C H A P T E R
28
Arsenic
BRUCE A. FOWLER, C.-H. SELENE J. CHOU, ROBERT L. JONES, DEXTER W. SULLIVAN JR,
AND C.-J. CHEN
ABSTRACT
Arsenic in the environment occurs in both organic
and inorganic compounds in its trivalent or pentava-
lent state. Certain fish and crustaceans contain very
high levels of organic arsenic, often as arsenobetaine.
In most other foodstuffs, levels of arsenic are low
and the form is not known. The total daily intake of
arsenic in the general population is reported to be
approximately a few tenths of a milligram, but var-
ies to a great extent depending on the amount of fish
consumed.
Both organic arsenic in seafood and inorganic arse-
nic in water, beverages, and drugs have been shown
to be readily absorbed (70-90%) by the gastrointestinal
tract. Some reports also indicate a fairly high degree of
absorption after the inhalation of arsenic.
Absorbed arsenic, irrespective of form, is widely
distributed in the body. After exposure to inorganic
arsenic, clearance of arsenic from the skin, upper gas-
trointestinal tract, epididymis, thyroid, and skeleton
is slower than from other organs. The highest levels
of arsenic in humans are normally found in the hair,
nails, and skin. The main route of excretion is through
the kidneys. After ingestion of arsenite or arsenate,
approximately 35% of the dose is excreted within 2
days. From animal experiments it seems that insoluble
inorganic arsenic inhaled through the airway is depos-
ited and retained in lung tissue for a relatively long
time. Animal data indicate arsenobetaine accumula-
tion in cartilage, testes, epididymis, and muscle. Of
ingested arsenobetaine, 50-80% is excreted in the urine
within 2 days.
Handbook on the Toxicology of Metals 4E
http://dx.doi.org/10.1016/B978-0-444-59453-2.00028-7
Biotransformation of inorganic arsenic has been
shown to occur in both animals and humans. Meth-
ylated compounds, such as methylarsonic acid and
dimethylarsinic acid, have been detected in the urine
after ingestion or inhalation of inorganic arsenic.
Reduction of arsenate and oxidation of arsenite in vivo
have been demonstrated in experimental animals.
Recently, a human arsenic methyltransferase has been
identified.
Medications, contaminated food, beverages, and
drinking water have given rise to a number of episodes
of arsenic poisoning.
Inorganic arsenic-induced skin lesions such as der-
matoses, which may include eruption, pigmentation,
or leukodermal hyperkeratosis, may ultimately lead
to the development of skin cancer and Bowen dis-
ease. Effects on the nervous system (e.g. peripheral
nervous disturbance), as well as on the heart and cir-
culatory system (e.g. abnormal electrocardiograms,
peripheral vascular disturbances with gangrene
of the extremities, ischemic heart disease, cerebral
infarction, and erectile dysfunction), have also been
reported after chronic exposure to inorganic arsenic.
Hematological changes after inorganic arsenic expo-
sure are characterized by anemia and leukopenia.
Chronic oral ingestion of inorganic arsenic in drink-
ing water has also been reported to cause internal
cancers (of the lung, bladder, kidney, and liver), dia-
betes, hypertension, cataract, pterygium, and devel-
opmental retardation.
Arsenic poisoning among industrial workers is
characterized by perforation of the nasal septum, skin
changes, and peripheral neuritis. There is substantial
581 Copyright © 2015 Elsevier B.V. All rights reserved.
582 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
epidemiological evidence of an excessive risk of lung
cancer among workers exposed to arsenic.
Arsine gas is a powerful hemolytic poison encoun-
tered under some industrial conditions. Arsine poison-
ing is characterized by nausea, vomiting, headache,
shortness of breath, and hemoglobinuria. Literature on
the toxicology and environmental aspects of arsenicals
has been reviewed by the World Health Organization
(WHO, 1981, 2001), in monographs by the Interna-
tional Agency for Research on Cancer (IARC, 1982,
2004, 2006, 2012), Fowler (1983), and by the National
Research Council (NRC) (1999).
1  PHYSICAL AND CHEMICAL PROPERTIES
Arsenic [As; Chemical Abstracts Service (CAS) No.
7440-38-2 for metallic arsenic]: atomic weight, 74.9;
atomic number, 33; metalloid. Allotropes: crystal-
line (hexagonal-rhombic) gray arsenic (stable), den-
sity 5.727 g/cm3 (25°C/4°C), melting point, 818°C
(36 atm), boiling point 615°C (sublimate), vapor pres-
sure 1 mmHg (372°C); yellow arsenic (metastable),
density 1.97 g/cm3, melting point 815°C (under addi-
tional pressure); and black arsenic, valence states
−3, 0, +3, and +5. When elemental arsenic is heated
at atmospheric pressure without oxygen, it sublimes
without melting and forms a yellow gas. Heating
arsenic in air will yield a white smoke consisting of
arsenic trioxide.
From both the biological and the toxicological
points of view, arsenic compounds may be classi-
fied into three major groups: (1) inorganic arsenic
compounds; (2) organic arsenic compounds; and (3)
arsine gas. The toxicology of this last compound,
which has special properties, will be dealt with sepa-
rately in Section 10 of this chapter. The most common
inorganic trivalent arsenic compounds are arsenic tri-
oxide, sodium arsenite, and arsenic trichloride. Pen-
tavalent inorganic compounds are arsenic pentoxide,
arsenic acid, and arsenate (e.g. lead arsenate and cal-
cium arsenate). Common organic arsenic compounds
are arsanilic acid, methylarsonic acid, dimethylar-
sinic acid (cacodylic acid), and arsenobetaine (NRC,
1999).
Arsenic trioxide is only slightly soluble in water;
in sodium hydroxide it forms arsenite, and with
concentrated hydrochloric acid it forms arsenic tri-
chloride. Sodium arsenite and sodium arsenate are
highly soluble in water. Interchanges in valence state
may occur in water solutions, depending on the pH
of the solution, as well as the presence of other sub-
stances that can be reduced or oxidized (Reay and
Asher, 1977).
CAS Nos for the major arsenic compounds are:
arsine, 7784-42-1; arsenic trioxide, 1327-53-3; sodium
arsenite, 7784-46-5; sodium arsenate, 7631-89-2; arsenic
pentoxide, 1303-28-2; monomethylarsenic acid, 124-58-
3; and dimethylarsinic acid, 75-60-5.
2  METHODS AND PROBLEMS OF
ANALYSIS
Until a few decades ago, the only available meth-
ods for analyzing arsenic, such as Reinsch’s method,
Marsh’s test, and Gutzeit’s test, were qualitative rather
than quantitative in nature. Because of this limitation,
the results of studies based on these methods must be
evaluated with caution.
The molybdenum blue method and the silver dieth-
yldithiocarbamate method are two reasonably good
quantitative colorimetric methods that have limits
of detection in the range of 1-50 μg/L in a 5-mL solu-
tion (Sandell, 1959; Vasak and Sedivec, 1952). Atomic
absorption spectrophotometric (AAS) measure-
ment of generated arsine gas (Holak, 1969) has been
widely used for the determination of total arsenic and
has a detection limit of 0.04 μg. Atomic fluorescence
spectrometry (AFS) with online hydride generation
(Karthiheyan and Hirata, 2003) has the advantage
of less scattering and matrix effects and has a detec-
tion limit of 0.03 μg/L. Neutron activation analysis
(NAA) has a detection limit of 0.1 ng for total arsenic
(Liebscher and Smith, 1968). Proton-induced X-ray
emission analysis (PIXEA), with a detection limit of
0.1 mg/kg, has been used for the simultaneous deter-
mination of arsenic and a number of other elements
in biological samples (Fowler et al., 1975; Walter et al.,
1974). Advancements in inductively coupled plasma
spectroscopy (ICP) have resulted in the general use
of either ICP-coupled optical emission spectroscopy
(ICP-OES) or mass spectroscopy (ICP-MS) detection
methods. Although the ICP-OES method showed
promise (Hueber and Winefordner, 1995), it has been
largely replaced with the ICP-MS method, with its
higher sensitivity, less interferences than ICP-OES,
and detection limits of 0.002 μg/L (Marawi et al., 1994).
The primary drawback of ICP-MS is the generation of
Ar-Cl interference in the plasma, which can be over-
come by either high-resolution ICP-MS (Townsend,
1999) or the use of a dynamic reaction cell (Nixon et al.,
2004; Tanner et al., 2000; Jarrett et al., 2007) or collision
cell (B’Hymer and Caruso, 2004; Nakazato et al., 2002)
technology. ICP-MS is the most widely used method
for the determination of total arsenic (Hung et al.,
2004). All of these methods are suitable for the mea-
surement of total arsenic.
 28 Arsenic
Several methods for the quantitative determination
of the various valence states and chemical forms of
arsenic have also been developed. Pulse polarography
(detection limit of 0.3 μg As/L water) is capable of dis-
tinguishing polarographically active As(III) from inac-
tive As(V) (Myers and Osteryoung, 1973). A method to
collect generated arsines in a cold trap, evaporate them
at different temperatures, and measure them by atomic
emission spectroscopy has been found to have a detec-
tion limit of the order of 1 ng (Braman and Foreback,
1973). With this method, it is possible to distinguish
As(III), As(V), methylarsonic acid, and dimethylarsinic
acid (DMA).
The speciation of arsenic in water and other matri-
ces such as urine has seen major advances because
of coupled techniques like ion chromatography (IC)
coupled to ICP (Sheppard et al., 1992). In this tech-
nique, IC separates the species of arsenic before their
introduction into the ICP-MS detector (or other detec-
tion method). This enables the automation of specia-
tion method(s) for the different matrices. The most
commonly used method for speciation of the various
arsenic species is high-performance liquid chroma-
tography (HPLC) in its various forms. Arsenic(III),
As(V), monomethylarsonic acid (MMA), DMA, and
arsenobetaine are separated by HPLC and determined
online by ICP-MS. Two forms of HPLC may be used,
ion pairing and ion exchange, with absolute detec-
tion limits for arsenic ranging between 50 and 300 pg
(Beauchemin et al., 1989). An ICP-MS detector in com-
bination with HPLC has been used for the analysis of
six arsenic compounds, with detection limits for arse-
nic species in the range of 10-30 pg. (Demesmay et al.,
1994). A more recent analytical method has been devel-
oped using HPLC-ICP-DRC (i.e Dynamic Reaction
Cell)-MS for biomonitoring the U.S. population that
enables the quantification of seven species of arsenic:
As(III), As(V), MMA, DMA, arsenobetaine, and tri-
methylarsine oxide (TMAO), with limits of detection
for the various species ranging from 0.4 to 1.7 μg/L
(Verdon et al., 2009).
More recent publications on the speciation of
arsenicals have taken advantage of advances in
sample preparation methods for ICP-MS technolo-
gies. These advances have permitted measurements
of speciated arsenicals in air (Lewis et al., 2012), sea-
food (Moreda-Piñeiro et al., 2010, 2011), urine (Davis
et al., 2010; Chen et al., 2012), and blood (Nunes et al.,
2010).
Methods and problems of arsenic analysis, includ-
ing speciation in various matrices, have been reviewed
by Braman (1977, 1983), Hung et al. (2004), Muñoz
and Palmero (2005), Gong et al. (2002), and Rose et al.
(2001).
583
3  PRODUCTION AND USES
3.1 Production
Arsenic is widely distributed in the Earth’s crust,
which contains about 3.4 ppm arsenic (Wedepohl,
1991). It usually exists in nature in sulfide ores.
Although there are more than 150 arsenic-bearing
minerals (Budavari et al., 2001; Carapella, 1992),
arsenopyrite is by far the most common. Arsenic
trioxide (white arsenic) is principally obtained as a by-
product of smelting copper, lead, or gold ores. When
these ores are smelted, the arsenic becomes gaseous
and is trapped by electrostatic precipitators as a crude
dust that is then roasted, whereby arsenic trioxide is
driven off. Purified arsenic trioxide is collected in a
cooling chamber, and the principal impurity is Sb2O3
(Pinto and McGill, 1953). Most commercially avail-
able arsenic compounds are produced from arsenic
trioxide. The average annual world production of
arsenic on the basis of limited data (1975-1977) was
approximately 60,000 tons, and this level of produc-
tion seems to be stable (WHO, 1981). In 2003, China
was the world leader in the production of com-
mercial-grade arsenic, followed by Chile and Peru
(Brooks, 2003). The United States is the world’s lead-
ing consumer of arsenic; however, the United States
ceased production in 1985.
3.2 Uses
Arsenic was known as a therapeutic agent as early
as 400 bc and has been widely used as such since then.
From the nineteenth century onward, an inorganic
arsenic compound known as Fowler’s solution (liquor
arsenicalis B.P. 1963; a potassium arsenite solution con-
taining 7.6 g As/L) has been used for the treatment of
leukemia, psoriasis, and chronic bronchial asthma,
and organic arsenic compounds have been extensively
used in the treatment of spirochetal and protozoal dis-
ease (Martindale, 1977; NRC, 1999). However, many
countries have now banned the use of Fowler’s solu-
tion. Recently, arsenic trioxide has reportedly been
used in the treatment of acute promyelocytic leukemia
(Gallagher, 1998; Wang, 2001). Recent studies have
reported that As3+ produces anticancer effects in leu-
kemic cells (Goussetis et al., 2010; Zheng et al., 2005)
and human glioblastoma cells (Pucer et al., 2010), and
induces autophagy and apoptosis in human fibrosar-
coma (Chiu et al., 2010) and ovarian cancer cells (Smith
et al., 2010). Altered gene regulation patterns are associ-
ated with decreased cell growth in As3+-exposed human
liver cancer (Yoo et al., 2009), bladder cancer (Jutooru
et al., 2010), and breast cancer (Zhang et al., 2011) cells.
584 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
The major current uses of arsenic are in pesticides
(e.g. lead arsenate, calcium arsenate, and sodium arse-
nite), herbicides [e.g. monosodium arsenate and caco-
dylic acid (i.e. DMA)]; cotton desiccants (e.g. arsenic
acid), and wood preservatives (e.g. copper chromium
arsenate). Arsenic is also used as a bronzing or decol-
orizing agent in the manufacture of glass and in the
fabrication of opal glass and enamels. It has also been
used in the manufacture of dyestuffs and chemical
warfare gases, and is still used in the purification of
industrial gases (sulfur removal). Elemental arsenic is
used as an additive in the production of several alloys
to increase hardness and heat resistance. In the live-
stock industry, organic arsenical is sometimes added
to swine and poultry feed as an antimicrobial medi-
cine. In 1999-2000, approximately 70% of the broiler
industry added roxarsone to broiler poultry feed
(Garbarino et al., 2003). Recently, artificial gallium
arsenide and indium arsenide crystals have become
important materials in semiconductors, solar cells, and
materials used for space research (Brooks, 2005; IARC,
2006; Yamauchi et al., 1992).
4  ENVIRONMENTAL LEVELS AND
EXPOSURES
4.1  Food and Daily Intake
With the exception of some kinds of fish, crusta-
ceans, and seaweed, most food contains low levels
of arsenic, normally below 0.25 mg/kg (Jelinek and
Corneliussen, 1977). The degree of arsenic uptake
in plants appears to be related to the concentration
of soluble arsenic in the soil, the chemical composi-
tion of the soil, and the plant species (Walsh et al.,
1977). Surface contamination with insecticides may
increase the concentration of arsenic in plants. Exten-
sive lists of arsenic concentrations in foodstuffs have
been published by the National Academy of Sciences
National Research Council (NRC, 1999). However, all
of the chemical forms of arsenic present in food have
not yet been established. Adair et al. (2006) reported
two chemical and enzymatic extraction methods fol-
lowed by IC-ICP-MS analysis for the analysis of DMA
and inorganic arsenic from rice cooked in arsenic-
contaminated water. Measured concentrations of
DMA ranged from 22 to 270 ngAs/g rice and of inor-
ganic arsenic ranged from 31 to 108 ngAs/g rice.
There is growing concern about the uptake of
­arsenic into certain plants (such as rice) from ­arsenic-
contaminated irrigation water, and this topic is consid-
ered in more detail in Chapter 6, “Toxic Metals in Food.”
This has been noted as a special problem for rice-based
infant foods (Burlo et al, 2012; Carbonell-Barrachina
et al., 2012), particularly for infants with celiac disease
who must consume gluten-free foodstuffs. For the gen-
eral population, a shift in a rice-based diet to one with
a lower arsenic content based on grains such as maize,
sorghum, or millet (Adomako et al., 2011) may reduce
dietary exposure to this element. Please see Chapter 6 for
a more complete discussion of arsenic in food.
Arsenic concentrations in marine organisms and
seaweed are, in general, considerably higher than
those in other foods. Many species of bony fish con-
tain between 1 and 10 mg/kg, whereas certain bottom-
feeding fish, crustaceans, and seaweed may contain
more than 100 mg As/kg (Lunde, 1973). Both lipid-
soluble and water-soluble organic arsenic compounds
have been isolated from marine organisms (Kurosawa
et al., 1980; Lunde, 1975; Penrose et al., 1977). Certain
algae grown in the presence of arsenate may contain
arsenophospholipids (Cooney et al., 1978; Irgolic et al.,
1977), whereas other researchers have shown that
brown kelp contains mainly arsenosugars (Edmonds
and Francesconi, 1981a). Arsenosugars are also found
in mussels, oysters, and clams (Le et al. 2004). Anaero-
bic decomposition of the brown kelp produces dimeth-
yloxarsylethanol, a possible precursor of arsenobetaine
(Edmonds et al., 1982). Arsenobetaine, the arsenic ana-
log of betaine, seems to be the most commonly occur-
ring water-soluble arsenical in fish and Crustacea
(Cannon et al., 1981; Edmonds and Francesconi, 1981b;
Edmonds et al., 1977; Kurosawa et al., 1980; Luten
et al., 1982). Indications of the presence of arsenocho-
line in some species have also been reported (Norin
and Christakopoulos, 1982). Arsenobetaine does not
seem to be harmful to humans and is excreted rapidly
and unchanged in urine (Cullen, 1998).
The amount of arsenic ingested daily by humans
through food is greatly influenced by the amount of
seafood in the diet. Jelinek and Corneliussen (1977)
noted that foods belonging to the meat, fish, and poul-
try groups contributed most of the arsenic ingested.
They estimated the average daily intake of arsenic
from food in the United States in the early seventies to
be 0.01-0.02 mg. A duplicate dietary study from Japan
(Mohri et al., 1990) reported daily dietary intake of
arsenic in four volunteers to be between 27 to 376 μg,
with a mean of 182 μg/day primarily as the methylate
arsenic species.
Schoof and colleagues (1999b) reported the analy-
sis of 40 commodities accounting for 90% of dietary
inorganic arsenic intake. Average inorganic arsenic in
seafood ranged from < 1 to 2 ng/g. The highest inor-
ganic arsenic concentrations were found in raw rice
(74 ng/g), followed by flour (11 ng/g), grape juice
(9 ng/g), and cooked spinach (6 ng/g). Schoof et al.
 28 Arsenic
(1999a) estimated that intake of inorganic arsenic in the
U.S. diet ranges from 1 to 20 μg/day, with a mean of
3.2 μg/day. Nriagu and Lin (1995) analyzed 26 brands
of wild rice sold in the United States and found arsenic
levels ranging from 0.006 to 0.142 μg/g dry weight. At
a mean level of chicken consumption of 60 g/­person/
day, Laskey et al. (2004) estimated that people may
ingest 1.38-5.24  μg/day of inorganic arsenic from
chicken.
Wine made from grapes sprayed with arsenic-­
containing insecticides may contain high levels of
­arsenic. Levels of up to 0.5 mg/L have been reported,
with most of the arsenic being in the trivalent inorganic
form (Crecelius, 1977a). Zoeteman and Brinkmann
(1976) reported a mean concentration of 0.02 mg/L
(range 0.001-0.19 mg/L) in bottled mineral water. The
arsenic in mineral water is probably of natural origin.
4.2 Water
Arsenic is widely distributed in surface water,
groundwater, and finished drinking water. Seawa-
ter generally contains 0.001-0.005 mg As/L (Ferguson
and Gavis, 1972). The arsenic concentration of rivers
and lakes varies considerably: most levels are well
below 0.01 mg/L, but in some instances they may even
be as high as about 1 mg/L (Andreae, 1978; Durum
et al., 1971; Sagner, 1973). A survey of 293 stations in
two nationwide sampling networks on major U.S.
rivers found median arsenic levels to be 1 μg/L; the
­75th-percentile level was 3 μg/L (Smith et al., 1987).
The natural concentration of total arsenic in ground-
water depends on the arsenic content of the bedrock.
Arsenic levels in groundwater average about 1-2 μg/L,
except in some western states of the USA with vol-
canic rock and sulfide mineral deposits high in arse-
nic, where arsenic levels up to 3.4 mg/L have been
observed (Robertson, 1989; Welch et al., 1988). Approx-
imately 13% of groundwater samples from 800 wells
in an area in Nova Scotia, Canada, where the arsenic
content of the bedrock is high, had concentrations
exceeding 0.05 mg As/L (Grantham and Jones, 1977).
Arsenic was detected in 1298 out of 3452 surface water
samples recorded in the STORET database for 2004 at
concentrations ranging from 0.138 to 1700 μg/L (EPA,
2005a). In Japan, concentrations of up to 1.7 mg As/L
have been recorded in hot-spring water (Kawakami,
1967). In Cordoba, Argentina, groundwater levels of
up to 3.4 mg As/L have been reported (Arguello et al.,
1938). In Taiwan, artesian well water has been shown
to contain up to 1.8 mg/L (Kuo, 1968).
