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Invited Reviews: Carcinogenic and Systemic Health Effects Associated with Arsenic Exposure−−A Critical
Review
Paul B. Tchounwou, Anita K. Patlolla and Jose A. Centeno
Toxicol Pathol 2003 31: 575
DOI: 10.1080/01926230390242007

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 Invited Reviews

Toxicologic Pathology, 31:575–588, 2003

Copyright 
C by the Society of Toxicologic Pathology

ISSN: 0192-6233 print / 1533-1601 online

DOI: 10.1080/01926230390242007

Carcinogenic and Systemic Health Effects Associated with Arsenic

Exposure—A Critical Review
PAUL B. TCHOUNWOU,1 ANITA K. PATLOLLA,1 AND JOSE A. CENTENO2
1
Molecular Toxicology Research Laboratory, NIH-Center for Environmental Health, School of Science and Technology,
Jackson State University, Jackson, Mississippi, USA and
2
Environmental and Toxicologic Pathology, Department of Armed Forces Institute of Pathology, Washington, DC, USA

ABSTRACT
Arsenic and arsenic containing compounds are human carcinogens. Exposure to arsenic occurs occupationally in several industries, including
mining, pesticide, pharmaceutical, glass and microelectronics, as well as environmentally from both industrial and natural sources. Inhalation is
the principal route of arsenic exposure in occupational settings, while ingestion of contaminated drinking water is the predominant source of
significant environmental exposure globally. Drinking water contamination by arsenic remains a major public health problem. Acute and chronic
arsenic exposure via drinking water has been reported in many countries of the world, where a large proportion of drinking water is contaminated
with high concentrations of arsenic. General health effects that are associated with arsenic exposure include cardiovascular and peripheral vascular
disease, developmental anomalies, neurologic and neurobehavioural disorders, diabetes, hearing loss, portal fibrosis, hematologic disorders (anemia,
leukopenia and eosinophilia) and multiple cancers: significantly higher standardized mortality rates and cumulative mortality rates for cancers of the
skin, lung, liver, urinary bladder, kidney, and colon in many areas of arsenic pollution. Although several epidemiological studies have documented
the sources of exposure and the global impact of arsenic contamination, the mechanisms by which arsenic induces health effects, including cancer,
are not well characterized. Further research is needed to provide a better understanding of the pathobiology of arsenic-induced diseases and to better
define the toxicologic pathology of arsenic in various organ systems. In this review, we provide and discuss the underlying pathology and nature of
arsenic-induced lesions. Such information is critical for understanding the magnitude of health effects associated with arsenic exposure throughout
the world.
Keywords. Arsenic pollution; human exposure; molecular mechanisms; systemic health effects; carcinogenicity.

INTRODUCTION parasitic diseases, including filariasis in dogs and black head

Arsenic is a ubiquitous element detected in low con-
centrations in virtually all environmental media. Arsenic
compounds represent a concern to environmental and oc-
cupational health when their presence in the environment
increases due to natural or anthropogenic sources (2). More
than 80% of arsenic compounds are used to manufacture
products with agricultural applications such as insecticides,
herbicides, fungicides, algicides, sheep dips, wood preserva-
tives, dye-stuffs, and medicines for the eradication of tape-
worms in sheep and cattle (109). Arsenic compounds have
been used for at least a century in the treatment of syphilis,
yaws, amoebic dysentery, and trypanosomaiasis. In 1887,
Hutchinson first described skin cancer in patients treated with
arsenic-containing medication for psoriasis and other skin
conditions (69, 70). Arsenical drugs are still used in treating
certain tropical diseases such as African sleeping sickness
and amoebic dysentery, and in veterinary medicine to treat
Address correspondence to: Dr. Paul B. Tchounwou, NIH-Center for
Environmental Health, Jackson State University, 1400 Lynch Street, Box
18540, Jackson, MS 39217; email: paul.b.tchounwou@sums.edu
575
in turkeys and chickens (109). Recently, arsenic has been used
as an anticancer agent in the treatment of acute promeylocytic
leukemia, and its therapeutic action has been attributed to the
induction of programmed cell death (apoptosis) in leukemia
cells (128).
A large number of people are exposed to arsenic chroni-
cally throughout the world. Exposure to arsenic occurs via
the oral route (ingestion), inhalation, dermal contact, and the
parenteral route to some extent (2). Arsenic is found natu-
rally, its concentrations in air in remote locations (away from
human releases) range from 1 to 3 ng/m3 , whereas concentra-
tions in cities may range from 20 to 100 ng/m3 . In water, the
concentrations of arsenic are usually less than 10 µg/L, al-
though higher concentrations can occur near natural mineral
deposits or man made sources. Natural levels of arsenic in soil
usually range from 1 to 40 mg/kg, but pesticide application
or waste disposal can produce much higher values. Arsenic
is also found in many foods at concentrations ranging from
20 to 140 ng/kg (2).
Diet, for most individuals is the largest source of exposure,
with an average intake of about 50 µg per day from food.
Intake from air, water, and soil are usually much smaller,

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576 TCHOUNWOU ET AL
but exposure from these media may become significant in
areas of arsenic contamination. Workers who produce or
use arsenic compounds in such occupations as vineyards,
ceramics, glass-making, smelting, pharmaceuticals, refining
of metallic ores, pesticide manufacturing and application,
wood preservation, or semiconductor manufacturing can be
exposed to substantially higher levels of arsenic (58).
Hazardous waste sites (HWS) constitute another possible
source of human exposure to arsenic. This element has been
identified at 781 sites of the 1,300 HWS that have been pro-
posed for inclusion on the national priority list (59). Exposure
at these sites may occur by a variety of pathways, including
of dusts in air, ingestion of contaminated water or soil, or
through the food chain.
Analyzing the toxic effects of arsenic is complicated be-
cause the toxicity varies according to its oxidation state, its
solubility (95, 161) and in many different inorganic and or-
ganic compounds. Several studies have indicated that the
toxicity of arsenic depends on the exposure dose, frequency
and duration, the biological species, age, and gender, as well
as on individual susceptibilities, genetic and nutritional fac-
tors (26). Most cases of human toxicity from arsenic have
been associated with exposure to inorganic arsenic. Inor-
ganic trivalent arsenite (AsIII ) is 2–10 times more toxic than
pentavalent arsenate (AsV ) (76). Gallium arsenide (GaAs)
is another inorganic arsenic compound of potential human
health concern because of its widespread use in the micro-
electronics industry (110). Contamination with high levels
of arsenic is of concern because arsenic can cause a number
of human health effects, including cancer (112). Interest in
the toxicity of arsenic has been heightened by recent reports
of large populations in West Bengal, Bangladesh, Thailand,
Inner Mongolia, Taiwan, China, Mexico, Argentina, Chile,
Finland, and Hungary that have been exposed to high con-
centrations of arsenic in their drinking water and are dis-
playing various clinico-pathological conditions, the major
effects being skin alterations and skin cancer besides car-
diovascular and peripheral vascular disease, developmental
anomalies, neurologic and neurobehavioural disorders, di-
abetes, hearing loss, portal fibrosis, hematologic disorders
(anemia, leukopenia, and eosinophilia), and carcinoma (23,
101). Several epidemiological studies have reported a strong
association between arsenic exposure and increased risks of
both carcinogenic and systemic health effects (112). In this
paper, we provide and discuss important information about
the molecular mechanisms of arsenic toxicity, as well as the
health effects associated with arsenic exposure.
MECHANISMS OF ARSENIC TOXICITY
AND CARCINOGENICITY
One of the mechanisms by which arsenic exerts its toxic
effect is through impairment of cellular respiration by the
inhibition of various mitochondrial enzymes, and the uncou-
pling of oxidative phosphorylation. Most toxicity of arsenic
results from its ability to interact with sulfhydryl groups of
proteins and enzymes, and to substitute phosphorous in a va-
riety of biochemical reactions (51). Arsenic in vitro reacts
with protein sulfhydryl groups to inactivate enzymes, such
as dihydrolipoyl dehydrogenase and thiolase, thereby pro-
ducing inhibited oxidation of pyruvate and betaoxidation of
fatty acids (12).
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TOXICOLOGIC PATHOLOGY
Tests for genotoxicity have indicated that arsenic com-
pounds inhibit DNA repair, and induce chromosomal aber-
rations, sister-chromatid exchanges, and micronuclei forma-
tion in both human and rodent cells in culture (11, 57, 73,
164) and in cells of exposed humans (159). The mechanism
of genotoxicity is not known, but may be due to the ability
of arsenate to inhibit DNA replicating or repair enzymes, or
the ability of arsenate to act as a phosphate analog (88). Re-
version assays with Salmonella typhimurium fails to detect
mutations that are induced by arsenic compounds. Although
arsenic compounds are generally perceived as weak mutagens
in bacterial and animal cells, they exhibit clastogenic proper-
ties in many cell types in vivo and in vitro (57, 72, 73, 164).
In the absence of animal models, in vitro cell transforma-
tion studies become a useful means of obtaining information
on the carcinogenic mechanisms of arsenic toxicity. Arsenic
and arsenical compounds are toxic to and induce morpho-
logic transformations of Syrian hamster embryo (SHE) cells
as well as mouse C3H10T1/2 cells and BALB/3T3 cells (79,
82, 146). Based on the comet assay, it has been reported
that arsenic trioxide induces DNA damage in human lym-
phocytes (132). Arsenical compounds have also been shown
to induce gene amplification, arrest cells in mitosis, inhibit
DNA repair, and induce expression of the c-fos gene and the
oxidative stress protein heme oxygenase in mammalian cells
(49, 107, 108, 127). They have been implicated as promoters
and comutagens for a variety of toxic agents (68).
The major metabolic pathway for inorganic arsenic in hu-
mans is methylation. This pathway of arsenic metabolism
and excretion is presented in Figure 1. Most of the inorganic
arsenic [As (III) and As (V)] is metabolized to monomethy-
larsonic acid [MMA (V)] and dimethylarsinic acid [DMA
(V)] before excretion in the urine. Methylation of arsenic in-
volves a two-electron reduction of pentavalent [eg, As (V) &
MMA (V)] to trivalent [eg, As (III) & MMA (III)] arsenic
species followed by the transfer of a methyl group from a
methyl donor, such as S-adenosylmethionine (35, 112, 149).
This methylation mechanism has been widely accepted, and
the metabolites MMA (V) and DMA (V) have been con-
sistently observed in human urine. A key intermediate for
the methylation of MMA (V) to DMA (V) is the MMA (III)
species. Several studies have indicated the presence of MMA
(III) species in rat liver cytosol and hepatocytes, and demon-
strated the important effects of the methylated trivalent ar-
senic species in biological systems (5, 89, 120, 142–145,
174, 175).
The generally held view of arsenic carcinogenesis in the
past was that arsenite was the most likely cause of carcino-
gensis and that methylation of arsenic species was a detox-
ification pathway. Several authors thought that methylation
of arsenic was of great importance in minimizing arsenic’s
toxicity and/or carcinogenicity (75). The present view of ar-
senic carcinogenesis is that there are many possible chemical
forms of arsenic that may be causal in carcinigenesis and that
methylation of arsenic may be a toxification, not a detoxifica-
tion, pathway. A great amount of evidence has accumulated,
in a short period of time about toxification pathway of methy-
lated arsenic.
MMA (III) has been found in urine of humans exposed
to arsenic without (5) and with concomitant treatment with
chelators (6). Some of the biological activities that MMA
(III) is known to possess in various experimental systems
Vol. 31, No. 6, 2003 ARSENIC EXPOSURE AND HEALTH EFFECTS 577

FIGURE 1.—Metabolism of arsenic in the liver: AsV → AsIII (Reduction); AsIII → AsV (Oxidation); AsIII → MMAsV (Methylation); SAM (S-Adenosyl-
methionine); SAH (S-Adenosylhomocysteine); GSH (Glutathione reduced); GSSG (Glutathione oxidized).

include enzyme inhibition (89, 144), cell toxicity (120), and
genotoxicity (96). MMA (III) is an excellent choice as a cause
of arsenic carcinogenesis.
DMA (III) has been detected in human urine of arsenic-
exposed humans administered a chelator (81). In a study of
hamsters given arsenate (130), substantial hepatic concentra-
tions of trivalent MMA and DMA were found in addition to
the expected pentavalent MMA and DMA. The capacity to
separate the trivalent forms of the methylated arsenic species
from the pentavalent forms has just been developed (37, 81,
130). Wei et al (167) demonstrated DMA to be a carcinogen
for the rat urinary bladder and suggested that DMA exposure
may be relevant to the carcinogenic risk of inorganic arsenic
in humans. Diverse genetic alterations observed in DMA-
induced urinary bladder tumors imply that multiple genes
are involved in stages of DMA-induced tumor development
(167).
Few data are currently available on the tissue concentra-
tions of trivalent methylated species. Some of the biological
activities that DMA (III) is known to possess in various ex-
perimental systems include enzyme inhibition (89, 144), cell
toxicity (120), genotoxicity, and clastogenecity (81).

