Arsenic: Toxicology and Health Effects

RW Kapp Jr., BioTox, Monroe Township, NJ, USA

ã 2016 Elsevier Ltd. All rights reserved.

Arsenic Occurrence in the Environment In addition to the normal levels of arsenic in air, water, soil,
and food, human exposure to arsenic can occur because of
Arsenic is found ubiquitously in the natural environment. In proximity to hazardous waste sites containing high levels of
nature, arsenic ranks 20th in order of abundance in the Earth’s arsenic, or occupational exposure to arsenic from copper or
crust, 14th in seawater, and 12th in the human body. Arsenic lead smelting, wood treating, and pesticide applications; use of
cannot be eliminated from the environment; however, it can arsenic-treated wood or arsenic-containing pesticides; or drink-
change its form and attach to or separate from existing particu- ing water with high levels of arsenic. The elemental form of
lar matter in the environment. Arsenic is a major constituent in arsenic is commonly used in alloys for lead-acid batteries and
more than 200 minerals, hence its wide distribution. The cable sheaths. Arsenic compounds are also used in semicon-
Committee on Medical and Biologic Effects of Environmental ductors and light-emitting diodes. The result is that humans
Pollutants of the National Academy of Sciences established that are exposed to arsenic from a myriad of places including food.
the average arsenic content of the Earth’s crust is 2.5 mg kg
1 In fact, the primary route of arsenic exposure for the general
with the concentration in soil ranging from 0.1 to 50 mg kg
1, population is via the ingestion of contaminated food or water.
which varies considerably among various regions in the world. The daily intake of total arsenic from food and beverages is
Arsenic is generally introduced into the environment from believed to be in the range of 20–300 mg per day. In 2001, the
either naturally occurring geologic sources or anthropogenic World Health Organization (WHO) determined that the daily
sources such mining, smelting, petroleum refining, and numer- dietary intake of total arsenic in Japan is higher than that of
ous types of chemical manufacturing. In addition, trace both Europe and the United States. WHO subsequently esti-
amounts of arsenic also enter the soil and water through various mated that approximately 25% of daily dietary arsenic intake is
biological sources that contain arsenic such as plants and from inorganic sources and arsenic intake is typically higher in
aquatic biota. Arsenic contained in soil is usually found in men than in women and children. The estimated arsenic intake
larger particles. These particles settle to the ground and are levels for various grouping are as follows:
subsequently separated from the particle by air or rain. Arsenic
• 1.3 mg per day for infants <1 year of age
that is attached to very small particles may be windblown and
• 4.4 mg per day for 2-year-olds
remain aloft for many days and travel long distances. Many of
• 9.9 mg per day for 25–30-year-old men
the more common arsenic compounds can dissolve in water
• 10 mg per day for 60–65-year-old women
and therefore can be found in lakes, rivers, or underground
• 13 mg per day for 60–65-year-old men
water by dissolving in rain or snow. Ultimately, most arsenic
ends up in the soil or sediment. Based on these numbers, one could speculate that a daily
Another source of environmental arsenic was through agri- requirement for humans would be about 12–15 mg per day
cultural use in pesticides such as Paris Green (an arsenic for individuals consuming approximately 2000 calories of a
pesticide); herbicides such as monosodium methanearsonate mixed-food diet. The Contaminants in the Food Chain
(CH4AsNaO3), sodium arsenite (NaAsO2), and disodium (CONTAM) Panel of the European Food Safety Authority
methanearsonate (CH3AsNa2O3); and phosphate fertilizers. extensively examined the arsenic content of foods in the Euro-
Besides elemental arsenic, these materials reportedly also release pean Union and published the results in 2009. Most food
calcium arsenate, magnesium arsenate, zinc arsenate, zinc categories contained low levels of arsenic (<0.02 mg kg
1):
arsenite, and lead arsenate into the soil. With the exception of some mean values include water (0.003 mg kg
1), rice
monosodium acid methanearsonate (MSMA), virtually all (0.14 mg kg
1), and seafood/shellfish (5 mg kg
1). The high-
arsenic-containing pesticide has been restricted by the US gov- est value reported was for a species of algae (30.9 mg kg
1).
ernment. Arsenic that accumulates in the environment can be The mean arsenic levels found in various food categories as
subject to various biotransformations – reduction, oxidation, determined by EFSA in 2009 are presented in Table 1.
and methylation. For instance, some plants, fish, and microor- The CONTAM Panel reviewed the provisional tolerable
ganisms affect the redistribution of arsenic through their inher- weekly intake (PTWI) of 15 mg kg
1 established by the Joint
ent bioaccumulation and biotransformation and eventual FAO/WHO Expert Committee on Food Additives (JECFA) in
volatilization. Some transformation results in less toxic forms 1989 and determined that dietary exposure to inorganic arse-
of arsenic. Methylation of inorganic arsenic in some bacteria nic should be reduced. The panel calculated that people con-
under anaerobic conditions can occur. Similarly, some marine sumed 0.3–8 mg kg
1 per day of inorganic arsenic. EFSA
algae can transform arsenate into less toxic nonvolatile meth- reexamined the arsenic levels in food in 2014 and calculated
ylarsonic acid and dimethylarsenic acid in seawater. On the a lower dietary exposure when compared to that published in
other hand, some fungi transform inorganic and organic arsenic the 2009 EFSA opinion ranging from 0.09 to 0.38 mg kg
1 per
compounds into highly toxic methylarsines. The arsenic concen- day. The EFSA report suggests that several factors could account
trations in agricultural plants are reported to range from 0.007 to for the discrepancies including the use of a more detailed
7.50 mg kg
1 while the arsenic concentration in some fish can codification to classify the foods (FoodEx), the exhaustive
be as high as 100 mg kg
1 (in organic forms). evaluation of the occurrence data carried out in the latter