Braman and Foreback (1973) and Crecelius (1977a,b)
noted several different forms of arsenic in natural
waters—arsenate, arsenite, methylarsonic acid, and
585
DMA—with the methylated forms generally in lower
concentrations than the inorganic ones. Andreae (1978)
reported that, in general, arsenate is the dominant form
in seawater. Clement and Faust (1973) found that only
approximately 8% of the total arsenic in well-aerated
stream water was in the form of As(III), whereas all
of the arsenic in anaerobic reservoirs seemed to be in
the form of As(III). The chemical form of arsenic in dif-
ferent groundwaters is largely unknown. Clement and
Faust (1973) found that 25-50% of the total arsenic in a
few groundwater samples was in the form of As(III).
The average daily intake of arsenic through drink-
ing water can vary widely, depending on the source of
the water. McCabe et al. (1970) reported that less than
1% of more than 18,000 community water supplies in
the United States had concentrations exceeding 0.01 mg
As/L. Engel and Smith (1994) investigated the levels of
arsenic in drinking water throughout the United States
between 1968 and 1984. They found that 30 counties
in 11 states had mean arsenic levels > 5 μg/L, 15 coun-
ties had mean levels of 5-10 μg/L, 10 counties had
mean levels of 10-20 μg/L, and 5 counties had levels
> 20 μg/L. The highest levels were found in Churchill
County, Nevada, where 89% of the population was
exposed to a mean arsenic concentration of 100 μg/L
and 11% to a mean of 27 μg/L. More recently, inves-
tigators at the U.S. Geological Survey (Focazio et al.,
2000) have developed an extensive map of the occur-
rence of arsenic in groundwater in the United States on
the basis of 18,850 sample locations; 2262 of these were
identified as public water supplies. The results of these
studies indicate a number of states in specific regional
areas (e.g. New England, the Midwest, the Rocky
Mountain states, and the Pacific Coast) with elevated
concentrations (> 10.0 μg/L) in the groundwater sup-
plies; therefore, the issue of elevated arsenic concentra-
tions in groundwater is national in scope. In January
2001, the U.S. Environmental Protection Agency pro-
posed lowering the Maximum Contaminant Level for
arsenic from 50 to 10 μg/L (EPA, 2001), with a compli-
ance date of 23 January, 2006 (http://water.epa.gov/
lawsregs/rulesregs/sdwa/arsenic/index.cfm).
With an assumed daily intake of 1.5 L drinking
water, a concentration of 0.01 mg/L will result in the
daily ingestion of 0.015 mg arsenic.
Some developing countries, such as Mexico, Bangla-
desh, India, and Vietnam, have highly elevated levels
of arsenic in drinking water in some regions (Bagla
and Kaiser, 1996; Berg et al., 2001; Tondel et al., 1999;
Wyatt et al., 1998a,b). In Bangladesh and West Bengal,
India, it is estimated that more than 1 million people
are drinking arsenic-contaminated water and tens of
millions more could be at risk in areas that have not
been tested for contamination. Analysis of 20,000
586 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
tube-well waters indicated that 62% have arsenic lev-
els above the WHO permissible exposure limit (PEL)
of 10 μg/L, with some as high as 3700 μg/L (Bagla and
Kaiser, 1996). Arsenic concentrations in water samples
from private small-scale tube-wells in Hanoi, Vietnam,
averaged 159 μg/L, ranging from 1 to 3050 μg/L (Berg
et al., 2001).
4.3 Soil
Arsenic is widely distributed in the Earth’s crust,
which contains about 3.4 ppm (Wedepohl, 1991). It
is mostly found in nature as minerals, and only to
a small extent in its elemental form. Typical arsenic
concentrations for uncontaminated soils range from
1 to 40 ppm (μg/g), with the lowest concentrations
found in sandy soils and soils derived from granites.
Higher arsenic concentrations are found in alluvial
soils and soils with a high organic content (Mandal
and Suzuki, 2002).
Soils in mining areas or near smelters may con-
tain high levels of arsenic. Arsenic concentrations up
to 27,000 mg/kg were reported in soils contaminated
with mine or smelter wastes (EPA, 1982). Soils at an
abandoned mining site in the Tamar Valley in south-
west England have arsenic concentrations that may
exceed 50,000 mg/kg (Erry et al., 1999).
Soil on agricultural lands treated with arsenical
pesticides may retain substantial amounts of arsenic.
A study reported an arsenic concentration of 22 mg/
kg in treated soil compared with 2 ppm in nearby
untreated soil (EPA, 1982). Soil samples from 13-year-
old fruit orchards in New York State, where lead arse-
nate had been used for pest control for many years,
had arsenic concentrations of 1.6-141 mg/kg (Merwin
et al., 1994).
Natural concentrations of arsenic in sediments are
usually < 10 μg/g dry weight, but can vary widely
around the world (Mandal and Suzuki, 2002). Contam-
ination by heavy metals is a serious problem in some
developing countries. Sepetiba Bay, a semi-enclosed
coastal lagoon in Brazil, had sediment arsenic concen-
trations up to 80,000 μg/g in an area adjacent to a plant
that produced zinc and cadmium (Moreira, 1996). The
literature regarding the cycling and effects of arsenic
in coastal marine environments has been reviewed by
Sanders et al. (1994).
It has recently been suggested that the wood pre-
servative, chromated copper arsenate, commonly used
in dock pilings and bulkheads, can be toxic to estua-
rine organisms. Wendt et al. (1996) measured arsenic
in surface sediments from creeks with high densities of
docks and from nearby reference creeks with no docks.
The average concentrations in the sediments ranged
from 14 to 17 μg/g throughout the study area, which is
within the range of natural background levels.
4.4 Air
Arsenic naturally occurs in soil and is present in
the atmosphere as airborne dust. It is also emitted
from volcanoes and is found in areas of dormant vol-
canism. Arsenic naturally occurs in seawater and veg-
etation, and is released into the atmosphere through
sea salt spray and forest fires (ATSDR, 2007). Smelting
of nonferrous metals, burning of coal, oil and wood
combustion, and the use of arsenicals as pesticides are
the major anthropogenic sources of airborne arsenic.
Chilvers and Peterson (1987) estimated global natu-
ral and anthropogenic arsenic emissions to the atmo-
sphere to be 73,500 and 28,100 metric tons per year,
respectively. Copper smelting and coal combustion
accounted for 65% of anthropogenic emissions. There
is evidence that anthropogenic emissions from smelt-
ers are lower now than they were in the 1980s. The
National Air Toxics Assessment reported the total
anthropogenic emissions of arsenic compounds in
the United States in 1996 to be 355 tons/year (EPA,
2005b).
Arsenic in ambient air is usually a mixture of
particular arsenite and arsenate (EPA, 2012). Mean
levels in ambient air in the United States have been
reported to range from < 1 to 3 ng/m3 in remote areas
and from 10 to 20 ng/m3 in urban areas. The 133 sta-
tions of the U.S. National Air Sampling Network
reported in 1964 that the annual average concentra-
tions of arsenic in air ranged from nondetectable
(< 0.01 μg/m3) to 0.75 μg/m3 (Sullivan, 1969). The
overall average was approximately 0.02 μg/m3. The
highest value (1.4 μg/m3) was a quarterly average
in El Paso, Texas, where a large copper smelter is
located. Daily mean concentrations of up to 1.6 μg/
m3 have been found near a smelter in Romania
(Gabor and Coldea, 1977).
Dousova and colleagues (2007) reported arse-
nic concentrations in ice and snow samples from the
Czech-Polish border taken for the two periods, 1984-
1986 and 2003-2005. They showed declines from
50 μg/L to 3 μg/L for ice and from 15 μg/L to < 2 μg/L
for snow. Inorganic arsenic, primarily as arsenic triox-
ide, has been reported from fossil fuel and industrial
processes (Pacyna, 1987). Arsenic trisulfide has also
been reported from coal combustion, organic arsines
from oil combustion, and arsenic trichloride from
refuse incineration.
Measurements of arsenic concentrations in cases
of occupational exposure have been rare. Patty (1962)
reported that the highest exposure in insecticide
 28 Arsenic
manufacturing was usually found in the mixing,
screening, drying, bagging, and drum-filling opera-
tions. He reported concentrations of arsenic in air
ranging from 0.5 to 45 mg/m3 during these operations.
High levels of exposure to arsenic fumes and dusts
may occur in the smelting industries. Lundgren (1954)
reported an average concentration ranging between
0.06 and 2 mg/m3 in a Swedish copper smelter. In a
Japanese copper refinery, arsenic concentrations in
the air of nine workshops were measured at 0.006-
0.011 mg/m3 under normally ventilated conditions
and 0.08-0.19 mg/m3 under unventilated conditions.
Average arsenic concentrations in the air of 0.001-
0.012 mg/m3 were found around furnaces in copper
and ferronickel smelters (Kodama et al., 1976).
When airborne arsenic in a U.S. copper smelter was
measured during 1943-1965, 8-h average levels in the
arsenic roaster, arsenic refinery, and main flue ranged
between 6.9 and 20 mg/m3 (Welch et al., 1982). Enter-
line and Marsh (1982) summarized some reports of
airborne arsenic concentrations in the area around an
arsenic plant in the United States for the period 1938-
1957. They found that levels varied but were very high,
particularly before 1951 (e.g. 0.8-62.4 mg/m3 in 1938).
All levels were very high in relation to the current PEL
of 0.01 mg/m3.
Substantial exposure to airborne arsenic may also
take place in individuals working with arsenic-con-
taining insecticides and wood preservatives. Han-
dling, including burning, of preserved wood could
also constitute a risk for the general population
(Peters et al., 1984). Nygren et al. (1992) investigated
occupational exposure to airborne dust, chromium,
copper, and arsenic in six joinery shops in Sweden,
where impregnated wood was used for production.
The mean airborne concentration of arsenic around
various types of joinery machines ranged from 0.54 to
3.1 μg/m3.
Workers at three microelectronics factories where
gallium arsenide was used have been reported to
have exposure at or above the Occupational Safety
and Health Administration (OSHA) action level for
arsenic of 5 μg/m3, with a maximum exposure of
8.2 μg/m3 (Sheehy and Jones, 1993). The toxicologi-
cal literature and carcinogenic potential of gallium
arsenide (GaAs) have been recently reviewed by the
International Agency for Research on Cancer (IARC,
2006), and GaAs was identified as a Class I human
carcinogen on the basis of the inorganic arsenic
component.
The current OSHA PEL is 0.010 mgAs/m3 [time-
weighted average (TWA)]. The American Conference of
Governmental Industrial Hygienists (ACGIH) thresh-
old limit value (TLV) is 0.01 mgAs/m3 (TWA) (NIOSH,
587
2006a). For arsine, the OSHA PEL is 0.05 mgAs/m3
(TWA). The ACGIH TLV for arsine is 0.05 mg/m3
(NIOSH, 2006b).
4.5 Tobacco
Arsenic in tobacco originates from insecticides,
especially lead arsenate. In the past, the arsenic con-
tent of various brands of American cigarettes averaged
12.6 μg/cigarette in 1932-1933 and increased to 42 μg/
cigarette in the early 1950s (Satterlee, 1956). After the
ban of arsenical pesticides, maximum arsenic levels
were reduced to 3 μg/g (Kraus et al., 2000). An inter-
national literature survey reports arsenic emissions of
0-1.4 μg/cigarette from mainstream (inhaled) cigarette
smoke (Smith et al., 1997). Arsenic emissions of 0.015-
0.023 μg/cigarette have been measured for sidestream
smoke from a burning cigarette (Landsberger and Wu,
1995). In Japan, cigarettes have been reported to con-
tain less than 1 μg/g (Maruyama et al., 1970).
5 METABOLISM
This section on arsenical metabolism is focused on
historical descriptive in vivo information related to
biological monitoring of arsenic in humans and ani-
mal models. Section 5.6.1 reviews more mechanistic
studies of arsenical metabolism and the relationships
between the formation of methylated arsenic species
and mechanisms of toxicity at the cellular and molecu-
lar levels of biological organization.
5.1 Absorption
5.1.1 Inhalation
Airborne arsenic is usually in the form of As2O3.
More than 23% of the particles (by particle count) in
samples of arsenic-polluted air were reported to be
larger than 5.5 μm (Pinto and McGill, 1953). Particles of
this nature will undergo a high rate of deposition in the
upper respiratory tract. As a result of deposition in the
nasopharyngeal region and mucociliary clearance in
the airways, much of the inhaled arsenic may be swal-
lowed and then absorbed from the gastrointestinal
tract. Analytical data on fly ash emitted from a coal-
fired power plant have indicated a pronounced con-
centration of arsenic in particles of 1.1-2.1-μm diameter
(Davison et al., 1974).
Very few data are available on the deposition and
absorption of inhaled arsenic in humans. In eight ter-
minal lung cancer patients, Holland et al. (1959) esti-
mated deposition to be approximately 40%, of which
75-85% was absorbed; thus, the overall absorption
588 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
(expressed as a percentage of inhaled arsenic) was
approximately 30-34%. However, great caution must be
exercised when relating these data to healthy humans.
In workers exposed to arsenic trioxide dusts in smelt-
ers, the amount of arsenic excreted in the urine (the
main route of excretion) was approximately 40-60% of
the estimated inhaled dose (Pinto et al., 1976; Vahter
et al., 1986). Absorption of arsenic trioxide dusts and
fumes (assessed by the measurement of urinary metab-
olites) correlated with TWA arsenic air concentrations
from personal breathing zone air samplers (Offergelt
et al., 1992). In contrast, arsenic sulfide and lead arse-
nate were cleared slowly (Marafante and Vahter, 1987),
indicating that the rate of absorption may be lower if
the inhaled arsenic is in a highly insoluble form.
5.1.2 Ingestion
Both human and animal data indicate that more
than 90% of an ingested dose of dissolved inorganic
trivalent or pentavalent arsenic is absorbed from the
gastrointestinal tract (Bettley and O’Shea, 1975; Char-
bonneau et al., 1978; Crecelius, 1977b; Marafante et al.,
1981; Pomroy et al., 1980; Vahter and Norin, 1980). The
most direct evidence is from a study that evaluated the
6-day elimination of arsenic in healthy humans given
water from a high-arsenic sampling site; it reported
approximately 95% absorption (Zheng et al., 2002). In
contrast, ingestion of arsenic triselenide did not lead
to a measurable increase in urinary excretion (Mappes,
1977), indicating that gastrointestinal absorption may
be much lower when highly insoluble forms of arse-
nic are ingested. Recent studies (Calatayud et al., 2012)
have implicated intestinal transporters in the absorp-
tion of inorganic arsenic species, and help to explain
on a mechanistic level the relatively high absorption
of inorganic arsenicals from the gastrointestinal tract
noted above. Other studies (Drobna et al., 2010) of arse-
nic membrane transporters in the human liver found
that the retention of inorganic arsenic and methylated
metabolites in human hepatocytes exposed to submi-
cromolar concentrations of As3+ was negatively associ-
ated with expression of the Canalicular multispecific
organic anion transporter 1/multidrug resistance-
associated protein 2 (MRP2). Expression of MRP2 was
positively associated with the production and release
of DMA species into the cell culture medium. At ele-
vated micromolar exposures of As3+, which inhibited
the formation of MMA and DMA species, there was a
positive association between expression of solute car-
rier family 2, facilitated glucose transporter member 2
(GLUT2) and hepatocyte retention of inorganic arsenic
and MMA species. The dose-dependent aspects of these
findings may be important for explaining the in vivo
dose-dependent effects of methylated arsenic species
in humans. Organic arsenic compounds in seafoods
are also readily absorbed (< 80%) from the gastrointes-
tinal tract in both animals and humans (Charbonneau
et al., 1978; Marafante et al., 1984; Munro, 1976; Tam
et al., 1982; Vahter et al., 1983). On the basis of uri-
nary excretion studies in volunteers, it seems that both
MMA and DMA are well absorbed (by at least 75-85%)
across the gastrointestinal tract (Buchet et al., 1981a).
Animal experiments indicate that growth promoters,
such as arsanilic acid, are absorbed to only 15-40%
(Calvert, 1975).
In the case of arsenic trioxide, which is only slightly
soluble in water, gastrointestinal absorption depends
on factors such as particle size and the pH of the gas-
tric juice.
5.1.3  Skin Absorption
Systemic toxic effects have resulted from occupa-
tional accidents in which arsenic acid or arsenic tri-
chloride has been splashed onto workers, indicating
that the skin is a possible route for arsenic absorption
(Garb and Hine, 1977). However, no quantitative stud-
ies have been located on the absorption of inorganic
arsenicals in humans after dermal exposure. Percu-
taneous absorption of 73As as arsenic acid has been
measured in skin from cadavers (Wester et al., 1993).
Labeled arsenic was applied to skin in diffusion cells,
and transit through the skin into receptor fluid mea-
sured. After 24 h, 0.93% of the dose passed through the
skin, and 0.98% remained in the skin after washing.
Dermal absorption of arsenic has been measured in
Rhesus monkeys (Wester et al., 1993). After 24 h, 6.4%
of 73 As as arsenic acid was absorbed systemically.
5.2  Transport and Distribution
After absorption by the lungs or the gastrointestinal
tract, arsenic is transported by the blood to other parts
of the body. After exposure to arsenite or arsenate,
most arsenic is cleared from the blood (Charbonneau
et al., 1978; Marafante et al., 1981; Mealey et al., 1959).
In rats, however, a substantial part of the absorbed
arsenic accumulates in red blood cells, where it is
firmly bound to hemoglobin (Hisanaga, 1982; Mara-
fante et al., 1982). Data from a number of investiga-
tors indicate that the main form of arsenic bound to
rat hemoglobin is DMA (Lerman and Clarkson, 1983;
Rowland and Davies, 1982; Vahter et al., 1984). As a
consequence of the efficient biotransformation of both
trivalent and pentavalent inorganic arsenic in vivo
(see later), tissue partitioning is somewhat similar for
the different forms of exposure. In humans as well as
 28 Arsenic
in most animal species, exposure to either arsenite or
arsenate leads to an initial accumulation in the liver,
kidneys, and lungs (Bertolero et al., 1981). Tissue anal-
ysis of organs taken from an individual after death
from ingestion of 3 g arsenic (in the form of arsenic tri-
oxide) showed a much higher concentration of arsenic
in the liver (147 μg/g) than in the kidney (27 μg/g) or
muscle, heart, spleen, pancreas, lungs, or cerebellum
(11-12 μg/g) (Benramdane et al., 1999). Small amounts
were also found in other parts of the brain (8 μg/g), in
the skin (3 μg/g), and in hemolyzed blood (0.4 μg/g).
Clearance from these tissues is, however, rather rapid;
in contrast, long-term retention of arsenic is seen in the
hair, skin, squamous epithelium of the upper gastroin-
testinal tract, epididymis, thyroid, lens, and skeleton
(Lindgren et al., 1982). Human autopsy data have also
shown high arsenic levels in the hair, nails, teeth, bone,
and skin (Kadowaki, 1960; Liebscher and Smith, 1968;
Sumino et al., 1975; Yukawa et al., 1980).
Arsenic passes through the placenta in hamsters
after intravenous injections of high doses of sodium
arsenate (Ferm, 1977). Kadowaki (1960) reported
that arsenic levels in the human fetus increased as
pregnancy progressed. Arsenic levels in bone, liver,
skin, and brain were 2-4 times higher in newborn
babies than in 7-month-old fetuses. In a population of
Andean women exposed to high concentrations (about
200 ppb) of inorganic arsenic in drinking water, arsenic
concentrations in breast milk ranged from about 0.0008
to 0.008 ppm (Concha et al., 1998a,b).
Although the distribution patterns seen after expo-
sure to different chemical forms of inorganic arsenic
are similar, recent studies in mice and rabbits have
shown that arsenite gives rise to higher concentrations
than arsenate in most tissues (Lindgren et al., 1982;
Vahter and Marafante, 1983; Vahter and Norin, 1980).
Only the kidneys and the skeleton had higher levels
in arsenate-treated than in arsenite-treated animals.
In mice, radiolabel from orally administered 74As was
widely distributed to all tissues, with the highest lev-
els in the skin, kidney, and liver (Hughes et al., 2003).
The major portion of injected radioactive arsenic accu-
mulated in the mammalian tissues has been found in
the protein fraction (Marafante et al., 1981). Trivalent
arsenicals can chemically combine with sulfhydryl
groups, which may explain their inhibition of enzy-
matic reactions (Webb, 1966), as well as their accumu-
lation in keratin-rich tissues such as hair, skin, and the
epithelium of the upper gastrointestinal tract.
It has also been found that the toxic effects of arsenic
can be reversed by parenteral administration of sulfhy-
dryl/thiol (SH) compounds of the reduced type, e.g.
glutathione, cysteine, and dimercaprol/British anti-
Lewisite (BAL) (Peters, 1955; Vallee et al., 1960; Webb,
589
1966). Arsenate, on the other hand, may interfere
with metabolic phosphorylation reactions, probably
because of its chemical similarity to phosphate (Fowler
et al., 1975; Mitchell et al., 1971). Such chemical simi-
larities can also explain the accumulation of arsenate
in the skeleton (Lindgren et al., 1982, 1984).
When particles of inorganic arsenic compounds
such as arsenic trioxide, calcium arsenate, and arsenic
trisulfide were endotracheally instilled into the lung
of rats or hamsters, arsenic trioxide and arsenic trisul-
fide rapidly disappeared from the lung, decreasing to
a level of approximately 0.1-1% of the given dose over
a period of 24 h to 1 week. However, half of the dose of
calcium arsenate given to Syrian Golden hamsters was
retained in the lung for 1-5 weeks (Inamasu et al., 1982;
Pershagen et al., 1984).
In hamsters, MMA and DMA formed in vivo by the
methylation of inorganic arsenic seem to be distrib-
uted to all tissues (Takahashi et al., 1988; Yamauchi
and Yamamura, 1985). This is supported by studies
in animals in which MMA and DMA were found in
all tissues after acute oral doses (Yamauchi and Yama-
mura 1984; Yamauchi et al., 1988). Studies on the tissue
distribution of arsenobetaine in mice and rabbits have
shown that this arsenical is rapidly cleared from most
tissues (Vahter et al., 1983). The longest retention was
observed in cartilage, testes, epididymis, and muscles.
