrogen, fluoride, and bicarbonate, have been intensively studied in both BFD-endemic and nonendemic areas.19 25 Arsenic level was found to be the only item that was significantly higher than maximum allowable limits and strikingly different in water from shallow wells and artesian wells. Arsenic is thus the main chemical in the water responsible for the increased mortality from ISHD in the endemic area. Although humic substances have been hypothesized as a cause of BFD,26 it has been documented that BFD and humic substance–induced gangrenous changes have very different pathological characteristics, despite their clinical similarities.27 Humic substances resulting from the decomposition of organic matter, particularly dead plants, are widespread contaminants of water supplies and are definitely not confined to the BFD-endemic area. Humic substances contain complex constituents with unstable physical and chemical properties, such as molecular weight. The measurement of fluorescent intensity used in previous reports to quantify humic substances in water cannot reflect the concentration of humic substances correctly. Moreover, there has been no epidemiological evidence to indicate correlations between exposure to humic substances and circulatory diseases.
Based on the strength, dose-response relation, consistency, and temporal correctness of the association between ISHD and cumulative arsenic exposure, it is reasonable to conclude that the association is causal. The higher ISHD mortality observed in BFD patients than in matched control subjects after adjustment for the effect of chronic arsenic exposure suggests that some residents in the endemic area may have a higher daily consumption of artesian well water, a higher arsenic concentration in the artesian well water of their households, and/or a greater susceptibility to the health hazards induced by ingested inorganic arsenic. This susceptibility may be a result of genetic components that are involved in the metabolism and atherogenicity of inorganic arsenic or environmental factors such as nutritional status. It is worthwhile to evaluate such an individual susceptibility.
The mechanism by which inorganic arsenic induces atherosclerosis still remains to be elucidated. Inorganic arsenic may increase ISHD risk through its effects on cardiovascular risk factors, including hypertension and diabetes, or on atherosclerosis directly. It has recently been reported that long-term exposure to ingested inorganic arsenic is associated with an increased prevalence of hypertension and diabetes in a dose-response relationship.28 29 Further studies are required to examine whether there are direct effects of inorganic arsenic on the atherogenic process by its interfering with lipid metabolism, causing endothelial injuries, and/or inducing monoclonal expansion of smooth muscle cells. A recent study reported definite evidence of noncirrhotic portal hypertension among 5 of 13 patients with arsenic-induced skin pigmentation and hepatomegaly in India.30 Since it was not possible for us to examine such a condition among our study subjects, it remains to be elucidated whether the portal hypertension may contribute to the ISHD in our study cohort.
The epidemiological evidence of shared risk factors for cancer and atherosclerosis has been reviewed recently.31 Exposure to carcinogenic environmental agents, including ionizing radiation, vinyl chloride monomer, arsenic, tobacco, and various industrial combustion effluents containing polycyclic aromatic hydrocarbons, is associated with an increased risk of atherosclerosis. Both arsenic and vinyl chloride monomer seem to have a specific capability to cause various vascular lesions, including angiosarcomas and atherosclerotic plaques. These observations suggest that somatic mutation and cell proliferation may play a role in the pathogenesis of atherosclerotic plaque. The dual effect of arsenic on carcinogenicity and atherogenicity reported previously5 is considered to further support the hypothesis that monoclonal expansion of smooth muscle cells is a key process for atherosclerosis.32
Arsenic has many chemical properties similar to those of nitrogen and phosphorus, which are important elements of DNA, RNA, and proteins. Since most enzymes are regulated by the process of phosphorylation and dephosphorylation, in which ATP plays a major role, arsenate may hinder normal enzymatic functions by disrupting the formation of ATP from ADP and orthophosphate. Because arsenite is known to react strongly with sulfhydryl groups of proteins, it may interfere with the normal biochemical functions of proteins that are regulated by the formation/destruction of –S–S– bonds involving the cysteine side chains in the proteins. For example, arsenite has been found to inhibit the binding capability of glucocorticoid receptor in such a way.33 Whether arsenic may induce ISHD through its interference with structural or functional proteins involved in atherosclerosis requires further investigations. Several genes may also be involved in the multifactorial pathogenesis of ISHD. Although arsenic does not cause point mutation, it does induce cell transformation, chromosomal aberrations, sister chromatid exchanges, and gene amplification.34 The possibility that arsenic induces ISHD through its actions on the structure and expression of related genes remains to be elucidated.