256 Encyclopedia of Food and Health http://dx.doi.org/10.1016/B978-0-12-384947-2.00043-X

 Arsenic: Toxicology and Health Effects 257

Table 1 Contribution of various food types to intake of arsenic Metabolism

1
Food identification Range of arsenic (mg kg )
Because of the presence of arsenic in the environment for
Cereals and cereal products 0.0536–0.0725 millions of years, living organisms have evolved a variety of
Sugar, sugar products, chocolate 0.0135–0.0321 resistance mechanisms to overt arsenic exposure. The most
Vegetable and animal fats 0.0062–0.0205 prominent of these include the following:
Vegetables and nuts 0.0261–0.0366
Starch/potatoes 0.0031–0.0142 1. Extracellular precipitation
Fruits 0.0058–0.0168 2. Chelation (bonding arsenic to nonmetal ions)
Juices, soft drinks, and bottled water 0.0024–0.0053 3. Intracellular sequestration (bonding it to another ion or
Coffee, tea, cocoa 0.0490–0.0613 molecule rendering it chemically inert)
Alcoholic beverages 0.0062–0.0127 4. Active extrusion (removal via active transport through the
Meat and meat products, offal 0.0051–0.0150 cell membrane)
Fish and seafood 2.3818–2.3837 5. Biochemical/bioelectrical transformation through reduc-
Milk and dairy-based products 0.0042–0.0136 tion/oxidation reactions
Tap water 0.0013–0.0022
6. Biochemical transformation through methylation
Data from EFSA (2009).
Inorganic Arsenicals
report, and the different occurrence data used and how they
were handled. Although a single, clear mode of action of toxicity has not been
In all cases, EFSA found the main contributor to dietary delineated for arsenic, data suggest that arsenic may replace
exposure to inorganic arsenic was ‘grain-based processed prod- phosphate in various biochemical reactions throughout the
ucts (nonrice-based)’ – specifically wheat bread and rolls. cell. Metabolic processes appear to be similar whether exposure
Other important contributors to inorganic arsenic exposure is by the inhalation, oral, or parenteral route. The metabolism
were rice, milk and dairy products, and drinking water. of inorganic arsenic has been extensively studied in humans
and animals. There are two primary metabolic processes found
in higher organisms:
Absorption
(1) Reduction/oxidation reactions
Inhalation (2) Methylation reactions
Inorganic arsenic occurs in the atmosphere as particulate The result of these processes is the reduction of inorganic
matter, and studies reveal that these particles are absorbed arsenate to arsenite, methylation to MMA(V), reduction to
into the lungs via two basic mechanisms: MMA(III), and methylation to DMA(V).
1. Deposition onto the lung surface Exposure of humans to either arsenates or arsenites results
2. Absorption of arsenic from the deposited material in increased levels of arsenite, arsenate, and MMA and DMA in
urine. Greater than 75% of the absorbed arsenic dose is
It is estimated that the overall rate of absorption of inhaled excreted in the urine. It is when the system is overwhelmed
arsenic is 30–34%. that the exposure then results in arsenic toxicity. DMA is the
Organic arsenic is also thought to be absorbed via the principal metabolite following long-term arsenic exposure,
inhalation route; however, there are no publicly available stud- with lower levels of inorganic arsenite, arsenate, and MMA.
ies that definitively address organic arsenic via the inhalation Studies in humans reveal the relative proportions are approx-
exposure route. imately 40–75% DMA, 20–25% inorganic arsenics, and
15–25% MMA.
Oral An alternative biotransformation pathway has been pro-
posed for arsenic involving the nonenzymatic formation of
The major site of absorption of inorganic arsenic is the small
glutathione complexing with arsenite yielding arsenic triglu-
intestine via a proton (H þ) gradient. The optimal pH for
tathione. The arsenic triglutathione is subsequently methylated
arsenic absorption is 5.0. Studies in humans indicate that
by arsenic (þ 3 oxidation state) methyltransferase (AS3MT) to
arsenates and arsenites are well absorbed as much as 95%
form monomethyl arsenic glutathione. Depending upon the
across the gastrointestinal tract; however, gastrointestinal
concentration of glutathione, either MMA (at low levels of
absorption may be considerably lower if highly insoluble
glutathione) or DMA (at high levels of glutathione) is formed.
forms of arsenic are ingested. Studies reveal that 75–85% of
Studies have shown that methylation of arsenic results in lower
organoarsenics such as MMA (CH4AsNaO3) and DMA
tissue retention of inorganic arsenic, and this process is con-
(C2H6AsO2) are absorbed across the gastrointestinal tract.
sidered to be a detoxification mechanism.