Animal data indicate that arsenocholine, like choline,
may be incorporated into phospholipids (Marafante
et al., 1984).
5.3 Biotransformation
The biotransformation of inorganic arsenic is com-
plicated by the different metabolites induced and by
differences among species. Two basic processes are
involved: (1) reduction/oxidation reactions that inter-
convert As(III) and As(V), and (2) methylation reac-
tions, which convert arsenite to MMA and DMA. The
resulting series of reactions result in the reduction of
inorganic arsenate to arsenite (if necessary), methyla-
tion to MMA(V), reduction to MMA(III), and methyla-
tion to DMA(V). These processes seem to be similar
whether exposure is by the inhalation, oral, or paren-
teral route.
That trivalent inorganic arsenic is oxidized in vivo
is indicated by the identification of pentavalent arse-
nic in the urine of both animals and humans exposed
to arsenite (Bencko et al., 1976; Mealey et al., 1959;
Vahter and Envall, 1983). The opposite reaction (i.e. the
reduction of arsenate to arsenite) has also been demon-
strated in mice and rabbits (Vahter and Envall, 1983).
Both arsenite and arsenate, after reduction to arsenite
(McBride et al., 1978), are methylated in vivo. The
590 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
major metabolite present in the urine of experimental
animals exposed to inorganic arsenic is DMA (Ber-
tolero et al., 1981; Charbonneau et al., 1979; Inamasu,
1983; Tam et al., 1978; Vahter, 1981). Guinea pigs, mar-
mosets, and tamarin monkeys do not methylate inor-
ganic arsenic (Healy et al., 1998; Vahter and Marafante,
1985; Vahter et al., 1982; Zakharyan et al., 1996). Expo-
sure of humans to either arsenites or arsenates results
in increased levels of inorganic As(III), As(V), MMA,
and DMA in the urine (Aposhian et al., 2000a,b). In
humans, urinary excretion at low dose levels consists
of approximately 20-25% inorganic arsenic, 15-25%
methylarsonic acid, and 40-75% DMA (Buchet et al.,
1981a; Crecelius, 1977b; Hopenhayn et al., 2003; Lof-
fredo et al., 2003; Mandal et al., 2001; Smith et al., 1977;
Tam et al., 1979; Yamauchi and Yamamura, 1979a,b).
Methylation efficiency decreases with increasing dose
levels (Mahieu et al., 1981; Vahter, 1981). The sub-
strate for methylation is As(III); As(V) is not methyl-
ated unless it is first reduced to As(III) (Buchet and
Lauwerys 1985, 1988; Lerman et al., 1983). Reduction
of arsenate to arsenite can be mediated by glutathi-
one (Menzel et al., 1994). The main site of methylation
seems to be the liver, where the methylation process
is mediated by methyltransferases that use S-adeno-
sylmethionine as a cosubstrate (Buchet and Lauwerys,
1985, 1988). The relative proportions of As(III), As(V),
MMA, and DMA in urine can vary, depending on the
chemical administered, time after exposure, dose level,
and exposed species. Arsenic derived from exposure to
particles of GaAs or InAs is methylated in manner sim-
ilar to that of As(III) (Yamauchi et al., 1986, 1992).With
relatively constant exposure levels, these metabolic
proportions remain similar over time (Concha et al.,
2002) and seem to be similar among family members
(Chung et al., 2002). It is expected that measurements
of MMA and DMA in urine will provide useful infor-
mation for risk assessment purposes once the relation-
ships between the in vivo formation of these major
metabolites of inorganic arsenic and risk of toxicity or
cancer are more fully delineated.
In this regard, a number of recent studies have
focused on arsenic methyltransferase and polymorphic
forms of this enzyme (AS3MT) in particular as being
of central importance in the generation of methylated
arsenical metabolites in animals (Drobna et al., 2009;
Hughes et al., 2010), and hence in tissue dosimetry of
methylated arsenical species. Other recent studies in
mice (García-Montalvo et al., 2011) reported the dose-
dependent formation of methylated arsenic species in
urine, indicating that the methylation process is subject
to saturation and/or inhibition at higher doses of arse-
nite. This information is potentially useful in the devel-
opment of a biologically based dose-response model in
mice. Polymorphic forms of the AS3MT enzyme sys-
tem, either alone or in combination with polymorphic
forms of enzymes such as glutathione S-transferase
(GST), in humans may play a role in explaining dif-
ferences in susceptibility to the various clinical mani-
festations of arsenical toxicity (Fujihara et al., 2010;
Gomez-Rubio et al., 2010; Song et al., 2011; Paiva et al.,
2010). AS3MT and low-level arsenic exposure has been
recently linked to cardiovascular diseases in several
rural counties in Texas (Gong and O’Bryant, 2012).
Other studies (Sampayo-Reyes et al., 2010) that exam-
ined arsenic-induced genotoxicity in Mexican chil-
dren environmentally exposed to arsenic in drinking
water reported that DNA damage was modulated by
both AS3MT and GSTO1 alleles. Wide variations in the
relative abundance of genetic variants of the AS3MT
system have been reported by Fujihara et al. (2011)
who studied Mexican and German populations. Stud-
ies into arsenic metabolism by human gastrointestinal
flora following incubation with arsenic-contaminated
soils reported extensive formation of MMA species
and suggested that future arsenic toxicokinetic stud-
ies should take presystemic metabolism of arsenical by
gastrointestinal flora into account in order to improve
aspects of risk characterization. These data suggest
that epidemiological studies in arsenic-exposed popu-
lations should consider the interactive effects of other
relevant enzyme systems that may be involved in cell
injury processes. Studies in Taiwan (Hsu et al., 2011)
did not find a close correlation between various GST
alleles and urothelial carcinoma except for GSTO1 and
GSTT1 at high arsenic exposure concentrations. Per-
sons living in the Red River Delta area of Vietnam have
also been recently reported (Agusa et al., 2012) to show
variations in arsenic metabolism in relation to GST and
AS3MT polymorphic forms.
Arsenobetaine appears not to be biotransformed
in vivo, but is excreted unchanged mainly in urine
(Cannon et al., 1981; Vahter et al., 1983). Arsenocholine
is, to a great extent, oxidized to arsenobetaine (Mara-
fante et al., 1984).
DMA and arsanilic acid are not converted to inor-
ganic arsenic in vivo (Buchet et al., 1981a; Marafante
et al., 1987; Stevens et al., 1977; Vahter et al., 1984;
Yoshida et al., 2001).
5.4 Excretion
The major route of excretion after exposure to inor-
ganic arsenic is through the kidneys. Only a low per-
centage is excreted in the feces (Apostoli et al., 1999;
Bertolero et al., 1981; Hunter et al., 1942; Mealey et al.,
1959). The rate of urinary excretion varies, depend-
ing on the chemical form of arsenic and the species
 28 Arsenic 591

exposed, as seen in a national survey of U.S. residents 5.5  Biological Half-Time

(Caldwell et al., 2009; CDC, 2013). The primary forms
Animals exposed to arsenic through inhalation or
of arsenic found in the urine of inhalation-exposed
drinking water will have increased tissue levels dur-
humans are DMA and MMA, with inorganic arsenic
ing the first weeks or months, but the levels will then
making up < 25% of the total urinary arsenic (Apostoli
decrease even if the exposure is prolonged (Bencko and
et al., 1999). In humans exposed to a single low dose of
Symon, 1969, 1970; Hisanaga, 1982; Katsura, 1958). It
arsenite, approximately 35% was excreted in the urine
has been suggested that the decrease of arsenic concen-
over a period of 48 h (Buchet et al., 1980, 1981a). At
trations in internal organs, such as the liver, after long-
low exposure levels, urinary arsenic levels generally
term exposure may be due to a higher rate of excretion.
increase linearly with increasing arsenic intake (Calde-
Changes in tissue retention in the case of chronic expo-
ron et al., 1999). Rabbits exposed to a similar low dose
sure should therefore be considered when evaluating
excrete approximately 80% (Bertolero et al., 1981), mice
biological half-times for arsenic compounds.
as much as 90% (Vahter, 1981), and marmoset monkeys
The biological half-time of arsenic in rats after
as little as 15% within the same period of time (Vahter
a single exposure is long (approximately 60 days)
et al., 1982). In the case of continuous human intake
because of the accumulation of arsenic in the blood.
over a few days, 60-70% of the daily dose is excreted
In humans and other animals, the major proportion of
in the urine (Buchet et al., 1981b; Mappes, 1977). After
arsenic is eliminated at a much higher rate. Generally,
exposure to arsenate, the limited human data available
whole body clearance is fairly rapid, with half-times
indicate a rate of excretion similar to that for arsenite
of 40-60 h in humans (Buchet et al., 1981b; Mappes,
(Pomroy et al., 1980; Yamauchi and Yamamura, 1979b).
1977). Three different phases of urinary excretion have
Animal data indicate a somewhat faster excretion rate
been demonstrated in humans after a single intrave-
for arsenate than for arsenite (Charbonneau et al., 1978;
nous injection of radiolabeled arsenite, with half-times
Hollins et al., 1979; Vahter, 1981).
of approximately 2 h, 8 h, and 8 days, respectively
During lactation, a very small percentage of ingested
(Mealey et al., 1959). After oral intake of radiolabeled
arsenic may also be excreted in breast milk (Concha
pentavalent arsenic, 66% was excreted with a half-time
et al., 1998a). Other routes of elimination of inorganic
of 2.1 days, 30% with a half-time of 9.5 days, and 3.7%
arsenic, although of less importance, include the skin,
with a half-time of 38 days in the three phases (Pomroy
hair, nails, and sweat (Molin and Wester, 1976).
et al., 1980).
Studies in humans indicate that ingested MMA
As stated previously, the major proportion of arse-
and DMA excreted are mainly in the urine (75-85%),
nic in ingested seafood is rapidly eliminated through
and that this mostly occurs within 1 day (Buchet
the kidneys. The biological half-time for these organic
et al., 1981a). After ingestion, by humans, of organic
compounds is estimated to be less than 20 h. Studies
arsenic compounds present in seafoods, 50-80% of
in humans indicate that ingested MMA and DMA are
the dose was eliminated in the urine within 2 days
mainly excreted in the urine (75-85%), and this occurs
(Tam et al., 1982). A similar rate of excretion was
mostly within 1 day (Buchet et al., 1981a).
seen in rabbits exposed to arsenobetaine (Vahter
The WHO International Programme on Chemical
et al., 1983).
Safety (WHO/IPCS, 2001) has examined a number of
The elimination of organic arsenic compounds used
issues related to the roles of elemental speciation in
as drugs was noted by Hogan and Eagle (1944). They
human health risk assessment.
found that trivalent organic arsenicals were elimi-
nated much more slowly than pentavalent arsenicals
in the urine of rabbits. More recent studies by Lin et al. 5.6  Mechanisms of Arsenical Toxicity
(2005) reported that the tissue-specific distribution and
5.6.1  Mechanisms of Arsenical Metabolism and
elimination rates for inorganic and methylated arsenic
Toxicity
species in rabbits after a single acute administration
of arsenic trioxide (AsIII) over a dose range of 0.2- Arsenical inhibition of cellular respiration as a pri-
1.5 mgAs/kg for up to 30 and 60 days. The elimination mary cause of cell death has been appreciated for a
pattern was nonlinear; the liver and lung showed the number of decades (ATSDR, 2007; NRC, 1999, 2001),
highest concentrations of DMA, which was the major and the methylation of inorganic arsenic to form meth-
metabolite measured, on day 30. Similar organ-specific ylated species such as MMA and DMA has also been
differences were observed in B6C3F1 mice after acute studied for a number of decades (Braman and Fore-
oral administration of arsenate [As(V)]. As for the rab- back, 1973; Challenger, 1945, 1951). In recent years, sci-
bits, DMA was the predominant methylated species at entific attention has focused on trying to understand
later time points (Kenyon et al., 2005). the relationships that must exist between the in vivo
592 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
methylation of inorganic arsenic and mechanisms of
arsenical toxicity. This issue is of great practical impor-
tance because the methylation of inorganic arsenic
was originally thought to be a detoxification pathway;
however, more recent studies (NRC, 1999) have sug-
gested that highly toxic reactive oxygen species (ROS)
generated by MMA(III) and DMA(III) mitochondrial
toxicity may also play an important role in both the
cellular toxicity and carcinogenicity of this element.
The increased presence of MMA(III) in the urine of a
Mexican population exposed to inorganic arsenic in
drinking water on a chronic basis was found to form
the basis for identifying subpopulations at a greater
risk of arsenic-induced toxicity and cancer (Steinmaus
et al., 2005a,b; Valenzuela et al., 2005). These studies
also reported a strong link between dietary intakes of
protein and other nutrients and the ability to meth-
ylate arsenicals such that persons with low dietary
intakes of these nutrients would be more susceptible
than others to arsenic-induced cancers. The central role
of oxidative stress induced by arsenic in cell death via
apoptosis or necrosis and carcinogenicity via oxidative
damage to cellular DNA cannot be underestimated
because it may permit attenuation of these deleterious
cellular effects through nutritional interventions and
stimulation of the cellular antioxidant systems.
5.6.2 Metabolism
The focus in this section on arsenical metabolism
is to review mechanistic linkages between the mecha-
nisms of inorganic arsenical methylation and mecha-
nisms of toxicity at the cellular and molecular levels of
biological organization.
5.6.2.1  Arsenical Reduction/Oxidation
A key step in the methylation pathway for inorganic
arsenicals is the reduction and oxidation of arsenic
between the −3, +3, and +5 oxidation states during the
various steps in the methylation pathway. Styblo and
Thomas (1995) reported the inhibition of glutathione
reductase by arsenoglutathione in vitro and demon-
strated that reduced glutathione (GSH) was required
for the in vitro methylation of arsenic.
More recent studies by Nemeti and Gregus (2005)
demonstrated the reduction of As5+ to As3+ in human
erythrocyte lysates and rat liver cytosol through an
arsenic reductase, which required glycolytic substrates,
GSH, and nicotinamide diamide (NAD) for its enzyme
activity. Zakharyan et al. (2005) studied the interaction
of selenite with the omega class human glutathione
S-transferase [GSTO-1; identical to monomethylar-
sonic acid reductase (MMA(V) reductase)], which cata-
lyzes the reduction of As(V), MMA(V), and DMA(V).
They found that selenite acts as a noncompetitive
inhibitor of this enzyme. The tissue dosimetry of pen-
tavalent and trivalent MMA was studied by Hughes
et al. (2005), who found that a much greater percentage
of the administered dose of MMA(III) was converted
to DMA than after administration of MMA (V).
5.6.2.2  Arsenical Methylation
The main characteristics of the pathway for inor-
ganic arsenic methylation have been established since
the pioneering work of Challenger (1945, 1951). The
pathway involves a series of reductions and oxidation
steps which interconvert As5+ to As3+ to As5+ during
the methylation steps, ultimately resulting in the for-
mation of MMA(V) and DMA(V). The further metabo-
lism and excretion of DMA and trimethylarsine oxide
has been extensively studied in rodents by Yamau-
chi and coworkers (Yamauchi and Yamamura, 1984;
Yamauchi et al., 1989, 1990). The enzyme responsible
for the reduction of As(V) to As(III) has not yet been
identified, but a GSH- and NAD-dependent As(V)
reductase activity linked to glycolysis was identified
in rat liver cytosol and human erythrocyte lysate by
Nemeti and Gregus (2005). During this metabolism,
MMA(III) and DMA(III) are also formed, and MMA(III)
and DMA(III) in particular have been demonstrated to
be highly toxic and reactive chemical species (Mass
et al., 2001). The kinetics of in vitro arsenic methyla-
tion in mouse hepatocytes were reported by Kedderis
et al. (2006), who found a concentration-dependent
formation of MMA(III) up to a concentration of about
2 μmol/L As(III), followed by a decline at higher con-
centrations. They also suggested a role for a glutathi-
one complex-based mechanism in this methylation
pathway. This hypothesis is consistent with obser-
vations from a number of other laboratories (Chang
et al., 1991; Csanaky et al., 2003; Hayakawa et al., 2005;
Hirano et al., 2004; Kala et al., 2004; Kobayashi et al.,
2005; Waters et al., 2004). The formation of arsenic-glu-
tathione complexes has also been reported (Cui et al.,
2004; Suzuki et al., 2001) to play important roles in the
biliary and urinary excretion of arsenic in rats.
In recent years, an arsenic methyltransferase
(AS3MT) has been identified (Drobna et al., 2005; Li
et al., 2005; Wood et al., 2006) and demonstrated to
exist in a number of polymorphic forms (Wood et al.,
2006). Zakharyan et al. (2005) studied the interactions
of arsenic species with selenite, glutathione, and the
omega class of human glutathione transferase. They
found that human MMA(V) reductase and human
GSTO-1 were identical proteins, and that selenite inhi-
bition of MMA(V) formation was reversed by dithioth-
reitol but not by GSH, which is the required substrate
of this enzyme. They found that three selenium atoms
 28 Arsenic
and three GSH molecules were bound to the mono-
meric form of the enzyme. This enzyme and its dem-
onstrated polymorphic forms may well explain the
differences in methylation patterns observed in both
animals and humans (NRC, 1999), as well as differ-
ences in susceptibility to a variety of toxic effects
including various cancers (Smith et al., 2006), hepato-
megaly (Guha Mazumder et al., 2005), and heme and
porphyrin metabolism (Fowler et al., 2005; Garcia-
Vargas et al., 1994; Ng et al., 2005; Woods and Fowler,
1978; Yamauchi et al., 1998).
5.6.3  Mechanisms of Arsenical Toxicity
5.6.3.1  Mitochondrial Inhibition and Oxidative Stress
Arsenical inhibition of mitochondrial respiration
supported by NAD-linked substrates that use the
lipoic acid cofactor for the pyruvate dehydrogenase
complex is regarded to be a primary mechanism by
which arsenicals produce cell injury/cell death and
cancer (Fowler and Woods, 1979; Fowler et al., 1979;
Chen et al., 1986; NRC, 1999). Inorganic arsenicals,
MMA, and DMA have each been shown to produce
oxidative stress by means of inhibiting mitochondrial
respiration, resulting in the formation of ROS, which
may cause DNA mutations and ultimately play a role
in the development of cancer (Liu et al., 2005). In addi-
tion, either acute or chronic exposure to arsenicals
was shown to produce a characteristic porphyrinuria
pattern in experimental animals (Conner et al., 1993,
1995; Fowler et al., 2005; Woods and Fowler, 1978) and
humans (Garcia-Vargas et al., 1994; Garcia-Vargas and
Hernandez-Zavala, 1996; Ng et al., 2002, 2005; Yamau-
chi et al., 1998), dominated by elevated levels of uro-
porphyrins with lesser amounts of coproporphyrin.
This pattern is, hence, conserved across species and
may serve as a useful biomarker for early arsenical
toxicity to target organs such as the liver and hemato-
poietic system. It should also be noted that porphyrins
are also toxic and capable of catalyzing the formation
of ROS, thus exacerbating direct arsenical toxicity.
5.6.3.2  Reactive Oxygen Species
The ROS generated by inhibition of mitochondrial
respiratory function and ATP depletion (Chen et al.,
1986) produce oxidative stress in a number of major
organ systems (Flora et al., 2005; Li et al., 2002; Ramos
et al., 1995) and elicit a number of cellular responses,
including upregulation of glutathione synthesis (Flora
et al., 2005), induction of the major stress protein fam-
ilies (Lee et al., 2005; Madden et al., 2002; Sen et al.,
2005), and altered regulation of signaling pathways
involving nitric oxide synthetase/endothelial nitric
oxide synthase (eNOS) (Tsou et al., 2005), and nuclear
593
factor-kappa-B (NF-κB) and activator protein-1 (AP-1)
(Felix et al., 2005). These various cellular responses to
arsenical-induced oxidative stress are discussed later
in greater detail.
5.6.3.3  Antioxidant Cellular Defense Systems
5.6.3.3.1  Glutathione  A major intracellular antioxi-
dant is GSH, which exists in many cell types at mil-
limolar concentrations. Increased production of this
small SH-rich molecule may occur by induction of
glutathione synthetase in response to ROS-mediated
oxidative stress. Glutathione depletion studies using
1-butathionine sulfoximine have produced increased
sensitivity among cells exposed to arsenic(III) in vitro
(Maiti and Chatterjee, 2001; Shimizu et al., 1998), indi-
cating the importance of this intracellular antioxidant
molecule in mediating arsenical toxicity in target cell
populations.
5.6.3.4  Stress Proteins/Heat Shock Proteins (HSPs 25/27,
32, 60, 70, and 90)
Arsenicals are known to induce a number of the
major stress protein families, presumably as a conse-
quence of ROS formation with the attendant oxidation
of protein side chains and the onset of proteotoxicity.
Cells of a similar nature vary in their susceptibility to
arsenicals, partly because of their ability to produce
stress proteins. This was demonstrated by Madden
et al. (2002), who showed that rat and human kidney
cell lines varied in their sensitivity as a function of 60-,
70-, and 90-kDa stress protein expression patterns. For
both cell lines, toxicity occurred once the capacity to
produce the stress proteins was exceeded at elevated
dose levels. Similar results have been reported for
HSp70 in lung cells (Han et al., 2005; Lau et al., 2004)
and in human epidermal cells (Lee et al., 2005). Similar
responses have been observed in female rat urothelial
cells after in vivo exposure to DMA for 28 days (Sen
et al., 2005) and the human UROtsa cell line exposed to
arsenite (Rossi et al., 2002). Arsenite induction of heat
shock 70 kDa protein (HSp70) has been consistently
observed by a number of investigators in a variety
of cell types, including hepatoma cell lines (Farzaneh
et al., 2005; Gottschalg et al., 2006), human MCF-7
breast cancer cells (Barnes et al., 2002), human lung
fibroblasts (HEL cells), human leukemia cells (THP-1
cells) (Rossner et al., 2003), rat oligodendrocytes
(Goldbaum and Richter-Landsberg, 2001), and chick
embryos (Papaconstantinou et al., 2003).
