Increased Prevalence of Hypertension and Long-term Arsenic Exposure
Abstract To examine the association between long-term exposure to inorganic arsenic and the prevalence of hypertension, we studied a total of 382 men and 516 women residing in villages where arseniasis was hyperendemic. Hypertension was defined as a systolic blood pressure of 160 mm Hg or greater, a diastolic blood pressure of 95 mm Hg or greater, or a history of hypertension treated regularly with antihypertensive drugs. The long-term arsenic exposure was calculated from the history of artesian well water consumption obtained through standardized interviews based on a structured questionnaire and the measured arsenic concentration in well water. Residents in villages where long-term arseniasis was hyperendemic had a 1.5-fold increase in age- and sex-adjusted prevalence of hypertension compared with residents in nonendemic areas. Duration of artesian well water consumption, average arsenic concentration in drinking water, and cumulative arsenic exposure were all significantly associated with hypertension prevalence. The higher the cumulative arsenic exposure, the higher the prevalence of hypertension. This dose-response relation remained significant after adjustment for age, sex, diabetes mellitus, proteinuria, body mass index, and serum triglyceride level. The results suggest that long-term arsenic exposure may induce hypertension in humans.
Arsenic is a widely distributed element present in various compounds throughout the earth’s crust. It is mainly transported in the environment by water. Arsenic is present in soil at levels ranging from 0.2 to 40 μg/kg, in urban air at levels around 0.02 μg/m3, and in water at levels averaging around 0.001 mg/L in the United States.1 The general population is exposed to inorganic and organic arsenic through medicinal, environmental, and occupational situations. Drugs containing inorganic arsenic have been used for the treatment of leukemia, psoriasis, and chronic bronchial asthma and as a home remedy. Both inorganic and organic arsenic are present in varying amounts in food. Seafood, for example, contains relatively high concentrations of organic arsenic. However, inorganic forms of arsenic are much more toxic than organic forms. Cigarette smokers may be exposed to arsenic in tobacco, but the chemical form of arsenic in smoke remains unclear. Workers involved in the processing of copper, gold, and lead ores; in the use of arsenic as pigments and dyes; in the production and use of agricultural pesticides; in the manufacturing of glass and various pharmaceutical substances; and in the chimney sweeping business 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 standard for arsenic in drinking water set by the US Environmental Protection Agency is 0.05 mg/L. In the United States, it has been estimated that about 350 000 people might drink water containing arsenic higher than this level, most of whom live in certain counties of Utah, California, Oregon, and Minnesota.3
Arsenic has been well documented as one of the major risk factors for blackfoot disease (BFD), a peripheral arterial disease characterized by systemic atherosclerosis as well as dry gangrene and spontaneous amputations of affected extremities.4 5 The disease was endemic in the southwestern coast of Taiwan where residents had used high-arsenic artesian well water for more than 50 years. BFD patients have a high prevalence of arsenic-induced skin lesions including hyperpigmentation, hyperkeratosis, and skin cancers.4 They also have a high risk of dying from cancers of the lung, liver, bladder, kidney, and prostate as well as ischemic heart disease.5 Peripheral vascular disease has also been reported among vintners who had consumed arsenic-contaminated wine in Germany and inhabitants exposed to high-arsenic drinking water in Chile and Mexico.2 The mortality from ischemic heart disease was also significantly higher among residents in BFD-endemic areas than the general population in Taiwan.6 There was a significant association between ingested arsenic level and mortality from ischemic heart disease.6 7 An association between exposure to arsenic and mortality from cardiovascular disease has also been reported among copper smelter workers in the United States and Sweden.2
Ingested inorganic arsenic might induce BFD and ischemic heart disease through a direct effect on the atherogenic process involving endothelial cells, smooth muscle cells, platelets, and macrophages8 and/or an indirect effect on risk factors of cardiovascular diseases such as hypertension, diabetes mellitus, and hyperlipidemia. However, cardiovascular risk factors have seldom been studied among residents in BFD-endemic areas. As hypertension is an important determinant of cardiovascular disease, it is worthwhile to examine the association between long-term exposure to inorganic arsenic and the development of hypertension. Previous epidemiological studies have reported a higher prevalence of hypertension among residents in a BFD-endemic area9 than those in other rural townships10 in the early 1960s. The prevalence of hypertension has not been compared between residents in BFD-endemic and nonendemic areas since then. There has never been a study on the association between long-term arsenic exposure and the development of hypertension in humans.