Dermal
Organic Arsenicals
Dermal exposure leads initially to arsenic binding to the skin,
and it has been shown that the bound arsenic may only very Organoarsenic or organic arsenicals such as MMA and DMA
slowly be taken up into the blood although it can occur post- appear to undergo scant metabolic change when ingested by
exposure because it is stored in the skin. humans. On the other hand, almost 85–90% of ingested
258 Arsenic: Toxicology and Health Effects

arsenosugars are excreted within 90 h; however, arsenosugars microorganisms have evolved to be able to utilize arsenic as a
have been shown to undergo metabolism. Arsenosugars per se metabolic energy source through either arsenite oxidation or
are generally not toxic; however, arsenosugar degradation can arsenate reduction. There is evidence that a trace amount of
result in toxic urinary metabolites such as trivalent methylated arsenic may be necessary in several metabolic processes includ-
arsenic. While DMA is the common metabolite from both ing methylation metabolism. Arsenocholine (C5H14AsO) can
inorganic sugars and arsenosugars, thiolated intermediate replace choline in phospholipids indicating that arsenocholine
forms of DMA can be formed and present considerably higher might have a role in the metabolism of labile methyl groups.
toxicity. Arsenic also appears to have a role in the conversion of methi-
onine to various metabolites such as S-adenosylmethionine
(C15H22N6O5S) and taurine (C2H7NO3S). Since arsenic
Excretion binds to sulfhydryl groups, it is possible that its presence may
decrease enzymatic catalysis as is commonly noted with other
Inhalation
metals. There is limited evidence that arsenic may be necessary
Urinary excretion of arsenic appears to account for a large part along with zinc in protein synthesis and degradation and
(30–60%) of the inhaled dose suggesting that most of the possible uric acid metabolism. Additional studies have also
arsenic found on respirable particles deposited in the lungs is shown that arsenic may also control gene expression at the
excreted in the urine. The primary forms of arsenic found in the transcriptional level via changes in the methylation of core
urine of inhalation-exposed humans are DMA and MMA. Inor- histones.
ganic arsenic constitutes <25% of the total urinary arsenic. A recent study indicates that arsenic may be crucial for
No data were available for inhaled organic arsenicals. longevity. Telomeres are complexes of tandem repeats of DNA
and protein that constitute the eukaryotic chromosomes. Telo-
meres shorten with normal aging and studies have shown that
Oral
this process can be accelerated by increased oxidative stress,
Urinary excretion in humans accounts for 55–87% of ingested kinase activity, and cellular inflammation. There is significant
inorganic arsenic. In contrast, ingestion of the highly insoluble evidence that telomere length may be affected by environmen-
arsenic triselenide (As2Se3) showed little urinary excretion tal chemicals that have frequently been associated with chronic
indicating that mostly soluble forms of arsenic are found in diseases such as black carbon, benzene, toluene, polycyclic
urine. Studies measuring arsenic excretion in humans indicate aromatic hydrocarbons (PAHs), and N-nitrosamines.
that minimal inorganic arsenic is excreted in the feces and Decreasing the length of telomeres is generally associated with
that approximately 50% is excreted in urine within 1–5 days. advancing age and exposure to a vast array of environmental
Arsenic is also excreted in the bile in the form of two arsenic– chemicals resulting in increased oxidative stress, increased
glutathione complexes (arsenic triglutathione and methylarse- kinase activity, and inflammation associated with some chronic
nic diglutathione). diseases. However, short-term arsenic exposure was shown to
Studies of organoarsenicals in humans indicate that be associated with increases in telomere length begging the
ingested MMA and DMA are excreted mainly in the urine question of what constitutes the underlying mechanism and
(80%) within 24 h, and these materials are found in both whether or not it could be a factor in longevity. It should be
the feces and urine mostly unchanged. noted, however, that there is little definitive evidence showing
that arsenic is essential for humans. If arsenic is an essential
element, it has a very limited range of safety, which might be
Dermal
from >12 to about 250 mg per day. More than this range could
No studies were available on the excretion of dermal exposure be toxic while less may not permit certain biochemical func-
of either inorganic arsenicals or organoarsenicals. tions as noted in the preceding text. The only available data are
from animals from which some guesstimates can be made with
respect to a daily requirement for arsenic in humans. Common
Biochemical Function and Nutritional Essentiality foods contain 11.5–40 mg total arsenic.

Animal studies conducted in 1975 demonstrated that arsenic

deprivation increased stillbirths of rat pups and depressed the Acute Toxicity
growth of those that survived. Other later studies revealed a
decrease in fertility among animals deprived of arsenic in the Acute data are mixed showing a variety of target organs. The
feed. These and other nutritional studies have suggested that lethal dose of acute inorganic arsenic ranges from 100 to
arsenic may be essential for reproduction and maternal milk 300 mg, while the Risk Assessment Information System data-
production. Arsenic deficiency has resulted in histological base states that “the acute lethal dose of inorganic arsenic to
changes in the mitochondria of the skeletal muscles and liver humans has been estimated to be about 0.6 mg kg
1 per day”
tissue. While specific intakes of arsenic are still not precise, it with death usually occurring within 24 h to 4 days. The clinical
has been shown that dietary consumption of <50 mg kg
1 is features of oral ingestion initially involve the gastrointestinal
arsenic-deficient. The range considered normal background for system due to a direct irritation of the gastrointestinal mucosa
arsenic in feed is 350–500 mg kg
1. including nausea, vomiting, abdominal pain, and copious
Arsenic active transport systems in cellular membranes watery diarrhea. Other symptoms of inorganic arsenic toxicity
are found in nearly all organisms. Interestingly, some can include excessive salivation, acute psychosis, skin rash,
 Arsenic: Toxicology and Health Effects 259