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578 TCHOUNWOU ET AL
Trimethylarsinic acid [TMA (III)] may be produced from
trimethylarsine oxide [TMAO] by reduction. Data from one
group suggest that only rats may have relatively high levels
of TMAO in their urine. A molecule of TMA (III) possesses
no ionizable hydroxyl groups to limit the ability of the triva-
lent arsenic species to interact with DNA. TMA (III) may
exist in higher concentrations in rat tissues than in human
tissues. Interaction of novel information on the formation,
fate, and actions of the methylated arsenicals in humans and
other species will reduce some of the uncertainties in the risk
assessment for arsenic.
Exposure to arsenic is considered a major public health
concern, particularly because of its clear carcinogenic
potential (112). However, the molecular mechanism by which
and the dose at which it causes cancer are still unclear. In
risk assessment of environmental arsenic, it is important to
know and to utilize both the mode of carcinogenic action
and the shape of the dose-response curve at low environ-
mental arsenic concentrations. Although much progress has
been recently made in the area of arsenic’s possible mode(s)
of carcinogenic action, a scientific concensus has not yet
been reached. Kitchin (75) in his review discussed 9 dif-
ferent possible modes of action of arsenic carcinogenesis:
induced chromosomal abnormalities (49, 88, 94, 166), oxida-
tive stress (3, 53, 90, 98, 165, 171, 172), altered DNA repair
(1, 67, 88), altered DNA methylation patterns (97, 179, 180),
altered growth factors (47, 136, 160), enhanced cell prolifer-
ation (8, 17, 121, 165, 170), promotion/progression (33, 55,
104), suppression of p53 (14, 20, 54, 65, 129), gene amplifi-
cation (83). Presently, 3 modes (chromosomal abnormality,
oxidative stress, and altered growth factors) for arsenic car-
cinogenesis have a degree of positive evidence, both in ex-
perimental systems (animal and human cells) and in human
tissues. The remaining possible modes of carcinogenic ac-
tion for arsenic (progression of carcinogenesis, altered DNA
repair, p53 suppression, altered DNA methylation patterns
and gene amplification) do not have as much evidence, par-
ticularly from in vivo studies with animals, in vitro studies
with human cells, or with human data from case or popu-
lation studies. Thus, the mode-of-action studies suggest that
the arsenic might be acting as a cocarcinogen, a promoter, or
a progressor of carcinogenesis (112).
Various hypotheses have been proposed to explain the
carcinigenicity of inorganic arsenic (75). Nevertheless,
molecular mechanisms by which this arsenical induces can-
cer are still poorly understood. Results of previous studies
indicated that inorganic arsenic does not act through classic
genotoxic and mutagenic mechanisms, but rather may be a
tumor promoter that modifies signal transduction pathways
involved in cell growth and proliferation (136). Inorganic ar-
senic (III) has been shown to modulate expression and/or
DNA-binding activities of several key transcription factors,
including nuclear factor kappa B (10), tumor suppressor 53
(p53) (129), and activating protein-1 (AP-1) (18, 22, 137).
Mechanisms of AP-1 activation by trivalent inorganic ar-
senic include stimulation of the mitogen-activated protein
kinase (MAPK) cascade with a consequent increase in the
expression and/or phosphorylation of the two major AP-1
constituents, c-Jun and c-Fos (136).
In another study, Trouba et al (151) concluded that long-
term exposure to high levels of arsenic might make cells more
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TOXICOLOGIC PATHOLOGY
susceptible to mitogenic stimulation and that alterations in
mitogenic signaling proteins might contribute to the carcino-
genic actions of arsenic. Collectively, several studies (27, 122,
162) have demonstrated that arsenic can interfere with cell
signaling pathways (eg, the p53 signaling pathway) that are
frequently implicated in the promotion and progression of a
variety of tumor types in experimental animal models and of
some human tumors.
Clinical trials have found that arsenic has therapeutic value
in the treatment of acute promyelocytic leukemia, and there
is interest in exploring its effectiveness in the treatment of a
variety of other cancers (106, 140). In acute promyelocytic
leukemia, the specific molecular event critical to the forma-
tion of malignant cells is known. The study by Puccetti et al
(123) found that forced overexpression of BCR-ABL sus-
ceptibility in human lymphoblasts cells resulted in greatly
enhanced sensitivity to arsenic-induced apoptosis. They also
concluded that arsenic is a tumor specific agent capable of in-
ducing apoptosis selectively in acute promyelocytic leukemia
cells. Several studies showed that arsenic induces apop-
tosis through alterations in other cell signaling pathways
(4, 135). In addition to acute peomyelocytic leukemia, arsenic
is thought to have therapeutic potential for myeloma (36). In
summary, numerous cancer chemotherapy studies in cell cul-
tures and in patients with acute promyelocytic leukemia and
myeloma demonstrate that arsenic can lead to cell-cycle ar-
rest and apoptosis in malignant cells.
Alterations in gene expression via hypo or hypermethyla-
tion of CpG sites in DNA have been reviewed (54, 77, 180).
An important mechanism for altering gene expression in re-
sponse to both endogenous and exogenous signals, including
toxins is altering nuclear transcription factor activities either
directly or via specific cell-signaling pathways that regulate
them (74). Several studies have examined p53 gene expres-
sion and mutation in tumors obtained from subjects with a
history of arsenic ingestion. The p53 participates in many
cellular functions, cell-cycle control, DNA repair, differen-
tiation, genomic plasticity and programmed cell death (52,
80, 86). The tumor suppressor protein p53 is one component
of the DNA damage response pathway in mammalian cells.
Some of these normal cellular functions of p53 can be mod-
ulated and sometimes inhibited by interactions with either
cellular proteins (eg, mdm2) or oncoviral proteins of certain
DNA viruses. Several different studies support the hypothe-
sis that arsenic can modulate gene expression in humans and
experimental models (91, 119, 157).
SYSTEMIC HEALTH EFFECTS
On the basis of epidemiological studies, ingestion of inor-
ganic arsenic is implicated in noncarcinogenic health effects
in various organs or systems including cardiovascular, der-
mal, reproductive, neurological, respiratory, hepatic, hema-
tological, renal, and gastrointestinal.
Dermatologic Effects: Chronic arsenic exposure causes
a characteristic pattern of noncarcinogenic dermal effects that
begins with spotted hyper-pigmentation and may later include
palmar and plantar hyperkeratosis (101). Arsenic contami-
nation of well water in Argentina, Chile, India, Taiwan, and
Thailand has caused cutaneous skin lesions such as keratosis,
and both hyperpigmentation, and hypopigmentation (101).
Vol. 31, No. 6, 2003 ARSENIC EXPOSURE AND HEALTH EFFECTS
The mechanisms for those latter dichotomous effects would
be unique and interesting. Characteristic skin lesions of ar-
senic toxicity may be used as an indicator of high exposure
and are distinctive in contrast to other clinical manifestations
of arsenic intoxication. Several studies have investigated ad-
verse health effects associated with ingestion of arsenic in
groundwater in the Gangetic plain of West Bengal, India and
neighboring Bangladesh, where over the past decade more
than 30 million people might have been consuming water
with arsenic concentrations in excess of 50 µg/L. This study
showed a higher prevalence rate of arsenic skin lesions in
males than females, with a clear dose-response relationship
(31).
Mazumder et al (101) conducted a cross-sectional survey
of the prevalence of hyperpigmentation and palmar-plantar
keratosis in a region of West Bengal, India with ground-
water arsenic concentrations ranging from nondetectable to
3,400 µg/L. This study found that males were more affected
than females for both hyperpigmentation and palmar-plantar
keratosis. Several studies found an association between skin
lesions and arsenic ingestion in India and Inner Mongolia
(156).
Cardiovascular Effects: Epidemiological studies have
shown that the cardiovascular system is particularly sen-
sitive to long-term ingestion of arsenic in drinking water.
Noticeable effects include hypertension and increased car-
diovascular disease mortality (113). Rahman et al (125) con-
ducted a cross-sectional evaluation of blood pressure in 1,595
adults (above 30 years of age) who resided all their life in a
rural area of Bangladesh. The area had a high level of arsenic
exposure resulting from the use of contaminated groundwater
for drinking water; wells were drilled because of microbial
contamination of surface water. At the time of this study no
subjects were taking antihypertensive medication. The diet,
lifestyle, and socioeconomic status of all subjects were simi-
lar. The study found that increasing arsenic in drinking water
increased the incidence and severity of hypertension (125).
An increased risk of coronary heart disease has been re-
lated to long-term exposure to inorganic arsenic. Blackfoot
disease patients have been reported to have increased mor-
tality from ischemic heart disease (ISHD) (28). Arsenic is a
major risk factor for what is known as blackfoot disease, that
is peripheral atherosclerosis resulting in dry gangrene and
spontaneous amputation of affected extremities. The disease
was named for its most striking clinical feature blackish dis-
coloration of the feet or hands (154). A recent study has
reported a biological gradient between cumulative arsenic
exposure through consuming artesian well water and lethal
ischemic heart disease (ISHD) in Taiwan (24). Environmen-
tal exposure to inorganic arsenic through drinking water has
been associated with increased mortality from cardiovascular
disease in Chile (176) and Japan (155), and from cardiovascu-
lar disease among chimney sweeps, copper smelter workers,
and glass blowers exposed to arsenic in their working envi-
ronments (66).
In India, individuals exposed to elevated inorganic arsenic
levels in drinking water showed a range of health effects
including peripheral vascular disease, noncirrhotic portal fi-
brosis, nasal septum perforation, bronchitis, and polyneu-
ropathy. In Taiwan, skin pigmentation changes and hyperker-
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579
atoses were the most sensitive indicators of inorganic arsenic
exposure (101).
Reproductive and Developmental Effects: Whereas ar-
senic exposure has been associated with a number of adverse
health outcomes, relatively little attention has been directed
toward the potential impact of arsenic on human reproduc-
tive system, despite studies in both humans and experimen-
tal animals demonstrating that arsenic and its methylated
metabolites cross the placenta (34). Evidence from human
studies suggests the potential for adverse reproductive im-
pacts among the offspring of employees and nearby residents
of a Swedish copper smelter where arsenic exposure were
documented (114–117). Female workers gave birth to lower
weight infants than women who resided outside the smelter
area, and the difference was greater if the mothers worked
in the more highly exposed jobs (117). An incremental trend
in the rates of spontaneous abortions was observed with in-
creasing occupational and residential exposure (115, 117).
Congential malformations appeared to be more frequent if
the expectant mother was employed in highly exposed jobs
during pregnancy (116). In Bulgaria, the incidence of tox-
emia of pregnancy and the mortality from congential malfor-
mations were significantly higher in an area near a smelter
with environmental contamination from various metals than
the national rates (178). Studies of populations exposed to
arsenic from drinking water have found increased rates of
spontaneous abortions and stillbirths in Hungary (16) and
Argentina (21). In the United States, three studies reported
adverse reproductive effects, including increases in mortal-
ity from congential cardiovascular anomalies (39, 181) and
spontaneous abortions (9). A study in Texas found an increase
in the rates of stillbirths in relation to residential exposures
from an arsenic pesticide factory (71).
Neurological Effects: In the past, studies of arsenic in-
duced neurological effects have generally focused on central
nervous system effects following acute, high-dose intoxica-
tion, and on the peripheral neuropathy that occurs following
chronic exposure (112). Two studies have focused on sub-
tle cognitive effects in children following chronic exposure
to arsenic. Siripitayakunkit et al (138) investigated the as-
sociation between environmental arsenic exposure and the
intelligence (IQ) of children in the Ronpiboon district of
Thailand, where shallow artesian wells were contaminated
with arsenic. To prove a significant association between ar-
senic and growth, head-hair arsenic concentrations and per-
formance on the Weschler Intelligence Scale Test for children
(WISTC) in 529 schoolchildren were analysed in a cross-
sectional evaluation. High arsenic levels measured in hair
affect height but not weight. Only 2 epidemiological studies
on the effects of arsenic on children’s growth exist in the lit-
erature. In these studies males were more susceptible than fe-