In addition to the major stress family proteins, the
formation of ROS also induces the SH-rich protein
metallothionein (MT), which also has antioxidant prop-
erties (Gottschalg et al., 2006; Liu et al., 2001). It should
also be noted that studies by Shimizu et al. (1998)
594 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
reported that zinc induction of MT exerted no discern-
ible protective effects on arsenical toxicity; therefore,
the potential mechanisms of protection against arseni-
cal toxicity may be complex and system dependent.
The lower molecular mass HSP25(rat)/HSP27(human)
have also been reported to be induced by arsenite
exposure in mouse kidney podocyte cultures (Eichler
et al., 2005, 2006) and also seem to play major roles in
the regulation of apoptosis via the extrinsic caspase-8
pathway (Eichler et al., 2006). It is interesting to note
that arsenic(III) induction of the stress protein response
for HSP27 and HSP70 has been shown to be regulated
by reducing agents such as dithiothreitol (Kato et al.,
1997) and by reduced levels of GSH in arsenic-exposed
cells (Ito et al., 1998), indicating the strong link between
arsenic-induced oxidative stress and stress protein
induction patterns. In addition, arsenite exposure of
cells has also been well documented to induce HSP32/
heme oxygenase 1 (HO-1), which is the rate-limiting
enzyme in the heme degradative pathway (Gong et al.,
2002; Lee et al., 2005) and plays a major role in the recy-
cling of heme iron.
5.6.3.5  Altered Cell Signaling Pathways
Arsenic-induced alterations of the blood vasculature
leading to the development of “Blackfoot disease” are
common findings among persons exposed to arsenic in
drinking water. Studies by Tsou et al. (2005) reported
arsenic-induced downregulation of eNOS, supporting
the hypothesis that altered eNOS function may play an
important role in mediating this clinically important
outcome. Studies by others (Wu et al., 1999, 2002) dem-
onstrated a number of alterations in cell signaling path-
ways, including the mitogen-activated protein kinase
(MAPKs), extracellular signal-regulated kinase (ERK),
and Ras via the epidermal growth factor receptor (EGFR)
pathway in a human airway epithelial cell line (BEAS-
2B). Similar alterations in the c-jun/AP-1 and NF-κB sig-
nal transduction systems, with concomitant alterations
in the expression of a number of the major stress protein
families (HSP32 and HSP72), were observed by Wijew-
eera et al. (2001) in precision-cut rat lung slices.
5.6.3.6  Mechanisms of Cell Death
5.6.3.6.1  Apoptosis Arsenite at low dose levels
in vitro has been demonstrated to produce apoptosis
in rat thymocytes (Bustamente et al., 1997). Subsequent
studies (Tian et al., 2005) demonstrated that As2O3
induces opening of the mitochondrial membrane per-
meability transition pore, with attendant release of
cytochrome c and intramitochondrial calcium stores.
Other investigators (Zhang et al., 2003; Zheng et al.,
2005) have shown that As2O3 also induces Bax activa-
tion in hematopoietic cells secondary to ROS formation.
In agreement with the role of ROS in mediating arseni-
cal induction of apoptosis, administration of antioxi-
dants such as ascorbic acid and α-tocopherol have been
shown (Ramanathan et al., 2005) to reduce tumor necro-
sis factor (TNF-α; encoded by TNF) levels and activate
the caspase cascade system. The value of arsenicals in
mediating apoptosis has been explored in relation to
the treatment of various cancers such as acute mega-
karyocytic leukemia (Lam et al., 2005) or promyelo-
cytic leukemia (Zheng et al., 2005), where As2O3 has
been shown to activate a number of central factors in
the apoptotic pathway. Similar delays in the recovery
of leukocytopenia and neutropenia during acute pro-
myelocytic leukemia have been reported after treat-
ment of patients with As2O3 relative to treatment with
all-trans retinoic acid (Shinjo et al., 2005). On the other
hand, long-term, low-level exposure of cultured human
keratinocytes to arsenite has been shown (Pi et al., 2005)
to produce a generalized resistance to the induction of
apoptosis, which may provide a role for arsenic as a
cocarcinogen with ultraviolet (UV) light in skin cancer,
as discussed later. A number of other investigators have
reported similar arsenic-induced alterations in apopto-
sis regulation in other cell types such as neuronal (Jou
et al., 2004; Namgung and Xia, 2000) and lymphoma
cell lines (Muscarella and Bloom, 2002) and in devel-
oping mouse embryos (Liu et al., 2003). Interestingly,
HSP70 (discussed earlier) has been reported to pro-
tect against arsenic-induced apoptosis (Mosser et al.,
2000) at a step in apoptotic pathway after cytochrome
c release and before caspase-3 activation (Li et al., 2000).
5.6.3.7 Necrosis
As with many toxic metals, cellular necrosis is usu-
ally observed after the administration of high-dose
arsenicals (Shen et al., 2006), and there is strong dose
dependency as to whether apoptosis or necrosis is
observed after exposure to this agent.
5.6.3.8 Cancer
In recent years, there have been many detailed
reports on the diagnosis, molecular markers, and possi-
ble underlying mechanisms of arsenic-induced cancers
in various organ systems. As with the mechanisms of
cell injury and apoptosis discussed previously, the gen-
eration of oxidative stress from the mitochondrial pro-
duction of ROS seems to be a central feature of cancer
initiation (NRC, 1999). Yu et al. (2006) reviewed arse-
nic-induced skin cancers and the probable combined
roles of arsenic exposure and UVB radiation in produc-
ing skin lesions. Kuo et al. (1997) examined the possible
roles p53 gene overexpression in skin cancer and con-
cluded that this was not a prerequisite for the devel-
opment of skin cancer. Dong (2002) noted increased
 28 Arsenic 595

phosphorylation of ERKs in cell lines and observed 6.1 Organs

that arsenic did not induce p53 transactivation. Waal-
Median arsenic concentrations in the organs of
kes et al. (2004) reported altered estrogen signaling in
healthy people from Scotland who died in accidents
male mice with hepatocellular carcinomas produced
ranged from 0.012 mg/kg in the brain to 0.46 mg/
by in utero exposure to arsenic. They concluded that
kg in hair (both dry weight) (Liebscher and Smith,
overexpression of estrogen receptor alpha (ERα), prob-
1968). Median concentrations in organs of people
ably through hypomethylation of the promoter region
from Japan who had generally consumed relatively
of this gene, may play a role in hepatocarcinogenesis
high amounts of seafood ranged from 0.02 mg/kg
in these mice. Subsequent studies by Cui et al. (2006)
wet weight in the pancreas to 0.89 mg/kg in the nails
demonstrated that arsenic trioxide does inhibit DNA
(Kadowaki, 1960). The first study used NAA on vac-
methyltransferase and activates methylation-inhibited
uum-dried samples and the second used polarogra-
genes in human HepG2 liver cancer cells. Hour et al.
phy. Values for all organs analyzed in the two studies
(2006) reported the differential expression of various
are given in Table 1.
molecular markers in surgical samples of uroepithelial
Tissue analysis of organs taken from an individ-
cells from arsenic-exposed and nonarsenic-exposed
ual after death from ingestion of 8 g arsenic trioxide
patients. They found a decreased GSH content in
(approximately 3 g arsenic) showed a much higher con-
cells from the arsenic-exposed patients and increased
centration of arsenic in the liver (147 μg/g) than in the
expression of apoptosis regulator Bcl-2 and proto-
kidneys (27 μg/g) or muscle, heart, spleen, pancreas,
oncogene c-Fos. Shen et al. (2006) examined the effects
lungs, or cerebellum (11-12 μg/g) (Benramdane, et al.
of three methylated arsenicals [MMA(V), DMA(V),
1999). Small amounts were also found in other parts of
and TMAO] on the urinary bladder epithelium of both
male and female rats exposed to these substances for
13 weeks. They noted metabolic differences between TABLE 1  Arsenic Concentrations in Human Organs and
males and females with regard to further metabolism Tissues in Scotland and Japana
and concluded that DMA(V) is more toxic to the blad-
Arsenic Concentration (mg/kg)
der epithelium of female rats, which are also more sus-
ceptible to bladder carcinogenesis from this agent. Scotland Japan
Mizoi et al. (2005) reported that oxidative stress (dry wt.) (wet wt.)
caused by DMA(III) generated as a reduction prod-
Tissue/organ Median Range Median
uct of DMA(V) seem to play a central role in lung and
skin tumors in mice exposed to DMA(V), as judged Adrenal 0.029 0.002-0.293 –
by the increased formation of 8-oxo-2ʹdeoxyguanosine Aorta 0.031 0.003-0.570 –
(8-OHdG) DNA adducts. It is also important to note Whole blood 0.038 0.001-0.920 –
Bone 0.057 0.010-0.240 0.118 (femur)
that an increased presence of 8-OHdG adducts has
Bone – – 0.074 (rib)
been reported in urine samples of persons living in Brain 0.013 0.001-0.036 0.034
Inner Mongolia (Fujino et al., 2005) and Cambodia Hair 0.460 0.020-8.17 0.174
(Kubota et al., 2006) exposed to arsenic in contami- Heart 0.024 0.002-0.078 0.041
nated drinking water, suggesting that these adducts Intestine, large – – 0.025
Intestine, small – – 0.022
may be potentially useful biomarkers for the long-
Kidney 0.033 0.002-0.363 0.041
term risk of arsenic-induced cancers such as Bowen Liver 0.028 0.005-0.246 0.042
disease (Matsui et al., 1999). It is important to note that Lung 0.082 0.006-0.514 0.047
the stress protein response discussed previously may Muscle 0.063 0.012-0.431 0.029
play an important regulatory role in mediating the car- Nail 0.300 0.020-2.90 0.892
Ovary 0.037 0.013-0.260 –
cinogenic or cocarcinogenic effects of arsenic through
Pancreas 0.045 0.005-0.410 0.020
interaction with a number of proto-oncogenes and the Prostate 0.046 0.010-0.090 –
apoptotic caspase system (Khalil et al., 2006; Stanhill Skin 0.090 0.009-0.590 0.064
et al., 2006; Yaglom et al., 2003). Spleen 0.020 0.001-0.132 0.021
Stomach 0.037 0.003-0.104 0.022
Teeth 0.050 0.003-0.635 0.078
Thymus 0.015 0.003-0.332 –
6  BIOLOGICAL MONITORING Thyroid 0.042 0.001-0.314 –
Uterus 0.031 0.010-0.188 0.036
A review by Mandal and Suzuki (2002) document
many cases of human arsenic exposures around the aCompiled from Liebscher and Smith (1968) and Kadowaki (1960),
world, as well as sources of arsenic in the environment. respectively
596 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
the brain (8 μg/g), in skin (3 μg/g), and in hemolyzed
blood (0.4 μg/g).
Inorganic arsenic can easily pass through the pla-
centa. High levels of arsenic were found in the liver,
kidney, and brain after autopsy of an infant prema-
turely born to a young mother who had ingested inor-
ganic arsenic at week 30 of gestation (Lugo et al., 1969).
Arsenic was detected in human breast milk at con-
centrations of 0.00013-0.00082 ppm (Somogyi and Beck,
1993). In a population of Andean women exposed to
high concentrations (approximately 200 ppb) of inor-
ganic arsenic in drinking water, concentrations of arse-
nic in breast milk ranged from about 0.0008-0.008 ppm
(Concha et al., 1998a).
It is not known to what extent arsenic concentra-
tions in human organs represent inorganic arsenic or
organic arsenic originating in the diet. Concentrations
of 0.014-0.21 mg As/kg wet weight have been observed
in the lungs of smelter workers who had retired 2-19
years before death; in contrast, unexposed controls had
0.001-0.018 mg/kg, indicating a long retention time of
arsenic in the lungs after inhalation, which may occur
in certain occupations (Brune et al., 1980).
6.2 Urine
Most arsenic absorbed from the lungs or the gas-
trointestinal tract is excreted in the urine within 1-2
days. Therefore, the urinary arsenic level is generally
accepted to be the most reliable indicator of recent
arsenic exposure, and this approach has proved useful
in identifying above-average exposures in populations
living near industrial point sources of arsenic (Polis-
sar et al., 1990). Normal levels of arsenic in the urine
of people with no known high exposure appear to be
in the range of 5-50 μg As/L (Baker et al., 1977; Bencko
and Symon, 1977; Braman and Foreback, 1973; Buchet
et al., 1980; Smith et al., 1977; Caldwell et al., 2009;
CDC, 2013). The ingestion of seafood may, however,
increase the concentration to more than 1 mg As/L
(Buchet et al., 1980; Norin and Vahter, 1981; Pinto et al.,
1976; Schrenk and Schreibeis, 1958).
In a study of As2O3 exposure in a smelter, Pinto et al.
(1976) found an average urinary arsenic concentration
of 0.053 mg/L among 200 workers who had not been
exposed to arsenic. The average arsenic concentra-
tion in the urine of 24 men who had been exposed to
a mean air concentration of 53 μg/m3 (range 3-295 μg/
m3) in the same factory was 0.038-0.539 mg/L, with an
overall average of 0.174 mg/L. They found a correla-
tion between airborne arsenic concentrations and arse-
nic in urine, but the values showed a wide scatter.
Watrous and McCaughey (1945) determined urinary
levels of arsenic among workers in a factory producing
arsphenamines from arsanilic acid. The mean arsenic
level was 0.44 mg/L, with a range of 0.04-3.8 mg/L.
Calderon et al. (1999) found a correlation between
the log of the mean total urinary arsenic concentra-
tion/creatinine (TAs/c; μg/mg) in people living in
areas with arsenic-contaminated drinking water
sources and the log of the inorganic arsenic concentra-
tion in the drinking water (lnAs; μg/L).
Arsenic concentration in urine may be used as an
index of exposure, but a number of factors such as a
diet containing mainly seafood and the time between
exposure and urine sampling have to be considered.
Because “fish arsenic” (i.e. arsenobetaine) is essentially
nontoxic, total urinary arsenic content may overesti-
mate exposures to arsenic species that are of concern
for health. Experience has shown that total urinary
arsenic may lead to the overestimation of exposure to
inorganic arsenic even if the subjects are requested to
refrain from eating seafood (Pinto et al., 1976). Dietary
habits should be examined thoroughly when the total
urinary arsenic concentration is to be used as an index
of exposure. Analytical differentiation of the different
forms of arsenic in the urine is an appropriate way of
determining how much and what form of arsenic has
been absorbed (Buchet et al., 1980; Norin and Vahter,
1981). The sum of urinary excretion of inorganic arse-
nic and its monomethylated and dimethylated metabo-
lites is a good indicator of exposure to inorganic arsenic
when there is some fish consumption. Buchet et al.
(2003) determined such values by means of hydride
generation combined with AAS or AAF and reported
a mean value of approximately 7 μg/g creatinine and
a 95% cutoff of 18 μg/g creatinine in a group from the
general population of Belgium. In a population group
from China not known to be exposed to inorganic arse-
nic, there was a mean of approximately 25 μg/g cre-
atinine and a 95% cutoff of 50 μg/g creatinine (Buchet
et al., 2003). Recently, Basu et al. (2011) noted that urine
creatinine concentration was the strongest biological
marker of arsenic methylation efficiency and therefore
should not be used to adjust for urine concentration in
arsenic studies.
6.3 Blood
Using NAA, Brune et al. (1966) found a mean con-
centration of 0.004 mg/kg in the whole blood of normal
people and 0.035 mg/kg in uremic patients. Heydorn
(1970) reported a mean arsenic concentration in whole
blood of 0.022 mg/L in Taiwanese subjects, also using
NAA.
In three studies of As-exposed populations, Vahter
et al. (1995) and Concha et al. (1998a,b) found the aver-
age total blood As to be 7.6, 9, and 10 μg/L, respectively.
 28 Arsenic
In one of these studies, the range of blood As concen-
tration of an unexposed population was 1-2 μg/L (Con-
cha et al., 1998b). Using HPLC-ICP-MS, Suzuki et al.
(2002) and Mandal et al. (2004) could separate and
quantify the As species in the blood of an As-exposed
population. They found arsenobetaine, DMA, MMA,
and inorganic As in the blood samples by speciating
the blood. They also found a total As concentration of
10.1 μg/L As in blood from an As-exposed individual.
Mandal et al. (2004) also separated the blood into red
blood cells and plasma, and determined the fraction of
the various species in these blood components.
As stated in Section 5.2, arsenic clearance from the
blood is very rapid. The period between exposure and
sampling will, therefore, be of importance if the blood
levels are being related to the exposure level. Fur-
thermore, the intake of seafood may greatly influence
blood arsenic levels. For these reasons, blood arsenic
cannot be regarded as a useful indicator of exposure.
A review by Taylor et al. (2004) tabulates both the
technologies used for the determination of As in blood,
hair, nails, and urine, and summarizes the basic find-
ings for the different biological matrices.
6.4 Hair
Attempts have been made to correlate normal
concentrations of arsenic in hair to exposure to inor-
ganic arsenic. Smith (1964) found that 80% of 1000
people tested had a concentration below 1 mg As/kg
in hair, with an average of 0.81 mg/kg and a median
of 0.51 mg/kg. Liebscher and Smith (1968) gave 0.02-
8.17 mg/kg as the range of arsenic concentrations in
hair, based on an examination of 1250 people without
known exposure to high levels of this element. Yang
et al. (2002), Mandal et al. (2003), and Uchino et al.
(2006) examined correlations between hair As and As
intake from water. They all found a correlation, but the
results differed by a factor of 2-3 for the level of As in
the hair versus the level of As in the water. This could
be due to many factors, including the mode of washing
the hair before analysis (to remove external contami-
nation), analytical methods (both used ICP-MS), and
digestion techniques. Yang et al. (2002) looked at the
average hair As as a function of the extent of arseni-
cism in the patients and found a range of 2-4.5 μg/g As,
depending on the extent of hyperkeratosis, depigmen-
tation, and pigmentation. Mandal et al. (2003) found
an average concentration of 4.5 μg/g As in hair, with
a range of 0.7-16.2 μg/g. Mandal et al. (2003) also spe-
ciated hair samples using HPLC-ICP-MS and found
As(III), As(V), MMA(V), and DMA(V). The main diffi-
culty in interpreting these results is the variation in the
speciation results depending on the technique used to
597
extract As from the hair. The average percentage recov-
ery of the species versus the total As analysis value
was 57%. This is common in these types of analysis, in
which the laboratory is extracting analytes from solid
matrices. Raab and Feldmann (2005) speciated As in
the hair of an exposed population and found As(III),
As(V), MMA(V), and DMA(V). The study also found
that the method of extraction varied with the abun-
dance of different species and the extraction efficiency
of the specific species relative to the total As concen-
tration. In all of these As speciation studies, the pres-
ence of arsenobetaine was not detected; therefore, the
assumption is that it does not accumulate in hair.
The mean concentration of arsenic in hair has been
found to reflect the degree of arsenic pollution in com-
munity air (Bencko and Symon, 1977; Bencko et al.,
1971; Hammer et al., 1971). Concentrations of arsenic
in hair were generally found to increase with the arse-
nic concentration in air. Hinwood et al. (2003) looked
at the general types of environmental and personal
As exposures, classified the population into exposure
categories, and determined the hair As concentration
of these different exposures. They classified the expo-
sures into high water, high soil, and personal exposure.
The greatest effect was for the high-water exposures,
in which they found a mean of 5.5 μg/g As in the hair
with a range of 1.2-20 μg/g.
Evaluating hair As from unexposed populations
such as the U.S. National Human Exposure Assessment
Survey, showed there to be no correlation between hair
As and food, drinking water, dust intake, or exposure
(Pellizzari and Clayton, 2006). The average hair As in
this population was 0.17 μg/g As, with a range of 0.06-
0.33 μg/g As (10th to 90th percentiles).
Arsenic trioxide (As2O3) has been used as a chemo-
therapeutic agent for some leukemia treatments. Shen
et al. (1997) looked at the incorporation of As in the
hair of several patients during a period when arsenic
trioxide was being administered. They found that As
was incorporated into the hair to a level of 2.5-2.7 μg/g
(about five to seven times greater than the baseline lev-
els) shortly after arsenic trioxide administration, and
that hair As levels decreased after drug administration
was stopped. The literature on the medicinal uses of
arsenical has been reviewed by Ratnaike (2003).
It should be noted that there are several caveats
related to the analysis of hair As that must be taken
into consideration when evaluating an individual or
population suspected to have undergone chronic or
acute As exposure or poisoning. It may not be possible
to distinguish between arsenic adsorbed onto the hair
from external contamination and arsenic incorporated
into hair from the internal body burden. Hindmarsh
(2002) has shown that one can measure As in hair well
598 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
before the As could have been incorporated through
hair growth. This could be due to As in the sweat or
other mechanisms contaminating the hair. He has also
shown that hair can take up As directly from water
containing As, and that As is not removed by the nor-
mal washing procedures used in analytical methods.
Therefore, one must be cautious when using hair As
as an indicator of absorbed arsenic, if the external con-
tamination cannot be controlled in some way (Vahter
et al., 1983).
7 EFFECTS
Inorganic arsenic has been recognized as a human
poison since ancient times. Arsenic-related human tox-
icity is systemic, involving a number of organ systems.
The acute, subacute, and chronic toxic effects of inor-
ganic arsenic exposure through inhalation and inges-
tion have been reviewed periodically (ATSDR, 2007;
Chen, 2011a,b; Chen et al., 1997a,b; IARC, 2004, 2006;
Jean et al., 2010; NRC, 1999; WHO, 1981, 2001).
7.1 Lethality
It has been estimated that the acute lethal dose of
ingested inorganic arsenic in humans is about 1-3 mg/
kg/day, whereas inhalation and dermal exposures to
inorganic arsenic have not been associated with acute
lethality (ATSDR, 2007). Animals are not as sensitive to
inorganic arsenic as humans, and this difference may
be due to differences in gastrointestinal absorption and
methylation capability (Vahter, 1994).
