[CANCER
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45, 5895-5899.
November 1985]
Malignant Neoplasms among Residents of a Blackfoot Disease-endemic
in Taiwan: High-Arsenic Artesian Well Water and Cancers1
Area
Chien-Jen Chen,2 Ya-Chien Chuang, long-Ming Lin, and Hsin-Yin Wu
Institute of Public Health, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China
ABSTRACT
The objective of this study is to elucidate the association
between high-arsenic artesian well water and cancers in endemic
area of blackfoot disease, a unique peripheral vascular disease
related to continuous arsenic exposure. As compared with the
general population in Taiwan, both the standardized mortality
ratio (SMR) and cumulative mortality rate were significantly high
in blackfoot disease-endemic areas for cancers of bladder, kid
ney, skin, lung, liver, and colon. The SMRs for cancers of bladder,
kidney, skin, lung, liver, and colon were 1100, 772, 534, 320,
170, and 160, respectively, for males, and 2009,1119, 652,413,
229, and 168, respectively, for females. A dose-response rela
tionship was observed between SMRs of the cancers and blackfoot disease prevalence rate of the villages and townships in the
endemic areas. SMRs of cancers were greater in villages where
only artesian wells were used as the drinking water source than
in villages using both artesian and shallow wells, and even
greater than in villages using shallow wells only.
INTRODUCTION
BFD3 is an endemic peripheral vascular disorder confined to a
limited area on the southwest coast of Taiwan (1). Clinically, the
disease starts with numbness or coldness of one or more
extremities and intermittent claudication which progresses to
black discoloration, ulcération,and gangrene. In end stages of
the disease, spontaneous amputation of the distal parts of the
affected extremities is common (2). Although its etiology is still
unclear, BFD has been related to drinking water derived from
artesian wells in the endemic areas (3). Substances including
organic chlorides and ergot alkaloids have been identified in
artesian well water; however, arsenic has been suggested as
the most important determinant of BFD (4-6).
Previous studies have shown that the crude mortality rate of
cancer was higher in BFD-endemic areas than the general pop
ulation in Taiwan (7). It has also been found that the prevalence
rate of skin cancer in a BFD-endemic area was as high as 10.6/
1000 (8), and a dose-response relationship was observed be
tween the prevalence rate of skin cancer and the arsenic con
centration of the well water in villages of the endemic area (9).
However, epidemiological characteristics of other cancers have
never been studied.
In order to examine cancer mortality rates in BFD-endemic
areas during the period from 1968 to 1982 and to explore their
1This study is supported by the Taiwan Provincial Department of Health.
2 To whom requests for reprints should be addressed, at Institute of Public
Health, NTU College of Medicine, 1, Jen-Ai Rd. Sec. 1, Taipei, Taiwan, Republic of
China.
3The abbreviations used are: BFD, blackfoot disease; SMR, standardized
mortality ratio: CMR, cumulative mortality rate.
Received 2/18/85; revised 6/10/85; accepted 7/17/85.
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possible associations with artesian well water and BFD endemicity, the specific aims of this study include: (a) to compare SMRs
and age-specific CMRs of various cancers in the BFD-endemic
area with those in Taiwan; (b) to compare SMRs of cancers in
townships with different BFD prevalence rates; (c) to compare
SMRs of cancers in villages with different BFD endemicity; and
(c/) to compare SMRs of cancers in villages using artesian wells
and/or shallow wells.
MATERIALS AND METHODS
Study Area. The area covered in this study was limited to the
townships of Reimen, Hsuechia, Putai, and Ichu where previous studies
have shown BFD to be distinctly prevalent with rates per 1000 of 5.57,
3.87, 2.02, and 0.64, respectively (1). These four neighboring townships
are located on the southwest coast of Taiwan. The soil of this area has
a high salt content, and the water from shallow wells (6 to 8 m in depth)
of this area also has a high salinity. For this reason, some residents of
this area have been using water from artesian wells (100 to 200 m deep),
since the 1920s, especially those living in villages along the coast (4).