males, and stature was more affected than weight (118, 134).
Anorexia, malabsorption, and weight loss may be present
because of low-dose arsenic ingestion (105). Two follow-up
studies of arsenic-poisoned Japanese victims, found that the
victim group showed retarded growth from the age of one
year to school age with average height of the victims less
than that of a same-age group (173).
A cross-sectional study in San Luis Potosi, Mexico (19) ex-
amined the impact of arsenic, lead and under-nutrition on the
580 TCHOUNWOU ET AL
neuropsychological performance of school children aged 6 to
9 years. Subjects included 41 children living within 1.5 Km
of a smelter complex (Morales Zone) with increasing arsenic
and lead concentrations, and 39 children living 7 Km up-
wind from smelter (Martinez Zone). The geometric mean to-
tal arsenic concentration in urine was higher in the Morales
children than in the Martinez children. Maternal and pater-
nal educational attainment, socioeconomic status was lower
in the Martinez group. Neuropsychological performance was
assessed using the Weschler Intelligence Scale for children,
Revised version, for Mexico (WISC-RM). The Morales chil-
dren scored significantly lower than the Martinez children on
the full-scale IQ test and other neuropsychological subscores
(19).
Respiratory Effects: Noncancer respiratory effects have
been reported in populations exposed to arsenic in drinking
water (112), but the database is sparse. Mazumder et al (102)
recently reported an association between arsenic ingestion in
drinking water and the prevalence of respiratory disorders.
Respiratory effects in West Bengal were first noted in 1995
when 57% of the 156 patients who lived in arsenic-affected
villages reported having chronic cough (100). Moreover, epi-
demiological studies in Chile have previously suggested an
association between arsenic and nonmalignant respiratory ef-
fects. The survey data collected from 1968 to 1972 in Antofa-
gasta, Chile, Zaldivar, and Ghai (177) reported that the preva-
lence of cough among 398 children correlated with mean
drinking water arsenic concentrations.
Zaldivar (176) also reported that the prevalence of
bronchiectasis was 23-fold greater among children with
arsenic-induced skin-lesions living in Antofagasta compared
to children living in the rest of Chile. A 1976 cross-sectional
survey in Antofagasta examined 144 school children with
arsenic-induced skin-lesions, and bronchopulmonary disease
occurred 2.5 times more often in these children compared to
children with normal skin (15). In a study, Smith et al (139)
found high relative rates for chronic obstructive pulmonary
disease (COPD) mortality among young men and women liv-
ing in the same arsenic-exposed region in Chile that includes
Antofagasta. A few occupational studies conducted in the
1950s in Sweden have also reported nonmalignant respira-
tory effects in copper smelter workers exposed to airborne
arsenic. In one of the clinical study of copper smelter work-
ers cited by Gerhard et al (46), a syndrome characterized
by lesions of the mucous membranes of the upper respiratory
system, emphysema, and decreased pulmonary function, was
described (45).
The relationship between ingested arsenic and nonmalig-
nant respiratory effects has so far only been reported from
Chile (30), India (93), and Bangladesh (103). Studies from
arsenic-affected regions in Taiwan, Chile, and Argentina
show marked increases in lung cancer mortality. The char-
acteristic feature of arsenic is that it seems to increase both
malignant and nonmalignant respiratory disease following
ingestion.
Milton et al (103) reported an association between chronic
arsenic ingestion and chronic bronchitis in a small cross-
sectional study of 94 individuals in Bangladesh with arsenic-
associated skin lesions. Chronic bronchitis was defined as
a history of cough productive of sputum on most days for
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TOXICOLOGIC PATHOLOGY
at least 3 consecutive months for more than 2 successive
years, combined with the presence of chest rhonchi and or
crepitations on physical examination. Males were at greater
risk for chronic bronchitis than the females.
Hepatotoxic Effects: Hernandez-Zavala et al (60) studied
liver function in individuals from three towns in the region
of Lagunera, Mexico. They determined the serum activity
of aspartate aminotransferase (SAT) and alanine aminotrans-
ferase (ALT) as indicators of hepatocellular injury and that
of gamma-glutamyl-transpeptidase (GGT) and alkaline phos-
phatase (ALP) as indicators of cholestasic injury. The main
findings of this study were predominantly conjugated hy-
perbilirubinemia and increased serum ALP activity which
were related to the concentration of total arsenic in urine,
suggesting the presence of cholestasis in arsenic exposed
individuals.
Armstrong et al (7) also observed increased concentra-
tions of total bilirubins in serum samples from 7 individu-
als ingested with arsenic via drinking water. Furthermore,
histological examination of livers of individuals chronically
exposed to high arsenic concentrations has revealed the pres-
ence of portal tract fibrosis, which occasionally causes por-
tal hypertension and bleeding from esophageal varices (99).
In a study by Santra et al (131), bilirubin or alkaline phos-
phatase increases were not a characteristic finding in patients
with firm hepatomegaly attributed to chronic arsenicosis in
West Bengal, India. In that study, liver biopsy results from
patients with clinical diagnosis of chronic arsenic poison-
ing revealed mild portal fibrosis, and cirrhosis. Clinical ev-
idence of portal hypertension (eg, esophageal varices) was
uncommon.
Hematologic Effects and Diabetes: Hernandez-Zavala
et al (61) studied the activities of some enzymes of the
heme biosyntheis pathway and their relationship with the
profile of urinary porphyrin excretion in individuals ex-
posed chronically to arsenic via drinking water in Region
Lagunera, Mexico. The more evident alterations in heme
metabolism observed were: small but significant increases
in porphobilinogen deaminase (PBG-D) and uroporphyrino-
gen decarboxylase (URO-D) activities in peripheral blood
erythrocytes; increases in the urinary excretion of total por-
phyrins, mainly due to coproporphyrin III (COPROIII) and
uroporphyrin III (UROIII); and increases in the COPRO/
URO and COPROIII/COPROI ratios. No significant
changes were observed in uroporphyrinogen III synthetase
(UROIII-S) activity. The direct relationships between en-
zyme activities and urinary porphyrins, suggest that the in-
creased porphyrin excretion was related to PBG-D, whereas
the increased URO-D activity would enhance coproporphyrin
synthesis and excretion at the expense of uroporphyrin. None
of the human studies available have reported the marked
porphyric response and enzyme inhibition observed in
rodents.
The main concern of arsenic on the endocrine system is the
association between arsenic exposure and diabetes mellitus.
As part of an ecological study examining multiple causes of
mortality in the area of Southwestern Taiwan where black-
foot disease is endemic, Tsai et al (152) examined mortal-
ity from diabetes mellitus in 4 townships, where artesian
well water containing arsenic had been consumed from the
Vol. 31, No. 6, 2003 ARSENIC EXPOSURE AND HEALTH EFFECTS
early 1900s until the mid-to-late 1970s. Diabetes mellitus
was listed as the underlying cause of death for 188 males and
343 females.
Tseng et al (153) reported a prospective cohort study ex-
amining the incidence of diabetes mellitus in three villages
from the arsenic endemic area of Southwestern Taiwan. The
study population consisted of three villages where artesian
well water (0.70 to 0.93 mg/L As) was used for drinking
and cooking until the mid-to-late 1970s. The population was
subjected to a follow-up examination that includes fasting
blood glucose and an oral glucose tolerance test. The re-
sults of this study show an association between long-term
arsenic exposure and diabetes mellitus, as found in the pre-
vious prevalence study. The prevalence of diabetes mellitus
was 2-fold higher in Southwestern area of Taiwan than in
Taipei city and the Taiwan area in general (78).
A dose-response relation between cumulative arsenic ex-
posure and the prevalence of diabetes mellitus was also
demonstrated after adjustment for multiple risk factors (78).
Rahman and Axelson (124) carried out a case-control study
on Swedish copper smelter workers. Using the death records
for 1960–1976, they compared three arsenic exposure cate-
gories with an unexposed group. They observed an increased
risk of dying from diabetes mellitus with increasing arsenic
exposure. In a similar study carried out among art glass work-
ers, indications of a relationship between arsenic exposure
and diabetes mellitus have also been reported (126). In a
community-based survey of diabetes mellitus in Bangladesh,
Rahman et al (125) observed a dose-response trend between
the prevalence of diabetes mellitus and the arsenic level in
drinking water.
Renal Effects: The kidneys are the major route of ar-
senic excretion, as well as a major site of conversion of pen-
tavalent arsenic into the more toxic and less soluble triva-
lent arsenic. Sites of arsenic damage in the kidney include
capillaries, tubules, and glomeruli (133, 141, 168). As in
other organs, capillary damage seems to be a basic event
leading to other cellular manifestations. Glomerular arteri-
oles dilate, permitting hematuria. Damaged proximal tubu-
lar cells lead to proteinuria and casts in the urine. Mito-
chondrial damage is also prominent in tubular cells (105).
Oliguria is a common manifestation, but if acute arsenic poi-
soning is sufficiently severe to produce shock and dehydra-
tion, there is real risk of renal failure, although dialysis has
been effective in overcoming this complication (48). Acute
cortical necrosis is an uncommon severe renal manifesta-
tion, but benefits from dialysis (46). Arsine-induced hemol-
ysis is likely to cause acute tubular necrosis with partial or
complete renal failure, requiring hemodialysis for removal
TABLE 1.—Mortality ratios or incidence of lung cancer in case-control studies on arsenic.
Study Location
Ferreccio et al (43) Northern Chile
∗
Odd ratios were used to estimate relative risks of exposure to various concentrations of arsenic in drinking water relative to a reference concentration of 0–10 ug/L.
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581
of the hemoglobin-bound arsenic (44, 148). Recovery may
leave interstitial fibrosis and thickened glomerular basement
membranes.
Gastrointestinal Effects: The effects of oral ingestion by
accident or with suicidal or homicidal intent, the direct ef-
fects on the gastrointestinal tract have been prominent and
duly noted by several authors (38, 50, 62, 133, 141, 158). Al-
though arsenic may produce direct irritant effects on gastroin-
testinal tissues with which it comes in contact, the greatest
degree of damage is produced by local submucosal capillary
damage from absorbed arsenic (32). The vascular damage is
thought to be the cause of submucosal vesicles, whose rupture
can create grossly visible erosions and major fluid and pro-
tein loss. Nausea and vomiting can be severe, as can colicky
abdominal pain and marked diarrhea. If sufficiently severe,
the acute gastroenteritis can lead to circulatory collapse with
renal damage and shutdown.
Arsenic poisoning from lesser doses of arsenic may man-
ifest as dry mouth and throat, heartburn, nausea, abdominal
pains and cramps, and moderate diarrhea. Chronic low-dose
arsenic ingestion may be without symptomatic gastrointesti-
nal irritation or may produce a mild esophagitis, gastritis,
or colitis with respective upper and lower abdominal dis-
comfort. Anorexia, malabsorption, and weight loss may be
present (105).
CARCINOGENIC HEALTH EFFECTS
Carcinogenesis is a multistage process involving the in-
appropriate activation of normal cellular genes to become
oncogenes, eg, ras, and the inactivation of other cellular
genes called tumor suppressor genes (56). The prototypic
tumor suppressor genes are well suited as a molecular link
between the causes of cancer, ie, carcinogenic chemical
and physical agents and certain viruses, and the develop-
ment of clinical cancer. The crucial differences between nor-
mal and cancer cells stem from discrete changes in specific
genes controlling proliferation and tissue homeostasis (56).
Progress in the fields of molecular carcinogenesis and molec-
ular epidemiology increases our ability to assess cancer risk.
Because regulatory decisions based on cancer risk assess-
ments have significant public health and economic con-
sequences, the scientific basis of risk assessment contin-
ues to be, and should continue to be, actively investigated
(111).
Long-term exposure to arsenic affects the gastrointestinal
tract, circulatory system, skin, liver, lung, kidneys, nervous
system, and heart. Evidence from epidemiological studies
clearly shows that exposure to inorganic arsenic increases
the risk of cancer. In workers exposed by inhalation, the
Exposure Number of cases Study outcome
Individual 40+ year average arsenic conc. 151 cases Age and sex adjusted odd ratios∗
from public water 419 controls
supply records
0–10 µg/L
10–29 µg/L 1.6 (0.5–5.3)
30–49 µg/L 3.9 (1.2–12.3)
50–199 µg/L 5.2 (2.3–11.7)
200–400 µg/L 8.9 (4.0–19.6)
582 TCHOUNWOU ET AL TOXICOLOGIC PATHOLOGY

