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To cite this article: Chin-Hsiao Tseng (2005): Blackfoot Disease and Arsenic: A Never-Ending Story, Journal of Environmental
Science and Health, Part C: Environmental Carcinogenesis and Ecotoxicology Reviews, 23:1, 55-74
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Journal of Environmental Science and Health, 23:55–74, 2005
Copyright C Taylor & Francis Inc.
ISSN: 1059-0501 (Print); 1532-4095 (Online)
DOI: 10.1081/GNC-200051860
Chin-Hsiao Tseng
Division of Endocrinology and Metabolism, Department of Internal Medicine, National
Taiwan University Hospital; National Taiwan University College of Medicine; School of
Public Health, Taipei Medical University, Taipei, Taiwan; and Division of Environmental
Health and Occupational Medicine of the National Health Research Institutes,
Taipei, Taiwan
Blackfoot disease (BFD) is an endemic peripheral vascular disease confined to the
southwestern coast of Taiwan. This article reviews the epidemiology, clinical manifes-
tations and diagnosis, pathology, etiology and pathogenesis of this disease. Sporadic
cases of BFD occurred as early as in the early 20th century, and peak incidence was
noted between 1956 and 1960, with prevalence rates ranging from 6.51 to 18.85 per
1,000 population in different villages. Typical clinical symptoms and signs of progres-
sive arterial occlusion mainly found in the lower extremities, but in rare cases, the
upper extremities might also be involved. Ulceration, gangrene and spontaneous or
surgical amputation were typical fate. An extensive pathological study concluded that
30% of the BFD patients had histologic lesions compatible with thromboangiitis oblit-
erans and 70% showed changes of arteriosclerosis obliterans. Epidemiologic studies
carried out since mid-20th century revealed that BFD was associated with the con-
sumption of inorganic arsenic from the artesian wells. Recent studies confirmed the
existence of preclinical peripheral vascular disease, subclinical arterial insufficiency
and defects in cutaneous microcirculation in the residents of the endemic villages.
A more recent study suggested that the methylation capacity of arsenic can inter-
act with arsenic exposure in the development of peripheral vascular disease among
residents of BFD-endemic areas. The incidence of BFD decreased dramatically after
the implementation of tap water in these villages over the past 2–3 decades. The
atherogenicity of arsenic could be associated with its effects of hypercoagulability, en-
dothelial injury, smooth muscle cell proliferation, somatic mutation, oxidative stress,
and apoptosis. However, its interaction with some trace elements and its association
with hypertension and diabetes mellitus could also explain part of its higher risk of
developing atherosclerosis. Although humic substances have also been suggested as
a possible cause of BFD, epidemiologic studies are required to confirm its etiologic
role.
55
56 C.-H. Tseng
INTRODUCTION
In a confined area located at the southwestern coast of Taiwan, the prevalence
of a unique peripheral vascular disease (PVD) was high (1, 2). The disease has
been known as blackfoot disease (BFD) after its characteristic progression from
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EPIDEMIOLOGY
Since the early 20th century, sporadic cases of a strange disease involving the
lower extremities have occurred, which was characterized by progressive black-
ish discoloration of the skin extending from the toes gradually upward towards
the ankles (1, 2). The patients also suffered from numbness or coldness of the
extremities and intermittent claudication before the development of gangrene.
Ulceration might also be found in the patients. The lesions might progress to
spontaneous amputation in some cases or surgical amputation was required
for saving lives. In rare cases, the fingers might also be involved (3). The mean
age of onset of BFD in a series of 1,300 cases was 52 years, with a sexual ratio
of men to women of 1.5 (1). However, the disease could afflict patients within a
wide range of age, from 2 to 87 years (1).
According to epidemiologic studies, the peak incidence of BFD was found be-
tween 1956 and 1960 (2). Most of the patients resided in a confined area located
along the southwestern coast of Taiwan. More than 72% of the cases occurred
in Hsueh-Chia Township and Pei-Men Village of Tai-Nan County, and Pu-Tai
Township and Yii-Chu Village of Chia-Yi County. These areas were called the
“old endemic areas.” Some cases were also found in the so-called “new endemic
areas” located on the periphery of the “old endemic areas.” These “new endemic
Blackfoot Disease and Arsenic 57
areas” were confined to the counties of Yun-Ling, Chia-Yii, Tai-Nan, and Ping-
Tung. A total of more than 1,600 cases had been discovered up to 1980s. In
a survey carried out from 1984 to 1985, a total of 1,220 prevalent cases (690
men and 530 women) were found in the “old endemic areas.” Among them,
374 (30.7%), 352 (28.9%), 309 (25.3%), and 185 (15.2%) cases were found in
Hsueh-Chia, Pu-Tai, Pei-Men, and Yii-Chu, respectively. The prevalence rates
in Pei-Men, Hsueh-Chia, Pu-Tai and Yii-Chu were 18.85, 11.57, 8.80 and 6.51
per 1,000 population, respectively.
