Document ID: FDA-2009-P-0405-0018
Agency: fda
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-09-30T04:00Z

HYPERLINK "http://www.atsdr.cdc.gov/csem/arsenic/" 
http://www.atsdr.cdc.gov/csem/arsenic/ 

Case Studies in Environmental Medicine (CSEM) 

Arsenic Toxicity

Physiologic Effects

Introduction

Because it targets ubiquitous enzyme reactions, arsenic affects nearly
all organ systems.

Arsenic is strongly associated with lung and skin cancers and may cause
other cancers.

Two mechanisms of arsenic toxicity that impair tissue respiration have
been described. Arsenic binds with sulfhydryl groups and disrupts
sulfhydryl-containing enzymes; As(III) is particularly potent in this
regard. As a result of critical enzyme effects, there is inhibition of
the pyruvate and succinate oxidation pathways and the tricarboxylic acid
cycle, impaired gluconeogenesis, and reduced oxidative phosphorylation.
Another mechanism involves substitution of As(V) for phosphorus in many
biochemical reactions. Replacing the stable phosphorus anion in
phosphate with the less stable As(V) anion leads to rapid hydrolysis of
high-energy bonds in compounds such as ATP. That leads to loss of
high-energy phosphate bonds and effectively "uncouples" oxydative
phosphorylation.

Unlike other arsenicals, arsine gas causes a hemolytic syndrome.

Arsine gas poisoning results in a considerably different syndrome from
that caused by other forms of arsenic. After inhalation, arsine rapidly
fixes to red cells, producing irreversible cell-membrane damage. At low
levels, arsine is a potent hemolysin, causing dose-dependent
intravascular hemolysis. At high levels, arsine produces direct
multisystem cytotoxicity.

Gastrointestinal, Hepatic, and Renal Effects

Gastrointestinal effects are seen primarily after arsenic ingestion, and
less often after inhalation or dermal absorption.

The gastrointestinal (GI) effects of arsenic generally result from
exposure via ingestion; however, GI effects may also occur after heavy
exposure by other routes. The fundamental GI lesion appears to be
increased permeability of the small blood vessels, leading to fluid loss
and hypotension. Extensive inflammation and necrosis of the mucosa and
submucosa of the stomach and intestine may occur and progress to
perforation of the gut wall. A hemorrhagic gastroenteritis may develop,
with bloody diarrhea as a presenting symptom.

Acute arsenic toxicity may be associated with hepatic necrosis and
elevated levels of liver enzymes.

Arsenic intoxication may also result in hepatic toxicity, including
toxic hepatitis and elevated liver enzyme levels. Autopsies of Japanese
children poisoned with arsenic-contaminated milk revealed hepatic
hemorrhagic necrosis and fatty degeneration of the liver. Chronic
arsenic ingestion may lead to cirrhotic portal hypertension. Case
reports have also linked chronic high-level arsenic exposure with
hepatic angiosarcoma, a rare form of cancer.

Arsenic is capable of causing acute renal failure, as well as chronic
renal insufficiency.

The systemic toxicity occurring in severe acute arsenic poisoning may be
accompanied by acute tubular necrosis, and acute renal failure; chronic
renal insufficiency from cortical necrosis has also been reported. The
actual cause of injury may be hypotensive shock, hemoglobinuric or
myoglobinuric tubular injury, or direct effects of arsenic on tubule
cells. Glomerular damage can result in proteinuria. The kidney is not a
major target organ for chronic toxicity.

Cardiovascular Effects

Acute arsenic poisoning may cause both diffuse capillary leak and
cardiomyopathy, resulting in shock.

The extent of cardiovascular injury may vary with age, arsenic dose, and
individual susceptibility. In acute arsenic poisoning-usually suicide
attempts-the fundamental lesion, diffuse capillary leak, leads to
generalized vasodilation, transudation of plasma, hypotension, and
shock. Delayed cardiomyopathy may also develop. Myocardial damage can
result in a variety of electrocardiographic findings, including
broadening of the QRS complex, prolongation of the QT interval, ST
depression, flattening of T waves, and atypical, multifocal ventricular
tachycardia.

Long-term ingestion of arsenic in drinking water has resulted in
pronounced peripheral vascular changes.