7.2  Acute and Subacute Effects
Both acute and subacute toxicity of arsenic are
shown in Table 2. They involve many organ sys-
tems, including the gastrointestinal, dermal, ner-
vous, renal, hepatic, hematological, cardiovascular,
respiratory, and ophthalmic systems. The earli-
est and most common presentation of ingestion of
a large dose of arsenic is the acute gastrointestinal
syndrome, which starts with a metallic or garlic-
like taste associated with a dry mouth, burning lips,
and dysphagia. Gastrointestinal syndrome, which
is caused by the paralysis of capillary control in the
digestive tract, may lead to a decrease in blood vol-
ume and blood pressure, electrolyte imbalance, and
shock. In acute arsenic poisoning, the fundamental
lesion of endothelial cellular toxicity accounts for
the predominant clinical features. Capillary damage
leads to generalized vasodilation, transudation of
plasma, and multiorgan failure. The sites of arsenic
TABLE 2  Acute and Subacute Toxicity of Arsenic
Organ System Symptoms and Sign
Gastrointestinal Nausea, vomiting, thirst, anorexia, heartburn,
abdominal pain, diarrhea with bloody stool
Dermal Dermatitis, vesticulation, melanosis
Neural Encephalopathy (hyperpyrexia, convulsion,
tremor, coma, disorientation), neuritis,
peripheral neuropathy (primarily sensory
type, paresthesia, hyperesthesia, numbness
of extremities, neuralgia, muscular cramp,
and weakness)
Renal Cortical necrosis, leukocyturia, glycosuria,
hematuria, oliguria, uremia
Hepatic Congestion, fatty infiltration, central necrosis,
acute yellow atrophy, cholangitis,
cholecystitis
Hematological Anemia, thrombocytopenia, leukopenia, bone
marrow suppression
Cardiovascular Cardiac abnormality (ventricular fibrillation
and atypical tachycardia), prolonged Q-T
interval, abnormal T wave; congestive heart
failure, hypotension
Respiratory Irritation of nasal mucosa, pharynx, larynx
and bronchi, pulmonary edema,
tracheobronchitis, bronchial pneumonia,
nasal septum performation
Ophthalmic Conjunctivitis
Sources: WHO, 1981, 2001; ATSDR, 2007; Gorby, 1994; Morton and
Dunnette, 1994; Chen et al., 1995; NRC, 1999.
damage in the kidney include capillaries, tubules,
and glomeruli. Neuropathy is mainly produced by
axonal degeneration, although myelin disruption
also presents. Most studies on the acute and subacute
toxicity of inorganic arsenic do not include details
of exposure dose and/or adequacy of sample size to
allow the assessment of dose-response relationships
(ATSDR, 2007; Chen et al., 1997a; Gorby, 1994; IARC,
2004; Morton and Dunnette, 1994; NRC, 1999, 2001;
WHO, 1981, 2001).
7.3  Chronic Noncardiovascular Effects
Chronic noncardiovascular effects of inorganic
arsenic also involve multiorgan systems, as shown
in Table 3. The clinical appearance of these clinical
manifestations of arsenic intoxication in humans is
insidious in onset and depends on the magnitude of
the dose and the time course of exposure. A multitude
of effects may ensue from interference by arsenic on
the action of enzymes, essential cations, and tran-
scriptional events in cells throughout the human body
(ATSDR, 2007; Chen, 2011b; Chen et al., 1997a; Gorby,
1994; IARC, 2004; Morton and Dunnette, 1994; NRC,
1999; WHO, 1981, 2001).
 28 Arsenic
TABLE 3  Chronic Noncardiovascular Toxicity of Arsenic
Organ System Symptoms and Signs
Dermal Hyperpigmentation with depigmentation,
facial edema, palmoplantar hyperkeratosis,
desquamation
Gastrointestinal Esophagitis, gastritis, colitis, abdominal
discomfort, anorexia, malabsorption, weight
loss
Neural Hearing loss, mental retardation, encephalopathy,
symmetrical peripheral polyneuropathy
(sensimotor type, resembling Landry-
Guillain-Barré syndrome), electromyographic
abnormalities
Hepatic Cirrhosis, hepatomegaly, portal hypertension
without cirrhosis, fatty degeneration
Hematological Bone marrow hypoplasis, aplastic anemia,
anemia, leukopenia, thrombocytopenia,
impaired folate metabolism, karyorrhexis
Respiratory Rhinopharyngolaryngitis, tracheobronchitis,
pulmonary insufficiency (emphysematous
lesions), chronic restrictive/obstructive
diseases
Metabolic Diabetes mellitus
Immunological Decreased progression of lymphocytes from S
phase to M phase of the cell cycle
Ophthalmic Lens opacity
Sources: WHO, 1981, 2001; ATSDR, 2007; Gorby, 1994; Morton and
Dunnette, 1994; Chen et al., 1997a; NRC, 1999; Chen et al., 1995.
7.3.1  Dermal Effects
The most distinct characteristics of arsenic toxic-
ity are the classical cutaneous manifestations, includ-
ing hyperpigmentation with depigmentation and
palmoplantar hyperkeratosis. These have been con-
sistently observed among those with occupational,
environmental, and medicinal exposures to arsenic
through inhalation and ingestion. Dermal effects
were most commonly reported after the ingestion
of arsenic-containing water in various regions of
the world, including Argentina, Bangladesh, Chile,
China, Japan, Mexico, Inner Mongolia, and Taiwan
(Chen, 2011a,b; IARC, 2004; NRC, 1999; WHO, 1981,
2001). The magnitude of arsenic dose and exposure
duration needed to induce hyperpigmentation and
hyperkeratosis have only been investigated to a lim-
ited extent. A dose-response relationship between the
arsenic concentration in drinking water and the prev-
alence of hyperpigmentation and hyperkeratosis was
observed in a survey of 40,421 inhabitants in coastal
areas of southwestern Taiwan (Tseng et al., 1968) and
in a survey of 7683 residents of West Bengal, India
(Guha Mazumder et al., 1998b). More recent studies
in Inner Mongolia (Guo et al., 2001, 2006), Bangladesh
(Ahsan et al., 2006), and West Bengal (Haque et al.,
2003; Mukherjee et al., 2005) have reported similar
599
dose-related increases in characteristic skin lesions in
human populations consuming arsenic-contaminated
drinking water. More recent studies by Dastgiri et al.
(2010) in Iran have reported marked elevations of
arsenical-induced skin lesions among persons living
in a village with elevated concentrations of arsenic in
the drinking water relative to those in another village
with no such exposure. Other studies in Bangladesh
(Lindberg et al., 2010), Nepal (Maden et al., 2011),
and Inner Mongolia (Mao et al., 2010) have reported
similar skin lesions related to arsenic exposures from
drinking water. Chronic arsenic exposure from drink-
ing water was associated with an increased incidence
of skin lesions even at low levels of arsenic exposure
(50.1-100 μg/L) in Bangladesh (Argos et al. 2011).
Overall, these findings indicate the increasing recog-
nition of the global nature of public health problems
related to arsenical contamination of drinking water,
as documented by the classic clinical manifestations
of arsenical toxicity.
7.3.2  Gastrointestinal Effects
Long-term, low-dose exposure to ingested arsenic was
reported to induce various gastrointestinal symptoms,
including gastroenteritis, dyspepsia, nausea, diarrhea,
anorexia, and abdominal discomfort in Japan, Chile,
China, India, and Mexico. However, the arsenic dose and
exposure duration required to induce the gastrointestinal
effects were not well characterized (IARC, 2004).
7.3.3  Neural Effects
Peripheral polyneuropathy is often among the
sequelae of acute oral arsenic poisoning. However,
the occurrence of the polyneuropathy is inconsistently
seen in individuals chronically exposed to arsenic at
low concentrations. Abnormal electromyographic
findings mostly suggestive of sensory neuropathy
were reported in Canada, India, Japan, and China.
However, neuropathy was not reported among resi-
dents drinking arsenic-containing water in Argentina
and Chile (IARC, 2004; NRC, 1999). There was no sig-
nificant association between nerve conduction veloc-
ity measurements and arsenic exposure in subjects
in Alaska (Kreiss et al., 1983) and Utah (Southwick
et al., 1983). In contrast, there was a significant asso-
ciation between chronic exposure to arsenic and slow
nerve conduction velocity among adolescents in Tai-
wan (Tseng et al., 2006). Peripheral neuritis and cog-
nitive and memory impairment have been reported
in arsenic-exposed residents in Texas (Kilburn, 1997),
whereas reduced intellectual function has been found
to be associated with arsenic exposure from drink-
ing water in Thailand (Siripitayakunkit et al., 1999)
600 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
and Bangladesh (Wasserman et al., 2004). A cross-
sectional study on neurobehavioral development in
adolescents in northeastern Taiwan found a signifi-
cant association with cumulative arsenic exposure
for pattern memory and switching attention but not
for continuous performance and symbol digit (Tsai
et al., 2003). Significantly decreased motor function
in neurobehavioral tests has been reported in chil-
dren exposed to arsenic in drinking water (Parvez
et al. 2011). Hamadani et al.(2011) found adverse
effects of early life arsenic exposure on the intelli-
gence quotient of girls, but not of boys at 5 years of
age. O’Bryant et al. (2011) also reported an associa-
tion between long-term, low-level arsenic exposure
and poorer neuropsychological functioning in adults
and seniors.
7.3.4  Hepatic Effects
Chronic exposure to arsenic in medicines and
drinking water was reported to induce liver cir-
rhosis, portal hypertension without cirrhosis,
and fatty degeneration (IARC, 2004; Morton and
Dunnette, 1994; NRC, 1999; WHO, 1981, 2001). Vine-
yard workers who ingested an arsenic-contaminated
wine were found to have a high prevalence of cir-
rhosis (Lüchtrath, 1983). The simultaneous use of
excessive ethanol may also contribute to the occur-
rence of liver cirrhosis. Increased mortality from
liver cirrhosis was also observed in two cohorts of
arsenic-exposed copper smelter workers (Axelson
et al., 1978; Welch et al., 1982). Hepatomegaly has
also been reported in cases of chronic arsenic toxic-
ity caused by drinking arsenic-contaminated water
in India and China (Guha Mazumder et al., 2005;
IARC, 2004; Guha Mazumder and Dasgupta , 2011).
More recent studies on arsenic-exposed populations
in Bangladesh (Islam et al., 2011) reported a clear
dose-response relationship between arsenic drink-
ing water exposures and both (1) arsenic in hair
and nails and (2) elevated activities of liver serum
enzyme such as alkaline phosphatase and alanine
and aspartate aminotransferases.
7.3.5  Hematological Effects
Long-term exposure to arsenic has a general depres-
sant effect on the hematopoietic system. Hematological
changes include normochromatic normocytic anemia,
megaloblastic anemia, erythrocyte karyorrhexis, gran-
ulocytopenia, thrombocytopenia, aplastic anemia, and
myelodysplasia. However, no hematological abnor-
mality was found to be associated with chronic arsenic
exposure through ingestion in populations in Alaska,
Arizona, Michigan, and Utah (Morton and Dunnette,
1994; NRC, 1999).
7.3.6  Respiratory Effects
Chronic respiratory effects of arsenic have been
primarily reported as a result of occupational expo-
sure through inhalation of arsenic-containing dust or
fumes (Morton and Dunnette, 1994), as well as envi-
ronmental exposure through the ingestion of arsenic-
containing drinking water (IARC, 2004; NRC, 1999).
Respiratory effects included rhinitis, pharyngitis, lar-
yngitis, tracheobronchitis, chronic cough, crepitation,
shortness of breath, and chronic restrictive and/or
obstructive lung diseases. More recent studies in West
Bengal (Guha Mazumder et al., 2005; von Ehrenstein
et al., 2005) and Chile (Adonis et al., 2005; Smith et al.,
2006) reported increased rates of both obstructive lung
lesions, including bronchiectasis and lung cancer in
persons exposed to arsenic through drinking water
that were exacerbated by smoking. Adonis et al. (2005)
reported that in men, the estimated risk of lung cancer
correlated with the CYP 1A1*2A (MspI) polymorphism
but not with the GSTM1 null genotype. Other studies
have found dose-response relationships between arse-
nic drinking water exposures and clinical symptoms
of respiratory diseases in Banglandesh (Parvez et al.,
2010) and decrements of lung function in arsenic-
exposed populations living along the Indus River in
Pakistan (Nafees et al., 2011). Arsenic exposure during
pregnancy increased the risk of lower respiratory tract
infection during infancy (Rahman et al., 2011).
7.3.7  Metabolic Effects
An increased prevalence of diabetes mellitus was
observed among residents in an endemic area of arse-
niasis in southwestern Taiwan, and there was a dose-
response relationship between cumulative arsenic
exposure and the prevalence of diabetes mellitus (Lai
et al., 1994; Tseng et al., 2000). There was excess mor-
tality from diabetes mellitus among residents who
lived in an arseniasis-endemic area of southwestern
Taiwan (Tsai et al., 1999). Arsenic-exposed workers in
both copper smelter and glass-producing plants were
reported to have an increased risk of diabetes melli-
tus (Rahman and Axelson, 1995; Rahman et al., 1996).
A dose-response relationship was reported between
the prevalence of diabetes mellitus and that of arse-
nic in drinking water in Bangladesh (Rahman et al.,
1998, 1999a), and between the incidence of diabetes
mellitus and the presence of arsenic in drinking water
in southwestern Taiwan (Tseng et al., 2000, 2002). Sig-
nificantly higher levels of glycosylated hemoglobin
were seen in arsenic-exposed workers than in unex-
posed ones in Denmark (Jensen and Hansen, 1998).
More recent epidemiological studies on this impor-
tant public health area have shown differences among
arsenic-exposed populations in various countries.
 28 Arsenic
Cross-sectional studies by Chen et al. (2010b) found
no association between drinking water arsenic expo-
sure and the prevalence of diabetes mellitus in a
population cohort. In contrast, studies by Del Razo
et al. (2011) showed a positive association in a cohort
living in regions of endemic arsenicosis in Mexico,
which was linked to production of the dimethylar-
sinite (DMAsIII) urinary metabolite. Using data from
the Korean NHANES study, which is representative
of the general Korean population, Kim and Lee (2011)
also reported a positive association between total
urinary arsenic concentrations and the prevalence of
diabetes mellitus. Differences among the findings of
these studies may be explained in part by genetic dif-
ferences in the production of the DMAsIII metabolite
produced by polymorphisms in the AS3MT, and or
a combined effect of variations in the GST or HO-1
enzyme systems, as discussed above. Previous epide-
miological studies are consistent with earlier experi-
mental animal studies (Ghafghazi et al., 1980; Schiller
et al., 1981), which demonstrated marked exacer-
bating interactive effects between arsenic exposure,
altered insulin responsiveness, and urinary markers
of diabetes in an alloxan-induced diabetes rodent
model. Other studies (Diaz-Villaseñor et al., 2006)
have reported impaired insulin secretion and tran-
scription in rat pancreatic cells treated in vitro with
arsenite (AsIII) over a concentration range of 0.5-
10 μmol/L As for 72 or 144 h. They observed both
altered cellular insulin secretion at 144 h in response
to glucose and decreased insulin mRNA expression at
72 h at the 5 μmol/L As concentration. Possible under-
lying mechanisms for arsenic-induced diabetes have
been reviewed by Tseng (2004). More recent studies
(Paul et al., 2011) in mice exposed to inorganic arsenic
in drinking water for 20 weeks and fed either a low-fat
or high-fat diet showed that a synergistic interaction
between arsenic exposure and a high-fat diet induced
obesity and glucose intolerance. In addition to these
suggestions, which are centered on altered molecu-
lar regulatory mechanisms, it should be noted that
the metabolic impairments of carbohydrate metabo-
lism at the level of mitochondrial respiration (noted
in Section 5.6) might represent an important basic
aspect of altered glucose regulation by arsenic. This
is reasonable, because mitochondria actively take up
arsenic, thus concentrating this element at even low
dose levels. The mitochondrion is also known to be
the major intracellular source of ROS in cells. The spe-
cific inhibition of NAD-linked substrate respiration/
loss of respiratory control by arsenic at low dose lev-
els has been shown to increase the formation of ROS,
which will stimulate a number of the stress protein
and intracellular signaling mechanisms on a second-
ary basis. The overall concept with regard to arsenic
601
stimulation of the diabetic response is that, even at
low dose levels, arsenic inhibition of mitochondrial
respiration will tax the finite capacity of hormonal/
intracellular carbohydrate regulatory systems to
compensate for this basic derangement of cellular
metabolism. The ability of these regulatory systems
to regulate carbohydrate metabolism would eventu-
ally be overwhelmed, resulting in the development
and/or exacerbation of an arsenic-induced insulin-
resistant diabetic state in susceptible individuals.
This would be of particular concern under chronic
exposure conditions.
7.3.8  Immunological Effects
The peripheral blood lymphocyte count of arsenic-
exposed subjects was slightly increased relative to the
unexposed controls, and the progression of lympho-
cytes from the S phase to M phase of cell cycle after
phytohemagglutinin incubation was decreased (Gon-
sebatt et al., 1994). The retardation in cell replication
of lymphocytes was much more striking in arsenic-
induced skin cancer patients than in matched controls
(Hsu et al., 1997).
7.3.9  Ophthalmic Effects
Long-term exposure to arsenic was reported to be
associated with an increased prevalence of lens opac-
ity. There was a dose-response relationship between
cumulative arsenic exposure and the prevalence of
posterior subcapsular opacity, but not with the prev-
alence of nuclear opacity and cortical opacity, after
adjustment for age, gender, diabetes mellitus, and
sunlight exposure (See, 2000). There was a significant
association between arsenic in drinking water and pte-
rygium, a fibrovascular growth of the bulbar conjunc-
tiva and underlying subconjunctival tissue that may
cause blindness, in southwestern Taiwan (Lin et al.,
2008).
7.3.10  Renal Effects
Proteinuria has been recognized as a marker for an
increased risk of chronic renal disease. An association
between exposure to arsenic in drinking water and
proteinuria has been reported in a Bangladeshi popu-
lation with low-to-moderate levels of arsenic exposure
(Chen, 2011b)
7.4  Chronic Cardiovascular Effects
Table 4 shows chronic cardiovascular effects of
long-term exposure to arsenic through ingestion
or inhalation. The cardiovascular effects included
electromyographic abnormalities, especially QT
602 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
TABLE 4  Chronic Cardiovascular Toxicity of Arsenic
Organ System Symptoms and Signs
Heart Arrythmias, pericarditis
Peripheral artery Blackfoot disease (gangrene with
spontaneous amputation), Raynaud
disease, acrocyanosis, intermittent
Coronary artery Ischemic heart disease
Cerebral artery Cerebral infarction
Atherosclerosis Carotid atherosclerosis
Blood pressure Hypertension
Microcirculation Microcirculation abnormalities
Sources: WHO, 1981, 2001; ATSDR, 2007; Engel et al., 1994; Tseng
et al., 1995; Chen et al., 1997a; NRC, 1999; Chiou et al., 2005.
prolongation and increased dispersion; peripheral,
coronary, and cerebral artery diseases; carotid athero-
sclerosis; hypertension; and microcirculation abnor-
malities (Chen 2011b; Chen et al., 1997a; IARC, 2004;
NRC, 1999; Wang et al., 2007; WHO, 1981, 2001).
7.4.1  Cardiac Effects
Characteristic arsenic-induced electromyographic
abnormalities include decreased nerve conduc-
tion amplitude with little change in nerve conduc-
tion velocity. Pericarditis and arrhythmias have also
been documented as arsenic-induced cardiac effects
(Gorby, 1994; Morton and Dunnette, 1994). A dose-
response relationship has been reported between
cumulative arsenic exposure and heart rate-corrected
increased QT dispersion and QT prolongation from
the endemic area of arseniasis in southwestern Tai-
wan (Wang, C.-H. et al., 2009). The arsenic-induced
QT dispersion is associated with atherosclerotic dis-
eases and predicts long-term cardiovascular mortal-
ity in residents with previous exposure to arsenic
(Wang et al., 2010).
7.4.2  Peripheral Vascular Diseases
Blackfoot disease, a unique peripheral arterial dis-
ease characterized by severe systemic arteriosclerosis,
as well as dry gangrene and spontaneous amputations
of affected extremities and end stages, has been well
documented as a characteristic vascular disease asso-
ciated with long-term arsenic exposure (Chen et al.,
1988b; Jean et al., 2010; Tseng, 1977). Diagnostic cri-
teria for Blackfoot disease include objective signs of
ischemia (i.e. absence or diminution of arterial pulsa-
tions, pallor on elevation, or rubor on dependency of
ischemic extremities) and various degrees of ischemic
changes in the skin, as well as subjective symptoms
of ischemia (i.e. intermittent claudication, pain at
rest, and ischemic neuropathy). Not all patients are
affected by black, mummified dry gangrene (Tseng
et al., 1961). Extensive pathological study showed
that 30% of Blackfoot disease patients had histologi-
cal lesions compatible with thromboangiitis oblit-
erans, and 70% showed changes of arteriosclerosis
obliterans. Marked generalized atherosclerosis was
observed in all autopsied cases of Blackfoot disease,
and the fundamental vascular changes of the disease
represent an unduly developed severe arteriosclero-
sis (Yeh and How, 1963).
The dose-response relationship between ingested
inorganic arsenic and Blackfoot disease has been
well documented in the endemic area of southwest-
ern Taiwan, where residents had used high-arsenic
artesian well water for more than 50 years (Tseng,
1977). Patients affected with Blackfoot disease have
a high prevalence of arsenic-induced skin lesions,
including hyperpigmentation, hyperkeratosis, and
skin cancers (Tseng, 1997). They also exhibit high
mortality from cancers of the lung, liver, bladder,
kidney, and prostate, as well as ischemic heart dis-
ease (Chen et al., 1988b). In addition to the duration
of artesian well water consumption and the arsenic-
induced skin lesions, the development of Blackfoot
disease is also associated with undernourishment
and a family history of Blackfoot disease (Chen
et al., 1988b).