cardiomyopathy, seizures, respiratory failure and pulmonary the growth of those that survived. Other studies showed that
edema, renal failure, general central nervous system malfunc- only 58% of arsenic-deprived goats and 62% of arsenic-
tions with acute psychosis, multiorgan failure, and eventually deprived miniature pigs produced offspring compared with
death. Hematological effects have been reported to include 92% and 100% of control animals. Fertility was severely
hemoglobinuria, coagulation, bone marrow depression, severe depressed. These and other data suggest that too little dietary
pancytopenia, and normocytic normochromic anemia and arsenic could be detrimental and there is a threshold for arse-
basophilic stippling. Acute, high-dose exposure can lead to nic toxicity. Data from numerous animal studies have demon-
encephalopathy, with clinical signs such as confusion and strated that excess arsenic can produce developmental toxicity,
hallucinations. including malformation, death, and growth retardation, in
In survivors of arsenic exposure, bone marrow depression, several species. Animal studies of oral inorganic arsenic expo-
hemolysis, hepatomegaly, melanosis, polyneuropathy, and sure have reported developmental effects; however, these
encephalopathy – with clinical signs such as confusion and effects were only observed at maternally toxic concentrations.
hallucinations – may be observed. After acute poisoning, The most sensitive species is the rabbit, which presented
atomic absorption spectrometry studies reveal that the highest increased resorptions and mortality with decreased viable
concentration of arsenic is in the kidneys and liver. In both fetuses/litter at 1.5 mg kg
1 per day and a developmental no
fatal and nonfatal inorganic arsenic exposure of humans, nau- observed adverse effect level (NOAELdevelopmental) of
sea, vomiting, and watery diarrhea are the most common 0.4 mg kg
1 per day of As. Oral dose studies indicate that
symptoms. death and growth retardation are produced by arsenic expo-
sure. Arsenic has been shown to transfer to the fetus and pro-
duces developmental toxicity in embryo cultures. Studies have
Chronic Toxicity identified increased inorganic or organic arsenic exposures to
result in decreased fertility and pregnancy rates in both rats and
Six-month dietary dog studies showed a dose-dependent mice. When females were dosed preimplantation and during
decrease in feed consumption and body weights and increased pregnancy, the primary effect of arsenic on reproduction was a
levels of aspartate aminotransferase suggesting hepatotoxicity dose-dependent increase in fetal mortality and in postnatal
at dose levels of 4 and 8 mg kg
1 per day of arsenite; however, growth retardation. On balance, the animal studies suggest
no confirmatory histopathology was noted. Conversely, histo- that arsenic exposures are primarily a risk to the developing
logical alterations in the kidney and liver were observed in rats fetus. Human data are limited but show an association with
exposed to 50 mg sodium arsenate per milliliter for 320 days in spontaneous abortion and stillbirth; however, interpretation
drinking water. of these studies is complicated because of multichemical expo-
In humans, clinical features of chronic inorganic arsenic sure history. There are no definitive data on the effects
toxicity reveal significant variations among individuals, popu- of reproduction in humans experiencing arsenic exposure.
lation and various subpopulation groups, and geographic loca- However, exposure to arsenic in drinking water has been
tions. Therefore, persons exposed to chronic arsenic poisoning associated with adverse reproductive outcomes showing
exhibit a wide range of clinical features generally with an onset increases in spontaneous abortions in women drinking water
of nonspecific symptoms of abdominal pain, diarrhea, and at 0.008 mg kg
1 per day for 5–10 years. Chronic exposure of
sore throat. The most serious resulting effect of this exposure pregnant women to arsenic in the drinking water has been
is an increased risk of cancer of the skin, lungs, bladder, and/or associated with low infant birth weights. Similar associations
kidneys. Other effects include skin changes in pigmentation have been made between late fetal mortality, neonatal mortal-
and hyperkeratosis with chronic toxicity diarrhea occurring in ity, and postneonatal mortality and exposure to 0.86 mg l
1
recurrent vomiting. Chronic exposure also causes direct myo- of arsenic in drinking water. These data are not definitive
cardial injury, cardiac arrhythmias and cardiomyopathy, and because of lack of sufficient study controls; however, arsenic
hypertensive heart disease. The most frequent neurological can cross the placenta and has been found in fetal tissue and in
finding is a peripheral neuropathy. The arsenic-related effects breast milk.
also include changes in behavior and memory loss. Increased
prevalence of cerebrovascular disease has also been observed
after long-term arsenic exposure in drinking water. Exposure to Genotoxicity
high concentrations of arsenic is associated with an increased
risk of diabetes mellitus and neutropenia. In chronic arsenic In vitro studies of inorganic arsenic in bacterial assays have
ingestion, it has been shown that arsenic accumulates in the generally been negative for gene mutations. However, in vitro
liver, kidneys, heart, and lungs and smaller amounts in various arsenic studies in various human, mouse, and hamster cells and
other tissues and organs. After about 2 weeks of ingestion, Syrian hamster embryo cells have been positive for DNA dam-
some arsenic is deposited in the keratin-rich tissues, namely, age and repair and enhancement or inhibition of DNA synthe-
nails, hair, and skin. sis and chromosome aberrations and sister chromatid
exchanges. Arsenic has also been shown to be positive in the
Comet assay. Animal and human data indicate that inhaled
Reproductive/Developmental Toxicity inorganic arsenic causes chromosomal aberrations. Chromo-
somal abnormalities in rats given oral doses of sodium arse-
Studies conducted in 1975 previously demonstrated that arse- nate (4 mg kg
1 per day) for 2–3 weeks produced an increase
nic deprivation increased stillbirths of rat pups and depressed in the number chromosomal aberrations. In contrast, studies
260 Arsenic: Toxicology and Health Effects