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Acknowledgments |
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This study was supported by grants from the National Science Council, Executive Yuan, Republic of China (NSC-80-0412-B002-17, NSC-81-0412-B002-122, NSC-82-0412-B002-262, and NSC-83-0412-B002-231).
Received May 25, 1995; accepted January 3, 1996.
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References |
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1. International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man: Some Metals and Metalloid Compounds. Vol 23. Lyon, France: International Agency for Research on Cancer; 1980:39-141.
2. World Health Organization. Environmental Health Criteria 18: Arsenic. Geneva, Switzerland: World Health Organization; 1981:43-102.
3. Smith AH, Hopehayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, Wood R, Kosnett MJ, Smith MT. Cancer risks from arsenic in drinking water. Environ Health Perspect. 1992;97:259-267. [Medline] [Order article via Infotrieve]
4. Tseng WP. Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic. Environ Health Perspect. 1977;19:110-119.
5.
Chen CJ, Wu MM, Lee SS, Wang JD, Cheng SH, Wu
HY. Atherogenicity and carcinogenicity of high-arsenic
artesian well water: multiple risk factors and related malignant
neoplasms of blackfoot disease.
Arteriosclerosis. 1988;8:452-460.
6. Tseng WP, Chen WY, Sung JL, Chen JS. A clinical study of blackfoot disease in Taiwan: an endemic peripheral vascular disease. Mem Coll Med Natl Taiwan Univ. 1961;7:1-18.
7. Borgono JM, Vincent P, Venturino H, Infante A. Arsenic in the drinking water of the city of Antofagasta: epidemiological and clinical study before and after the installation of the treatment plant. Environ Health Perspect. 1977;19:103-105. [Medline] [Order article via Infotrieve]
8. Cebrian ME. Some potential problems in assessing the effects of chronic arsenic poisoning in north Mexico. In: Preprints of Papers Presented at the American Chemical Society, Division of Environmental Chemistry, 194th Meeting. 1987:114-116.
9. Grobe JW. Peripheral circulatory disorders and acrocyanosis with arsenic [in German]. Berufs Dermatosen. 1976;24:78-84.
10. Lagerkvist BE, Linderholm H, Nordberg GF. Arsenic and Raynaud's phenomenon: vasospastic tendency and excretion of arsenic in smelter workers before and after the summer vacation. Int Arch Occup Environ Health. 1988;60:361-364. [Medline] [Order article via Infotrieve]
11. Axelson O, Dahlgren E, Janssen CD, Rehnlund SO. Arsenic exposure and mortality: a case reference study from a Swedish copper smelter. Br J Ind Med. 1978;35:8-15. [Medline] [Order article via Infotrieve]
12. Welch K, Higgins I, Oh M, Burchfiel C. Arsenic exposure, smoking, and respiratory cancer in copper smelter workers. Arch Environ Health. 1982;37:325-335. [Medline] [Order article via Infotrieve]
13.
Hansen ES. Mortality from cancer and
ischemic heart disease in Danish chimney sweeps: a
five-year follow-up. Am J Epidemiol. 1983;117:160-164.
14. Gustavsson P, Gustavsson A, Hogstedt C. Excess mortality among Swedish chimney sweeps. Br J Ind Med. 1987;44:738-743. [Medline] [Order article via Infotrieve]
15. Wingren G, Axelson O. Mortality in the Swedish glassworks industry. Scand J Work Environ Health. 1987;13:412-416. [Medline] [Order article via Infotrieve]
16.
Wu MM, Kuo TL, Hwang YH, Chen CJ.