The present study was carried out in villages where BFD was hyperendemic and the tap water supply system has been implemented for more than 20 years. The specific aims of this study included (1) the comparison of hypertension prevalence among residents in three arseniasis-hyperendemic villages and in nonendemic areas to examine whether a higher prevalence of hypertension was still observed among people who lived in hyperendemic villages, and (2) the elucidation of the dose-response relation between long-term arsenic exposure and hypertension prevalence within the populations of three study villages.
The study area included Homei, Fuhsin, and Hsinming villages in Putai Township of Chiayi County located on the southwestern coast of Taiwan island. Residents in this study area had the highest prevalence of BFD in Taiwan, with prevalence as high as 13.6% in Homei, 9.6% in Fuhsin, and 10.3% in Hsinming.11 Because of the high salinity of shallow well water, residents in the area had used water from artesian wells for more than 50 years. The median arsenic concentration of the artesian well water was found to range from 0.70 to 0.93 mg/L in the early 1960s.12 A tap water supply system was implemented in the study villages in the early 1960s, but its coverage remained low until the early 1970s. Artesian well water was no longer used for drinking and cooking after the mid-1970s.
Names and addresses of all adult residents in the three study villages were abstracted from household records kept in a local household registration office where sociodemographic characteristics including sex, birth date, marital status, education, migration, and occupation of all members in every household are registered and annually updated. The selection of study subjects from the household registration system was effective and efficient because of the completeness and accuracy of the registration information. To recruit a cohort of residents for a long-term follow-up study on health hazards associated with long-term arsenic exposure, we selected as eligible only those people who lived at least 5 days a week in the study villages. A total of 2258 residents over 30 years of age were registered in the study villages, but only 1571 of them were eligible for this study. Most of another 687 registered residents worked in Chiayi City and its suburban area, returning to the study villages during the weekend. All eligible subjects were interviewed at home from September 1988 through June 1989. A total of 1081 eligible subjects, including 468 men and 613 women who were interviewed between September and December 1988, were invited to participate in a health examination in January and February 1989 on a voluntary basis. Another 490 eligible subjects who were interviewed after December 1988 were not invited to participate in the examination. Four hundred eight men and 533 women participated in the health examination in January and February 1989. Blood pressure measurement and status of regularly treated hypertension were available for 382 male and 516 female participants. Fig 1⇓ shows a flow chart for the recruitment of study subjects. This study was approved by an institutional review committee, and the procedures followed were in accordance with institutional guidelines.
Questionnaire Interview and Arsenic Exposure Index
A standardized personal interview based on a structured questionnaire was carried out by two public health nurses who were well trained in interview techniques and questionnaire details. Information obtained from the interview included history of high-arsenic artesian well water consumption, residential history, socioeconomic and demographic characteristics, alcohol intake, cigarette smoking, physical activities, consumption of dried sweet potato and/or rice as a staple food, as well as personal and family history of hypertension, diabetes, and cardiovascular disease. Because it was difficult for study subjects to recall their quantitative consumption of various dietary constituents, only the duration and frequency of dried sweet potato and/or rice consumption as a staple food during various time intervals of life were obtained. We were thus unable to quantitate individual intake of nutrients such as protein, saturated fat, sodium, potassium, magnesium, and calcium.
Detailed information was obtained on cigarette smoking including age cigarette smoking was started, average number of cigarettes smoked per day, and age cigarette smoking was stopped. Age alcohol drinking began, average frequency of alcohol consumption per week, average quantity of alcohol intake, and age alcohol drinking was stopped were also obtained. Physical activity level at work was assessed based on the type of job and working hours per day.