The prognosis of BFD is relatively poor after the onset of clinical symptoms.
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and the induction period of BFD is about 20–30 years (2), the circulation of
the lower extremity can be better assessed by more sophisticated laboratory
examinations than its severe clinical manifestations as BFD. Later studies car-
ried out since the 1990s have focused on the use of more objective diagnostic
methods such as the Doppler ultrasound (7, 8), laser Doppler flowmetry (9) and
a combination with exercise test (10). These later studies not only confirmed
a higher rate of PVD in residents of the BFD areas with or without clinical
manifestations of full-blown disease, subclinical arterial insufficiency and mi-
crocirculatory defects were also demonstrated in seemingly normal subjects
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PATHOLOGY
The only pathological study in the BFD patients was done by Yeh and How dur-
ing the late 1950s and early 1960s at the National Taiwan University Hospital
(3). The study reported the pathological findings of a total of 63 limbs taken from
52 BFD patients (35 men and 17 women). The age ranged from 12 to 76 years.
Except for one ring finger taken from a female patient, all others were taken
from the lower extremities. This extensive pathological study concluded that
30% of the BFD patients had histologic lesions compatible with thromboangiitis
obliterans and 70% showed changes of arteriosclerosis obliterans. The common
histological features in the thromboangiitis obliterans group include 1) fibri-
noid necrosis of the whole vessel wall of arterioles, venules or precapillaries;
Blackfoot Disease and Arsenic 59
2) proliferation and activation of vascular endothelium; and 3) diffuse infiltra-
tion of inflammatory cells throughout the whole vessel wall, giving rise to a
picture of nodular non-suppurative, non-thrombotic panarteritis. Histological
features of vessels found in arteriosclerosis obliterans group include 1) throm-
bus formation with newly formed vessels having reduced number and size,
leaving a poorly vascularized, hyalinized dense fibrous tissue like an old scar
tissue; 2) intimal sclerosis; 3) medial calcific change; and 4) adventitial change
of periarterial fibrosis.
Autopsy was performed in 3 of the BFD patients, including two men aged
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39 and 62 years, respectively, and one woman aged 24 years. It was interesting
to note that all of them had generalized atherosclerosis, especially involving
the coronary arteries, even in the young woman. This finding suggested that
the clinical manifestations of BFD were only part of a systemic involvement of
atherosclerosis in the patients.
ETIOLOGY
The etiology of BFD was unknown initially, but after a series of investigations
in the mid-20th century, the suspected cause had been focused on the artesian
well water consumed by the residents of the endemic area. Because of the high
content of salt in shallow well water, residents in these endemic villages have
used water from artesian wells as deep as 100–300 meters since the 1920s (5).
Arsenic, ergot alkaloid, organic chlorides, and humic acid have been identified
in high concentrations from the water (6). In addition, trace elements, such as
molybdenum, mercury, copper, and cadmium, were reported to be detectable in
the serum and/or urine of BFD patients and in groundwater they used (11, 12).
However, extensive epidemiologic studies favor arsenic as the most probable
cause (1, 7, 8). The median arsenic concentration of the artesian well water in
these BFD-hyperendemic villages ranged from 0.70 to 0.93 mg/L (4, 5), while
the shallow well water in other areas had an arsenic content between non-
detectable and 0.30 mg/L with a median of 0.04 mg/L (5). The standard for
arsenic in drinking water set by the World Health Organization is 0.01 mg/L
and 0.05 mg/L by the United States Public Health Service (13). A survey of the
arsenic contents of 83,563 wells all over Taiwan showed that 29.1% of the wells
in BFD-endemic areas had an arsenic content greater than 0.05 mg/L and 5.2%
greater than 0.35 mg/L with the highest value being 2.5 mg/L. In other areas of
Taiwan, only 5.7% of the wells had an arsenic content greater than 0.05 mg/L
and 0.3% greater than 0.35 mg/L (14).
Besides arsenic intake from well water, residents of the BFD areas could
be exposed to arsenic from a variety of other sources. Most residents in the
BFD areas were engaged in farming, fishery and salt production. The arsenic
60 C.-H. Tseng
content of the soil was high and ranged from 5.3 to 11.2 mg/kg with a median of
7.2 mg/kg (14). While artesian well water was extensively used for agricultural
and piscicultural purposes, the residents could also be exposed to arsenic from
farm products and fish (15). The amount of arsenic ingested by residents in
BFD-hyperendemic areas was estimated to be as high as 1 mg per day (16).