Totally, there were 84 villages in the study area: 31 villages using only
artesian wells; 27 using both artesian and shallow wells; 24 using only
shallow wells; and 2 using surface water in the stream (3). Even after
1956 when the piped water was first supplied, some people still use the
artesian well water for agriculture, pisciculture, and for drinking and
washing (5).
It was noted in an early report that the arsenic content of artesian well
water in BFD-endemic areas ranged from 0.35 to 1.14 ppm with a
median of 0.78 ppm, while the shallow well water in BFD-endemic areas
had arsenic content between 0.00 and 0.30 ppm with a median of 0.04
ppm (4). A more recent study in which a total of 83,565 wells from all
over Taiwan was examined showed that 29.1% of the wells had an
arsenic content greater than 0.05 ppm, and 5.2% of the wells had an
arsenic content greater than 0.35 ppm with a highest value of 2.5 ppm
in the BFD-endemic area, while only 5.7% of the wells had an arsenic
content greater than 0.05 ppm; and 0.3% of the wells had an arsenic
content greater than 0.35 ppm in other areas of Taiwan (10). The arsenic
content of surface soil samples in BFD-endemic areas ranged from 5.3
mg/kg to 11.2 mg/kg with a median of 7.2 mg/kg, and farm products
and fishes also had significantly high arsenic content in areas where
artesian well water was extensively used for agriculture and pisciculture
(11). It was estimated that the total daily arsenic ingested by residents
in BFD-endemic areas was as high as 1 mg (12).
The BFD was first observed in this area in late 1920s after artesian
wells were implemented, and none of these BFD cases was reported in
villages where only shallow well water or surface water was used (3).
There was a decreasing gradient of BFD prevalence rate following the
order of villages using artesian wells only, villages using both types of
wells, and villages using only shallow wells (3). Villages in the study area
were grouped into three subareas according to their BFD endemicity:
hyperendemic area including 21 villages with a BFD prevalence greater
than 5.0/1000; endemic area including 25 villages with a BFD prevalence
between 0.1 and 5.0/1000; and nonendemic area including 38 villages
where no BFD case was reported (1).
Study Population. It is obligatory to register any event of birth, death,
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HIGH-ARSENIC
ARTESIAN
WELL WATER AND CANCERS
marriage, divorce, and migration in the household registration offices,
and the registered household information is annually checked through a
home-visit interview by the registration office. Highly accurate and com
plete population and vital statistics are continuously produced, which
makes reliable demographic data available since 1905 (13). The midyear
population in Taiwan increased steadily from 13,682,588 in 1968 to
18,515,754 in 1982 with an annual natural increase rate of 21.8%, and
only a small percentage of people migrated to foreign countries (0.54%).
The population in the BFD-endemic area decreased from 141,733 in
1968 to 120,607 in 1982, with an average natural increase rate of 15.6%
and an average emigration rate of 27.0%. Although youths and young
adults tended to emigrate to metropolitan areas as in the case of other
rural townships in Taiwan, those who aged 45 or more yr old emigrated
to metropolitan areas with a much lower rate of 6.0%. Most of the
residents in the BFD-endemic areas engaged in farming, fishery, and salt
production. Their educational level and socioeconomic status were below
the average as compared with the general population in Taiwan.
As cancer mortality rates from 1968 to 1982 were studied, the average
population for each age-sex group during this period of time was used
to calculate CMRs and SMRs. When age-adjusted mortality rates of
cancers were computed, the 1976 world population was used as the
standard population (14).
Mortality Analysis. As it is mandatory for local household registration
offices to submit standardized certificates of each death to the Depart
ment of Health, the vital statistics are thus very complete in Taiwan (15).
According to a recent report, all the cancers except liver cancer were
more than 85% confirmed either histologically or cytologically (16). The
crude death rate in Taiwan decreased from 5.38% in 1968 to 4.77% in
1983, mainly due to the decline of the infant mortality rate. The ageadjusted cancer mortality rate in Taiwan increased from 89.4/100,000 in
1968 to 107.4/100,000 in 1982, while it increased from 160.9/100,000
in 1968 to 225.5/100,000 in 1982 in the BFD-endemic area. In this study,
all the certifications of cancer deaths obtained from the Information
Center of the Taiwan Provincial Department of Health were further
reviewed by the researchers.