In Blackfoot disease, overt peripheral vascular dis-
ease was not reported in other arsenic-exposed pop-
ulations. However, comparable peripheral vascular
disorders with varying degrees of severity, including
Raynaud disease, microangiopathies, vasospastic
tendency, and acrocyanosis, have also been reported
among workers who were exposed to inorganic
arsenic through copper smelting (Lagerkvist et al.,
1986), pesticide handling, wall painting, and wood
burning; among vintners who had consumed arse-
nic-contaminated wine in Germany; among patients
treated with arsenic-containing drugs; and among
inhabitants exposed to high-arsenic drinking water
in Poland, Chile, Mexico, Argentina, Japan, Bangla-
desh, and Xinjiang, China (Garcia-Vargas et al., 1994;
Chen et al., 1997a; Engel et al., 1994; Hotta, 1989;
IARC, 2004; Jean et al., 2010; NRC, 1999; Rahman
et al., 1999b; Wang and Huang, 1994; WHO, 1981,
2001). Lynn et al. (2000) reported that NADH oxi-
dase activation is involved in oxidative DNA dam-
age to human aorta vascular smooth muscle cells
produced by As(III). Such an underlying mechanism
is consistent with the broad spectrum of oxidative
 28 Arsenic
damage produced by arsenical exposure in a num-
ber of organ systems (NRC, 1999).
There was a decline in the incidence of Blackfoot
disease after the implementation of a surface water
supply system in the endemic area, and most newly
developed cases were older residents who had con-
sumed high-arsenic artesian well water (Wang et al.,
1985). A survey has shown a dose-response relation-
ship between cumulative arsenic exposure and subclin-
ical peripheral vascular disorder detected by Doppler
ultrasonography among seemingly normal subjects
after the cessation of drinking artesian well water in
the endemic area of Blackfoot disease in Taiwan. In a
recent ecological study, the prevalence of peripheral
vascular disease among diabetic and nondiabetic resi-
dents was significantly higher in arseniasis-endemic
than nonendemic areas in southwestern Taiwan (Wang
et al., 2003). Arsenic methylation capacity is associated
with the arsenic-related peripheral vascular disease
(Tseng et al., 2005).
In a recent study, an increased risk of erectile
dysfunction associated with exposure to arsenic in
drinking water was reported (Hsieh et al., 2008). Arse-
nic-related oxidative stress has been suggested to be a
major cause of this male reproductive failure.
7.4.3  Ischemic Heart Diseases
Both ingested and inhaled inorganic arsenic have
been related to increased mortality from cardiovas-
cular disease, especially ischemic heart disease (Chen
et al., 1997a; Engel et al., 1994; IARC, 2004; Wang et al.,
2007; WHO, 1981, 2001). Mortality from cardiovascu-
lar disease was significantly higher among residents
in endemic areas of Blackfoot disease than among
the general population in Taiwan (Wu et al., 1989). A
significant dose-response relationship between the
ingested arsenic level and the risk of ischemic heart
disease was observed in cohort and case-control stud-
ies in southwestern Taiwan (Chen et al., 1996). In a
recent ecological study, the prevalence of coronary
artery disease among diabetic and nondiabetic resi-
dents was significantly higher in arseniasis-endemic
than nonendemic areas in southwestern Taiwan (Wang
et al., 2003). Myocardial infarction has been related to
high-arsenic drinking water in several autopsy studies
in Antofagasta, Chile (Chen et al., 1997a; Engel et al.,
1994). However, details of arsenic exposure and popu-
lation at risk were not available for further evaluation
of the dose-response relationship.
The association between long-term exposure to arse-
nic and increased mortality from cardiovascular disease
has also been reported among copper smelter workers in
603
the United States and Sweden, among chimney sweeps
in Sweden and Denmark, among glassblowers in
Sweden, and among workers and neighboring residents
of an arsenic refinery in Japan (Chen et al., 1997a; Engel
et al., 1994; IARC, 2004; WHO, 1981, 2001).
A significant reverse dose-response relationship
was observed between arsenic-induced ischemic heart
disease and serum levels of α- and β-carotene after
adjustment for age, gender, body mass index, and
hypertension, as well as the ratio between total choles-
terol and high-density lipoprotein cholesterol (Hsueh
et al., 1998).
7.4.4 Stroke
A survey carried out in I-Lan County of northeast-
ern Taiwan showed a significant dose-response rela-
tionship between the arsenic concentration in drinking
water and the prevalence of strokes, especially cerebral
infarction (Chiou et al., 1997). The biological gradient
of stroke by arsenic in drinking water remained sta-
tistically significant after adjustment for age, gender,
body mass index, disease status of hypertension and
diabetes mellitus, cigarette smoking, and alcohol con-
sumption. In an ecological study in southwestern Tai-
wan, increased mortality from stroke was observed
for residents who lived in arseniasis-endemic areas of
southwestern Taiwan (Tsai et al., 1999). In a recent eco-
logical study, the prevalence of coronary artery disease
among diabetic and nondiabetic residents was signifi-
cantly higher in arseniasis-endemic than nonendemic
areas in southwestern Taiwan (Wang et al., 2003). In an
ecological study, exposure to low levels of arsenic was
thought to be associated with a higher risk of incident
stroke (Lisabeth et al., 2010).
7.4.5  Carotid Atherosclerosis
In a cross-sectional survey of residents in southwest-
ern Taiwan, a dose-response relationship between the
prevalence of carotid atherosclerosis and long-term
exposure to arsenic from drinking well water was
observed (Wang et al., 2002). The biological gradients
remained significant after adjustment for age, gender,
hypertension, diabetes mellitus, cigarette smoking,
alcohol consumption, waist-to-hip ratio, and serum
levels of total cholesterol and low-density lipoprotein
cholesterol. Arsenic methylation capability is associ-
ated with the risk of carotid atherosclerosis associ-
ated with arsenic exposure (Huang et al., 2009). More
recent studies in Taiwan (Hsieh et al., 2011) reported
an increased risk of carotid atherosclerosis from arse-
nic exposure and linked this effect to polymorphisms
in arsenic metabolism genes in a case-control study,
604 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
specifically the PNP A-T haplotype and at least vari-
ants of the AS3MT or GSTO1 haplotypes.
7.4.6 Hypertension
A cross-sectional study in southwestern Taiwan
reported an increased prevalence of hypertension
among residents in the arseniasis-endemic area
than those in a nonendemic area, as well as a dose-
response relationship between ingested inorganic
arsenic and the prevalence of hypertension (Chen
et al., 1995). The biological gradient remained sig-
nificant after adjustment for age, gender, diabetes
mellitus, proteinuria, body mass index, and serum
triglyceride levels. Another study in Bangladesh
also found a dose-response relationship between
ingested arsenic and hypertension prevalence
after adjustment for age, gender, and body mass
index (Rahman et al., 1999b). Increased hyperten-
sion prevalence was also observed among patients
affected with arsenic-induced skin lesions in an
area in Chile where well water had a high arsenic
concentration (Borgono et al., 1977; Zaldívar, 1980).
Arsenic-exposed workers were reported to have a
higher systolic blood pressure compared to unex-
posed workers in Denmark (Jensen and Hansen,
1998). Arsenic methylation capability is associated
with a risk of arsenic-related hypertension in south-
western Taiwan (Huang et al., 2007). More recent
studies from Taiwan (Wu et al., 2010, 2011) have
shown that the short GT-repeat polymorphic form of
HO-1 may play a protective role against the risk of
carotid artery atherosclerosis from arsenic exposure
and more generally in blood pressure regulation
and cardiovascular mortality risk in hypertensive
persons with exposure to agents such as arsenic.
TABLE 5  Various Cancers with Increased Risks Caused by Arsenic Exposure Through Inhalation and Ingestion
Ingestion
Cancer Site Drinking Water Contaminated Wine
Skin + +
Lung + +
Urinary bladder + +
Kidney + +
Nasal cavity +
Larynx +
Prostate +
Breast +
Hepatic angiosarcoma + +
Hepatocellular carcinoma + +
Gastrointestial tract + +
Hematolymphatic system + +
Brain and nervous system
7.4.7  Microcirculation Abnormality
Based on laser Doppler flowmetry, seemingly nor-
mal men living in villages where Blackfoot disease was
hyperendemic were found to have poorer peripheral
microcirculation than matched controls in nonendemic
areas (Tseng et al., 1995). However, the dose-response
relationship between ingested inorganic arsenic and
abnormal peripheral microcirculation was not examined.
7.4.7.1  Microvascular Diseases
In a recent ecological study, the prevalence of micro-
vascular diseases, including renal disease, retinopathy,
and neurological disorders among diabetic and non-
diabetic residents was significantly higher in arsenia-
sis-endemic than nonendemic areas in southwestern
Taiwan (Wang et al., 2003).
A significant ecological correlation between the
arsenic content of drinking water and the mortality
from cancer of the nasal cavity was reported recently
(Chen and Wang, 1990). Although perforation of the
nasal septum has been documented among smelter
workers exposed to high levels of inorganic arsenic
(WHO, 1981), there were no other reports of an asso-
ciation between nasal cavity cancer risk and exposure
to arsenic through inhalation or ingestion.
7.5  Carcinogenic Effects
Ingested and inhaled arsenic through occupational,
environmental, and medicinal exposure is involved in
the development of several cancers in humans with no
apparent organotropism, as shown in Table 5 (Chen
et al., 1997b; IARC, 2004; NRC, 1999; WHO, 1981,
2001). Ecological, case-control, and cohort studies
have shown a significant dose-response relationship
Inhalation
Fowler’s Solution Copper Smelter Pesticide Factory
+ +
+ + +
+ +
+
+ + +
+
+
+
+
 28 Arsenic
between arsenic in drinking water and increased risk
of cancers of the liver, nasal cavity, lung, skin, urinary
bladder, kidney, and prostate in southwestern and
northeastern Taiwan (Chen et al., 1988a, 1992, 2004;
Chiou et al., 1995, 2001). Based on sufficient evidence
that arsenic in drinking water causes cancers of the
urinary bladder, lung, and skin in humans, arsenic in
drinking water has been classified as a group 1 carcin-
ogen to humans (IARC, 2004). It should be noted that
data from a number of laboratories are discussed in
Section 5.6.3. Recent studies (Luna et al., 2010; Jomova
et al., 2011; Flora, 2011) have implicated the formation
of arsenical-induced ROS as a common driver for the
production of cellular oxidative stress, including oxi-
dative DNA damage, which could lead to cancer out-
comes in a number of tissues. Cellular responses to this
oxidative stress include the induction of stress proteins
such as HO-1 (Liu et al., 2011).
7.5.1  Skin Cancer
There is clear evidence that long-term oral expo-
sure to inorganic arsenic through drinking water,
grape wine, or medication increases the risk of skin
cancer (Chen et al., 1997b; IARC, 2004; NRC, 1999;
WHO, 1981, 2001). Inhaled arsenic has also been docu-
mented to induce skin cancer among workers produc-
ing sheep-dip powder from sodium arsenite (Hill and
Faning, 1948). The largest study of arsenic-induced
skin cancer was carried out in southwestern Taiwan,
and a dose-response relationship between the arsenic
content of drinking water and the prevalence of skin
cancer was observed (Tseng et al., 1968). In addition
to long-term exposure to high-arsenic artesian well
water, chronic liver disease and malnutritional status
have recently been reported to be associated with the
development of arsenic-induced skin cancer (Hsueh
et al., 1995). The risk of skin cancer was significantly
associated with elevated serum arsenic levels and
decreased serum β-carotene level in a dose-response
relationship, but no significant differences in serum
levels of selenium and zinc were observed between
patients affected with arsenic-induced skin cancer and
matched healthy controls (Hsueh et al., 1997). Arsenic
methylation capability has been found to be associated
with the development of skin cancer. Increased skin
cancer was observed among those who had an elevated
proportion of MMA in the total urinary metabolites of
inorganic arsenic (Hsueh et al., 1997; Yu et al., 2000).
An increased risk of arsenic-induced skin cancer was
observed among those who had at least one null or
variant genotype of GSTM1, GSTT1, or GSTP1 (Tseng,
1999). More recent studies related to arsenic-induced
skin cancers have focused on molecular factors that
605
could mediate this health outcome. Banerjee et al.
(2011) reported that polymorphisms in the TNF and
IL10 [encoding interleukin-10 (IL-10)] gene promoters
can modulate arsenic-induced skin lesions and other
nonskin effects such as ocular and respiratory diseases.
They found the GA/AA and TA/AA TNF alleles to be
associated with an increased risk of these disorders and
the −3575 IL10 allele to be associated with decreased
IL-10 production. Sun et al. (2011) studied the possible
interaction between UV light and arsenic exposures in
human skin cells. They reported evidence of interplay
between the oxidative stress effects of arsenic and UV
light on a number of important regulators of apoptosis,
leading to enhanced cellular survival and carcinogenic
transformation. Subsequent studies by Sun et al. (2012)
examined the possible roles of stem cells in the devel-
opment of skin cancers in mice. These authors found
2.5 times more stem cells in an arsenite-transformed
human skin cell line (HaCaT), suggesting a relation-
ship between a malignant phenotype and increased
numbers of stem cells. Other in vitro studies using the
HaCaT skin cell line (Komissarova and Rossman, 2010)
showed that As3+-induced poly (ADP-ribosyl)lation of
the p53 tumor suppressor gene is a possible mecha-
nism of arsenic-induced carcinogenesis.
7.5.2  Lung Cancer
An increased risk of cancers of the lung and nasal
cavity has been associated with long-term exposure to
inorganic arsenic through inhalation and ingestion in a
dose-response relationship (Chen et al., 1997b; IARC,
2004; NRC, 1999; Pinto et al., 1978; WHO, 1981, 2001).
An excess of deaths caused by lung cancer has been
observed among workers exposed to inorganic arse-
nic through inhalation in the production and use of
pesticides, in gold mining, and in the smelting of non-
ferrous metals, especially copper. Individuals living
within several kilometers of inorganic arsenic-emit-
ting industries were also reported to have an increased
risk of lung cancer (Chen et al., 1997b; WHO, 1981,
2001). The dose-response relationship between inhaled
inorganic arsenic and lung cancer risk was mainly
observed in two large cohorts of copper smelter work-
ers in Anaconda, Montana (Brown and Chu, 1983; Hig-
gins et al., 1981; Lee-Feldstein, 1983), and in Tacoma,
Washington (Enterline and Marsh, 1982). The observed
effects might be confounded by cigarette smoking and
exposures to other chemicals. An interaction between
inhaled inorganic arsenic and cigarette smoking in
the risk of developing lung cancer has been reported
(Järup and Pershagen, 1991).
An increased risk of lung cancer from exposure to
> 100 μg/L arsenic in drinking water has been reported
606 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
among Bangladeshis who smoked (Mostafa et al.,
2008). A significant association between ingested arse-
nic and lung cancer risk has been observed in patients
treated with arsenic-containing medicine, in vintners
exposed to arsenic pesticide-contaminated grape wine,
and in persons exposed to inorganic arsenic from
drinking water (Chen et al., 1997b; Guo, 2004; IARC,
2004; NRC, 1999; WHO, 1981, 2001). A dose-response
relationship between ingested inorganic arsenic and
lung cancer has been reported in cohort studies in
Taiwan (Chiou et al., 1995), Japan (Tsuda et al., 1995)
and most recently in Argentina based on studies in
Cordoba, Argentina (Steinmaus et al., 2010), which
reported that persons exposed to arsenic in drinking
water and whose percentage MMA was in the high-
est quartile had an elevated risk of lung cancer relative
to those in the lowest quartile. The data suggest the
importance of differences in arsenical metabolism in
relation to the risk of lung cancer. Both cigarette smok-
ing and signs of arseniasis (i.e. skin cancer or Blackfoot
disease) were reported to increase the risk of arsenic-
induced lung cancer in these two studies. A synergis-
tic effect on the development of lung cancer between
cigarette smoking and ingested arsenic was observed
in the endemic areas of arseniasis in southwestern and
northeastern Taiwan (Chen et al., 2004).
These results are consistent with the positive inter-
active effects between benzo(a)pyrene and arsenic in
producing lung cancers in hamsters after concomitant
exposures to both agents (Pershagen et al., 1984).
7.5.3  Urothelial Cancer
Both inhaled and ingested inorganic arsenic have
been well documented to induce cancers of the bladder
and kidney, especially urothelial cancers (Chen et al.,
1997b, 1985, 1986; IARC, 2004; NRC, 1999; WHO, 2001).
Recent studies by Yokohira et al. (2011) reported dose-
related As3+-induced effects on the bladder urothelium
of wild-type and AS3MT-knockout mice exposed to
As3+ in drinking water for 4 weeks. More pronounced
cytotoxic effects were observed in AS3MT-knockout
mice, but a no-effect level of 1.0 ppm was calculated
for both strains. There have been several reports of
an increased risk of bladder cancer among patients
treated with Fowler’s solution (Chen et al., 1997b). In
a cohort study of patients treated with Fowler’s solu-
tion, a significant association between the cumulative
dose of arsenic intake and mortality from bladder can-
cer was observed (Cuzick et al., 1992). Moselle vint-
ners who consumed arsenic pesticide-contaminated
grape wine were found to have increased mortal-
ity from bladder cancer (Lüchtrath, 1983). Increased
kidney cancer mortality following a 50-year latency
period following drinking-water arsenic exposures in
Chile and 25 years after reductions in exposures was
reported by Yuan et al. (2010). Alterations in urinary
arsenic methylation profiles have also been reported
15 years after cessation of drinking water exposures
with a higher percentage of MMA(V) in the urine in
an elderly cohort subject from Taiwan (Huang et al.,
2009), indicating that the arsenical methylation pro-
cess in humans is also dynamic and may change as a
function of age. Possible explanations for latency in
arsenic-induced cancers may be related to epigenetic
mechanisms, which are discussed in the mechanisms
of toxicity section of this chapter. Recent studies from
Taiwan (Wang, C.-H. et al., 2009; Wang, Y. H. et al.,
2009; Chung et al., 2011) and the USA (Lesseur et al.,
2012) report a link between (1) susceptibility to arsenic-
induced cancer of the bladder and urothelial system
and (2) specific GST and AS3MT alleles. Wang, Y. H.
et al. (2009) reported an increased risk of urothelial
cancers in arsenic-exposed persons with diplotypes
GSTO1 and GSTO2. Persons with chemical exposures
from cigarette smoking, alcohol consumption, arsenic,
and occupational exposures had the highest risk factor
and were likely to have two or more genotypes/dip-
lotypes of CYP2E1, GSTO1, and GSTO2. Subsequent
studies by Chung et al. (2011) focused on GSTO1 and
GSTO2 alleles and found a positive significant asso-
ciation between total urinary arsenic, percentage of
inorganic arsenic, percentage of MMA, and urothelial
cancers. The DMA percentage was inversely related to
urothelial cancers. The MMA percentage was found
to be associated with the wild-type form of GSTO1
(140ALA/ALA), compared to those with the GSTO1
(Ala/Asp) or GSTO1 (140Asp/Asp) genotypes. The
GSTO2 (Asp/Asp) allele was found to be inversely
associated with urothelial cancer risk. In vitro studies
by Kojima et al. (2009) showed that arsenic biometh-
ylation was a requirement for oxidative DNA damage
in UROtsa human urothelial cells exposed to As3+. In
a case-control study of bladder cancer in New Hamp-
shire, Lesseur et al. (2012) studied a number of gene
alleles associated with the outcomes of arsenic expo-
sure and found elevated bladder cancer risk associated
with the GSTO2 (Asn142Asp) and GSTZ1 (Glu32Lys)
homozygous variants. Karagas et al. (2012) screened
bladder cancer cases from an ongoing arsenic case-
control study and reported that polymorphisms in sol-
uble carrier 39 member 2 (SLC39A2), a member of the
ZIP family of metal transporters, and fibrous sheath
interacting protein 1 (FSIP1) were potential modifiers
of arsenic-related bladder cancer.
It should be noted that epigenetic mechanisms
involving DNA methylation and attendant regulation
of major gene families involved in arsenic-induced
 28 Arsenic
cancers form an important area of current research
(Reichard and Puga, 2010) because these processes
may explain the observed long delays in the formation
of cancers following cessation of exposure, such as has
been reported in Chile. Ecological studies in Taiwan
have well documented the dose-response relationship
between ingested arsenic from drinking water and
mortality from cancers of the urinary bladder and kid-
ney (Chen and Wang, 1990; Chen et al., 1988a). A sig-
nificant dose-response relationship between ingested
inorganic arsenic from drinking water and the risk of
bladder cancer has been documented in cohort studies
in Taiwan (Chiou et al., 1995, 2001), Japan (Tsuda et al.,
1995), and, more recently, in Finland (Kurttio et al.,
1999), Argentina (Bates et al., 2004), and the United
States (Steinmaus et al., 2006). Those who show signs
of arseniasis (i.e. skin cancer or Blackfoot disease)
were found to have an increased risk of bladder cancer
from drinking high-arsenic well water (Chiou et al.,
1995; Tsuda et al., 1995). Cigarette smoking was sig-
nificantly associated with the development of arsenic-
induced bladder cancer in northeastern Taiwan (Yang
et al., 2014), but not in southwestern Taiwan (Chiou
et al., 1995). A significant dose-response relationship
between bladder cancer risk and arsenic exposure was
observed only among cigarette smokers in the United
States (Bates et al., 1995). A decreased ratio between
urinary levels of DMA and MMA was associated with
an increased risk of bladder cancer (Chen et al., 2003).
Studies by Steinmaus et al. (2006) support the findings
from Taiwan and demonstrate that persons with higher
urinary levels of MMA are at greater risk of developing
arsenic-induced cancers.