in mice given sodium arsenite (50 mg kg
1 per day) for up to also be noted that arsenic has been referred to as a ‘paradoxical’
8 weeks showed no consistent increase in chromosomal aber- human carcinogen since the animal data are mostly negative
rations in either gonadal or somatic cells. Data from two for carcinogenesis and are not judged to be reliable for deter-
populations of individuals exposed to mean concentrations mining the levels of significant human exposure. The American
of either 5 or 109 mg l
1 in drinking water found no significant Conference of Industrial Hygienists (ACGIH), the USEPA,
differences in the frequency of chromosomal aberrations or the International Agency for Research on Cancer (IARC), the
sister chromatid. These studies suggest that ingested arsenic Maximale Arbeitsplatz-Konzentration (MAK) of Germany,
may cause chromosomal effects, but these data are too limited the National Institute for Occupational Safety and Health
to draw a firm conclusion. While ingested arsenic studies (NIOSH), the National Toxicology Program (NTP), and the
suggest that arsenic may cause chromosomal effects, these Occupational Safety and Health Administration (OSHA) con-
data have yet to be confirmed. cur that inorganic arsenicals are human carcinogens and have
Several studies on organoarsenicals reveal that DMA and officially classified them as such.
roxarsone may be able to cause chromosome aberrations,
mutations, and deoxyribonucleic acid (DNA) strand breaks.
However, in vitro studies with MMA did not find significant Other Effects of Arsenic Exposure
increases in the occurrence of chromosome aberrations, bacte-
rial mutations, or unscheduled DNA synthesis. Other data The primary incidental effect of long-term oral exposure to
show reversible DNA damage in in vivo rat and mouse tissue inorganic arsenic is a pattern of skin changes. These skin
at 1500 mg kg
1 of DMA. Interpretation of these data with changes are also associated with changes in the blood vessels
respect to health risk is unclear. of the skin, which result in patches of darkened skin. These
patches are usually accompanied by small wart-type blemishes
on the palms of the hand and soles of the feet (palmar keratosis
and solar keratosis, respectively). Leukonychia striata can occur
Carcinogenesis with arsenic exposure. This is a condition also referred to as
Aldrich–Mees’ lines, which are lines of discoloration across the
Animal studies of both inhalation and oral exposure to inor- nails of the fingers and toes. Other incidental effects from
ganic arsenic have not resulted in increased incidence of cancer inorganic arsenic ingestion could include a decreased produc-
formation in adult animals. However, there is strong evidence tion of red and white blood cells, which may ultimately cause
that inorganic arsenic exposure to pregnant mice results in fatigue, abnormal heart rhythm, blood vessel damage resulting
their offspring showing transplacental carcinogenesis. Further, in bruising, and impaired nerve function. The nerve damage
one study in mice exposed to pentavalent arsenic in drinking can cause the sensation of ‘pins and needles’ in the hands and
water at 500 mg per day for 2 years showed an increased feet. Inhalation of inorganic arsenic can present throat and
incidence in tumors of the lungs, liver, gastrointestinal tract, respiratory irritation, while dermal contact can be irritating to
and skin. The organoarsenic DMA has been shown to be car- the skin causing both erythema and edema. Arsenic inactivates
cinogenic in a 2-year drinking water study in rats. almost 200 enzymes involved in cellular energy pathways and
Evidence for the association of cancer in humans exposed DNA synthesis and repair. Hence, the effects are widespread.
to arsenic in drinking water comes from studies in five areas of Children residing in areas of known high natural or anthro-
the world with extremely elevated levels of naturally occurring pomorphic arsenic are at higher risk because of the tendency of
inorganic arsenic. These areas include the following: young children to consume nonnutritive objects (pica), specif-
ically soil or clay (geophagy). Because of this pica activity,
• China/Taiwan
children are at higher risk than adults because it is an addi-
• Chile
tional pathway to arsenic exposure. There is also some limited
• Argentina
evidence that suggests that long-term exposure of developing
• Bangladesh
children to inorganic arsenic may contribute to lower IQ
• India
scores. There is some evidence that transplacental exposure to
Additionally, inorganic arsenic has been shown to be a human arsenic during gestation and overt arsenic exposure during
carcinogen by both the inhalation and oral exposure routes. early childhood may increase mortality in young adults.
There is a large body of evidence that inhalation exposure of
humans to arsenic significantly increases the risk of lung can-
cer. In addition, there is evidence that the incidence of skin, Therapeutic Uses of Arsenic
liver, and gastrointestinal tumors can occur following inhala-
tion exposure. The strongest evidence that arsenic is responsi- Historically, elemental arsenic was available as solutions, tab-
ble for the observed lung cancer comes from quantitative lets, and pastes and in injectable forms and used as a healing
dose–response data relating specific arsenic exposure levels to agent after Greek physicians Galen and Hippocrates popular-
lung cancer risk. Cumulative exposure to 0.75 mg m
3 over a ized its use. In the eighteenth century, Fowler’s solution (1%
year has been associated with an increased risk of lung tumors. arsenic trioxide) was used for the relief of various ailments and
Most of the study data have been from arsenic exposure at remained very popular for over 150 years. Fowler’s solution
copper smelting operations. A limitation of the inhalation was used to treat leukemia, skin conditions (psoriasis,
studies is the inability to control for exposure to other chemi- dermatitis, and eczema), stomatitis and gingivitis in infants,
cals, such as sulfur dioxide, and cigarette smoking. It should and Vincent’s angina up until the 1950s. Salvarsan (also
 Arsenic: Toxicology and Health Effects 261