The lethal dose in human beings is estimated to be 1 mg/kg/day (17).
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(SMI = DMAV /MMAV ) were calculated. The association between PVD and uri-
nary arsenic parameters was evaluated with consideration of the interaction
with CAE and the confounding effects of age, sex, body mass index, total choles-
terol, triglycerides, cigarette smoking and alcohol consumption. Results showed
that PVD risk increased with a higher CAE and a lower capacity to methylate
arsenic to DMAV after taking into account the potential effect of confounders.
The multivariate-adjusted odds ratios for CAE of 0, 0.1–15.4 and >15.4 mg/L ×
year were 1.00, 3.41 (0.74–15.78) and 4.62 (0.96–22.21), respectively ( p < 0.05,
trend test); and for PMI ≤ 1.77 and SMI > 6.93, PMI > 1.77 and SMI > 6.93,
PMI > 1.77 and SMI ≤ 6.93, and PMI ≤ 1.77 and SMI ≤ 6.93 were 1.00, 2.93
(0.90–9.52), 2.85 (1.05–7.73) and 3.60 (1.12–11.56), respectively ( p < 0.05, trend
test). It was concluded that individuals with a higher arsenic exposure and a
lower capacity to methylate inorganic arsenic to DMAV have a higher risk of
developing PVD in BFD areas in Taiwan. This is the first study showing an
effect of arsenic methylation capacity on the development of arsenic-induced
PVD. Therefore, the results of recent studies suggested that PVD susceptibil-
ity is not only related to the exposure dosage of arsenic in the BFD areas, the
metabolism of arsenic has a significant and great impact on the susceptibility
and development of PVD in subjects chronically exposed to arsenic: the more
efficient to methylate to DMAV , the lower the risk.
The association between arsenic exposure and BFD is also supported by the
observation that patients with BFD had a high co-occurrence of arsenic-related
skin lesions such as hyperpigmentation, hyperkeratosis, and skin cancer (19)
and a higher risk of sensory neuropathy (20), which is well known for acute
arsenic intoxication. The co-occurrence of skin lesions and higher risk of neu-
ropathy among the residents of BFD areas could not be attributed to chance
alone, and chronic arsenic exposure could play an important etiologic role.
The different rates of BFD between residents consuming well water and
those consuming tap water in the same areas and the dramatic decline of BFD
after implementation of tap water supply system to the endemic villages also
support arsenic from the artesian well water as a cause of BFD. Tap water
supply to the endemic areas was not available before the 1960s and its coverage
remained low until the 1970s. The incidence rates per 100,000 person-years
for men and women were 44.3 and 36.5, respectively, for those who consumed
62 C.-H. Tseng
artesian well water; and were 2.9 and 3.1 for men and women, respectively, for
those who used tap water in the same areas (2). Most new cases of BFD after
the 1970s occurred in people above 50 years of age in both genders, while BFD
might occur in those below 30 years of age before the 1950s (2). The occurrence
of BFD decreased dramatically over the past 2–3 decades after tap water supply
was implemented in the endemic region (2). A recent study also showed that
ischemic heart disease mortality declines gradually about 17 to 21 years after
the cessation of consumption of high-arsenic artesian well water in the BFD
areas, which is contrary to an increasing trend of cardiovascular mortality in
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the general population of Taiwan (21). These findings strengthen the likelihood
that an association exists between arsenic exposure and the development of
atherosclerotic diseases.
Another evidence supporting the arsenic hypothesis was the similar obser-
vation of arsenic-induced PVD among residents in Chile and Mexico, Moselle
vintners, and copper smelter workers (22). Residents in the BFD areas also have
a significantly increased risk of (23, 24) and mortality from (24, 25) ischemic
heart disease and stroke (26), which were also correlated with arsenic exposure
in a dose-responsive pattern. These findings were compatible with the patholog-
ical findings of severe generalized atherosclerosis in BFD patients as shown by
Yeh and How (3), and with the finding of cardiovascular disease representing a
major cause of death (44%) in the BFD patients (1). Therefore, arsenic-induced
atherosclerosis can be consistently demonstrated in epidemiologic studies and
the process is systemic.
A recent study treating ApoE−/− /LDLr−/− mice with 133 µM (10 ppm)
sodium arsenite in drinking water for 18 weeks has successfully induced a
significant increase in atherosclerotic plaques in the innominate artery while
compared to controls (27). This animal model provided evidence for biological
plausibility of arsenic-induced atherosclerosis observed in humans in epidemi-
ologic studies.
composition of organic matter, particularly dead plants, they are widely spread
contaminants of water supplies and definitely not confined to the BFD areas.