TABLE 2.—Mortality ratios or incidence of bladder cancer in epidemiological studies on arsenic (Cohort studies).

Study Location Exposure Number of cases Study outcome

Chiou et al (29) NE Taiwan Conc. of arsenic in Incidence rate Relative risk
household well H2 O
≤10 µg/L 37.6 (3) 1.5
10–50 µg/L 4.8 (3) 2.2
50.1–100 µg/L 66.4 (2) 4.8
>100 µg/L 134.1 (7)
Lewis et al (87) Utah Cumulative arsenic exposure during Male Female Male Female
residence in study towns
<1.000 ppb-yr 3 2 0.36 1.18
1.000–4.998 ppb-yr — —
>5,000 ppb-yr 0.95 1.10
All 0.42 0.81
(0.08–1.23) (0.10–2.93)
Chiou et al (30) SW Taiwan Cumulative arsenic Incidence rate Relative risk
<0.1 mg/L × yr 4 1.0
0.1–19.9 mg/L × yr 7 2.1 (0.6–7.2)
≥20 mg/L × yr 9 5.1 (1.5–17.3)
Average arsenic
<0.05 mg/L 6 1.0
0.05–0.70 mg/L 7 1.8 (0.6–5.3)
≥0.71 mg/L 7 3.3 (1.0–11.1)

predominant carcinogenic effect is an increased risk of lung
cancer (40, 85), when exposure occurs orally, the main car-
cinogenic effect is increased risk of skin cancer. In addition to
skin cancer, increased risk of several internal cancers (mainly
of liver, kidney, lung, colon, and bladder) have been reported
with arsenic exposure (147).
In a region of Northern Chile with a history of increased
concentrations of arsenic in drinking water, Ferreccio et al
(43) conducted a case control study of incident lung can-
cer in eight public hospitals in regions I, II and III from
1994 through 1996 and frequently matched hospital controls
(Table 1). The study identified 152 cases and 419 controls.
Historical exposure to arsenic in drinking water for each re-
spondent was estimated by linking residential history infor-
mation on arsenic concentrations in public water supplies for
40+ years. Odds ratios were used to estimate relative risks of
exposure to various concentrations of arsenic in drinking wa-
ter relative to a reference concentration of 0–10 µg/L. Odd ra-
tios were calculated using unconditional logistic regression,
adjusted for age, socioeconomic status, smoking and work-
ing in a copper smelter. An association between lung cancer
incidences and arsenic concentrations in drinking water was
found.
Two studies of arsenic exposure and cancer in Chile are
also documented. The first, an ecological cohort study, used
community estimates of arsenic in water and age-specific in-
gestion rates (42). This study found an association between
arsenic in drinking water at 50 µg/L and skin cancer as well
as 4 internal cancers. The second, a case control study, found
an association between bladder cancer and arsenic exposure,
as reflected in significant changes in odds ratios with an es-
timated lifetime cumulative exposure to arsenic (42).
A prospective cohort study of 8,102 persons was carried
out in the Lanyang basin of northeastern Taiwan (29), a re-
gion where arsenic-contaminated shallow wells were used for
drinking water over the past 50 years (Table 2). Relative risks
were calculated using subjects with exposures <10 µg/L as
a reference population. The outcome of the study was a rel-
ative risk of total urinary tract cancer incidence (including
kidney, bladder and urethral), specifically of the most com-
mon cell type of urinary cancer, transitional cell carcinoma
(29).
In the United States, a retrospective cohort mortality study
was conducted in Utah based on community estimates of
arsenic exposure (Table 2). The results of this study indicated
an association between inorganic arsenic and certain cancers

TABLE 3.—Mortality ratios or incidences of bladder cancer in epidemiological studies on arsenic (Ecological studies).

Number of cases Study outcome (SMR)a

Study Location Exposure Females Males Females Males

Tsai et al (152) Blackfoot endemic area of SW Taiwan Arsenic endemic area 295 312 14.07 (12.51–15.78)b 8.92 (7.96–9.96)b
17.65 (5.70–19.79)c 10.50 (9.37–11.73)c
Smith et al (139) Region II Northern Chile 5-year average, 420 µg/L average 64 93 8.2 (6.3–10.5) 6.0 (4.8–7.4)
Hopenhayn-Rich Cordoba Province, Argentina County group
et al (63, 64) Low 39 113 1.21 (0.9–1.6) 0.80 (0.7–1.0)
Medium 24 93 1.58 (1.0–2.4) 1.42 (1.1–1.7)
High 27 131 1.82 (1.2–2.6) 2.14 (1.8–2.5)
Wu et al (169) Southwest Taiwan Average arsenic
<0.30 ppm 30 23 25.6 22.6
0.30–0.59 ppm 36 36 57.0 61.0
≥0.60 ppm 30 26 111.3 92.7
Chen et al (25) Southwest Taiwan Blackfoot disease endemic area 165 167 20.09 (17.0–23.2) 11.00 (9.3–12.7)
a
Standardized mortality ratios.
b
Regional rate.
c
National rate.

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Vol. 31, No. 6, 2003 ARSENIC EXPOSURE AND HEALTH EFFECTS 583

TABLE 4.—Mortality ratios of incidents of lung cancer in epidemiological studies on arsenic (Ecological studies).

Number of cases Study outcome (SMR)a

Study Location Exposure Females Males Females Males

Tsai et al (152) Black foot endemic area Arsenic endemic area 471 699 4.13 (3.77–4.52)b 3.1 (2.88–3.34)b
of SW Taiwan 3.5 (3.19–3.84)c 2.64 (2.45–2.84)c
Smith et al (139) Region II 5-year average 154 554 3.1 (2.7–3.7) 3.8 (3.5–4.1)
Northern Chile 420 µ/L average
Hopenhayn-Rich et al (63, 64) Cordoba province, County group
Argentina Low 194 826 1.24 (1.06–1.62) 0.92
Medium 138 914 1.34 (1.12–1.58) 1.54
High 156 708 2.16 (1.83–2.52) 1.77
Wu et al (169) Southwest Taiwan Average arsenic
<0.30 ppm 43 53 36.1 49.16
0.30–0.59 ppm 40 62 60.82 100.67
≥0.60 ppm 38 32 122.16 104.08
Chen et al (25) Southwest Taiwan Blackfoot disease endemic area 233 322 4.13 3.20
a
Standardized mortality ratios.
b
Regional rate.
c
National rate.