known as arsphenamine) is an organoarsenic with a chemical effects occur with the administration of these agents such as
formula of C12H12As2N2O2. It was the primary treatment for nausea, vomiting, gastrointestinal distress, and hemolysis and
syphilis from its discovery by Drs. Sahachirō Hata and Paul elevated liver enzymes. Since each of these chelators has its
Ehrlich in 1910. In fact, arsenicals were the drug of choice in limitations, additional research is ongoing seeking better treat-
the treatment of syphilis until the advent of penicillin during ment for arsenic exposure. Hemodialysis in arsenic-exposed
World War II. Some of the side effects from salvarsan included individuals has shown that only very minimal amounts of
rashes, liver damage, and risks of life and limb and were arsenic are removed, and it is only used where there is renal
thought to be due to the fact that salvarsan was highly unstable failure. Dimaval of DMPS was also developed for mercury
in air and has an IV LD50 range of 37–91 mg kg
1. The orga- poisoning; however, it is only approved for use in Germany
noarsenic melarsoprol is still used in the treatment of African and Taiwan and not in the United States.
trypanosomiasis, Chagas disease, and West African sleeping
sickness and has toxicity similar to that of the inorganic arse-
nics with an IV LD50 range of 788–2400 mg kg
1.
Regulations/Guidelines/Legislation
Based on the induction of apoptosis via the apoptosis-
inducing factor (AIF), arsenic trioxide (As2O3) is widely used
The Comprehensive Environmental Response, Compensation,
to induce remission in patients with acute promyelocytic leu-
and Liability Act (CERCLA), as amended in 1986, by the Super-
kemia. In China, arsenic sulfide (realgar) is used to treat pso-
fund Amendments and Reauthorization Act (SARA), required
riasis, syphilis, asthma, rheumatism, hemorrhoids, cough, and
that the Agency for Toxic Substances and Disease Registry
pruritus and is used as an anti-inflammatory agent. In India,
(ATSDR) develop jointly with the US Environmental Protec-
some hematological malignancies are treated with arsenic-
tion Agency (EPA) a list of hazardous substances most com-
containing medications, while in Korea, arsenic is used in
monly found at facilities on the CERCLA National Priorities
herbal preparations to treat hemorrhoids.
List, prepare toxicological profiles for each substance on the
priority list of hazardous substances, and determine the asso-
ciated acute, subacute, and chronic health effects. The ATSDR
Clinical Management of Arsenic Exposure
Minimal Risk Levels (MRLs) were developed as an initial
response to that mandate to derive substance-specific health
Acute arsenic poisoning must be managed aggressively with life
guidance levels for nonneoplastic end points. An MRL is
support monitoring along with electrolytes and fluid balance
defined as an estimate of the daily human exposure to a haz-
to try to minimize cerebral and pulmonary edema. Gastroin-
ardous substance that is likely to be without appreciable risk of
testinal irrigation is indicated in cases of arsenic poisoning. The
adverse noncancer health effects over a specified duration of
use of activated charcoal or bentonite is sometimes contra-
exposure. These substance-specific estimates, which are
indicated because of the nausea and vomiting associated with
intended to serve as screening levels, are used to identify con-
the arsenic exposure. Nasogastric suction can be used to
taminants and potential health effects that may be of concern
remove recirculating biliary secretions. Chronic arsenic expo-
at hazardous waste sites. While the MRLs do not have the force
sure is less aggressive; however, gastric decontamination with
of law, they are highly regarded guidelines from which other
activated charcoal is indicated with oral ingestion.
regulations have been derived. Since arsenic was one of the
The medical treatment of both acute and chronic arsenic
listed hazardous chemicals found on the CERLCA National
toxicity is also generally conducted with chelating agents.
Priorities List, the following oral MRLs have been established:
These agents link the arsenic molecules forming a complex
ringlike structure converting the arsenic to a chemically inert • Acute oral exposure (< 14 days) to inorganic arsenic: MRL
form that can be excreted without further interaction with the of 0.005 mg kg
1 per day
body. Arsenite inhibits the binding of steroids to the glucocor- ○ No intermediate-duration oral MRL was derived for
ticoid receptor, but not other steroid receptors; therefore, bind- inorganic arsenic.
ing of arsenite to protein at nonessential enzyme sites is • Chronic oral exposure (> 1 year) to inorganic arsenic: MRL
believed to be one detoxification mechanism. Chelators have of 0.0003 mg kg
1 per day
been used clinically as antidotes for acute and chronic poison- ○ No acute-duration oral MRL was derived for MMA.
ing. The most common chelators include dimercaprol, DMSA, • Intermediate-duration oral exposure (15–364 days) to
and Dimaval. D-Penicillamine was a chelator used previously, MMA: MRL of 0.1 mg kg
1 per day
but is no longer recommended because of serious reactions • Chronic oral exposure (> 1 year) to MMA: MRL of
involving the hematologic system (thrombocytopenia, leuko- 0.01 mg kg
1 per day
penia, agranulocytosis, and aplastic anemia) and renal system ○ No acute- or intermediate-duration oral MRLs were
(proteinuria, hypoalbuminemia, and nephrotic syndrome). derived for DMA.
Dimercaprol or British anti-Lewisite was developed by British • Chronic oral exposure (> 1 year) to DMA: MRL of
scientists as an anecdote to an arsenic-containing weapon 0.02 mg kg
1 per day
called lewisite. DMSA (meso-2,3-dimercaptosuccinic acid) ○ No acute-, intermediate-, or chronic-duration inhalation
was developed as a chelator for mercury poisoning. All three MRLs were derived for inorganic or organic arsenic
chelating agents bind with arsenic to form a stable 1,2,5- compounds.
arsadithiolane that effectively inactivates the arsenic. Although From about 1850 to the introduction of organic pesticides in
body burden is not reduced, chelators bind free arsenic and the 1940s, inorganic arsenic compounds were the primary
serve to reduce the biologically active arsenic. Serious side pesticides used in the United States. These included calcium
 262
Table 2 Arsenic guidelines and regulations

