The Journal of Dermatology

Vol. 29: 123–130, 2002

Review article
Peripheral Vascular Diseases Resulting from Chronic
Arsenical Poisoning
Hsin-Su Yu, Chih-Hung Lee and Gwo-Shing Chen

Abstract
Drinking water contaminated by arsenic remains a major public health problem. Long-
term arsenic exposure has been found to be associated with peripheral vascular diseases in
a variety of studies. Reports of vascular effects of arsenic in drinking water, which span al-
most 100 years, have been published in Taiwan, Chile, Mexico, and China. This paper re-
viewed the association of peripheral vascular diseases resulting from arsenic exposure to
drinking water from the clinical and pathological points of view. An endemic peripheral
vascular disorder called “blackfoot disease” has been noticed in a limited area in Taiwan.
This disease results in gangrene in the extremities. It has been associated with the inges-
tion of high concentrations of arsenic-tainted artesian well water. Epidemiological studies
confirmed a dose-response relationship between long-term arsenic exposure and the oc-
currence of blackfoot disease. Whereas arsenic has induced various clinical manifestations
of vascular effects in Chile, Mexico and China, they do not compare in magnitude or
severity to the blackfoot disease found in Taiwan. The pathogenesis of vascular effects in-
duced by arsenic is still controversial. The possible mechanisms include endothelial cell
destruction, arsenic-associated atherogenesis, carotene and zinc deficiency, and/or some
immunological mechanism. Microcirculatory assessments revealed that deficits of capil-
lary blood flow and permeability exist in clinically normal skin of patients with chronic ar-
senical poisoning. The vascular effects of chronic arsenic poisoning may involve cardio-
vascular and cerebrovascular systems as well. In view of the increasing public health prob-
lems caused by arsenic exposure, vascular effects should be included in the future study of
health effects of arsenic.
Key words: arsenic; vascular effect; blackfoot disease; microcirculation; pathogenesis

food, a variety of inorganic arsenites and ar-

Introduction
Arsenic is the twentieth most abundant el-
ement and is widely distributed in the envi-
ronment (1). Humans are exposed to inor-
ganic and organic arsenic through environ-
mental, medicinal, and occupational
sources. Inorganic forms of arsenic are
much more toxic than organic forms. The
most common form of inorganic arsenic in
the air is arsenic trioxide; in water, soil or
Department of Dermatology, Kaohsiung Medical
University, Taiwan.
Reprint requests to: Hsin-Su Yu, M.D., Department
of Dermatology, No 100, Shih-Chuan 1st Road, Kaoh-
siung 807, Taiwan.
senates occur (1). Gallium arsenide is an-
other inorganic arsenic compound of po-
tential human health concern because of its
widespread use in the microelectronics in-
dustry (1). Drinking water contamination by
arsenic is a major public health problem.
General health effects associated with
chronic arsenic exposure include cancers
(bladder, kidney, skin, liver, lung and
colon), cardiovascular and peripheral vascu-
lar diseases (2–6), and other pathological
conditions such as developmental anom-
alies (7–9), neurological and neurobehav-
ioral disorders, diabetes (10), lung fibrosis,
and hematological disorders (11, 12). The
carcinogenic effects of chronic inorganic ar-
124 Yu et al
a Clinically, the patients suffer from coldness,
b
Fig. 1. Blackfoot disease resulted in gangrene
in the hand (a) and lower extremity (b).
senic exposure have received a great deal of
academic and governmental attention,
whereas the vascular effects of chronic ar-
senic exposure have attracted much less
concern.
Since Geyer’s 1898 report of an increased
occurrence of gangrene in Reichenstein,
Silesia (13), an increased risk of peripheral
vascular disease as a result of drinking water
containing arsenic has been reported from
Taiwan (14), Chile (11), Mexico (15) and
China (16). This paper reviews the associa-
tion of perpheral vascular diseases resulting
from arsenic exposure from drinking water
from clinical and pathological points of
view.