Inhaled inorganic arsenic has also been found to
be associated with the risk of mortality from bladder
cancer among copper smelter workers in the United
States and Japan (Bates et al., 1992; Chen et al., 1997b)
and among residents who lived near a plant roasting
arsenopyrite in Japan and were exposed to inorganic
arsenic through inhalation and ingestion (Hotta, 1989).
There are no reports examining the dose-response rela-
tionship between inhaled arsenic and bladder cancer.
Excess mortality from kidney cancer was observed
among copper smelter workers and patients treated
with Fowler’s solution (Chen et al., 1997b). A dose-
response relationship between ingested inorganic
arsenic and kidney cancer mortality was also observed
among residents in the endemic area of arseniasis in
Taiwan (Chen et al., 1988a, 1992; Chiou et al., 1995).
7.5.4  Liver Cancer
Both hepatic angiosarcoma and hepatocellular car-
cinoma have been associated with long-term exposure
607
to ingested and inhaled arsenic (Bates et al., 1992; Chen
et al., 1997b; Falk et al., 1981a,b; IARC, 2004; NRC, 1999;
WHO, 1981, 2001). In these cases, exposure was from
ingestion of arsenic-contaminated wine, high-arsenic
drinking water, and Fowler’s solution, and from inha-
lation through copper smelting and the production and
application of arsenic-containing pesticides. Because
hepatic angiosarcoma is a very rare disease, its associa-
tion with exposures to inorganic arsenic does not seem
likely to be a matter of chance.
Long-term exposure to inorganic arsenic through
ingestion and inhalation has been associated with the
development of hepatocellular carcinoma. Exposure to
ingested arsenic was from high-arsenic artesian well
water and arsenic-contaminated grape wine, and that
of inhaled arsenic was from copper smelting (Chen
et al., 1997b). Ecological studies have shown a dose-
response relationship between ingested inorganic
arsenic from drinking water and the risk of hepatocel-
lular carcinoma among residents in the endemic area
of arseniasis in southwestern Taiwan (Chen and Wang,
1990; Chen et al., 1988a).
7.5.5  Other Internal Cancers
Inhaled and ingested inorganic arsenic have been
associated with an increased risk of gastrointestinal
cancers, hematolymphatic malignancies, and malig-
nant neoplasms of the nervous system (Chen et al.,
1997b; IARC, 2004; NRC, 1999; WHO, 1981, 2001).
Excess mortality from cancers of the digestive tract
has been observed among copper smelter workers,
Moselle vintners, and residents in the endemic area
of arseniasis in Taiwan. Workers in copper smelters
and pesticide manufacturing plants were reported to
have increased mortality from malignant neoplasms of
lymphatic and hematopoietic tissues. Copper smelter
workers also had increased mortality from malignant
neoplasms of the brain and nervous system.
There are no reports on the association between
exposure to ingested inorganic arsenic and mortality
from malignant neoplasms of the hematolymphatic
and nervous systems. Ingested inorganic arsenic
through drinking high-arsenic artesian well water has
been found to be significantly associated with mortal-
ity from prostate cancer in a dose-response relationship
(Chen and Wang, 1990; Chen et al., 1988a,b). There are
no reports of an association between inhaled inorganic
arsenic and prostate cancer.
A significant ecological correlation between the arse-
nic content of drinking water and mortality from can-
cer of the nasal cavity was reported recently (Chen and
Wang, 1990). Although perforation of the nasal septum
has been documented among smelter workers exposed
608 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
to high levels of inorganic arsenic (WHO, 1981), there
are no other reports of an association between nasal
cavity cancer risk and exposure to arsenic through
inhalation or ingestion.
7.5.6  Lifetime Cancer Risk Induced by Arsenic
As shown in Table 6, the lifetime risk of developing
cancers of the skin, lung, bladder, liver, and kidney have
been estimated on the basis of Armitage-Doll multistage
models. The lifetime risk of developing skin cancer from
the ingestion of 1 μg/kg/day inorganic arsenic was esti-
mated according to the prevalence of skin cancer among
residents in an endemic area of arseniasis and an unex-
posed control area (Tseng et al., 1968). The lifetime risk
of developing lung cancer from 1 μg/kg/day arsenic
through inhalation was based on the data from copper
smelter workers in Anaconda, Montana (Brown and
Chu, 1983; Higgins et al., 1981; Welch et al. 1982; Lee-
Feldstein, 1983), and in Tacoma, Washington (Enterline
and Marsh, 1982; Enterline, et al., 1987).
An excessive risk of lung cancer has been reported
from oral exposure to 100-300 μg/L arsenic (Chen
et al., 2010a). The lifetime risks of developing cancer
of the lung, liver, bladder, and kidney from 1 μg/kg/
day inorganic arsenic through ingestion were based
on the mortality data of residents in the endemic
area of arseniasis southwestern Taiwan (Chen et al.,
1992). The lifetime risks of developing cancers of the
skin, lung, liver, bladder, and kidney from ingested
inorganic arsenic were within a sevenfold range of
magnitude. The risks were practically identical for
both men and women within a twofold range of
magnitude, indicating no gender difference in arse-
nic-induced carcinogenic responses. Arsenic expo-
sure during infancy to contaminated milk powder
may lead to pancreatic and hematopoietic cancer
TABLE 6  Lifetime Risk of Developing Cancers of Skin, Lung, Liver, Bladder, and Kidney Caused by 1 mg/kg/day
Inorganic Arsenic Through Ingestion and Inhalation
Cancer Site Exposure Type Study Area
Skin Ingestion Taiwan
Lung Inhalation Anacoda
Tacoma
Ingestion Taiwan
Bladder Ingestion Taiwan
Kidney Ingestion Taiwan
Liver Ingestion Taiwan
Sources: EPA, 1984; Chen et al., 1992.
(Yorifuji et al., 2011). Long-term exposure to rela-
tively low levels of arsenic from birth may increase
urinary cancer risk much later in life (Chen et al.,
2010b). Other recent epidemiological studies (Smith
and Steinmaus, 2009) have highlighted strong asso-
ciations between (1) in utero and early life exposures
to arsenic in drinking water and (2) the development
of a spectrum of adverse health effects later in life,
including a number of cancers, chronic renal disease
and cardiovascular effects. Epidemiological studies
into arsenic-induced development and reproduc-
tive effects have been reviewed periodically (Chen
et al., 1997b; NRC, 1999; WHO, 1981, 2001). Babies
born to female employees of a copper smelter who
were exposed to inorganic arsenic through inhala-
tion during pregnancy were reported to have an
increased incidence of congenital malformation and
low birth weight; there was also an increase in spon-
taneous abortion (Nordstrom et al., 1979a,b). Low
birth weight was also observed among newborns in
smelter areas relative to those in nonsmelter areas
(Tabacova et al., 1994).
An increased, but not statistically significant, risk of
coarctation of the aorta was found to be associated with
elevated arsenic levels in drinking water (Zierler et al.,
1988). Arsenic in drinking water has been reported
to increase the mortality from congenital anomalies
of the heart in females, and the mortality from con-
genital anomalies of the circulatory system for both
sexes in the United States (Engel and Smith, 1994).
Arsenic in drinking water was reported to be associ-
ated with an increased risk of spontaneous abortion in
two studies (Aschengrau et al., 1989; Borzsonyi et al.,
1992), and with a significantly increased risk of still-
birth in two studies (Borzsonyi et al., 1992; Ihrig et al.,
1998). Arsenic in drinking water was also reported
to be associated with increased neonatal mortality in
Lifetime Risk (per 1000)
Reference Male Female
Tseng et al., 1968 3.0 2.1
Higgins et al., 1981 17.0 –
Lee-Feldstein, 1983 9.8 –
Brown and Chu, 1983 4.6 –
Enterline and Marsh, 1980 24.0 –
Chen et al., 1992 1.2 1.3
Chen et al., 1992 1.2 1.7
Chen et al., 1992 0.4 0.5
Chen et al., 1992 0.4 0.4
 28 Arsenic
Chile (Hopenhayn-Rich et al., 2000). Similar findings
of increased rates of spontaneous abortion, stillbirth,
and infant mortality have been reported among popu-
lations consuming arsenic-contaminated well water in
Bangladesh (Milton et al., 2005) and West Bengal (von
Ehrenstein et al., 2005).
7.6  Experimental System Cancer Studies
No studies of cancer incidence in humans after oral
exposure to organic arsenicals have been reported, but
there are some animal studies into the carcinogenic-
ity of organic arsenicals. In an early 2-year study of
roxarsone (3-nitro-4-hydroxyphenylarsonic acid) tox-
icity in animals, no increase in tumor frequency was
detected in dogs, rats, or mice given 1.5, 2.9, or 3.8 mg
arsenic/kg/day, respectively (Prier et al., 1963). Life-
time studies of roxarsone at doses up to 1.4 mg arse-
nic/kg/day yielded no evidence of carcinogenicity in
male or female mice or female rats, although a slight
increase in pancreatic tumors was noted in male rats
(NTP, 1980). Carcinogenesis studies with inorganic
arsenic in hamsters (Inamasu et al., 1982; Pershagen
et al., 1984) were also positive, particularly in com-
bination with other organic carcinogens (see Section
7.7). Arnold et al. (2003) exposed male and female rats
to 0, 50, 400, or 800 ppm MMA and male and female
B6C3F1 mice to 0, 10, 50, 200, or 400 ppm MMA in
the diet for 104 weeks; estimated average daily doses
were up to 47.3 mg arsenic/kg/day for female rats
and up to 48.5 mg arsenic/kg/day for female mice.
No treatment-related neoplastic changes were seen in
either sex of either species. A similar lack of carcinoge-
nicity of MMA was reported by Shen et al. (2003), who
exposed male F344 rats to 0, 50, or 200 ppm MMA(V)
in drinking water for 104 weeks. Wei et al. (1999, 2002)
exposed male F344 rats to 0, 12.5, 50, or 200 ppm DMA
for 104 weeks in the diet; the average daily doses were
0, 0.03, 0.14, or 0.53 mg arsenic/kg. Increases in the
number of animals with bladder tumors were seen in
the two highest dose groups. No increases in tumor
incidence were seen in other organs. Hayashi et al.
(1998) reported that mice exposed to 400 ppm DMA
for 50 weeks, but not those exposed to 50 or 200 ppm,
showed an increased incidence of papillary adenomas
and an elevated average number of lung tumors per
mouse. DMA, which is a major methylated metabo-
lite of inorganic arsenic, has been reported by Hayashi
et al. (1998) to exhibit tumorigenicity and to stimu-
late tumor progression in mice after drinking water
exposure at 400 ppm for up to 50 weeks. These data
are consistent with epidemiological studies of humans
who developed lung cancer from the drinking water
exposures noted above.
609
7.6.1  Developmental and Reproductive Effects
7.6.1.1  Teratogenic Effects
Until recently, there were very few reports on
the teratogenicity of inorganic arsenic in humans.
Congenital malformations were observed in chil-
dren whose mothers worked, during pregnancy, at a
Swedish copper smelter and were exposed to arsenic,
other heavy metals, and sulfur dioxide. The observed
incidence was five times greater than that in children
born to other mothers from the same region (Nord-
strom et al., 1979a,b). However, no conclusion can be
drawn as to whether arsenic is responsible for these
malformations. Teratogenic effects have been shown
to occur after a single administration of a high dose
(6-10 mg As/kg body weight) of sodium arsenate to
pregnant golden hamsters (Ferm, 1977). The com-
pound was given intravenously to the hamsters on
the eighth day of gestation. Rates of both fetal reab-
sorption and malformation increased with increas-
ing doses of the arsenate. The teratogenic effects
were characterized by anencephaly, renal agenesis,
and rib malformations. Similar teratogenic effects
have been induced in mice intraperitoneally injected
with sodium arsenate at a dose of 11 mg As/kg body
weight (Hood and Bishop, 1972) and in rats intraperi-
toneally injected with 5-12 mg As/kg body weight
(Beaudoin, 1974). However, in all cases, the doses
required to cause these effects resulted in significant
maternal toxicity or even lethality. Recent studies in
mice, rats, and rabbits found no evidence of develop-
mental effects at exposure levels that did not produce
maternal toxicity (Holson et al., 1999, 2000; Nemec
et al., 1998; Stump et al., 1999).
7.6.2  Genotoxic Effects and Mutagenicity
There have been a large number of studies into the
genotoxic effects of arsenic. The results are mixed but,
in general, it seems that the inorganic arsenicals are
either inactive or weak mutagens (Jacobson-Kram and
Montalbano 1985), although they are able to produce
chromosomal effects (aberrations, sister chromatid
exchange) in most systems. An increased incidence
of chromosome abnormalities has been observed in
lymphocytes of workers exposed to arsenic (Beckman
et al., 1977) and of patients therapeutically treated with
arsenicals (Petres et al., 1977).
When cultured human lymphocytes were exposed
to NaAsO2 (trivalent) and Na2HAsO4 (pentavalent),
significantly increased frequencies of chromosome
aberrations were found for trivalent, but not for pen-
tavalent, arsenic (Nordenson et al., 1981). Sodium arse-
nite was found to be effective in increasing the rate of
sister chromatid exchange, but cultured lymphocytes
610 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
obtained from 13 patients with Blackfoot disease did
not differ from those of healthy persons in terms of the
frequency of sister chromatid exchange after exposure
to sodium arsenite (Wen et al., 1981). Arsenical inter-
ference with normal DNA repair processes has also
been noted (Fong et al., 1980; Jung et al., 1969; Jung,
1971; Rossman et al., 1977), suggesting that induction
of cellular genome damage is a consequence.
In mutagenicity tests using Salmonella and Esch-
erichia coli systems and the Chinese hamster cell line
V79, both trivalent and pentavalent inorganic arsenic
failed to produce point mutations (Lofroth and Ames,
1978; Rossman et al., 1980). Arsenic trichloride, sodium
arsenite, and arsenic pentoxide, however, gave posi-
tive results in the rec assay in Bacillus subtilis (Kada
et al., 1980; Nishioka, 1975).
Morphological transformation of Syrian hamster
embryo cells derived from 13- to 14-day-old embryos
occurred at concentrations of 2.5-5.0 μg/mL sodium
arsenate using a cell culture method (DiPaolo and
Casto, 1979).
The genotoxic effects of organic arsenicals such as
DMA and roxarsone have been tested. They are shown
to be able to cause mitotic arrest, chromosome aber-
rations, mutations and DNA strand breaks (ATSDR,
2007).
7.7  Interaction Between Arsenic and Other
Compounds
An interaction between arsenic and selenium has
been described by Levander (1977). He concluded that
arsenic has a protective effect against the toxicity of
selenium in several species. Likewise, selenium can
decrease the effects of arsenic, including clastogenic-
ity, cytotoxicity, and teratogenicity (Babich et al., 1989;
Biswas et al., 1999; Holmberg and Ferm, 1969). The
mechanism of this mutual inhibition of effects is not
known, but may be related to the formation of a com-
plex that is excreted more rapidly than either arsenic
or selenium alone (Cikrt et al., 1988; Levander, 1977) or
caused by selenium-induced changes in arsenic meth-
ylation (Styblo and Thomas 2001; Walton et al., 2003).
Combined exposure to arsenic and lead led to
additive effects on tissue respiration and functional
changes in the central nervous system (Novakova,
1969). Mahaffey and Fowler (1977) first reported that
rats given cadmium and arsenic (50 mg/kg) in food for
10 weeks showed lower serum alkaline phosphatase
levels than those treated with either metal alone. The
additive effects of dietary arsenic and lead (200 mg/
kg) in coproporphyrin excretion were also subse-
quently noted (Fowler and Mahaffey, 1978; Mahaffey
et al., 1981). More recent studies in rats using combined
drinking water exposures to lead (25 mg Pb/L), cad-
mium (10 mg Cd/L), and arsenic (5.0 mgAs/L; the
lowest observed effect level doses) for 30, 90, or 180
days produced similar biochemical effects that showed
strong dependency on the duration of exposure (Fowler
et al., 2004). Please see Chapter 11, “Interactions and
Mixtures in Metal Toxicology” and the review by Mad-
den and Fowler (2000) for a more complete discussion
on interactions among metals.
Arsenic has been shown to cause an increase in
total plasma cholesterol in rats; coadministration of
chromium(III) counteracts this effect (Aguilar and
Martinez-Para, 1997).
A possible interaction among cigarette smoking,
inhalation of arsenic, and the risk of lung cancer has
not been extensively investigated. Smoking seemed to
increase lung cancer risk synergistically in one study
of smelter workers (Pershagen et al., 1981), although
the data are not adequate to exclude a simple additive
interaction (Thomas and Whittemore, 1988). Cigarette
smoking has been shown to increase the occurrence
of lung cancer and urothelial carcinoma in people
exposed to high levels of arsenic in the drinking water
(Chiou et al., 1995; Tsuda et al., 1995; Yang et al., 2014).
Coexposure to ethanol and arsenic may exacerbate
the toxic effects of arsenic. Simultaneous exposure
of rats to ethanol (10% in drinking water) and arse-
nic for 6 weeks produced a significant increase in the
concentration of arsenic in the kidney, a nonsignifi-
cant increase or arsenic in the liver, and a significant
increase in the concentration of glutathione in the liver,
compared with rats treated with either ethanol or arse-
nic alone (Flora et al., 1997a,b). Histological damage to
the liver, but not to the kidneys, was increased in rats
treated with both ethanol and arsenic compared with
those receiving only arsenic.
Please see Chapter 11 for a more detailed discussion.
8  DOSE-EFFECT AND DOSE-RESPONSE
RELATIONSHIP IN ARSENIC POISONING
The dose-effect relationship in acute exposure to
arsenic may be estimated from the 220 poisoning
cases associated with an episode of arsenic contamina-
tion of soy sauce in Japan, reported by Mizuta et al.
(1956). The soy sauce was contaminated with approxi-
mately 0.1 mg As/mL, probably as calcium arsenate.
Arsenic intake in the affected individuals was esti-
mated by the researchers to be 3 mg/day (0.05 mg/
kg/day; assuming an average body weight of 55 kg
for the Asian population). The duration of exposure
was 2-3 weeks in most cases. The primary symptoms
were initially edema of the face and gastrointestinal
 28 Arsenic
and upper respiratory symptoms, followed by skin
lesions and neuropathy in some patients. Other effects
included mild anemia and leukopenia, mild degenera-
tive liver lesions, and hepatic dysfunction, abnormal
electrocardiogram, and ocular lesions. An acute oral
guidance value of 0.005 mg/kg/day (ATSDR, 2007)
may be derived based on the lowest observed adverse
effect level (LOAEL) of 0.05 mg/kg/day, by applying
an uncertainty factor of 10 for extrapolation from a
LOAEL to a no observed adverse effect level (NOAEL)
and 1 for intraindividual variability. This guidance
value is supported by the case of a husband and wife
in upstate New York who experienced gastrointestinal
symptoms (nausea, diarrhea, and abdominal cramps)
almost immediately after beginning the intermittent
consumption of arsenic-contaminated drinking water
at an estimated dosed of 0.05 mg/kg/day (Franzblau
and Lilis, 1989). The uncertainty factor of 1 for intra-
individual variability reflects the fact that the data-
base includes persons of different ethnicities and age
groups, including infants.
Hamamoto (1955) reported on Japanese infants who
ingested milk contaminated with arsenic over a period
of 33 days. The amount of arsenic ingested was about
1.3-3.6 mg/day. When a total of about 80 mg arsenic
had been ingested, these victims developed symptoms
of arsenic poisoning, including pigmentation, swelling
of the liver, and anemia. A total of 12,131 cases of poi-
soning with 130 deaths have been reported: impaired
learning and clinical functions such as hearing were
described among those who survived (Yamashita
et al., 1972).
In areas in Cordoba, Argentina, with endemic
arsenicosis, the main symptoms described among
the inhabitants were symmetrical palmar and plantar
hyperkeratosis. Concentrations in drinking water have
been reported to be 0.9-3.4 mg As/L (Wickstrom, 1972).
The dose-effect relationship in chronic exposure
may be estimated from reports by Tseng et al. (1968)
and Tseng (1977), who investigated the incidence of
Blackfoot disease and dermal lesions in a large num-
ber of poor farmers (both males and females) exposed
to high levels of arsenic in well water in Taiwan. A
control group consisting of over 7500 people was
identified. The incidence of dermal lesions increased
with dose, but individual doses were not provided.
Incidence data were provided based on stratifica-
tion of the exposure population into low (< 300 μg/L),
medium (300-600 μg/L), or high (> 600 μg/L) exposure
groups according to the arsenic concentration in the
well water. Doses were calculated from group mean
arsenic concentrations in well water, assuming the
intake parameters described by Abernathy et al. (1989).
The arithmetic mean concentration of arsenic in well
611
water was converted to exposure doses by assuming
a water intake of 4.5 L/day, a body weight of 55 kg,
and an estimation of arsenic intake of 0.003 mg/As/
kg/day from food. The control, low, medium, and
high exposure levels corresponded to doses of 0.0008,
0.014, 0.038, 0.065 mg/kg/day, respectively. A clear
dose-response relationship was observed for charac-
teristic skin lesions: 0.0008 mg/kg/day was identified
as the NOAEL; at 0.014 mg/kg/day, hyperpigmenta-
tion and keratosis of the skin were observed; and at
0.038-0.065  mg/kg/day, an increased incidence of
dermal lesions was observed. A chronic health guid-
ance value of 0.0003 mg/kg/day may be derived from
the NOAEL of 0.0008 mg/kg/day; an uncertainty fac-
tor of 3 was applied in consideration of the fact that
most of the control population was less than 20 years
of age and the incidence of skin lesions increased as
a function of age, and because the estimates of water
intake and dietary arsenic intake are highly uncer-
tain (ATSDR, 2007). Schoof et al. (1998) estimated that
dietary intakes of arsenic from rice and yams might
have been 15-211 μg/day (mean, 61 μg/day), based on
arsenic analyses of foods collected in Taiwan in 1993-
1995. Use of the 50-μg/day estimate would result in
an approximate doubling of the NOAEL (0.0016 mg/
kg/day). This health guidance value is supported by
a number of well-conducted epidemiological studies
that identify reliable NOAELs and LOAELs for dermal
effects. Southwick et al. (1981) identified a NOAEL of
0.006-0.007 mg/kg/day for dermal lesions in several
small populations in Utah. Harrington et al. (1978)
identified a NOAEL of 0.003 mg/kg/day for dermal
effects in a small population in Alaska. Guha Mazum-
der et al. (1988) identified a NOAEL of 0.009 mg/kg/
day and a LOAEL of 0.006 mg/kg/day for pigmenta-
tion changes and hyperkeratosis in a small population
in India. Haque et al. (2003) identified a LOAEL of
0.002 mg/kg/day for hyperpigmentation and hyper-
keratosis in a case-control study in India. Cebrian et al.