Epidemiological evidence indicates that chronic arsenic exposure is
associated with vasospasm and peripheral vascular insufficiency.
Gangrene of the extremities, known as Blackfoot disease, has been
associated with drinking arsenic-contaminated well water in Taiwan,
where the prevalence of the disease increased with increasing age and
well-water arsenic concentration (10 to 1,820 ppb). Persons with
Blackfoot disease also had a higher incidence of arsenic-induced skin
cancers. However, investigators believe other vasoactive substances
found in the water may have been contributory.

Raynaud's phenomenon and acrocyanosis resulted from contamination of the
city's drinking water supply in Antofagasta, Chile, at arsenic
concentrations ranging from 20 to 400 ppb. Autopsies of Antofagasta
children who died of arsenic toxicity revealed fibrous thickening of
small and medium arteries and myocardial hypertrophy. Similar vascular
disorders, as well as abnormal electrocardiographs (ECGs), have been
noted in vineyard workers exposed to arsenical pesticides.

Neurologic Effects

Arsenic-exposed patients develop destruction of axonal cylinders,
leading to peripheral neuropathy.

Peripheral neuropathy is a common complication of arsenic poisoning. The
classic finding is a peripheral neuropathy involving sensory and motor
nerves in a symmetrical, stocking-glove distribution. Sensory effects,
particularly painful dysesthesia, occur earlier and may predominate in
moderate poisoning, whereas ascending weakness and paralysis may
predominate in more severe poisoning. Those cases may at first seem
indistinguishable from Guillain-Barré syndrome (i.e., acute
inflammatory demyelinating polyneuropathy). Cranial nerves are rarely
affected, even in severe poisoning. Encephalopathy has been reported
after both acute and chronic exposures.

Onset may begin within 24 to 72 hours following acute poisoning, but it
more often develops slowly as a result of chronic exposure. The
neuropathy is primarily due to destruction of axonal cylinders
(axonopathy). Nerve conduction and electromyography studies can document
severity and progression. Subclinical neuropathy, defined by the
presence of abnormal nerve conduction with no clinical complaints or
symptoms, has been described in chronically exposed individuals.

Recovery from neuropathy induced by chronic exposure to arsenic
compounds is generally slow, sometimes taking years, and complete
recovery may not occur. Follow-up studies of Japanese children who
chronically consumed arsenic-contaminated milk revealed an increased
incidence of severe hearing loss, mental retardation, epilepsy, and
other brain damage. Hearing loss as a sequela of acute or chronic
arsenic intoxication has not been confirmed by other case reports or
epidemiologic studies.

Dermal Effects

Pigment changes and palmoplantar hyperkeratosis are characteristic of
chronic arsenic exposure.

Benign arsenical keratoses may progress to malignancy.

The types of skin lesions occurring most frequently in arsenic-exposed
humans are hyperpigmentation, hyperkeratosis, and skin cancer. Patchy
hyperpigmentation, a pathologic hallmark of chronic exposure, may be
found anywhere on the body, but occurs particularly on the eyelids,
temples, axillae, neck, nipples, and groin. The classic appearance of
the dark brown patches with scattered pale spots is sometimes described
as "raindrops on a dusty road." In severe cases, the pigmentation
extends broadly over the chest, back, and abdomen. Pigment changes have
been observed in populations chronically consuming drinking water
containing 400 ppb or more arsenic.

Arsenical hyperkeratosis occurs most frequently on the palms and soles.
Keratoses usually appear as small corn-like elevations, 0.4 to 1 cm in
diameter. In most cases, arsenical keratoses show little cellular atypia
and may remain morphologically benign for decades. In other cases, cells
develop marked atypia (precancerous) and appear indistinguishable from
Bowen disease, which is an in situ squamous cell carcinoma discussed in
Carcinogenic Effects.

Respiratory Effects

Inhalation of high concentrations of arsenic compounds produces
irritation of the respiratory mucosa.

Smelter workers experiencing prolonged exposures to high concentrations
of airborne arsenic at levels rarely found today had inflammatory and
erosive lesions of the respiratory mucosa, including nasal septum
perforation. Lung cancer has been associated with chronic arsenic
exposure in smelter workers and pesticide workers.

Hematopoietic Effects

Bone marrow depression may result from acute or chronic arsenic
intoxication and may initially manifest as pancytopenia.

Both acute and chronic arsenic poisoning may affect the hematopoietic
system. A reversible bone marrow depression with pancytopenia may occur.
Anemia and leukopenia are common in chronic arsenic toxicity, and are
often accompanied by thrombocytopenia and mild eosinophilia. The anemia
may be normocytic or macrocytic, and basophilic stippling may be noted
on peripheral blood smears.