Detailed residential history including villages of residence and duration as well as history of water consumption including water source and duration were obtained from the questionnaire interview. Answers were used to derive the overall duration of the consumption of artesian well water. Arsenic levels in artesian well water of villages where study subjects had lived were obtained from reports of previous studies carried out in the 1960s.12 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.13
Some study subjects had moved from one village to another, and the arsenic concentration in the artesian well water of these villages was different. As both the duration and arsenic level of artesian well water may be associated with the prevalence of hypertension, an index of cumulative arsenic exposure was derived to reflect the overall exposure to arsenic for each study subject. The cumulative arsenic exposure (milligrams per liter-years) was defined as the sum of products, derived by multiplying the arsenic concentration in well water (in milligrams per liter) by the duration of water consumption (in years) during consecutive periods of living at different villages. In other words, cumulative arsenic exposure was derived by the following formula: Σ(Ci×Di), where Ci is the median arsenic concentration in the well water of the village where a given study subject lived during the period i, and Di is the duration of drinking well water in the village during the period i. An index of average arsenic concentration in drinking water was also derived by the formula Σ(Ci×Di)/Σ(Di).
Both cumulative arsenic exposure and average arsenic concentration in drinking water were calculated only for those subjects who had complete information on arsenic exposure from drinking 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 well water in any village where the subject had lived during his or her lifetime was not available. Some study subjects moved into the study villages after they had lived for several years in other areas, and some others moved out for studying or working for several years and returned to the study area. Because the arsenic concentration in drinking water was not available in other areas, the average arsenic concentration in drinking water and cumulative arsenic exposure could not be calculated for 165 (18.4%) study subjects. In the data analysis, average concentration in drinking water and cumulative arsenic exposure were categorized into groups using cut points determined arbitrarily before the analysis.
Blood Pressure Measurement and Hypertension Status
The standard protocol for measuring blood pressure recommended by the World Health Organization14 was used in this study. After study subjects had rested for 20 minutes or longer, both systolic and diastolic blood pressures (SBP and DBP) were measured three times with a mercury sphygmomanometer with subjects sitting. SBP and DBP were defined at the first and fifth Korotkoff sounds, respectively. The average of three measurements was used for analysis. Some study subjects had a history of hypertension and were regularly treated with antihypertensive drugs. Although they might have had SBP and/or DBP within a normal range, they were defined as hypertensive. In other words, hypertension status was defined in this study as an average SBP of 160 mm Hg or greater, an average DBP of 95 mm Hg or greater, and/or a history of hypertension regularly treated with antihypertensive drugs.
Biospecimen Collection and Laboratory Examinations
Each study subject was instructed not to have any food after dinner the evening before the health examination. Fasting blood samples were collected from study subjects for examination of serum levels of cholesterol, triglycerides, uric acid, insulin, and glucose. Blood samples 2 hours after subjects were given 0.075 kg glucose dissolved in 0.3 L boiled water were also collected for a glucose tolerance test. The status of diabetes mellitus was defined as (1) a fasting glucose level of 7.8 mmol/L or greater and/or a 2-hour glucose level of 11.1 mmol/L or greater, or (2) a history of diabetes mellitus, for which the subject was currently receiving regular treatment with insulin or sulfonylurea agents. Urine protein level was examined by a test strip with a computerized reader (Ames Co). Proteinuria was defined as a level of 300 mg/L or greater.
Height and body weight, triceps skinfold thickness, and arm circumference were measured according to standard protocols. Standing height and body weight were measured with a rigid vertical height measurement and a standard medical balance scale, with subjects not wearing shoes and in light clothes. Height was measured to the nearest 0.5 cm and weight to the nearest 100 g. Body mass index was measured as weight (kilograms) divided by height (meters) squared. A subject with a body mass index between 25.0 and 29.9 was classified as overweight and 30.0 or higher as obese. Triceps skinfold was measured on the back of the unclothed pendant right arm at a level midway between the tip of the acromion and the tip of the olecranon. The skinfold was lifted parallel to the long axis of the arm and measurement was made to the nearest 0.5 mm. Arm circumference was measured with a snugly applied tape measure on the unclothed pendant right arm at the midpoint between the tip of the acromion and the tip of the olecranon.