as well as noncancer effects. The most predominant types of
cancer that were found in the population were bladder and
other urinary organ cancers. Males were affected more than
the females (87).
A case-control study of skin cancer, in Hungary found an
increased risk of basal cell carcinoma associated with el-
evated levels of atmospheric arsenic from coal combustion.
This was particularly apparent in cases diagnosed before 1982
as compared to cases diagnosed after 1986. In addition, the
same investigators reported that basal cell carcinomas were
associated with elevated occupational exposure to airborne
arsenic (1).
According to an epidemiological study from a blackfoot
disease-endemic area of Taiwan, a high mortality was found
in males and females for skin, liver, lung, bladder, kidney,
and nasal cancers, and possibly other sites. The outcomes of
this study corroborate the results of several other studies sug-
gesting a relationship between arsenic exposure and cancers
of the internal organs (152). Arsenic has also been implicated
as a bladder carcinogen in separate studies from Argentina,
Chile, and Taiwan (13, 63) (Table 3). In addition, the results
of a study in Cordoba, Argentina add to the evidence that ar-
senic ingestion increases the risk of kidney cancers (64). The
association between carcinoma of the lung and inhaled ar-
senic is well established (Table 4); more studies have shown
that ingested inorganic arsenic may also be an etiological
factor in the development of lung cancer (152).
Significant excess mortality from cancers of the diges-
tive tract has been observed among copper smelter workers
in Anaconda, Montana, with a standardized mortality ratio
of 1.3 (41); only a slight excess in mortality from digestive
tract cancer was observed among smelter workers in Tacoma,
Washington (163). Increased mortality from stomach cancer
has been reported among copper smelter workers in Sweden
with a standardized mortality ratio of 1.7 (92), and among
Moselle vinters with a standardized mortality ratio of 2.4
(150). Colon cancer mortality has also been significantly as-
sociated with chronic exposures to inorganic arsenic among
copper smelter workers in Tacoma, Washington, with a sig-
nificant standardized mortality ratio of 2.1 for those who em-
ployed before respirators were implemented in the smelter
(41), and among smelter workers in Japan with a standard-
ized mortality ratio of 5.1 (25).
There was no apparent increase in stomach cancer mortal-
ity among residents in the area of endemic blackfoot disease
in Taiwan, but significantly increased colon cancer mortality,
with a standardized mortality ratios of 1.6 for men and 1.7
for women, was observed in the area (25).
CONCLUSIONS
Integration of the available scientific information on ar-
senic indicates that geogenic and anthropogenic contamina-
tion of natural resources represents a major public health
problem in many countries of the world. Exposure to arsenic
occurs via ingestion, inhalation, and dermal contact. Such
exposure has been associated with a significant number of
systemic health effects in various organs and tissue systems
including skin, lung, liver, kidney, bladder, gastrointestinal
tract, respiratory system, and hematopoetic system. Evidence
from recent studies has linked arsenic consumption in drink-
ing water with two non-cancer health conditions (hyperten-
sion and diabetes mellitus) that are a major cause of morbidity
and mortality. A small number of studies have investigated
the relationship between arsenic exposure in humans and ad-
verse reproductive effects, including studies of populations
in Chile and Bangladesh exposed to increased concentra-
tions of arsenic in drinking water. There is some evidence
from these studies that arsenic increases stillbirths, sponta-
neous abortions, preterm births, and infant mortality. Find-
ings from a large prevalence study in West Bengal, a small
prevalence study in Bangladesh, and an ecological mortality
study in the area of Southwestern Taiwan where arsenic is en-
demic indicated an association between arsenic ingestion and
non-cancer respiratory effects. Two recent investigations of
neurocognitive function in young schoolchildren suggest that
arsenic exposure might be associated with an (IQ) adverse ef-
fect. Experiments in animals and in vitro have demonstrated
that arsenic has many biochemical and cytotoxic effects at low
doses of human exposure. Those effects include induction of
oxidative damage, altered DNA methylation and gene ex-
pression; changes in intracellular levels of mdm2 protein and
p53 protein; inhibition of thioredoxin reductase; inhibition of
pyruvate dehydrogenase; altered colony-forming efficiency;
induction of protein-DNA cross-links; induction of apop-
tosis; altered regulation of DNA-repair genes, thioredoxin,