Arsenic: Toxicology and Health Effects

Regulating body Standard Classification/value

International
International Agency for Research on Cancer (IARC) Carcinogenicity Group 1a
World Health Organization (WHO) Air quality unit risk factor for lifetime exposure to a concentration of 1 mg m
3 1.5  103
Air quality guideline: lifetime risk level (1:100.000) 0.0066 mg m
3
Drinking water 0.01 mg l
1
Australia Drinking water 0.007 mg l
1
Argentina Drinking water 0.05 mg l
1
Bangladesh
Chile
China
Croatia
Ecuador
Ghana
India
Nepal
Thailand
Vietnam
Canada Drinking water 0.01 mg l
1
European Union
Japan
Taiwan
Australia/New Zealand Air quality guideline 0.0055 mg m
3
Food 1 mg kg
1
Salt 0.5 mg kg
1
Canada Ambient Air Quality Criteria (AAQC) 0.3 mg m
3/24-h
Foods 0.1–3.5 ppm
Veterinary drugs 0.5–2 ppm
European Union Air quality 6 ng m
3
German – MAKb Carcinogenicity Class 1c
The United States
American Conference of Industrial Hygienists (ACGIH) TLVd 0.01 mg m
3
Carcinogenicity TLV-A1e
National Institute for Occupational Safety and Health (NIOSH) RELf 0.002 mg m3
IDLHg 5 mg m3
Carcinogenicity Cah
Occupational Safety and Health Administration (OSHA) PELi organic As 0.5 mg m
3
PEL inorganic As 10 mg m3
PEL arsine (AsH3) 0.2 mg m
3
PELi organic As: industry þ shipyards 0.5 mg m
3
Carcinogenicity Caj
Air quality guideline: inhalation unit risk 4.3  103 mg m
3
EPA Risk-specific concentration (RsC) [1:100.000] 0.002 mg m
3
Drinking Water Equivalent Level (DWEL) 0.01 mg l
1
Drinking water unit risk 5  105 mg l
1
Water: Maximum Contaminant Level (MCL) 0.01 mg l
1
Residue tolerance: DMA 2.8 ppm
Residue tolerance: MMA 0.35–0.9 ppm
Residue tolerance: arsanilic acid 2 ppm
Carcinogenicity Group Ak
RfCl No data
RfDm 3  104 mg kg
1 per day
FDA Drinking and bottled water 0.01 mg l
1
Food: poultry meat and eggsn 0.5 mg kg
1
Food: swine 0.5–2 mg kg
1
Food additives: as in titanium dioxide 1 mg kg
1
Food additives: synthetic iron oxides 3 mg kg
1
Pesticide/herbicide As2O3 residue in fruits and vegetables 0.35 mg kg
1
National Toxicology Program (NTP) Carcinogenicity Ko
US Department of Agriculture (USDA) Prohibited in organic crop production Arsenic
a
Carcinogenic to humans.
b
Maximale Arbeitsplatz-Konzentration (MAK) (Germany).
c
Substances that cause cancer in man.
d
Threshold limit value.
e
Confirmed human carcinogen.
f
Recommended exposure limit.
g
Immediately dangerous to life or health.
h
Potential occupational carcinogen.
i
Permissible exposure limit.
j
Carcinogen.
k
Human carcinogen.

Arsenic: Toxicology and Health Effects

l
Reference concentration (RfC) – an estimate of a continuous inhalation exposure concentration to people (including sensitive subgroups) that is likely to be without risk of deleterious effects during a lifetime.
m
Reference dose (RfD) – an estimate of a continuous oral exposure level to people (including sensitive subgroups) that is likely to be without risk of deleterious effects during a lifetime.
n
Chickens are not to be fed with arsenic supplements within 5 days of slaughter.
o
Known human carcinogen.