Humic acids contain complex constituents with unstable physical and chemical
properties such as varying molecular weights. The measurement of fluorescent
intensity used in previous reports to quantify humic acids in water cannot
reflect the concentration of humic acids correctly. Ergotamine, D-lysergic acid
and/or ergometrine have been mentioned initially (82). However, these findings
have not been confirmed, and they were not mentioned again in more recent
studies. Furthermore, there is no known successful method to quantify humic
acids in human blood or tissues, whether humic acids with such large molecular
weights can be absorbed efficiently through gastrointestinal tract is not known
and the metabolism of humic acids remain unclear. Therefore, there has been
no epidemiologic evidence indicating the correlation between human exposure
to humic acids and circulatory diseases. Extrapolating the effects observed in
in vitro studies to humans can be very misleading. The association between hu-
mic acids and BFD, even if it could be demonstrated in an epidemiologic study,
could also be due to the confounding effect of the strong relation of BFD with
arsenic exposure. BFD patients has been shown to have hypercoagulability and
increased platelet aggregation (32) and to have a 30% less 6-keto-prostaglandin
F1α level and a normal level of thromboxane B2 (83). However, whether this is
due to an effect of humic acids or arsenic is not known. In recent studies, humic
acids have also been shown to induce the generation of nitric oxide in human
umbilical vein endothelial cells leading to cell injury (84), induce apoptosis (85),
and increase the adhesibility of neutrophils (86); however, all of these effects can
also be demonstrated with arsenic exposure. Humic acids have not been shown
to cause the dermatological or neurological defects, which are typically seen in
humans (19, 20) or animals (87, 88) exposed to arsenic. Because humic acids
are characterized by phenolic and phenolic carboxylic polymer structures con-
taining both –COOH and –OH as their main functional groups, they can form
complex with a variety of inorganic elements including arsenic (89). Whether
an interaction between humic acids and arsenic can play a role on the develop-
ment of BFD awaits further investigations. One of the possible interactions is
that humic acids may chelate large amounts of inorganic arsenic in the water
and release the arsenic in the gastrointestinal tract where it is absorbed.
68 C.-H. Tseng
A comparison of the current evidences for arsenic and humic acids as po-
tential etiology of BFD is shown in Table 3.
CONCLUSIONS
The key features of BFD are summarized in Table 4. BFD in Taiwan can be
eradicated by cutting off the source of exposure (i.e., drinking artesian well
Features Remarks
Mean age of onset, years 52 (2–87)
Man:women 1.5:1
Hyperendemic areas Pei-Men, Hsueh-Chia, Pu-Tai and Yii-Chu
Peak incidence 1956–1960
Total cases (up to 1980s) >1,600
Prevalence in hyperendemic 6.51 to 18.81 per 1,000 population
areas in 1980s
Limb affected Mostly lower limbs, in rare cases fingers might be
involved
Clinical symptoms/signs Numbness, coldness, intermittent claudication,
absence of peripheral pulsation
Pathology 30% thromboangiitis obliterans and 70%
arteriosclerosis obliterans
Typical fate Ulceration, gangrene, spontaneous or surgical
amputation and death
Prognosis Annual death rate: 4.84 per 100 patient-years,
mean age at death: 62 years.
Major cause of death Cardiovascular disease
Blackfoot Disease and Arsenic 69
water), even the etiology of this devastating disease remains controversial. Al-
though arsenic is the most probable cause of BFD, the potential role of other
factors such as the humic acids cannot be completely excluded. The effects of
arsenic and humic acids may not be mutually exclusive and their interaction
on the promotion of BFD required further investigation. It has been a century
since the earlier cases of BFD were identified among residents of the south-
western coast of Taiwan. Science has solved the public health problems of BFD,
but more questions remain to be answered with regards to the real etiology and
the pathogenetic mechanisms of potential etiologic factors. Global problems of
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arsenic-contaminated drinking water are emerging (13, 90–92) rather than sub-
merging. Although the current devastating public health problems associated
with arsenic-contaminated drinking water in Bangladesh and West Bengal,
India can also be effectively tackled by the replacement of the contaminated
water with clean tap water, it may not be easy because of the wide geographical
distribution and the economic status of the countries. The story of BFD will
always be remembered and will not be ended in the foreseeable future.
ACKNOWLEDGEMENTS
The author thanks the National Science Council, Executive Yuan, Repub-
lic of China (NSC-86-2314-B-002-326; NSC-87-2314-B-002-245; NSC-88-2621-
B-002-030, NSC-89-2320-B-002-125 NSC-89-2318-B-002-007, NSC-90-2320-
B-002-197, NSC-92-2320-B-002-156 and NSC-93-2320-B-002-071), and the
Department of Health, Executive Yuan, Republic of China (DOH89-TD-1035)
for their support on the epidemiologic studies of blackfoot disease and diabetes
mellitus.
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