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584 TCHOUNWOU ET AL
glutathione reductase, and other stress-response pathways;
stimulation or inhibition of normal human keratinocyte pro-
liferation, depending on the concentration; and altered func-
tion of the glucocorticoid receptor. Additionally, the evidence
of carcinogenicity in humans is very strong, especially for
cancer of the skin, lung, liver, kidney, and bladder.
Further epidemiological studies are highly recommended
to investigate the dose-response relationship btween arsenic
ingestion and noncancer endpoints. Because of the very large
populations exposed, these endpoints are common causes of
morbidity and mortality, even small increases in relative risk
at low doses of arsenic exposure could be of considerable
public-health significance. Such information is also impor-
tant in developing a comprehensive risk assessment and man-
agement program for arsenic.
ACKNOWLEDGEMENTS
This research was supported by a grant from the National
Institutes of Health (Grant No. 1G12RR13459) through the
RCMI-Center for Environmental Health at Jackson State Uni-
versity. We thank Dr. Jennie Hunter-Cevera, President of the
University of Maryland Biotechnology Institute, and other
members of the External Advisory Board for their technical
advice on this project.
REFERENCES
1. Abernathy CO, Liu YP, Longfellow D, Aposhian HV, Beck B, Fowler B,
Goyer R, Menzer R, Rossman T, Thompson C, Waalkes M (1999). Arsenic:
Health effects, mechanisms of actions and research issues. Environ Health
Perspect 107: 593–597.
2. Agency for Toxic Substances and Disease Registry (ATSDR) (2000).
Toxicological Profile for Arsenic TP-92/09. Center for Disease Control,
Atlanta, Georgia.
3. Ahmad S, Kitchin KT, Cullen WR (2000). Arsenic species that cause
release of iron from ferritin and generation of activated oxygen. Arch
Biochem Biophys 382: 195–202.
4. Alemany M, Levin J (2000). The effects of arsenic trioxide on human
megakaryocyticleukemia cell lines with a comparison of its effects on
other cell lineages. Leuk Lymphoma 38(1–2): 153–163.
5. Aposhian HV, Gurzau ES, Le XC, Gurzau A, Healy SM, Lu X, Ma M,
Yip L, Zakharyan RA, Maiorino RM, Dart RC, Tircus MG, Gonzalez-
Ramirez D, Morgan DL, Avram D, Aposhian MM (2000a). Occurrence
of monomethylarsonous acid in urine of humans exposed to inorganic
arsenic. Chem Res Toxicol 13(8): 693–697.
6. Aposhian HV, Zheng B, Aposhian MM, Le XC, Cebrian ME, Cullen W,
Zakharyan RA, Ma M, Dart RC, Cheng Z, Andrewes P, Yip L, O’Malley
GF, Maiorino RM, Van Voorhies W, Healy SM, Titcomb A (2000b).
DMPS-arsenic challenge test II. Modulation of arsenic species, including
monomethylarsonous acid (MMA (III)), excreted in human urine. Toxicol
Appl Pharmacol 165: 74–83.
7. Armstrong CW, Stroube R, Rubio T (1984). Outbreak of fatal arsenic
poisoning caused by contaminated drinking water. Arch Environ Health
39: 276–279.
8. Arnold LL, Cano M, St. John M, Eldna M, Van Gemert M, Cohen SM
(1999). Effects of dietary dimethylarseinic acid on the urine and urothelium
of rats. Carcinogenesis 20: 2171–2179.
9. Aschengrau A, Zierler S, Cohen A (1989). Quality of community drinking
water and the occurrence of spontaneous abortion. Arch Environ Health
44: 283–290.
10. Barchowsky A, Dudek EJ, Treadwell MD, Wetterhahn KE (1996). Arsenic
induces oxidant stress and NFκB activation in cultured aortic endothelial
cells. Free Radic Biol Med 21: 783–790.
Downloaded from tpx.sagepub.com at UNIV OF UTAH SALT LAKE CITY on June 25, 2014
TOXICOLOGIC PATHOLOGY
11. Barrett JC, Lamb PW, Wang TC, Lee TC (1989). Mechanisms of
arsenic-induced cell transformation. Biol Trace Elem Res 21: 421–
429.
12. Belton JC, Benson NC, Hanna ML, Taylor RT (1985). Growth inhibition
and cytotoxic effects of three arsenic compounds on cultured Chinese
hamster ovary cells. J Environ Sci Health 20A: 37–72.
13. Biggs ML, Haque R, Moore L, Smith A (1998). Arsenic-laced water in
Chile. Science 281: 785.
14. Boonchai W, Walsh M, Cummings M, Chenevix-Trench G (2000). Ex-
pression of p53 in arsenic-related and sporadic basal cell carcinoma. Arch
Dermatol 136: 195–198.
15. Borgono JM, Vicent P, Venturino H, Infante A (1977). Arsenic in the
drinking water of the city of Antofagasta: epidemiological and clinical
study before and after the installation of a treatment plant. Environ Health
Perspect 19: 103–105.
16. Borzsonyi M, Bereczky A, Rudnai P, Csanady M, Horvath A (1992). Epi-
demiological studies on human subjects exposed to arsenic in drinking
water in Southwest Hungary. Arch Toxicol 66: 77–78.
17. Brown J, Kitchin KT (1996). Arsenite, but not cadmium, induces ornithine
decarboxylase and heme oxygenase activity in rat liver: Relevance to ar-
senic carcinogenesis. Cancer Lett 98: 227–231.
18. Burleson FG, Simeonova PP, Germolec DR, Luster MI (1996). Dermato-
toxic chemical stimulate of c-jun and c-fos transcription and AP-1 DNA
binding in human keratinocytes. Res Commun Mol Pathol Pharmacol 93:
131–148.
19. Calderon J, Navarro ME, Jimenez-Capdeville ME, Santos-Diaz MA,
Golden A, Rodriguez-Leyva I, Borja-Aburto V, Diaz- Barriga F (2001).
Exposure to arsenic and lead and neuropsychological development in Mex-
ican children. Environ Res 85(2): 69–76.
20. Castren K, Ranki A, Welsh JA, Vahakangas KH (1998). Infrequent p53
mutations in arsenic-related skin lesions. Oncol Res 10: 475–482.
21. Castro JA (1982). Efectos carcinogenicos, mutagenicos y teratogenicos
del arsenico. Acta Bioquim Clin Latinoam 16: 3–17.
22. Cavigelli M, Li WW, Lin A, Su B, Yoshioka K, Karin M (1996). The tu-
mor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phos-
phatase. EMBO J 15: 6269–6279.
23. Chappell W, Beck B, Brown K, North D, Thornton I, Chaney R, Cothern R,
Cothern CR, North DW, Irgolic K, Thornton I, Tsongas T (1997). Inorganic
arsenic: A need and an opportunity to improve risk assessment. Environ
Health Perspect 105: 1060–1067.
24. Chen CJ, Chiou HY, Chiang MH, Lin LJ, Tai TY (1996). Dose-response re-
lationship between ischemic heart disease mortality and long-term arsenic
exposure. Arterioscler Thromb Vasc Biol 16: 504–510.
25. Chen CJ, Chuang YC, Lin TM, Wu HY (1985). Malignant neoplasms
among residents of a blackfoot disease-endemic area in Taiwan: High-
arsenic artesian well water and cancers. Cancer Res 45: 5895–5899.
26. Chen CJ, Lin LJ (1994). Human carcinogenicity and atherogenicity in-
duced by chronic exposure to inorganic arsenic. In: Arsenic in the Envi-
ronment; Part II: Human Health and Ecosystem Effects, Nriagu JO (ed).
John Wiley & Sons, New York, pp 109–131.
27. Chen NY, Ma WY, Huang C, Ding M, Dong Z (2000a). Activation of
PKC is required for arsenite-induced signal transduction. J Environ Pathol
Toxicol Oncol 19(3): 297–306.
28. Chen CJ, Wu MM, Lee SS, Wang JD, Chen SH, Wu HY (1988). Athero-
genicity and carcinogenicity of high-arsenic artesian well water: multiple
risk factors and related malignant neoplasms of blackfoot disease. Athe-
riosclerosis 8: 452–460.
29. Chiou HY, Chiou ST, Hsu YH, Chou YL, Tseng CH, Wei ML, Chen CJ
(2001). Incidence of transitional cell carcinoma and arsenic in drinking
water: a follow-up study of 8,102 residents in an arseniasis-endemic area
in Northeastern Taiwan. Am J Epidemiol 153(5): 411–418.
30. Chiou Hy, Hsueh YM, Liaw KF, Horng, SF, Chiang MH, Pu YS, Lin JS,
Huang CH, Chen CJ (1995). Incidence of internal cancers and ingested
inorganic arsenic: a seven-year follow-up study in Taiwan. Cancer Res 55:
1296–1300.
31. Chowdhury UK, Biswas BK, Chowdhury TR, Samanta G, Mandal BK,
Basu GC, Chanda CR, Lodh D, Saha SC, Mukherjee SK, Roy S, Kabir S,
Vol. 31, No. 6, 2003 ARSENIC EXPOSURE AND HEALTH EFFECTS
Quamruzzaman Q, Chakraborti D (2000). Groundwater arsenic contam-
ination in Bangladesh and West Bengal, India. Environ Health Perspect
108(5): 393–397.
32. Clarkson TW (1991). Inorganic and organometal pesticides. In: Handbook
of Pesticide Toxicology, Hayes WJ Jr, Laws ER Jr (eds). Academic Press,
San Diego, pp 545–552.
33. Clayson DB, Kitchin KT (1999). Interspecies differences in response to
chemical carcinogens. In: Carcinogenicity: Testing, Predicting, and In-
terpreting Chemical Effects, Kitchin K (ed). Marcel Dekker, New York,
pp 837–880.
34. Concha G, Vogler G, Lezeano D, Nermell B, Vahter M (1998). Exposure
to inorganic arsenic metabolites during early human development. Toxicol
Sci 44: 185–190.
35. Cullen WR, McBride BC, Reglinski J (1984). The reduction of trimethy-
larsine oxide to trimethylarsine by thiols: a mechanistic model for the
biological reduction of arsenicals. J Inorg Biochem 21: 45–60, 179–
194.
36. Deaglio S, Canella D, Baj G, Arnulfo A, Waxman S, Malavasi F (2001).
Evidence of an immunologic mechanism behind the therapeutic effects of
arsenic trioxide on myeloma cells. Leuk Res 25(3): 237–239.
37. Del Razo LM, Styblo M, Thomas DJ (2000). Determination of trivalent
methylated arsenic species in water, cultured rat hepatocytes, and human
urine. 4th International Conference on Arsenic Exposure and Health Ef-
fects, Poster 10. San Diego, California, USA.
38. Ellenhorn MJ, Barceloux DG (1988). Medical Toxicology: Diagnosis and
Treatment of Human Poisoning. Elsevier, New York, pp 1012–1016.
39. Engel RE, Smith AH (1994). Arsenic in drinking water and mortality from
vascular disease: an ecological analysis in 30 counties in the United States.
Arch Environ Health 49: 418–427.
40. Enterline PE, Henderson VL, Marsh GM (1987). Exposure to arsenic and
respiratory cancer: a reanalysis. Am J Epidemiol 125: 929–938.
41. Enterline PE, Marsh GM (1982). Cancer among workers exposed to ar-
senic and other substances in a copper smelter. Am J Epidemiol 116: 895–
911.
42. Ferreccio C, Gonzalez C, Milosavlijevic V, Marshall G, Sancha AM
(1998). Lung cancer and arsenic exposure in drinking water: a case control
study in Northern Chile. Cad Saude Publica 14: 193–198.
43. Ferreccio C, Gonzalez C, Milosavlijevic V, Marshall G, Sancha AM, Smith
AH (2000). Lung cancer and arsenic concentrations in drinking water in
Chile. Epidemiology 11(6): 673–679.
44. Fowler BA, Weissberg JB (1974). Arsine poisoning. N Engl J Med 291:
1171–1174.
45. Gerhardsson L, Brune D, Nordberg GF, Wester PO (1988). Multielemental
assay of tissues of deceased smelter workers and controls. Sci Total Environ
74: 97–110.
46. Gerhardt RE, Hudson JB, Rao RN, Sobel RE (1978). Chronic renal insuf-
ficiency from cortical necrosis induced by arsenic poisoning. Arch Intern
Med 138: 1267–1269.
47. Germolec DR, Spalding T, Boorman GA, Wilmer JL, Yoshida T,
Simeonova PD, Bruccoleri A, Kayama F, Gaido K, Tennant R, Burleson F,
Dong W, Lang RW, Luster MI (1997). Arsenic can mediate skin neoplasia
by chronic stimulation of keratinocyte-derived growth factors. Mutat Res
386: 209–218.
48. Giberson A, Vaziri ND, Mirahamadi K, Rosen SM (1976). Hemodialysis
of acute arsenic intoxication with transient renal failure. Arch Intern Med
136: 1303–1304.
49. Gonsebatt ME, Vega L, Salazar AM, Montero R, Guzman P, Blas J, Del
Razo LM, Garcia-Vargas G, Albores A, Cebrian ME, Kelsh M, Ostrosky-
Wegman P (1997). Cytogenetic effects in human exposure to arsenic. Mutat
Res 386: 219–298.
50. Gorby MS (1988). Arsenic poisoning. West J Med 149: 308–315.
51. Goyer RA (1996). Toxic effects of metals. In: Cassarett & Doull’s
Toxicology—The Basic Science of Poisons, Klaassen CD (ed). McGraw
Hill, New York, pp 691–736.
52. Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994). Mutations
in the p53 tumor suppressor gene: clues to cancer etiology and molecular
pathogenesis. Cancer Res 54: 4855–4878.
Downloaded from tpx.sagepub.com at UNIV OF UTAH SALT LAKE CITY on June 25, 2014
585
53. Gurr J, Liu F, Lynn S, Jan K (1998). Calcium-dependent nitric oxide pro-
duction is involved in arsenite-induced micronuclei. Mutat Res 416: 137–
148.
54. Hamadeh HK, Vargas M, Lee E, Menzel DB (1999). Arsenic disrupts
cellular levels of p53 and mdm2: a potential mechanism of carcinogenesis.
Biochem Biophys Res Commun 263(2): 446–449.
55. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell 100:
57–70.
56. Harris CC (1996). p53 tumor suppressor gene: at the crossroads of molec-