Both SMRs (17) and CMRs (18) in the BFD-endemic area and Taiwan
were compared for various cancers grouped according to the eighth
revision of the International Statistical Classification of Diseases, Injuries,
and Causes of Death. Age- and sex-specific mortality rates of various
cancers in Taiwan were used as the standard rates to calculate SMRs
of the cancers in the BFD-endemic area; i.e., the SMR for each cancer
in Taiwan was 100. In addition to the comparisons of SMRs and CMRs
between the BFD-endemic area and Taiwan, the SMRs were further
analyzed with respect to the BFD prevalence rate of the townships, the
BFD endemicity of the villages, and the type of wells used in the villages.
RESULTS
SMRs of Cancers in the BFD-endemic Area. The SMRs with
their 95% confidence intervals of various cancers were classified
according to the codes of the eighth revision of the International
Statistical Classification of Diseases, Injuries, and Causes of
Death shown in Table 1. The SMRs were significantly higher (P
< 0.05) in the BFD-endemic area than in Taiwan for cancers of
bladder, kidney, skin, lung, liver, and colon for both sexes with
higher SMRs for females than males. The SMR for cancer of the
small intestine was as high as 298 for males, but only 97 for
females. Mortality rates of cancers of the esophagus, nasophar
ynx, leukemia, rectum, stomach, and thyroid were about the
same in the BFD-endemic area and in Taiwan. The age-adjusted
mortality rates for various cancers are also shown in the Table
1. The age-adjusted mortality rates for liver cancer and nasopharyngeal cancer were greater in Taiwan than in other countries
of the world, while those for other cancers were within the
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normal range of the world.
CMRs of Cancers in the BFD-endemic Area. The age-spe
cific CMRs for cancers of the bladder, kidney, skin, lung, liver,
and colon in the BFD-endemic area and in Taiwan are illustrated
in Chart 1. The CMRs of these cancers were higher in the BFDendemic area than in Taiwan for all age groups. The older the
age, the larger the difference in CMRs between the BFD-endemic
area and Taiwan for these cancers except colon cancer. The
differences in CMRs between the BFD-endemic area and Taiwan
were greater in females than in males for all age groups. The
CMRs of females in the BFD-endemic area were higher than
those of males in Taiwan for all these cancers except for liver
cancer.
SMRs of Cancers in Townships and Villages with Different
BFD Endemicity. Chart 2 indicates sex-specific SMRs for can
cers of the bladder, kidney, skin, lung, liver, and colon in town
ships of Reimen, Hsuechia, Putai, and Ichu following a declining
gradient of BFD prevalence rate. The SMRs were higher in
females than in males for all the cancers in all the townships
besides the colon cancer in Putai. Generally speaking, the higher
the BFD prevalence rate of a township, the greater the SMRs
for cancers of bladder, kidney, skin, and lung of the township.
However, the declining gradient of SMRs was not in the order
of the BFD prevalence rates of the townships for cancers of liver
and colon. Chart 3 depicts age- and sex-adjusted SMRs in
villages where BFD was hyperendemic, endemic, or nonendemic.
A dose-response relationship was observed between BFD en
demicity and SMRs of cancers of the bladder, kidney, skin, lung,
and liver, but not between BFD endemicity and SMR of colon
cancer. The villages without any BFD case still showed SMRs
greater than 150 for these cancers.
SMRs of Cancers in Villages Using Different Types of Wells.
SMRs of various cancers in villages with different types of wells
are shown in Chart 4. The SMRs for cancers of the bladder,
kidney, skin, lung, and liver were highest in villages where only
artesian wells were used and lowest in villages where only
shallow wells were used. However, villages using only shallow
wells still had SMRs greater than 150 for these cancers.
DISCUSSION
The extraordinarily high prevalence of BFD in the limited area
on the southwest coast of Taiwan has attracted researchers to
explore its risk factors and etiological mechanism. Epidemiological studies did show that artesian well water was significantly
associated with the disease. It has been reported that BFD
patients, their family members, and healthy controls in the BFDendemic area had much higher arsenic content in their hair and
urine than residents of other areas in Taiwan (19).