The prevalence of hypertension observed in this study was compared with that reported in previous studies carried out in BFD-endemic and nonendemic areas.9 10 15 Only those studies that met the following two criteria were selected for comparison: (1) the study had to use a comparable protocol for blood pressure measurement and the same definition for hypertension, and (2) it had to be carried out in both BFD-endemic and nonendemic areas where residents had a similar socioeconomic status and living conditions in the same calendar year. The study in BFD-endemic areas in 1963 was carried out in Peimen, Hsuehchia, Putai, and Ichu Townships of Tainan and Chiayi Counties with a response rate of 81%9 ; the study in a nonendemic area in 1963 was carried out in Chiehting Township of Kaohsiung County with a response rate of 66%10 ; and the study in a nonendemic area in 1989 was carried out in Potzu Township of Chiayi County with a response rate of 75%.15 In the comparison of hypertension prevalence in different areas, prevalence was adjusted for age and sex using the 1976 world population as the standard population.14
In the analysis of the associations between indexes of long-term arsenic exposure and hypertension prevalence, age- and sex-adjusted odds ratios and their 95% confidence intervals (CI) were derived from multiple logistic regression models.16 Logistic regression analyses were also carried out to estimate the multivariate-adjusted odds ratio and its 95% CI.
A total of 898 adult residents including 382 men and 516 women participated in this study. There were 212 (24%), 216 (24%), 306 (34%), and 164 (18%) subjects in the age groups of 30 to 39, 40 to 49, 50 to 59, and more than 60 years, respectively. Most (78%) subjects had lived in the study area for more than 30 years. A total of 293 (33%) subjects were illiterate, 437 (49%) had an educational level of elementary school, and 168 (19%) had a level of junior high school and above. They were mainly employed in the fishing industry, salt production, and farming.
Table 1⇓ shows age- and sex-specific prevalence of hypertension. Hypertension prevalence increased with age in both men and women. Men had a higher hypertension prevalence than women before age 40, men and women aged 40 to 59 had a similar prevalence, and women had a higher prevalence than men after age 60. Men had a slightly lower age-adjusted prevalence than women.
The prevalence of hypertension observed in this study was compared with that reported in previous studies carried out in BFD-endemic and nonendemic areas.9 10 15 Because of the different age ranges covered by different studies, only prevalences for the 40 to 49, 50 to 59, and 60 or older age groups were compared. As shown in Fig 2⇓, residents in BFD-endemic areas had a higher hypertension prevalence than those who lived in nonendemic areas in 1963 and 1989. The age- and sex-adjusted prevalence (95% CI) was 23.2% (19.3 to 27.1), 22.0% (20.1 to 23.9), 14.4% (12.9 to 15.9), and 14.3% (11.8 to 16.9), respectively, for residents older than 40 years in BFD-hyperendemic villages in 1989, the BFD-endemic area in 1963, the nonendemic area in 1989, and the nonendemic area in 1963.
Among 898 study subjects, 119 (13.3%) had never used artesian well water for drinking. Among 779 study subjects who had drunk artesian well water for a certain period of time, 770 (98.8%) had consumed artesian well water since birth. As shown in Table 2⇓, there was a significant association between the duration of artesian well water consumption and hypertension prevalence. Hypertension prevalence was found to increase with the duration of artesian well water consumption from less than 10 years to 11 to 30 years and decline for the group of more than 30 years. The age- and sex-adjusted odds ratios for the groups of 11 to 20 and 21 to 30 years of artesian well water consumption were statistically significant (P<.05). Table 2⇓ also shows a significant dose-response relation between hypertension prevalence and average arsenic concentration in drinking water after adjustment for age and sex (P<.01 for trend). Cumulative arsenic exposure was significantly associated with hypertension prevalence in a dose-response relation (P<.001 for trend), as also shown in Table 2⇓.
Table 3⇓ shows the hypertension prevalence for groups stratified by both duration of artesian well water consumption and average arsenic concentration in drinking water. There was a dose-response relation between hypertension prevalence and duration of artesian well water consumption in both groups with different average arsenic concentrations in the drinking water. Similarly, hypertension prevalence was associated with the average arsenic concentration in a dose-response relation in both groups of different duration of artesian well water consumption. After adjustment for age and sex, both variables had independent effects on hypertension prevalence under the logistic regression model.
Table 4⇓ shows the prevalence of hypertension by duration after cessation of arsenic exposure for 770 study subjects who had used artesian well water for drinking. No significant difference in hypertension prevalence was observed among four groups with different duration after cessation of arsenic exposure after adjustment for age and sex.