ular carcinogenesis, molecular epidemiology, and cancer risk assessment.
Environ Health Perspect 104(suppl 3): 435–439.
57. Hartmann A, Speit G (1994). Comparative investigations of the Geno-
toxic effects of metals in the single cell gel assay and the sister-chromatid
exchange test. Environ Mol Mutagen 23: 299–305.
58. Hartwig A, Groblinghoff UD, Beyersmann D, Natarajan AT, Filon R,
Mullenders LHF (1997). Interaction of Arsenic (III) with nucleotide exci-
sion repair in UV-irradiated human fibroblasts. Carcinogenesis 18: 399–
405.
59. Hazardous Chemicals Data (HAZDAT) (1992). Agency for Toxic Sub-
stances and Disease Registry. Atlanta, Georgia.
60. Hernandez-Zavala A, Del Razo LM, Aguilar C, Garcia-Vargas GG, Borja
VH, Cebrian ME (1998). Alteration in bilirubin excretion in individuals
chronically exposed to arsenic in Mexico. Toxicol Lett 99(2): 79–84.
61. Hernandez-Zavala A, Del Razo LM, Garcia-Vargas GG, Aguilar C, Borja
VH Albores A, Cebrian ME (1999). Altered activity of heme biosynthesis
pathway enzymes in individuals chronically exposed to arsenic in Mexico.
Arch Toxicol 73(2): 90–95.
62. Hindmarsh JT, McCurdy RF (1986). Clinical and environmental aspects
of arsenic toxicity. CRC Crit Rev Clin Lab Sci 23: 315–347.
63. Hopenhayn-Rich C, Biggs ML, Fuchs A, Bergoglio R, Tello EE, Nicolli H,
Smith AH (1996). Bladder cancer mortality associated with arsenic in
drinking water in Argentina. Epidemiology 7: 117–124.
64. Hopenhayn-Rich C, Biggs ML, Smith A (1998). H. Lung and kidney cancer
mortality associated with arsenic in drinking water in Cordoba, Argentina.
Int J Epidemiol 27: 561–569.
65. Hsu CH, Yang SA, Wang JY, Lin SR (1999). Mutational spectrum of p53
gene in arsenic-related skin cancers from the blackfoot disease endemic
area of Taiwan. Br J Cancer 80: 1080–1086.
66. Hsueh YM, Wu WL, Huang YL, Chiou HY, Tseng CH, Chen CJ (1998).
Low serum carotene level and increased risk of ischemic heart dis-
ease related to long-term arsenic exposure. Atherosclerosis 141: 249–
257.
67. Hu Y, Su L, Snow ET (1998). Arsenic toxicity is enzyme specific and its
affects on ligation are not caused by the direct inhibition on DNA repair
enzymes. Mutat Res 408: 203–218.
68. Huang SC, Lee TC (1998). Arsenite inhibits mitotic division and perturbs
spindle dynamics in HeLa S3 cells. Carcinogenesis 19: 889–896.
69. Hutchinson J (1887a). Arsenic cancer. Br Med J 2: 1280–1281.
70. Hutchinson J (1887b). On some examples of arsenic-keratosis of the skin
and of arsenic-cancer. Trans Pathol Soc Lond 39: 352–363.
71. Ihrig MM, Shalat SL, Baynes C (1998). A hospital-based case-control
study of stillbirths and environmental exposure to arsenic using an atmo-
spheric dispersion model linked to a geographical information system.
Epidemiology 9: 290–294.
72. Jacobson Kram D, Montalbano D (1985). The reproductive effects as-
sessment group’s report on the mutagenicity of inorganic arsenic. Environ
Mutagen 7: 789–804.
73. Jha AN, Noditi M, Nilsson R, Natarajan AT (1992). Genotoxic effects of
sodium arsenite on human cells. Mutat Res 284: 215–221.
74. Kaltreider RC, Davis AM, Lariviere JP, Hamilton JW (2001). Arsenic
alters the function of the glucocorticoid receptor as a transcription factor.
Environ Health Perspect 109(3): 245–251.
75. Kitchin KT (2001). Recent advances in arsenic carcinogenesis: modes of
action, animal model systems, and methylated arsenic metabolites. Toxicol
Appl Pharmacol 172: 249–261.
76. Kosnett MJ (1994). Arsenic. In: Poisoning and Drug Overdose, Olson KK
(ed). Appleton & Lange, Norwalk, Connecticut, pp 87–89.
586 TCHOUNWOU ET AL
77. Kuo TT, Hu S, Lo SK, Chan HL (1997). p53 expression and proliferative
activity in Bowen’s disease with or without chronic arsenic exposure. Hum
Pathol 28(7): 786–790.
78. Lai MS, Hsueh YM, Chen CJ, Shyu MP, Chen SY, Kuo TL, Wu MM, Tai
TY (1994). Ingested inorganic arsenic and prevalence of diabetes mellitus.
Am J Epidemiol 139: 484–492.
79. Landolph JR (1989). Molecular and cellular mechanisms of transformation
of C3H/10T1/2C18 and diploid human fibroblasts by unique carcinogenic,
nonmutagenic metal compounds. A review. Biol Trace Elem Res 21: 459–
467.
80. Lane DP, Benchimol S (1990). p53: oncogene or anti-oncogene. Genes
Dev 4: 1–8.
81. Le XC, Lu X, Ma M, Cullen WR, Aposhian HV, Zheng B (2000). Speci-
ation of key arsenic metabolic intermediates in human urine. Anal Chem
72: 5172–5177.
82. Lee TC, Oshimura M, Barrett JC (1985). Comparison of arsenic-induced
cell transformation, cytotoxicity, mutation and cytogenetic effects in
Syrian hamster embryo cells in culture. Carcinogenesis 6(10): 1421–1426.
83. Lee TC, Tanaka N, Lamb PW, Gilmer TM, Barrett JC (1988). Induction
of gene amplification by arsenic. Science 241: 79–81.
84. Lee-Feldstein A (1983). Arsenic and respiratory cancer in man: follow-up
of an occupational study. In: Arsenic: Industrial, Biomedical, and Envi-
ronmental Perspectives, Lederer W, Fensterheim R (eds). Van Nostrand-
Reinhold, New York, pp 245–254.
85. Lee-Feldstein A (1986). Cumulative exposure to arsenic and its relation-
ship to respiratory cancer among copper smelter employee. J Occup Med
28: 296–302.
86. Levin AJ, Momand J, Finlay CA (1991). The p53 tumor suppressor gene.
Nature. 351: 453–456.
87. Lewis DR, Southwick JW, Oullet-Hellstrom R, Rench J, Calderon RL
(1999). Drinking water arsenic in Utah: a cohort mortality study. Environ
Health Perspect 107: 359–365.
88. Li JH, Rossman TC (1989). Inhibition of DNA ligase activity by arsenite:
a possible mechanism of its comutagenesis. Mol Toxicol 2: 1–9.
89. Lin S, Cullen WR, Thomas DJ (1999). Methylarsenicals and arsinoth-
iols are potent inhibitors of mouse liver thioredoxin reductase. Chem Res
Toxicol 12: 924–930.
90. Liu J, Kadiiska M, Liu Y, Qu W, Mason RP, Waalkes MP (2000). Acute
arsenic-induced free radical production and oxidative stress-related gene
expression in mice. Toxicologist 54: 280–281.
91. Lu T, Liu J, LeCluyse EL, Zhou YS, Cheng ML, Waalkes MP
(2001). Application of cDNA microarray to the study of arsenic-induced
liver diseases in the population of Guizhou, China. Toxicol Sci 59(1):
185–192.
92. Luchtrath H (1983). The consequences of chronic arsenic poisoning among
Moselle wine growers: pathoanatomical investigations of post-mortem ex-
aminations performed between 1960 and 1977. J Cancer Res Clin Oncol
105: 173–182.
93. Madal BK, Chowdhury TR, Samanta G, Basu GK, Chowdhury PP, Chanda
CR, Lodh D, Karan NK, Dhar RK, Tamili DK (1996). Arsenic in ground-
water in seven districts of West Bengal, India: the biggest arsenic calamity
in the world. Curr Sci 70: 976–986.
94. Mahata J, Basu A, Ghoshal S, Sarkar JN, Roy AK, Poddar G, Nandy AK,
Banerjee A, Ray K, Natarajan AT, Nilsson R, Giri AK (2003). Chromo-
somal aberrations and sister-chromatid exchanges in individuals exposed
to arsenic through drinking water in West Bengal, India. Mutat Res 534:
133–143.
95. Marafante E, Vahter M (1987). Solubility, retention, and metabolism of
intratracheally and orally administered inorganic arsenic compounds in
the hamster. Environ Res 42: 72–82.
96. Mass MJ, Tennant A, Roop B, Kundu K, Brock K, Kligerman A, Demarini
D, Wang C, Cullen W, Thomas D, Styblo M (2001). Methylated arsenic
(III) species react directly with DNA and are potential proximate or ulti-
mate genotoxic forms of arsenic. Toxicologist 60: 358.
97. Mass MJ, Wang L (1997). Arsenic alters cytosine methylation patterns
of the promoter of the tumor suppressor gene p53 in human lung cells: a
model for a mechanism of carcinogenesis. Mutat Res 386: 263–277.
Downloaded from tpx.sagepub.com at UNIV OF UTAH SALT LAKE CITY on June 25, 2014
TOXICOLOGIC PATHOLOGY
98. Matsui M, Nishigori C, Toyokuni S, Takada J, Mitsuhiko A, Ishikawa
M, Imamura S, Miyachi Y (1999). The role of oxidative DNA damage in
human arsenic carcinogenesis: detection of 8-hydroxy-2 -deoxyguanosine
in arsenic-related Bowen’s disease. J Invest Dermatol 113: 26–31.
99. Mazumder G, Chakraborty A, Ghose A, Gupta JD, Dey SD, Chattopadhyay
N (1988). Chronic arsenic toxicity from drinking tubewell water in rural
West Bengal. Bull WHO 66: 499–506.
100. Mazumder Guha DN, Gupta Das J, Santra A (1997). Non-cancer effects
of chronic arsenicosis with special reference to liver damage. In: Arsenic
Exposure and Health Effects, Abernathy C, Calderon RL, Chappel WR
(eds). Chapman and Hall, London, pp 112–123.
101. Mazumder DN, Haque R, Ghosh N, De BK, Santra A, Chakraborty D,
Smith A (1998). Arsenic levels in drinking water and the prevalence of
skin lesions in West Bengal, India. Int J Epidemiol 27: 871–877.
102. Mazumder DN, Haque R, Ghosh N, De BK, Santra A, Chakraborti D,
Smith AH (2000). Arsenic in drinking water and the prevalence of res-
piratory effects in West Bengal, India. Int J Epidemiol 29(6): 1047–
1052.
103. Milton AH, Hasan Z, Rahman A, Rahman M (2001). Chronic arsenic
poisoning and respiratory effects in Bangladesh. J Occup Health 43(3):
136–140.
104. Moolgavkar SH (1986). Carcinogenesis modeling: from molecular biology
to epidemiology. Annu Rev Public Health 7: 151–169.
105. Morton WE, Dunnette DA (1994). Health effects of environmental arsenic.
In: Arsenic in the Environment Part II; Human Health and Ecosystem
Effects, Nriagu JO (ed). John Wiley & Sons, Inc, New York, pp 17–34.
106. Murgo AJ (2001). Clinical trials of arsenic trioxide in hematologic and
solid tumors: overview of the National Cancer Institute Cooperative Re-
search and Development Studies. Oncologist 6(suppl 2): 22–28.
107. Nakamuro K, Sayato Y (1981). Comparative studies of chromosomal
aberration induced by trivalent and pentavalent arsenic. Mutat Res 88:
73–80.
108. Natarajan AT, Boei JJ, Darroudi F, Van Diemen PC, Doulout F, Hande MP
and Ramalho AT (1996). Current cytogenetic methods for detecting ex-
posure and effects of mutagens and carcinogens. Environ Health Perspect
104(Suppl.3): 455–458.
109. National Academy of Science (1977). Arsenic. Author, Washington, DC.
110. National Institutes of Health (NIH) (1999). National Toxicology Program’s
Technical Report on the Toxicology and Carcinogenesis Studies of Gallium
Arsenide in F344/N Rats and B6C3F1 Mice. NTPTR 492. NIH publication
No. 99-3951. Bethesda, Maryland, USA.
111. National Research Council (1994). Science and Judgement in Risk As-
sessment. Assessment of Toxicology, National Academy of Sciences (eds).
National Academy Press, Washington, DC, pp 56–67.
112. NRC (National Research Council) (1999). Arsenic in Drinking Water.
Author, Washington, DC.
113. NRC (National Research Council) (2001). Arsenic in Drinking Water:
Update. National Academy Press, Washington, DC.
114. Nordstrom S, Beckman L, Nordenson I (1978a). Occupational and envi-
ronmental risk in and around a smelter in northern Sweden. I: variations
in birth weight. Hereditas 88: 43–46.
115. Nordstrom S, Beckman L, Nordenson I (1978b). Occupational and envi-
ronmental risk in and around a smelter in northern Sweden. III: frequencies
of spontaneous abortion. Hereditas 88: 51–54.
116. Nordstrom S, Beckman L, Nordenson I (1979a). Occupational and envi-
ronmental risk in and around a smelter in northern Sweden. V: spontaneous
abortion among female employees and decreased birth weight in their off-
spring. Hereditas 90: 291–296.
117. Nordstrom S, Beckman L, Nordenson I (1979b). Occupational and envi-
ronmental risk in and around a smelter in northern Sweden. VI: congential
malformations. Hereditas 90: 297–302.
118. Paigen B, Goldman LR, Magnant MM, Highland JH, Steegmann Jr, AT
(1987). Growth of children living near the hazardous waste site, Love
canal. Human Biol 59: 489–508.
119. Parrish AR, Zheng XH, Turney KD, Younis HS, Gandolfi AJ (1999). En-
hanced transcription factor DNA binding and gene expression induced by
arsenite or arsenate in renal slices. Toxicol Sci 50(1): 98–105.
Vol. 31, No. 6, 2003 ARSENIC EXPOSURE AND HEALTH EFFECTS
120. Petrick JS, Ayala-Fierro F, Cullen WR, Carter DE, Aposhian HV (2000).
Monomethylarsonous acid (MMAIII ) is more toxic than arsenite in Chang
human hepatocytes. Toxicol Appl Pharmacol 163: 203–207.
121. Popovicova J, Moser GJ, Goldsworthy TL, Tice RR (2000). Carcinogenic-