Dose-response relation between arsenic concentration in well water
and mortality from cancer and vascular disease. Am J
Epidemiol. 1989;130:1123-1131.
17. Zaldivar R. A morbid condition involving cardiovascular, broncho-pulmonary, digestive and neural lesions in children and young adults after dietary arsenic exposure. Zentralbl Bakteriol. 1980;170:44-56.
18. Tsuda T, Nagira T, Yamamoto M. An epidemiological study on cancer in certified arsenic poisoning patients in Toroku. Ind Health. 1990;28:53-62. [Medline] [Order article via Infotrieve]
19. Chen KP, Wu HY, Wu TC. Epidemiologic studies on blackfoot disease in Taiwan, 3: physicochemical characteristics of drinking water in endemic blackfoot disease areas. Mem Coll Med Natl Taiwan Univ. 1962;8:115-129.
20. Kuo TL. Arsenic content of artesian well water in endemic area of chronic arsenic poisoning. Rep Inst Pathol Coll Med Natl Taiwan Univ. 1964;20:7-13.
21. Rothman KJ. Modern Epidemiology. Boston, Mass: Little, Brown & Co; 1986:29-32.
22. Lo MC, Hsen YC, Lin BK. Arsenic Content of Underground Water in Taiwan: Second Report. Taichung, Taiwan: Taiwan Provincial Institute of Environmental Sanitation; 1977:1-17.
23.
Vach W, Blettner M. Biased estimation of the
odds ratio in case-control studies due to the use of ad hoc methods
of correcting for missing values for confounding variables.
Am J Epidemiol. 1991;134:895-907.
24.
Weinberg CR. Toward a clearer definition of
confounding. Am J Epidemiol. 1993;137:1-8.
25. Yeh SJ, Yang MH. Trace elements in water samples from the endemic area of blackfoot disease and biospecimens from blackfoot disease patients: a preliminary report. Blackfoot Dis Res Rep. 1980;8:22-28.
26. Lu FJ. Blackfoot disease: arsenic or humic acid. Lancet. 1990;336:115-116. [Medline] [Order article via Infotrieve]
27. Chen CJ. Blackfoot disease. Lancet. 1990;336:442. Letter. [Medline] [Order article via Infotrieve]
28.
Lai MS, Hsueh YM, Chen CJ, Shyu MP, Chen SY, Kuo TL, Wu
MM, Tai TY. Ingested inorganic arsenic and prevalence of
diabetes mellitus. Am J Epidemiol. 1994;139:484-492.
29.
Chen CJ, Hsueh YM, Lai MS, Shyu MP, Chen SY, Wu MM, Kuo
TL, Tai TY. Increased prevalence of hypertension and
long-term arsenic exposure.
Hypertension. 1995;25:53-60.
30. Guha Mazumder DN, Chakraborty AK, Ghose A, Gupta JD, Chakraborty DP, Dey SB, Chattopadhyay N. Chronic arsenic toxicity from drinking tubewell water in rural west Bengal. Bull World Health Organ. 1988;66:499-506. [Medline] [Order article via Infotrieve]
31. Hansen ES. Shared risk factors for cancer and atherosclerosis: a review of the epidemiological evidence. Mutat Res. 1990;239:163-179. [Medline] [Order article via Infotrieve]
32.
Lilienfeld DE. Arsenic, geographical isolates,
environmental epidemiology, and
atherosclerosis.
Arteriosclerosis. 1988;8:449-451. Editorial.
33. Lopez S, Miyashita Y, Simons SS Jr. Structurally based, selective interaction of arsenite with steroid receptor. J Biol Chem. 1990;165:16039-16042.
34. Chen CJ, Lin LJ. Human carcinogenicity and atherogenicity induced by chronic exposure to inorganic arsenic. In: Nriagu JO, ed. Arsenic in the Environment, Part II: Human Health and Ecosystem Effects. New York, NY: John Wiley & Sons, Inc; 1994:109-131.
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