Significantly high mortality rates of cancers in the BFD-en
demic area might be due to some local risk factors which were
either unique or in much greater quantity in this area than other
areas of Taiwan. The exposure and/or effects of these local risk
factors might be accumulated gradually over a long period of
time and thus contribute to the increased difference in SMRs
between the BFD-endemic area and Taiwan with the increase in
age. Greater SMR discrepancy between the BFD-endemic area
and Taiwan in females than in males might be attributable to the
fact that males are exposed to more risk factors in addition to
local ones than are females. The relative impact of the local risk
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ARTESIAN
WELL WATER AND CANCERS
Table 1
Standardized mortality ratios with their 95% confidence intervals for various cancers by sex in blackfoot disease-endemicarea in Taiwan, 1968-1982
deathsNo. of
codes)Bladder
Cancer (ICD
ratio"Ratio1100200977211195346523204131702291601682989
mortality
confidence
rate in
Taiwan*2.711.260.850.811.491.1517.088.3426.729.195.495.380.910.767.291.633.741.553.362.722.852.3722.1710.910.240.
interval933-12671702-2316537-1007838-140
expected15.28.25.45.58.67.5103.856.5179.463.733.836.35.75.242.810.626.111.331.624.617.5
observed16716642624649332233305146546117553122617452221151128212No.
(188)Kidney
(189.0)Skin
(172)Lung
(162)Liver
(155)Colon
(153)Small
52)Esophagus
intestine (1
(150)Nasopharynx
(147)Leukemia
(204-208)Rectum
(154)Stomach
(151)Thyroid
(193)SexMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFem
" Age-adjusted mortality rate per 100,000 using 1976 world population as standard population.
0 Age-specific mortality rates in Taiwan were used as standard rates to calculate the standardized mortality ratio; i.e., SMR for each cancer in Taiwan is 100.
factors is thus much more reduced in males than in females of
the BFD-endemic area.
The dose-response relationships between the BFD prevalence
rate and cancer mortality rates suggested that BFD and these
cancers might share some common local risk factors. The as
sociation between artesian well water and cancers was also
suggested by the declining gradient of cancer mortality following
the order of villages using artesian well only, villages using both
types of wells, and villages using shallow wells only.
A high content of arsenic in artesian well water might be one
of the most important determinants of cancers in BFD-endemic
areas, as the artesian well water was used not only for drinking
but also for daily washing, agriculture, and pisciculture. The
surface soil and farm products in the BFD-endemic area have
been found to have a high arsenic content. There were possibil
ities for residents of the BFD-endemic area to be exposed to
arsenic by either skin contact or respiratory deposition in addition
to gastrointestinal absorption. The p.o. and i.v. administration of
radiolabeled arsenic to mice, rabbits, guinea pigs, hamsters,
chickens, and monkeys did show wide distribution of the isotope
in the body. The highest levels of arsenic were observed in liver,
kidney, skin, lung, large intestine, and spleen (20-24). Following
injection of radiolabeled arsenites in patients terminally ill with
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malignant diseases, the isotope was found to be widely distrib
uted in the body just as in the case of experimental animals (25).
Although long-term animal tests for the carcinogenicity of
arsenic did not show positive results (26, 27), occupational,
environmental, and medicinal exposures to inorganic arsenics
were related to lung cancer, skin cancer, and liver cancer (9, 28,
29). The association between arsenic exposure and cancers of
lung and skin has long been documented. It is obvious that the
increase in mortality rates of these two cancers in the BFDendemic area is related to arsenic exposure. The arsenic com
pounds were found to be associated with hepatic angiosarcoma
of the liver (30, 31), but most liver cancers in Chinese are
hepatocellular carcinoma with cirrhosis which has been related
to the hepatitis B viral infection (32). It thus remains to be
elucidated whether or not the development of liver cancer in the
BFD-endemic area has resulted from the interactive effects of
exposures to arsenic, hepatitis B virus, and aflatoxin.
The association between arsenic exposure and bladder can
cer, kidney cancer, and colon cancer has not been documented.