263
264 Arsenic: Toxicology and Health Effects

arsenate, lead arsenate, and sodium arsenite. The use of many carcinogen (carcinogenic to humans). EPA has determined
inorganic arsenic compounds in agriculture was voluntarily that arsenic is a human carcinogen by both the inhalation
terminated by the mid-1960s. However, lead arsenate was and oral routes and is classified as a group A carcinogen. EPA
not officially banned by the EPA until 1988. While uses on has calculated an oral cancer slope factor of 1.5 mg kg
1 per
food crops and the use of arsenic acid as a defoliant on cotton day and a drinking water unit risk of 5  105 mg l
1 for inor-
plants were voluntarily terminated in 1993, EPA officially ganic arsenic based upon human dose–response data. The
canceled the last agricultural use of arsenic acid in the United inhalation unit risk for cancer is calculated to be
States on 3 November 1999. All arsenic-containing pesticides 0.0043 mg m
3.
were officially restricted in the United States in 2013 with only Advisory values are generated by ATSDR, ACGIH, IARC
MSMA remaining on the market as of the date of writing of this NIOSH, and WHO targeting public health professionals
article. In 1987, USEPA terminated the use of inorganic arsenic involved in preventing health risks of environmental expo-
for nonwood pesticides. Effective 31 December 2003, treat- sures, as well as specialists and authorities involved in the
ment of wood with CCA for residential uses was completely regulation of chemicals. While they provide a scientific basis
phased out by both EPA and the EU. However, CCA is still used for legally enforceable standards, the values generated by these
in some far eastern Pacific Rim countries as of the date of organizations alone are not enforceable. The EPA RfDs are not
writing of this article. Arsenic is no longer produced in the enforceable standards. However, EPA uses RfDs as risk assess-
United States; all of the arsenic used in the United States is ment benchmarks to generate regulations to maintain levels
imported. not to exceed the RfD. The more common global arsenic
The EPA’s Integrated Risk Information System (IRIS) has guidelines and regulations are presented in Table 2.
derived a chronic oral reference dose (RfD) of 0.0003 mg As/
kg/day for inorganic arsenic. This value was based on a no
observed adverse effect level (NOAEL) of 0.0008 mg As/kg/
See also: Arsenic: Properties and Determination; Carcinogenic:
day for dermal effects, and possible vascular complications of
Carcinogenic Substances in Food; Food Fraud; Rice: Types and
individuals exposed to arsenic in well water using an uncer-
Composition; Toxins in Food: Naturally Occurring; Trace Minerals and
tainty factor of 3 (to account for the lack of reproductive data
Trace Elements.
and uncertainty in whether the NOAEL accounts for all sensi-
tive subpopulations of individuals) were applied. No reference
concentration (RfC) for chronic inhalation exposures to arse-
nic was reported. EPA has been assessing the IRIS document on
inorganic arsenic since 2003. As of late 2014, this revision/
Further Reading
reassessment is still in progress. Abernathy CO, Calderon RL, and Chappell WR (eds.) (2012) Arsenic: exposure and
In 2008, FDA set 23 ppb as the ‘level of concern’ for inor- health effects. Abernathy, TX/Dordrecht, The Netherlands: Springer Science
ganic arsenic in apple and pear juices based on non- Business Media Dordrecht.
Agency for Toxic Substances and Disease Registry (ATSDR) (2007) Toxicological
carcinogenic effects. In 2011, the ‘Dr. Oz’ television show
profile for arsenic. Atlanta, GA: U.S. Department of Health and Human Services,
broadcast a program revealing results of its own testing of Public Health Services.
apple juice samples revealing 36 ppb arsenic in apple juice, Bolt HM (2012a) Arsenic: an ancient toxicant of continuous public health impact, from
but their studies neglected to separate inorganic from organic iceman Ötzi until now. Archives of Toxicology 86(6): 825–830.
arsenic. Later that year, Consumer Reports magazine tested 88 Bolt HM (2012b) Arsenic: an ancient toxicant of continuous public health impact, from
iceman Ötzi until now. Archives of Toxicology 86(6): 825–830.
samples of apple and grape juices and found that 25% of the Consumer Reports (2015) How much arsenic is in your rice? January, 2015. http://
samples exceeded federal drinking water standards of 10 ppb. www.consumerreports.org/cro/magazine/2015/01/index.htm.
Consumer Reports recommended that the arsenic limit for Dembitsky VM and Levitsky DO (2004) Arsenolipids. Progress in Lipid Research
apple juice be set at 3 ppb; however, based upon these data 43: 403–448.
and public pressure, in July 2013, FDA revisited the 23 ppm European Food Safety Authority (2009) Scientific opinion on arsenic in food, EFSA
panel on contaminants in the food chain. EFSA Journal 7(10): 1351.
value and determined that it should be the same as the pre- Francesconi KA and Raber A (2013) Arsenic in foods: current issues related to analysis,
existing arsenic limit for bottled drinking water – 10 ppb. The toxicity and metabolism. Chapter 17In: Rose M and Fernandes A (eds.) Persistent
January 2015 issue of Consumer Reports reviewed the FDA organic pollutants and toxic metals in foods, 414–429.
data on rice and grains and conducted tests on 697 samples Hughes MF, Beck BD, Chen Y, Lewis AS, and Thomas DJ (2011) Arsenic exposure and
toxicology: a historical perspective. Toxicol Sciences 123(2): 305–332.
of its own. They developed and proposed a point system for
IARC (2012). Arsenic, metals, fibers, and dusts. IARC Monogr Eval Carcinog Risks
managing rice exposure since the inorganic arsenic content of Hum, 100C: P. 35–94. Available online: http://monographs.iarc.fr/ENG/
rice varies greatly depending on the type of rice and where it Monographs/vol100C/mono100C.pdf.
was grown. Based upon the test data, they have identified International Water Association (2012) Arsenic contamination in the world: an
better choices with much lower levels of inorganic arsenic international sourcebook. London, UK: International Water Association.
Ratnaike RN (2003) Acute and chronic arsenic toxicity. Postgraduate Medical Journal
exposure, including white basmati rice from India, Pakistan, 79: 391–396.
or California and sushi rice grown in the United States. Addi- WHO (2001) Arsenic and arsenic compounds. Environmental Health Criteria
tionally, they call upon FDA to set standards for arsenic in rice- 224Geneva: United Nations Environment Programme. International Labour
based foods. Organisation. World Health Organization Available online: http://www.inchem.org/
documents/ehc/ehc/ehc224.htm.
IARC indicates that there is sufficient evidence of a relation-
WHO (2011) Guidelines for drinking-water quality, 4th ed. Geneva, Switzerland: WHO
ship between exposures to arsenic and inorganic arsenic com- Press, World Health Organization Available online: http://whqlibdoc.who.int/
pounds and human cancer to classify arsenic as a group 1 publications/2011/9789241548151_eng.pdf?ua¼1.
 Arsenic: Toxicology and Health Effects 265

Relevant Websites http://www.epa.gov/ – US Environmental Protection Agency (USEPA).

http://europa.eu/ – European Union (EU).
http://www.atsdr.cdc.gov/ – Agency for Toxic Substances and Disease Registry http://www.fda.gov/ – US Federal Drug Administration (USFDA).
(ATSDR). http://www.iarc.fr/ – International Agency for Research on Cancer (IARC).
http://www.efsa.europa.eu/ – European Food Safety Authority (EFSA). http://www.who.int/en/ – World Health Organization (WHO).