Peripheral vascular diseases resulting from
arsenic exposure from drinking water
Blackfoot disease in Taiwan
An endemic peripheral vascular disorder
called “blackfoot disease” has been noticed
in a limited area on the southwestern coast
of Taiwan. This disease results in gangrene
in the extremities. The toes and feet are pri-
marily involved, with occasional occurrence
in the fingers (Fig 1). Onset and exacerba-
tion are associated with cold weather and in-
juries (17). In the early stages, erythematous
swelling is noticed in the involved limbs. Ag-
onizing pain is the accompanying symptom
from the early stages, and it gets worse and
worse as the disease progresses (14, 17).
numbness, and intermittent claudication of
the lower legs, which may progress to ulcer-
ation and gangrene. The agonizingly
painful condition ultimately results in spon-
taneous or surgical amputation in 68% of
blackfoot disease patients (17). Among pa-
tients with blackfoot disease, the age at
onset of symptoms ranges from 2 years to 87
years, with 28% of patients being under the
age of 40 years. Gangrene develops within a
few months to 2 years after disease onset
(17). From the first reported cases in 1954,
more than 1455 patients had been reported
by 1977 (18). The total population of this
endemic area is approximately 100,000.
Blackfoot disease thus had an overall preva-
lence rate of 8.9 per thousand in 1968 (2).
It had been noticed that blackfoot disease
was limited to people drinking deep well
water which showed variable but high con-
centrations of arsenic (19, 20). Because of
the high salinity of shallow well water, swal-
low wells were replaced by deep wells that
came into use between 1900 and 1930 (17,
21). An association between the consump-
tion of artesian well water and the occur-
rence of blackfoot disease was established by
an ecological study (20). High levels of ar-
senic (0.01~1.81 ppm) were found in arte-
sian well water in the endemic area (20, 22),
and arsenic was suspected as the main cause
of blackfoot disease. Case-control studies
confirmed that the risk of blackfoot disease
was related to the cumulative arsenic expo-
sure among inhabitants of the endemic area
(3). Furthermore, a dose-response relation-
ship between long-term arsenic exposure
 Vascular Effects of Chronic Arsenical Poisoning
Fig. 2. Angiography of patient with blackfoot
disease showed prominent occlusion of poste-
rior tibial artery (arrow) with some collateral
circulation.
and periphearal vascular disease was
demonstrated in the blackfoot disease en-
demic area, using the ankle-brachial index
as the indicator for the presence of periph-
eral vascular disease (23). In addition to ar-
senic, humic substances in the drinking
water have been proposed to cause black-
foot disease (24). In vitro studies revealed
that the humic substances influence para-
meters of the blood coagulation system and
capillary permeability (25, 26). The role of
humic substances in blackfoot disease has
not been substantiated by epidemiologic or
animal studies (27). A causal role for arsenic
in the induction of blackfoot disease offers
the best explanation for the observations in
Taiwan (28).
Blackfoot disease is characterized by the
progressive narrowing of peripheral arter-
ies, especially those in the lower extremities
(29). A decrease in pulsation was noticed in
the affected limbs. Angiography showed
stenosis of major arteries with variable col-
lateral circulation in the affected extremi-
ties (Fig 2). An extensive pathological study
demonstrated that 30% of the blackfoot dis-
ease patients had histological features com-
patible with thromboangiitis obliterans, and
70% showed changes of arteriosclerosis
obliterans (30). In an early stage of black-
125
foot disease, thickening and fibrinoid de-
generation of the blood vessel wall and
perivascular small round cell infiltration of
the affected skin have been described. Gan-
grenous limbs showed proliferation and di-
lation of the dermal vessels and occlusion of
subcutaneous arterioles with thrombosis
and proliferation of their vaso vasorum
(26).
Peripheral vascular disease in Latin Amer-
ica
Populations in Chile (11), Mexico (12)
and Argentina (31) have been exposed to
high concentrations of arsenic in drinking
water. The skin manifestations of the affect-
ed inhabitants in the endemic areas are typ-
ical of chronic arsenical poisoning. Some
patients in Chile exhibited Raynaud’s dis-
ease (with vascular spasm of the fingers, feet
and tongue) and myocardial infarction, and
one case suffered from gangrene of a finger
(32, 33). However, no occurrence of black-
foot disease has been described. In Mexico,
there have not been any papers reporting
peripheral vascular disorders, gangrene, or
amputation other than one short article re-
porting two cases of gangrene with amputa-
tion (34). In Argentina, peripheral vascular
diseases have not been described in the en-
demic area (31).