In the univariate analyses, no significant associations with hypertension prevalence were found for lifestyle variables including cigarette smoking, alcohol consumption, physical activity at work, and duration of dried sweet potato consumption as a staple food. Compared with nonsmokers as the referent group, the age- and sex-adjusted odds ratios (95% CI) of being affected with hypertension were 0.6 (0.3 to 1.2) and 0.9 (0.6 to 1.4) for subjects who had smoked cigarettes for less than 20 years and 20 years or more, respectively. Compared with alcohol nondrinkers as the referent group, the age- and sex-adjusted odds ratios (95% CI) of being affected with hypertension were 1.0 (0.2 to 2.3) and 0.8 (0.4 to 1.7) for subjects who had an alcohol drinking habit for less than 20 years and 20 years or more, respectively. The age- and sex-adjusted odds ratio (95% CI) of being affected with hypertension for study subjects who had a low physical activity at work was 1.2 (0.8 to 1.8) compared with subjects who worked with a high physical activity as the referent group. Study subjects who consumed dried sweet potato as a staple food for 20 years or less had an age- and sex-adjusted odds ratio (95% CI) of 1.1 (0.9 to 1.3) compared with subjects who consumed dried sweet potato as a staple food for more than 20 years.
Body mass index, fasting serum triglyceride levels, and disease status of diabetes mellitus and proteinuria were all significantly associated with hypertension prevalence after adjustment for age and sex. Table 5⇓ shows multivariate-adjusted odds ratios for cumulative arsenic exposure in milligrams per liter-years analyzed by multiple logistic regression analysis. After adjustment for age, sex, disease status of diabetes mellitus and proteinuria, body mass index, and fasting serum triglyceride levels, the cumulative arsenic exposure remained significantly associated with hypertension prevalence in a dose-response relation.
Ingested inorganic arsenic has been related to the development of peripheral vascular disease and ischemic heart disease among residents consuming water with high arsenic concentrations in Taiwan,4 5 6 7 Chile,17 18 19 and Mexico.20 Vintners exposed to arsenic-based pesticides have been reported to have peripheral vascular lesions similar to BFD.21 It was also documented that copper smelter workers had a moderate excess mortality attributed to cardiovascular diseases.22 23 Evidence of altered blood vessel function was observed in copper smelter workers exposed to arsenic levels of approximately 50 μg/m3 in air.24 However, associations between long-term arsenic exposure and risk factors for cardiovascular diseases have seldom been examined.
In the present study, a significantly higher prevalence of hypertension was found among residents in the endemic area of arseniasis compared with those in nonendemic areas. This finding is consistent with that observed in 1963.9 10 During both time periods, surveys of the BFD-endemic areas exhibited higher response rates (81% versus 66% in 1963 and 83% versus 75% in 1989). If people with known hypertension were more likely to volunteer to be examined, this could have introduced a bias into the comparisons in the direction of the differences observed. On the other hand, if people with known hypertension were less likely to participate, the differences could have been underestimated. Increased hypertension prevalence was also observed among patients affected with arsenic-induced skin lesions in an area where well water had a high arsenic concentration in Chile.25 However, no assessment of the association between arsenic exposure level and hypertension has been made in these studies. A significant dose-response relation between cumulative arsenic exposure and hypertension prevalence was found in the present study. To the best of our knowledge, this is the first report on the dose-response relation between ingested inorganic arsenic and hypertension in humans.
However, this study has some limitations. Not all eligible study subjects were invited to participate in the health examination during the period from January through February 1989. Only those who were interviewed during 1988 and 1989 were invited. However, the frequency distribution of age, sex, education level, occupation, lifestyle variables, personal and family history of disease, and long-term arsenic exposure was similar between subjects who were interviewed before and after 1989. Study subjects who participated in the health examination were found to have a higher proportion of women and a slightly higher mean age than those who did not participate, whereas other factors were found to be similar between participants and nonparticipants. Adjustment for age and sex was thus carried out in the data analysis.
Because arsenic levels in the drinking water of some areas other than the BFD-endemic area were not always available, the average and cumulative arsenic exposure levels were unknown for 165 (18%) of the study subjects. The duration of artesian well water consumption, which was available for all study subjects, was similar for subjects with information on arsenic exposure and those without it. Furthermore, the odds ratio for those without arsenic exposure levels was between the odds ratios for the lowest and highest exposure groups, as shown in Table 2⇑. The unavailability of arsenic exposure data for some study subjects seems not to affect the assessment of the association between exposure to arsenic and prevalence of hypertension. Unfortunately, no information on the amount of water consumed by each study subject during different periods of his or her lifetime was obtained in this study. It has to be assumed that each study subject consumed a similar amount of water. To adjust for the difference in water consumption between men and women, we included a gender variable in the logistic regression analyses. 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. As more than 98% of study subjects who had consumed artesian well water started their exposure immediately after birth, it is not possible to assess the effect of age of the start of arsenic exposure on the development of hypertension.