ity and co-carcinogenicity of sodium arsenite in p53+/− male mice. Tox-
icologist 54: 134.
122. Porter AC, Fanger GR, Vaillancourt RR (1999). Signal transduction
pathways regulated by arsenate and arsenite. Oncogene 18(54): 7794–
7802.
123. Puccetti ES, Guller S, Orleth A, Bruggenolte N, Hoelzer D, Ottmann
OG, Ruthardt M (2000). BCR-ABL mediates arsenic trioxide-induced
apoptosis independently of its aberrant kinase activity. Cancer Res 60(13):
3409–3413.
124. Rahman M, Axelson O (1995). Diabetes mellitus and arsenic exposure: a
second look at case-control data from a Swedish copper smelter. Occup
Environ Med 52: 773–774.
125. Rahman M, Tondel M, Ahmad SA, Chowdhury IA, Faruquee MH, Axelson
O (1999). Hypertension and arsenic exposure in Bangladesh. Hyperten-
sion. 33(1): 74–78.
126. Rahman M, Wingren G, Axelson O (1996). Diabetes mellitus among
Swedish art glassworkers- an effect of arsenic exposure. Scand J Work
Environ Health 22: 146–149.
127. Ramirez P, Eastmond DA, Laclette JP, Ostrosky-Wegman P (1997). Dis-
ruption of microtubule assembly and spindle formation for the induction
of aneuploid cells by sodium arsenite and vanadium pentoxide. Mutat Res
386: 291–298.
128. Rousselot P, Laboume S, Marolleau JP, Larghero T, Noguera ML, Brouet
JC, Fermand JP (1999). Arsenic trioxide and melarsoprol induce apoptosis
in plasma cell lines and in Plasma cells from myeloma patients. Cancer
Res 59: 1041–1048.
129. Salazar AM, Ostrosky-Wegman P, Menendez D, Miranda E, Garcia-
Carranca A, Rojas E (1997). Induction of p53 protein expression by sodium
arsenite. Mutat Res 381: 259–265.
130. Sampayo-Reyes A, Zakharyan RA, Healy SH, Aposhian HV (2000).
Monomethylarsonic acid reductase and monomethylarsonous acid in ham-
ster tissue. Chem Res Toxicol 13: 1181–1186.
131. Santra A, Gupta Das J, De BK, Roy B and Mazumder DN (1999). Hepatic
manifestations in chronic arsenic toxicity. Indian J Gastroenterol 18(4):
152–155.
132. Schaumloffel N, Gebel T (1998). Heterogeneity of the DNA damage pro-
voked by antimony and arsenic. Mutagenesis 13: 281–286.
133. Schoolmaster WL, White DR (1980). Arsenic poisoning. South Med J 73:
198–208.
134. Schwartz J, Angle C, Pitcher H (1986). Relationship between childhood
blood lead level and stature. Pediatrics 77: 281–288.
135. Seol JG, Park WH, Kim ES, Jung CW, Hyun JM, Kim BK, Lee YY (1999).
Effect of arsenic trioxide on cell cycle arrest in head and neck cancer cell-
line PCI-1. Biochem Biophys Res Commun 265(2): 400–404.
136. Simeonova PP, Luster MI (2000). Mechanisms of arsenic carcinogenicity:
genetic or epigenetic mechanisms? J Environ Pathol Toxicol Oncol 19:
281–286.
137. Simeonova PP, Wang S, Toriumi W, Kommineni C, Matheson J, Unimye
N, Kayama F, Harki D, Ding M, Vallyathan V, Luster MT (2000). Arsenic
mediates cell proliferation and gene expression in the bladder epithelium:
association with AP-1 transactivation. Cancer Res 60: 3445–3453.
138. Siripitayakunkit U, Visudhiphan P, Pradipasen M, Vorapongsathon T
(1999). Association between chronic arsenic exposure and children’s
intelligence in Thailand. In: Arsenic Exposure and Health effects,
Chappell, WR, Abernathy CO, Calderon RL (eds). Elsevier, New York,
pp 141–150.
139. Smith AH, Goycolea M, Haque R, Biggs ML (1998). Marked increase in
bladder and lung cancer mortality in a region of Northern Chile due to
arsenic in drinking water. Am J Epidemiol 147: 660–669.
140. Soignet S, Calleja E, Cheung NK, Pezzulli S, Vongphrachanh P, Spriggs
D, Warrell RP (1999). A Phase 1 study of arsenic trioxide in patients
with solid tumors, Memorial Sloan-Kettering Cancer Center, New York,
NY. Program/Proceedings Abstracts for 35th Annual Meeting of the
Downloaded from tpx.sagepub.com at UNIV OF UTAH SALT LAKE CITY on June 25, 2014
587
American Society of Clinical Oncology, Atlanta, Georgia, May 15–18,
Vol. 18.
141. Squibb KS, Fowler BA (1983). The toxicity of arsenic and its compounds.
In: Biological and Environmental Effects of Arsenic, Fowler BA (ed).
Elsevier, New York, pp 233–269.
142. Styblo M, Del Razo LM, LeCluyse EL, Hamilton GA, Wang C, Cullen
WR, Thomas DJ (1999). Metabolism of arsenic in primary cultures of
human and rat hepatocytes. Chem Res Toxicol 12: 560–565.
143. Styblo M, Hughes MF, Thomas DJ (1996). Liberation and analysis of
protein-bound arsenicals. J Chromatogr B 677: 161–166.
144. Styblo M, Serves SV, Cullen WR, Thomas DJ (1997). Comparative inhi-
bition of yeast glutathione reductase by arsenicals and arsenothiols. Chem
Res Toxicol 10: 27–33.
145. Styblo M, Yamauchi H, Thomas DJ (1995). Comparative in vitro methyla-
tion of trivalent and pentavalent arsenicals. Toxicol Appl Pharmacol 135:
172–178.
146. Takahashi M, Barrett JC, Tsutsui T (2002). Transformation by inorganic
arsenic compounds of normal Syrian hamster embryo cells into a neoplastic
state in which they become anchorage-independent and cause tumors in
newborn hamsters. Int J Cancer 99: 629–634.
147. Tchounwou PB, Wilson B, Ishaque A (1999). Important considerations
in the development of public health advisories for arsenic and arsenic-
containing Compounds in drinking water. Rev Environ Health 14(4): 211–
229.
148. Teitelbaum DT, Kier LC (1969). Arsine poisoning. Arch Environ Health
19: 133–143.
149. Thompson DJ (1993). A chemical hypothesis for arsenic methylation in
mammals. Chem-Biol Interact 88: 89–114.
150. Tokudome S, Kuratsune M (1976). A cohort study on mortality from cancer
and other causes among workers at a metal refinery. Int J Cancer 17: 310–
317.
151. Trouba KJ, Wauson EM, Vorce RL (2000). Sodium arsenite-induced dys-
regulation of proteins involved in proliferative signaling. Toxicol Appl
Pharmacol 164(2): 161–170.
152. Tsai S, Wang T, Ko Y (1999). Mortality for certain diseases in areas with
high levels of arsenic in drinking water. Arch Enivron Health 54: 186–193.
153. Tseng CH, Tai TY, Chong CK, Tseng CP, Lai MS, Lin BJ, Chiou HY,
Hsueh YM, Hsu KH, Chen CJ (2000). Long-term arsenic exposure and
incidence of non-insulin-dependent diabetes mellitus: A cohort study in
arseniasis-hyperendemic villages in Taiwan. Environ Health Perspect 108
(9): 847–851.
154. Tseng WP (1989). Blackfoot disease in Taiwan: a 30-year follow-up study.
Angiology 40: 547–558.
155. Tsuda T, Nagira T, Yamamoto M (1990). An epidemiological study on
cancer in certified arsenic poisoning patients in Toroku. Ind Health 28:
53–62.
156. Tucker SB, Lamm SH, Li FX, Wilson R, Byrd DM, Lai S, Tong Y, Loo
L (2001). Relationship between Consumption of Arsenic-Contaminated
Well Water and Skin Disorders in Huhhot, Inner Mongolia. Inner Mon-
golia Cooperative Arsenic Project (IMCAP) study. Final Report. Dept. of
Dermatology, University of Texas, Houston, and Dept. of Environmental
Epidemiology, Institute of Environmental Engineering, Chinese Academy
of Preventive Medicine, Beijing, China.
157. Tully DB, Collins BJ, Overstreet JD, Smith CS, Dinse GE, Mumtaz MM,
Chapin RE (2000). Effects of arsenic, cadmium, chromium and lead on
gene expression regulated by a battery of 13 different promoters in recom-
binant HepG2 cells. Toxicol Appl Pharmacol 168(2): 79–90.
158. Vahter ME (1988). Arsenic. In: Biological Monitoring of Toxic Metals,
Clarkson TW, Friberg L, Nordberg GF, Sager PR (eds). Plenum, New York,
pp 303–321.
159. Vega L, Gonsebatt ME, Ostrosky-Wegman P (1995). Aneugenic effect of
sodium arsenite on human lymphocytes in vitro: an individual susceptibil-
ity effect detected. Mutat Res 334(3): 365–373.
160. Vega L, Styblo M, Patterson R, Cullen W, Wang C, Germolec D (2001).
Differential effects of trivalent and pentavalent arsenicals on cell prolif-
eration and cytokine secretion in normal human epidermal keratinocytes.
Toxicol Appl Pharmacol 172(3): 225–232.
588 TCHOUNWOU ET AL
161. Venugopal B, Lucky TD (1978). Metal Toxicity in Mammals. Plenum Press,
New York.
162. Vogt BL, Rossman TG (2001). Effects of arsenite on p53, p21 and cyclin
D expression in normal human fibroblasts—a possible mechanism for
arsenite’s comutagenicity. Mutat Res 478(1–2): 159–168.
163. Wall S (1980). Survival and mortality pattern among Swedish smelter
workers. Int J Epidemiol 9: 73–87.
164. Wang Z, Rossman TG (1996). In: The Toxicology of Metals, vol 1, Cheng
LW (ed). CRC Press, Boca Raton, Florida, pp 221–243.
165. Wanibuchi H, Hori T, Meenakshi V, Ichihara T, Yamamoto S, Yano Y,
Otani S, Nakae D, Konishi Y, Fukushima S (1997). Promotion of rat hepa-
tocarcinogenesis by dimethylarsinic acid as assessed in rat in vivo models:
a review. Mutat Res 386: 353–361.
166. Warner ML, Moore LE, Smith MT, Kalman DA, Fanning E, Smith AH
(1994). Increased micronuclei in exfoliated bladder cells of individuals
who chronically ingest arsenic-contaminated water in Nevada. Cancer
Epid Biomarker Prevent 3: 583–590.
167. Wei M, Wanibuchi H, Morimura K, Iwai S, Yoshida K, Endo G, Nakae
D, Fukushima S (2002). Carcinogenicity of dimethylarsinic acid in male
F344 rats and genetic alterations in induced urinary bladder tumors. Car-
cinogenesis 23(8): 1387–1397.
168. Winship KA (1984). Toxicity of inorganic arsenic salts. Adv Drug React
Acute Poisoning Rev 3: 129–160.
169. Wu MM, Kuo TL, Hwang YH, Chen CJ (1989). Dose-response relation-
ship between arsenic concentration in well water and mortality from can-
cers and vascular diseases. Am J Epid 130: 1123–1132.
170. Yamamoto S, Konishi Y, Matsuda T, Murai T, Shibata M, Matsui-Yuasa
I, Otani S, Kuroda K, Endo G, Fukushima S (1995). Cancer induction by
an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in
F344/DuCrj rats after pretreatment with five carcinogens. Cancer Res 55:
1271–1275.
171. Yamanaka K, Hoshino M, Okanoto M, Sawamura R, Hasegawa A, Okada
S (1990). Induction of DNA damage by dimethylarsine a metabolite of
inorganic arsenics, is for the major part likely due to its peroxyl radical.
Biochem Biophys Res Commun 168: 58–64.
172. Yamanaka K, Mizoi M, Kato K, Hasegawa A, Nakano M, Okada S (2001).
Oral administration of dimethylarsinic acid, a main metabolite of inor-
Downloaded from tpx.sagepub.com at UNIV OF UTAH SALT LAKE CITY on June 25, 2014
TOXICOLOGIC PATHOLOGY
ganic arsenics, promote skin tumorigenesis in mice. Biol Pharm Bull 24:
510–514.
173. Yamashita N, Doi M, Nishio M, Hojo H, Tanaka M (1972). Recent ob-
servations of Kyoto children poisoned by arsenic tainted “Morinaga Dry
Milk.” Jpn J Hyg 27: 364–399.
174. Zakharyan RA, Ayala-Fierro F, Cullen WR, Carter DM, Aposhian HV
(1999). Enzymatic methylation of arsenic compounds VII. Monomethy-
larsonous acid (MMAIII ) is the substrate for MMA methyltransferase
of rabbit liver and human hepatocytes. Toxicol Appl Pharmacol 158:
9–15.
175. Zakharyan RA, Aposhian HV (1999). Enzymatic reduction of arsenic
compounds in mammalian systems: the rate-limiting enzyme of rabbit
liver arsenic biotransformation is MMAV reductase. Chem Res Toxicol
12: 1278–1283.
176. Zaldivar R (1980). A morbid condition involving cardiovascular, bron-
chopulmonary, digestive and neural lesions in children and young
adults after dietary arsenic exposure. Zentralbl Bakteriol 170: 44–
56.
177. Zaldivar R, Ghai GL (1980). Clinical epidemiological studies on endemic
chronic arsenic poisoning in children and adults, including observations
on children with high and low-intake of dietary arsenic. Zentralbl Bakte-
riol. 1. Abt Originale B: Hygiene, Krankenhaushygiene, Betriebshygiene,
Praventive Medizin 170: 409–421.
178. Zelikoff JT, Bertin JE, Burbacher TM, Hunter ES, Miller RK, Silbergeld
EK, Tabacova S, Rogers JM (1995). Health risks associated with prenatal
metal exposure. Fundam Appl Toxicol 25: 161–170.
179. Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP (1997). Associ-
ation of arsenic-induced malignant transformation with DNA hypomethy-
lation and aberrant gene expression. Proc Natl Acad Sci USA 94: 10907–
10912.
180. Zhong CX, Wang L, Mass MJ (2001). Differentially methylated DNA
sequences associated with exposure to arsenate in cultures of human cells
identified by methylation-sensitive arbitrarily-primed PCR. Toxicol Lett
122(3): 223–234.
181. Zierler S, Theodore M, Cohen A, Rothman KJ (1988). Chemical quality
of maternal drinking water and congenital heart disease. Int J Epidemiol
17: 589–594.