Peripheral vascular disease in China
In China, chronic arsenism has been re-
ported only in recent years. However, the sit-
uation and the spread of the disease are very
serious. Sources of arsenic exposure can be
divided into three routes: drinking water,
coal burning, and industrial exposure (16).
The exposed population is over 2 million,
and diagnosed arsenism patients number
up to 20,000. In an endemic area of Inner
Mongolia, arsenic naturally occurs in
ground water at concentrations ranging
from <50 µg/L to 1.8 mg/L with 30% of the
wells higher than 50 µg/L (35). A study of
530 individuals from the endemic area
showed 55% with arsenism, and these cases
also showed elevated rates of cardiovascular
(41% with abnormal ECG) and peripheral
vascular diseases, as well as peripheral and
126
a b
Fig. 3. An increase in the number of dilated tortuous nailfold capillary loops
was noticed in the early stages of the affected finger (a) as compared to a nor-
mal one (b).
central nervous system dysfunction (35).
The co-occurrence of blackfoot disease
with arsenical cancers
Among the inhabitants of the blackfoot
disease endemic area, a remarkable per-
centage of cases of chronic arsenism mani-
fested as hyperpigmentation, keratosis and
skin cancer has been observed. The overall
rates for hyperpigmentation, keratosis, and
cancer in 1968 were 183.5, 71.0, and 10.6
per thousand, respectively (2). It has been
established that ingestion of inorganic ar-
senic causes skin cancer, usually as multiple
lesions. In the blackfoot disease endemic
area, arsenical skin cancers include Bowen’s
disease, type B arsenical keratosis, epider-
moid carcinoma, basal cell carcinoma, and a
combined form (36). The association of
blackfoot disease and chronic arsenism is
significantly high. Arsenical skin cancer was
associated with blackfoot disease in 15.3%
of the cases, and blackfoot disease was seen
in patients with arsenical skin cancer in
32.83% of the cases (2). There is also evi-
Yu et al
dence that ingestion of inorganic arsenic
causes internal cancers of the bladder, kid-
ney, liver, lung and colon. An ecologic inves-
tigation revealed that higher standardized
mortality ratios for skin, bladder and kidney
cancers were observed among the inhabi-
tants in the blackfoot disease endemic area
than in the general Taiwanese population
(37). Standardized mortality ratios for skin,
bladder and kidney cancers were 5.34, 11.00
and 7.72 in males and 6.52, 20.09 and 11.19
in females, respectively (37). Compared
with mortality rates in the blackfoot disease
endemic area, blackfoot disease patients
showed standardized mortality ratios of
1.60, 2.55 and 4.51 for kidney, bladder and
skin cancers, respectively (3).
Toxic effects on the cardiovascular and
cerebrovascular systems and
arsenic exposure
Long-term exposure to inorganic arsenic
has toxic effects on the cardiovascular sys-
tem. Environmental exposure to inorganic
arsenic through drinking water has been as-
 Vascular Effects of Chronic Arsenical Poisoning
sociated with an increased mortality from
cardiovascular diseases among residents in
Taiwan (38), Chile (39) and Japan (40).
The relative mortality risks for the blackfoot
disease endemic area compared with Tai-
wan as a whole were 3.5 for diseases of the
arteries, arterioles and capillaries, 1.3 for
cardiovascular diseases, and 1.1 for cere-
brovascular diseases (38). Blackfoot disease
patients were found to have a significantly
higher ischemic heart disease mortality rate
than non-BFD residents, showing a multi-
variated-adjusted relative risk of 2.5 (38).
Chiou et al. reported that long-term expo-
sure to inorganic arsenic from well water in
an area with endemic arseniasis (other than
the blackfoot disease endemic area) was as-
sociated with an increased prevalence of
cerebrovascular diseases (41).