(1983) identified a NOAEL of 0.0004 mg/kg/day and a
LOAEL of 0.022 mg/kg/day in two regions of Mexico.
Borgono and Greiber (1972) and Zaldívar (1974) iden-
tified a LOAEL of 0.02 mg/kg/day for abnormal skin
pigmentation in patients in Chile, and Borgono et al.
(1977) identified a LOAEL of 0.01 mg/kg/day for the
same effects in schoolchildren in Chile. Valentine et al.
(1985) reported a NOAEL of 0.02 mg/kg/day for der-
mal effects in several small populations in California.
Collectively, these studies indicate that the threshold
dose for hyperpigmentation and hyperkeratosis is
approximately 0.002 mg/kg/day.
Fierz (1965) discussed the dose-response relation-
ship between skin cancer and the total dose of Fowl-
er’s solution ingested as medication. He reviewed 262
612 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
patients who had been treated for weeks or for several
years with Fowler’s solution for various chronic der-
matoses. A total of 10-2600 mL of the solution had been
administered to the patients. Among those patients
who developed late effects from this treatment, 40%
had hyperkeratosis and 8% had skin cancer. A clear
positive relationship between the incidence of both
hyperkeratosis and cancer and the dose of arsenic was
indicated (Fierz, 1965).
Dose-response relationships between skin cancer
and arsenic have been discussed by Tseng et al. (1968)
and Tseng (1977) for Taiwanese populations exposed to
arsenic-contaminated well water. Out of a total popu-
lation of 40,421, arsenical skin cancer was found in 428
persons (10.6/1000). There were no patients younger
than 20 years of age. The minimal amount of arsenic
in well water necessary to induce skin cancer was esti-
mated to be less than 0.29 mg/L. Based on this study,
the WHO Task Group on Environmental Health Crite-
ria for arsenic (WHO, 1981) concluded that the lifetime
risk for skin cancer is approximately 25% per mg As/L
drinking water. Based on the Taiwan skin cancer data
using the multistage model, the U.S. Environmental
Protection Agency (EPA) calculated a cancer unit risk
for drinking water of 5 × 10-5 per μg/L (EPA, 2012). The
EPA is currently developing the Integrated Risk Infor-
mation System (IRIS) toxicological review of inorganic
arsenic (cancer and noncancer effects of oral expo-
sures) (EPA, 2012). There is increasingly convincing
evidence that long-term exposure to arsenic can result
in the development of bladder cancer (Bates et al.,
2004; Chen et al., 1992; Chiou et al., 1995, 2001; Cuzick
et al., 1992; Guo, 2000), with transitional cell cancers
being the most prevalent. Chiou et al. (1995) reported
a dose-response relationship between long-term arse-
nic exposure from drinking artesian well water and the
incidence of lung cancer, bladder cancer, and cancers
of all sites combined (after adjustment for age, gen-
der, and cigarette smoking) in four townships in Tai-
wan exposed to inorganic arsenic in drinking water
(0-1.14 mg/L). In a later follow-up study of the same
cohort, the increase in bladder cancer was found to be
statistically significant only in subjects exposed for 40
years or longer (Chiou et al., 2001). Cuzick et al. (1992)
evaluated a cohort treated with Fowler’s solution in
Lancashire, England, during the period 1945-1969
and followed through 1991; the cohort of 478 patients
showed a significant excess of bladder cancer, but no
excess of other causes of death. Of a subcohort of 142
patients examined for signs of arsenicism around 1970,
all 11 subsequent cancer deaths occurred in those with
signs of arsenicism (P = 0.0009). Hopenhayn-Rich et al.
(1996) investigated bladder cancer mortality for the
years 1986-1991 in 26 counties of Cordoba, Argentina,
and reported that bladder cancer standardized mortal-
ity ratio (SMRs) were consistently higher in counties
with documented arsenic exposure; a later case-con-
trol study by the same authors (Bates et al., 2004) did
not report statistically significant increases in blad-
der cancers resulting from arsenic exposure, except in
individuals exposed for 50 years or longer. Guo (2000)
reported significantly increased rate differences for
bladder cancer in men and women in Taiwan exposed
to 0.64 mg arsenic/L in the drinking water, but not at
lower exposure levels.
A study of arsenic-exposed individuals in north-
ern Chile reported significantly increased odd ratios
for lung cancer among subjects with > 30 μg As/L
drinking water (Ferreccio et al., 2000), although when
adjusted for socioeconomic status, smoking, and other
factors, the increase was only significant at 60 μg/L or
greater. Guo (2004) reported significantly increased
rate differences for lung cancer for Taiwanese men and
women exposed to 0.64 mg arsenic/L or greater, with
those older than 50 years of age being particularly at
risk. Nakadaira et al. (2002) suggested that even com-
paratively short exposure durations (less than 5 years)
might be sufficient for the development of arsenic-
induced lung cancer.
The NRC (1999, 2001) analyzed the Taiwan data and
estimated the excess lifetime risk of bladder and lung
cancer with various arsenic levels in drinking water: at
a concentration of arsenic in drinking water of 3 μg/L,
the lifetime risk estimates for bladder and lung can-
cer combined are approximately 4 and 10 per 10,000
using the Taiwan or U.S. background rates of these
cancers, respectively. The EPA has not yet calculated
a unit risk value or slope factor for arsenic-induced
internal tumors. As mentioned previously, the EPA is
currently developing the IRIS toxicological review of
inorganic arsenic (cancer and noncancer effects of oral
exposures) (EPA, 2012).
Some data on dose-response relationships for respi-
ratory cancer have been given by Pinto et al. (1977).
They found an almost linear increase in respiratory
cancer with an increasing “exposure index.” From
the data, it can be estimated that exposure to airborne
arsenic of about 50 μg/m3 for more than 25 years might
increase the risk for developing respiratory cancer
nearly threefold.
The data must be interpreted with caution because
of the possible confounding factors. As for workers
engaged in production of insecticides such as lead
arsenate, calcium arsenate, copper acetoarsenite, and
magnesium arsenite, a positive dose-response rela-
tionship between the degree of arsenic exposure and
lung cancer was indicated (Blejer and Wager, 1976;
Ott et al., 1974). The ratio of observed to expected
 28 Arsenic
respiratory cancer deaths ranged from 0.6 in the lowest
exposure category to 7.0 in the highest. However, this
dose-response relationship for lung cancer should be
reevaluated after epidemiological adjustment for the
smoking histories of the workers.
Järup et al. (1989) reported significantly increased
lung cancer mortality [SMR 372, 95% confidence inter-
val (CI) 304-450] based on 106 lung cancer deaths in a
cohort of 3916 male workers employed for at least 3
months between 1928 and 1967 at the Ronskar smelter
and followed for mortality through 1981. Workers
were separated into low, medium, and high arsenic
exposure groups, with mean TWA exposure estimates
of 0.05, 0.2, and 0.4 mg/m3, respectively. Lung cancer
mortality was significantly increased in all three expo-
sure groups in a concentration-related fashion (SMR of
201, 353, and 480, respectively). A nested case-control
analysis of 102 lung cancer cases and 190 controls from
the cohort showed that lung cancer risk increased
with increasing arsenic exposure in nonsmokers, light
smokers, and heavy smokers (Järup and Pershagen,
1991).
Enterline and Marsh (1982) reported a significant
increase in respiratory cancer mortality (SMR 189.4)
based on 104 observed respiratory cancer deaths, with
only 54.9 expected, over the years 1941-1976 in a cohort
of 2802 male workers employed for at least 1 year
between 1940 and 1964 at the ASARCO smelter. Enter-
line et al. (1987) reanalyzed these data using improved
exposure estimates that incorporated historical mea-
surements of arsenic in the ambient and personal
breathing zone of workers. Respiratory cancer mor-
tality was significantly increased in a concentration-
related fashion in the low (SMR 213.0), medium (SMR
312.1), and high (SMR 340.9) arsenic exposure groups,
which had mean estimated TWA arsenic exposures of
0.213, 0.564, and 1.487 mg/m3, respectively.
Respiratory cancer mortality was shown to be sig-
nificantly increased (SMR 285) on the basis of 302
observed respiratory cancer deaths between 1938 and
1977 in a cohort of 8045 white male workers employed
for at least 1 year at the Anaconda smelter (Lee-Feld-
stein, 1986). Analysis of a subset of the Anaconda cohort
(n = 1800, including all 277 employees with heavy arse-
nic exposure) that included information on smoking
and other occupational exposures showed that lung
cancer mortality increased with increasing TWA arse-
nic exposure, with a small nonsignificant increase in
the “low” group (SMR 138) exposed to 0.05 mg/m3
and significant increases in the “medium” (SMR 303),
“high” (SMR 375), and “very high” (SMR 704) groups
exposed to 0.3, 2.75, and 5.0  mg/m3, respectively.
Lubin et al. (2000) recalculated the exposure concen-
tration on the basis of duration and time of exposure
613
and reevaluated the effects of exposure. Relative risks
for respiratory cancer increased with increasing dura-
tion. SMRs were significantly elevated after exposure
to 0.58 mg/m3 (SMR 3.01, 95% CI 2.0-4.6) or 11.3 mg/
m3 (SMR 3.68, 95% CI 2.1-6.4) for 10 or more years, and
after exposure to 0.29 mg/m3 (SMR 1.86, 95% CI 1.2-
2.9) for 25 or more years.
On the basis of the dose-response relationships
between arsenic exposure and excess lung cancer
mortality in workers at the Anaconda smelter and the
ASARCO smelter, the EPA (2012) derived a unit risk
estimate (the excess of lung cancer associated with life-
time exposure to 1 μg inhaled inorganic arsenic/m3) of
4.3 × 10−3 per μg/m3.
9  DIAGNOSIS, TREATMENT, AND
PROGNOSIS
When specific exposures have occurred, poison
control centers and medical toxicologists should be
consulted for medical advice. There are several medi-
cal toxicology texts that provide specific information
about clinical treatment after exposures to arsenic
(Ellenhorn, 1997; Goldfrank et al., 1998; Tintinalli et al.,
1996).
9.1  Acute Poisoning
9.1.1  Inhalation Diagnosis
Acute intoxication caused by the inhalation of arse-
nic is unusual except in the case of arsine (see Section
10), although respiratory symptoms may occur among
workers suddenly exposed to high concentrations of
arsenic in smelters. Gerhardsson et al. (1988) reported
a case of a smelter worker who inhaled a large quan-
tity of arsenic-containing dust (80% As2O3) and died
several hours later. Autopsy findings disclosed wide-
spread hemorrhages in the respiratory tree and con-
gestion of the major organs. Acute skin lesions such
as contact and allergic dermatitis could be observed
around the eyes and mouth, as well as on the face
and neck. The diagnosis of such cases is based on the
knowledge of a history of arsenic exposure. The mea-
surement of arsenic in the urine may be useful, pro-
vided the specimen is taken within a few days after
exposure.
9.1.1.1  Treatment and Prognosis
Conservative treatment is usually applied to skin
lesions. Dimercaprol/BAL may be given in cases of
severe symptoms of the respiratory system or the
skin. Chelation therapy is most effective when insti-
tuted within a few hours of exposure, and efficacy
614 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
decreases with increasing time after exposure (McFall
et al., 1998; Peterson and Rumack, 1977). In gen-
eral, chelating agents should be used with caution
because they may have serious side effects such as
pain, fever, hypotension, and nephrotoxicity. Some
water-soluble and less toxic analogs of BAL such as
dimercaptosuccinic acid (DMSA), dimercaptopro-
pyl phthalamadic acid, and dimercaptopropane sul-
fonic acid are currently under investigation and may
prove to be promising treatments for arsenic poison-
ing (Aposhian et al., 1997; Guha Mazumder, 1996;
Kreppel et al., 1995). A recent article by Vantroyen
et al. (2004) described a case of a massive arsenic tri-
oxide overdose that was successfully treated by con-
tinuous gastric irrigation with sodium bicarbonate,
forced diuresis, and the administration of BAL and
DMSA.
9.1.2  Ingestion Diagnosis
The determination of arsenic in the urine, hair, and,
in some cases, blood or stomach contents, is useful
for diagnosis if exposure to arsenic cannot be readily
identified.
9.1.2.1  Treatment and Prognosis
The treatment for acute arsenic poisoning by oral
ingestion is referred to in standard medical text-
books (e.g. Haddad and Winchester, 1990). Prognosis
will depend on both dose and elapsed time between
the ingestion of arsenic and the first treatment. In
some cases where the patient has recovered from
acute poisoning, dermatitis and peripheral neuritis
may persist for a relatively long time (Le Quesne and
McLeod, 1977).
9.2  Chronic Poisoning
9.2.1 Diagnosis
In the diagnosis of chronic arsenic poisoning, it is
important to differentiate between senile pigmenta-
tion, senile leukodermia, and arsenical dermatoses,
as well as between peripheral polyneuritis caused by
arsenic poisoning and that caused by other diseases.
This is especially true for individuals exposed to arse-
nic through ingestion.
Concentrations of arsenic in biological tissues may
be within the normal range at the time of diagnosis.
In such cases, a well-designed epidemiological study
may be required if it is thought that a whole group
of people might have been exposed to arsenic. White
striae in the fingernails (Mees lines) are also a useful
clue in the diagnosis of arsenical polyneuritis because
urine and hair arsenic concentrations may be within
normal limits despite the presence of this condition
(Heyman et al., 1956).
Recognition of damage to the upper respiratory
tract, specifically perforation of the nasal septum, may
be quite helpful in the diagnosis of chronic arsenic poi-
soning caused by somewhat higher exposures to inor-
ganic arsenic.
Liver damage, including cirrhosis and angiosar-
coma, which may be seen in an arsenic-exposed indi-
vidual, may require differentiation in terms of the
cause-effect relationship. Among younger people
exposed to inorganic arsenic-contaminated food and
water, cardiac and pulmonary symptoms are useful
for diagnosis.
9.2.2  Treatment and Prognosis
BAL has been used for the treatment of chronic
arsenic poisoning, particularly in cases of dermatosis.
Pinto and McGill (1953) administered BAL to people
with arsenic dermatitis. They succeeded in augment-
ing arsenic excretion into the urine, but not in improv-
ing skin changes such as melanosis and keratosis. A
randomized placebo trial of 2,3-DMSA as a therapy
for chronic arsenicosis caused by drinking contami-
nated water found no significant difference between
patients treated with 2,3-DMSA and those treated
with a placebo (Guha Mazumder et al., 1998a). Apart
from the often-questionable use of BAL, the treat-
ment of chronic arsenic poisoning should generally be
conservative.
Skin changes and neuropathy may persist for a
number of years. The skin changes seen in simple
keratosis may progress into Bowen disease, which will
spread over the entire body in multiple forms.
10 ARSINE
Arsine (hydrogen arsenide, AsH3) is a colorless,
flammable gas with a slight garlic odor. It is generated
whenever nascent hydrogen is liberated in material
containing arsenic. Because arsenic is present as an
impurity in many metal ores, arsine may be generated
in metal industries, in nonferrous metal refineries, and
in the manufacture of silicon steel if the ores being pro-
cessed accidentally come into contact with acid. Arsine
may also be released when hydrogen ions are formed
by hydrolysis and in the reaction of moisture with
arsenic-containing dross.
The toxicity and toxicological mechanisms of arsine
are quite different from those of other inorganic or
organic arsenic compounds. Arsine acts as a powerful
hemolytic poison in cases of both acute and chronic
exposure.
 28 Arsenic
Henderson and Haggard (1943) observed that the
lethal dose of arsine for humans was 250 mg/m3 for
30 min, and that symptoms of poisoning occur after
a few hours of exposure to 3-10 mg/m3. Elkins (1959)
reported a serious, nonfatal, acute case of arsine poi-
soning in a person who had worked in an atmosphere
contaminated with an average of 0.5 mg arsine/m3.
Five workers, examined by Kipling and Fothergill
(1964), developed typical arsine poisoning when
working in a plant where an acetylene-like odor was
detected. This odor occurred during the slag-dissolving
process that took place in a rotating drum. The concen-
tration of arsine in this factory was 5 mg/m3.
Morse and Setterlind (1950) studied two fatal cases
of arsine poisoning in which aluminum had been used
to extract arsenic. The concentration of arsine in this
instance was 70-300 mg/m3.
Arsine poisoning is characterized by nausea,
abdominal colic, vomiting, backache, and shortness
of breath, followed by dark, blood-colored urine and
jaundice (Kipling and Fothergill, 1964). According to
Bulmer et al. (1940), the following symptoms appeared
after various lengths of exposure to arsine: short-
ness of breath on exertion, general malaise, nausea,
poor appetite, palpitation on exertion, and headache.
In some groups of workers, a tingling sensation in
the feet, chills, garlic breath, changes in complexion,
weakness, vomiting, and drowsiness were observed.
Jaundice was also noted in a number of people. Some
of the workers with the longest exposure had anemia.
Arsenic in the urine was almost always elevated and
ranged from 0.04 to 4.3 mg/L. Even after the workers
had left the arsine-contaminated area, arsenic in urine
ranged from 0.04 to 0.1 mg/L. Peripheral neuritis was
seen in arsine-exposed workers. Liver disturbances
may accompany arsine poisoning. In most fatal cases,
renal failure caused by blockage of the renal tubules
by hemoglobin casts seems to be the cause of death
(Fowler and Weissberg, 1974). Residual functional
impairment of the kidneys has been reported in one
person after an acute episode of arsine poisoning
(Muehrcke and Pirani, 1968).
The use of BAL for arsine poisoning has not had
desirable results. Symptomatic therapy, which is gen-
erally used, is considered more reliable, particularly
in the treatment of anuria. Blood transfusions may be
necessary for severe anemia. Arsine toxicity and treat-
ment have been reviewed extensively by Fowler and
Weissberg (1974).
The mechanisms of arsine gas toxicity and more
recent studies in experimental animal/in vitro model
systems have also been studied over the last 20 years,
primarily because of possible health effects related to
its use in the semiconductor industry.
615
Arsine is used in doping the silicon-based chips and
in producing group III semiconductors, such as GaAs
and InAs. Before the recent uses of arsine gas in the
semiconductor industry, the main concerns regard-
ing human health were related to its use as a war gas
and from industrial accidents (Fowler and Weissberg,
1974). In the past, the chief clinical effects observed
in persons with acute occupational arsine exposure
were massive hemolysis followed by death from renal
failure. Patients typically presented with decreased
hematocrit values and red, “port wine”-colored urine
because of the presence of hemoglobin. Histopatho-
logical evaluations of postmortem kidney samples
demonstrated the presence of renal tubular obstruc-
tion from hemoglobin casts that resulted in renal fail-
ure. With the development of renal dialysis, mortality
from acute exposure has been greatly reduced in recent
decades (Fowler and Weissberg, 1974).
10.1  Experimental Model Studies
Prolonged inhalation exposures of rodents to arsine
at lower sublethal doses (Blair et al., 1990a,b; Fowler
et al., 1989; Hong et al., 1989; Morrissey et al., 1990;
Rosenthal et al., 1989) have been shown to produce a
regenerative anemia with immature erythrocytes and
the presence of Howell-Jolley bodies in the peripheral
blood. Splenomegaly and the characteristic arsenical-
induced porphyrinuria (Woods and Fowler, 1978)
dominated by increased excretion of uroporphyrins
with reduced quantities of coproporphyrin (Fowler
et al., 1989) are also major manifestations of arsine tox-
icity to the hematopoietic system. Other effects include
alterations in immune system function that have been
noted in animals exposed to arsine for prolonged peri-
ods (Rosenthal et al., 1989), indicating concomitant
perturbation of this important biological defense sys-
tem. No negative reproductive and developmental
outcomes are seen in rodents exposed to arsine (Mor-
rissey et al., 1990).
Studies conducted in cell culture systems exposed
to arsine in vitro (Ayala-Fierro and Carter, 2000;
Carter et al., 2003; Hatlelid and Carter, 1997; Hatlelid
et al., 1996; Rael et al., 2000; Winski et al., 1997) have
shown methemoglobin formation and ultrastruc-
tural effects on erythrocyte membrane structure, with
concomitant loss of ion regulation capabilities with
attendant red cell lysis. Based on these in vivo and
in vitro experimental studies, arsine is clearly a highly
toxic chemical agent that exerts toxicity on a number
of organ systems. Target cells in the hematopoietic
and immune systems and in the liver, and kidney are
clearly sensitive to arsine toxicity after either short-
term or more chronic exposures. The mechanisms by
616 Bruce A. Fowler, C.-H. Selene J. Chou, Robert L. Jones, Dexter W. Sullivan Jr, and C.-J. Chen
which this agent produces hemolysis seem to require
oxygen and the internalization of arsine into the red
cells with subsequent oxidation and inhibition of
membrane ion regulatory mechanisms. Pharmaco-
logical factors such as dose and duration of expo-
sure, as well as susceptibility factors such as age and
nutritional status of those exposed, will also have an
impact on prognosis.
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