Reproductive Effects

Increased frequency of spontaneous abortions and congenital
malformations has been linked to arsenic exposure.

Arsenic is a reproductive toxicant and a teratogen. It is readily
transferred across the placenta, and concentrations in human cord blood
are similar to those in maternal blood. A published case report
described acute arsenic ingestion during the third trimester of
pregnancy leading to delivery of a live infant that died within 12
hours. Autopsy revealed intra-alveolar hemorrhage and high levels of
arsenic in the brain, liver, and kidneys.

A study of women working at or living near a copper smelter where
ambient arsenic levels were elevated reported increased frequencies of
spontaneous abortions and congenital malformations. The frequency of all
malformations was twice the expected rate and the frequency of multiple
malformations was increased fivefold. However, a number of other
chemicals, including   HYPERLINK
"http://www.atsdr.cdc.gov/csem/lead/index.html"  lead , cadmium, and
sulfur dioxide were also present, and thus it is difficult to assess the
role of arsenic in the etiology of these effects.

Carcinogenic Effects

The carcinogenicity of arsenic in humans has been established, but no
animal model has been developed.

In humans, chronic arsenic ingestion is strongly associated with an
increased risk of skin cancer, and may cause cancers of the lung, liver,
bladder, kidney, and colon; chronic inhalation of arsenicals has been
closely linked with lung cancer. The precise mechanism of
arsenic-related carcinogenicity is unknown. Arsenic does not induce
genetic mutations in most test systems, but chromosomal damage has been
reported in cultured mammalian cells, possibly as a result of arsenic's
effects on the enzymes involved in DNA replication and repair.
Paradoxically, cancer associated with arsenic exposure has not been
produced in experimental animals.

Skin Cancer

Latency for skin cancer associated with ingestion of arsenic may be 3 to
4 decades, whereas the noncarcinogenic skin effects typically develop
several years after exposure.

An increased risk of skin cancer in humans is associated with chronic
exposure to inorganic arsenic in medication, contaminated water, and the
workplace. Arsenic-induced skin cancer is frequently characterized by
lesions over the entire body, mostly in unexposed areas such as the
trunk, palms, and soles. More than one type of skin cancer may occur in
a patient. Most of the Taiwanese who developed skin cancer in
association with ingestion of arsenic-contaminated drinking water had
multiple cancer types. The most commonly reported types, in order of
decreasing frequency, were intraepidermal carcinomas (Bowen disease),
squamous cell carcinomas, basal cell carcinomas, and "combined forms."
Seventy-two percent of the Taiwanese with skin cancer also had
hyperkeratosis, and 90% had hyperpigmentation.

Some hyperkeratinized lesions can develop into intraepidermal carcinoma,
which may ultimately become invasive. The lesions are sharply demarcated
round or irregular plaques that tend to enlarge; they may vary in size
from 1 millimeter to >10 centimeters. Arsenical basal cell carcinomas
most often arise from normal tissue, are almost always multiple, and
frequently occur on the trunk. The superficial spreading lesions are
red, scaly, atrophic, and are often indistinguishable from Bowen disease
by clinical examination. Arsenic-associated squamous cell carcinomas are
distinguished from UV-induced squamous cell carcinomas by their tendency
to occur on the extremities (especially palms and soles) and trunk
rather than on sun-exposed areas such as the head and neck. However, it
may be difficult to distinguish other arsenic-induced skin lesions from
those induced by other causes.

Epidemiological studies indicate that a dose-response relationship
exists between the level of arsenic in drinking water and the prevalence
of skin cancers in the exposed population. Excessive mortality rates due
to arsenic-induced skin cancer have also been observed in vineyard
workers with dermal and inhalation exposure.

Lung Cancer

In arsenic-exposed workers, there is a systematic gradient in lung
cancer mortality rates, depending on duration and intensity of exposure.

An association between lung cancer and occupational exposure to
inorganic arsenic has been confirmed in several epidemiologic studies. A
higher risk of lung cancer was found among workers exposed predominantly
to arsenic trioxide in smelters and to pentavalent arsenical pesticides
in other settings. Neither concomitant exposure to sulfur dioxide nor
cigarette smoke were determined to be essential co-factors in these
studies.