Cutaneous microcirculation in chronic
arsenical poisoning
In the early stages of blackfoot disease,
the affected toes and fingers revealed an in-
creased number of dilated tortuous nailfold
capillary loops (Fig 3). In contrast, morpho-
logic analysis of the capillary loops of the
nonaffected toes and fingers showed no sig-
nificant differences from those of normal
controls (42, 43). The parameters for the
cutaneous microcirculation including rest-
ing capillary blood cell velocity, peak capil-
lary blood cell velocity, and time to peak
capillary blood cell velocity were significant-
ly disturbed in both the affected and nonaf-
fected toes and fingers in the blackfoot dis-
ease patients (43). Deficits in cutaneous mi-
crocirculation of the toes were demonstrat-
ed among clinically normal subjects living in
the blackfoot disease endemic area (44).
Furthermore, an increase in permeability of
nailfold capillary loops was noticed in clini-
cally normal fingers of blackfoot disease pa-
tients (45). In China, nailfold capillaries in
patients with chronic arsenical poisoning
displayed short and abnormal shapes. Nail-
fold microcirculation revealed an aggrega-
tion of erythrocytes and slow blood flow
(46). These findings indicate that microcir-
127
culatory disturbances may occur in the early
stages of chronic arsenical poisoning.
Pathogenesis of peripheral vascular
diseases resulting from chronic
arsenical poisoning
Although the association between arsenic
and atherosclerosis is well documented, the
pathogenesis is still controversial. Arsenic
has been shown to have a specific affinity for
the vascular bed, to be toxic to endothelial
cells (47) and to cause smooth-muscle cell
proliferation (48). These effects may play a
role in arsenic-associated atherogenesis.
The epidemiological evidence of shared risk
factors for cancer and atherosclerosis has
been reviewed (49). Arsenic and some car-
cinogenic environmental agents such as ion-
izing radiation, vinyl chloride monomer, to-
bacco, and various industrial combustion ef-
fluents containing polycyclic aromatic hy-
drocarbons possess the dual effect of athero-
genicity and carcinogenicity. These observa-
tions suggest that somatic mutations and
cell proliferation may play roles in the
pathogenesis of atherosclerotic plaque (49).
A case-control study revealed a role for nu-
trition in blackfoot disease. It was noted that
the longer the consumption duration of
high-arsenic artesian well water, the lower
the serum α- and β-carotene concentration,
resulting in a higher ischemic heart disease
rate in the blackfoot disease endemic area
(50). The possible role of zinc deficiency in
blackfoot disease is suggested by lower zinc
levels in whole blood, plasma, urine, and
hair of blackfoot disease patients compared
with controls (51). Low zinc could make en-
dothelial cells more vulnerable to arsenic,
because zinc seems to be important in vas-
cular endothelial barrier function, mem-
brane integrity, and anti-atherosclerotic ef-
fects (52, 53). The roles of nutrients and
trace elements in the pathogenesis of ar-
senic-induced peripheral vascular disease
remain to be further investigated. Most of
the toxins appear to affect only a small pop-
ulation of the exposed individuals, often less
than 1%. Certain individuals appear to be
128
genetically susceptible to vascular disease
(54). A recent study revealed that serum
IgG from patients with blackfoot disease,
but not from normal controls, induced con-
centration-dependant cytotoxicity in cul-
tured vascular endothelial cells. Only per-
sons who produce the IgG anti-endothelial
cell antibody are potential victims of black-
foot disease (45). These findings strongly
suggest that immunological mechanisms
play a significant role in the pathogenesis of
blackfoot disease.
Conclusion
There is good epidemiologic evidence that
chronic arsenic consumption at high levels is a
cause of severe peripheral vascular disorders
that result in gangrene of the limbs. A major
characteristic of the early stages of these disor-
ders is endothelial dysfunction. The vascular en-
dothelium in certain susceptible individuals is
very sensitive to arsenic insults. The vascular ef-
fects of chronic arsenic exposure are not only
confined to the peripheral vessels, but may also
induce cardiovascular and cerebrovascular dis-
eases as well. In view of the increasing public
health problems caused by arsenic, vascular ef-
fects should be included in the future study of
health effects of arsenic.
Acknowledgments
This study was supported by
(1) grants from National Health Research Institute
(NHRI-GT-EX90-8929SL), Taiwan.
(2) grants from Chen, Jieh-Chen Scholarship
Foundation, Tainan, Taiwan.
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