We used the prevalence rather than incidence of hypertension to assess the association between ingested inorganic arsenic and the disease. If the elevated level of long-term arsenic exposure were associated with both the development of hypertension and the poor survival of patients affected with the disease, the relative risk of developing hypertension estimated by the prevalence odds ratio might thus be underestimated. This underestimation is especially likely for the group with the highest exposure. Based on such a conservative estimation, a significantly increased prevalence of hypertension was still found to be associated with the elevated level of cumulative arsenic exposure. This association remained significant after adjustment for other risk factors of hypertension through the multiple logistic regression analysis.
Alcohol consumption, physical activity at work, and dietary nutrients have been documented as risk factors for hypertension. However, alcohol consumption and physical activity at work were not significantly associated with hypertension prevalence in this study. As our study subjects were recruited from three neighboring villages where residents had similar occupations, socioeconomic status, lifestyles, and dietary patterns, the variation in these variables among subjects may be too small to detect significant associations with hypertension prevalence. Because it was difficult for study subjects to recall their consumption quantity of various dietary constituents, only the consumption of dried sweet potato and/or rice as a staple food was obtained. There was no association between consumption of dried sweet potato and prevalence of hypertension. The insensitive measurement of dietary nutrients may result in the lack of association. However, it is unlikely that such factors were confounding the associations reported for arsenic exposure, because the findings were based on duration of exposure and arsenic concentration in the water rather than on amount of water consumed and also because of the strength of these associations.
Physical and chemical characteristics of drinking water such as pH value and levels of arsenic, sodium, calcium, magnesium, manganese, iron, mercury, chromium, lead, nitrite and nitrate nitrogen, fluoride, and bicarbonate have been intensively studied in both BFD-endemic and nonendemic areas.26 27 Arsenic level was found to be the only item that was significantly higher than the maximal allowable limit and strikingly different in water from shallow wells and artesian wells. Arsenic may thus be the main chemical in the water responsible for the increased prevalence of hypertension in the endemic areas.
The effect on the development of hypertension of long-term exposure to inorganic arsenic has rarely been studied, and the mechanism for inorganic arsenic to induce hypertension remains unclear. Long-term arsenic exposure has been documented to be associated with the development of peripheral neuropathy. Characteristic electromyographic changes include decreased nerve conduction amplitude, with little changes in nerve conduction velocity.28 Arsenic neuropathy has been classified as a distal axonopathy with axonal degeneration, especially of large myelinated fibers of both sensory and motor neurons.29 Arsenic has been reported to induce chronic renal insufficiency from cortical necrosis,30 and signs of arsenic-induced renal injury include hematuria, leukocyturia, and glycosuria.31 Whether the arsenic-related hypertension observed in the present study is the result of possible neurological and renal defects induced by arsenic needs further exploration.
Arsenic, a member of the group VB elements, has many chemical properties similar to nitrogen and phosphorus, which are important elements of DNA, RNA, and proteins. As most enzymes are regulated by the process of phosphorylation/dephosphorylation in which ATP plays a major role, arsenate may hinder normal enzymatic functions by disrupting the formation of ATP from ADP and orthophosphate. As 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 and 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 the glucocorticoid receptor in such a way.32 Whether arsenic may induce hypertension through its interference with the functions of structural or functional proteins involved in blood pressure control also requires further investigation.
Several genes are involved in the development of hypertension. Although arsenic does not cause point mutation, it does induce cell transformation, chromosomal aberrations, sister chromatid exchanges, and gene amplification.33 The possibility of arsenic inducing hypertension through its actions on the structure and expression of related genes remains to be elucidated.
This study was supported by grants from the National Science Council, Executive Yuan, Republic of China (NSC-82-0412-B002-262, NSC-81-0412-B002-122, NSC-80-0412-B002-17).
- Received October 28, 1993.
- Revision received December 13, 1993.
- Accepted September 9, 1994.
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