Most residents of BFD-endemic areas engaged in farming, fish
ery, and salt production, and schistosomiasis has never been
reported in this area. Neither the occupational exposure nor the
Schistosoma haematobium infection seems likely to be an im-
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HIGH-ARSENIC
BLADDER
KIDNEY
ARTESIAN
WELL WATER AND CANCERS
100
SKIN
BOO
000
1000
BtADDER
KIDNEY
SKIN
LUNG
I..
LIVER
COLON
LUNG
Hyporendemic area
Endemic area
Nonandamic araa
LIVER
COLON
ri
» •
AGE
Chart 1. Age-specific cumulative mortality rates of bladder cancer, kidney can
cer, skin cancer, lung cancer, liver cancer, and colon cancer for males and females
in the BFD-endemic area and in Taiwan. Age-specific curves are shown for four
groups: males in the BFD-endemic area (bold solid line); females in the BFDendemic area (bold broken line)', males in Taiwan (fine solid line)', and females in
Chart 3. SMRs for cancers of the bladder, kidney, skin, lung, liver, and colon in
three areas with different endemicity of BFD: hyperendemic area where the BFD
prevalence rate was greater than 5.0/1000; endemic area where the BFD preva
lence rate was between 0.1 and 5.0/1000; and nonendemic area where no BFD
case was reported. Age- and sex-specific mortality rates of these cancers in Taiwan
were used as standard rates. (Scale of SMR is in logarithm.)
IDO
Taiwan (fine broken line).
eoo
BOO
1000
3000
BOOO
BLADDER
KIDNEY
SKIN
LUNG
ARTESIAN
BOTH
SHALLOW
LIVER
WELL
WELL
COLON
MALE
FEMALE
Chart 2. Sex-specific SMRs for cancers of bladder, kidney, skin, lung, liver, and
colon in the townships of Reimen, Hsuechia, Putai, and Ichu where Wackfoot
disease prevalence rates were 5.57,3.87, 2.02, and 0.64/1000, respectively. Agespecific mortality rates of these cancers in Taiwan were used as standard rates.
(Scale of SMR is in logarithm.)
portant reason for the high mortality rate of bladder cancer in
this area. Cigarette smoking has been related to cancers of
kidney and bladder, but the extraordinarily high SMRs of these
two cancers were not readily explained by the relatively higher
cigarette smoking rate in the BFD-endemic area than in Taiwan
(40% versus 32%). The dietary pattern of residents in the BFDCANCER
RESEARCH
Chart 4. SMR for cancers of the bladder, kidney, skin, lung, liver, and colon in
three areas where different types of wells were used as drinking water source:
area where only artesian wells were used; area where both artesian and shallow
wells were used; and area where only shallow wells were used. Age- and sexspecific mortality rates of these cancers in Taiwan were used as standard rates.
(Scale of SMR is in logarithm.)
endemic area was not different from that of the general popula
tion in Taiwan. They even consume more vegetables, fiber, and
complex carbohydrates than do residents of other socioeconomically better developed areas in Taiwan. The only significant
difference in environment between the BFD-endemic areas and
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ARTESIAN
WELL WATER AND CANCERS
other areas is the arsenic content of the drinking water, surface
soil, and farm products derived from artesian well water. The
high mortality rates of cancers of the bladder, kidney, and colon
in the BFD-endemic area are thus most probably attributable to
the high-arsenic artesian well water of the areas. However,
further investigations through prospective study of cancers
among residents in the BFD-endemic area are needed to confirm
the relationship between artesian well water and cancers.
12.
13.
14.
15.
16.
17.
ACKNOWLEDGMENTS
18.
The authors wish to thank Dr. M. D. Malison and Dr. J. D. Wang for their helpful
comments and suggestions and Y. J. Chen for his technical assistance.
19.
20.
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Malignant Neoplasms among Residents of a Blackfoot
Disease-endemic Area in Taiwan: High-Arsenic Artesian Well
Water and Cancers
Chien-Jen Chen, Ya-Chien Chuang, Tong-Ming Lin, et al.
Cancer Res 1985;45:5895-5899.
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