Tishk International University

College of Pharmacy
Pharmacology Department

Toxicology
Arsenic Toxicity
Prepared by:
• Dyar Mudhafar,
• Ali Khalid
• Muhammed Saeed
• Ali Amjed
Dr. Ansam Jalal Aram
• Hawro Gailani
B.Sc. M.Sc. Pharmacology and Toxicology
Outline
• What is Arsenic?
• Sources of Arsenic
• Exposure of Arsenic
• Mechanism of Toxicity
• Arsenic Carcinogenicity
• Diagnosis
• Treatment
• Fatality
• Real Case
What is Arsenic?
• Arsenic (As) is a toxic and carcinogenic metalloid, Ubiquitous
in the environment and has a low solubility.
• It is an abundant element in the earth’s crust that is an
odorless, tasteless, silver-grey, brittle, semi-metallic solid.
• It is encountered routinely in small doses in the air, water,
and food.
• The most common inorganic trivalent arsenic compounds are
arsenic trioxide and sodium arsenite.
Some Facts About Arsenic
• Arsenic is the most common cause of acute heavy metal poisoning in adults
and is number 1 on the ATSDR's "Top 20 List.
• Metallic Arsenic (Shiny Grey) And Not Poisonous. (insoluble in water).
• Compounds of Arsenic:
1. Inorganic arsenic is generally more toxic than organic arsenic.
2. Arsenite and Arsenate are the inorganic forms such as Arsenic trioxide,
Sodium arsenate, Arsenic sulphide, Copper arsenate, etc.
3. Arsenobetaine and Arsenocholine are the organic forms known as “ Fish
arsenic” found in seafood.
4. Arsine gas is the most toxic arsenical.
The most common inorganic
trivalent arsenic compounds are
arsenic trioxide and sodium
arsenite, while common
pentavalent inorganic
compounds are sodium
arsenate, arsenic pentoxide, and
arsenic acid.
Sources of Arsenic
• Natural
1. Volcanos
2. Forest fires
3. Ground water
• Man-made
1. Smelting of metals
2. Fossil fuel burning
3. Waste incineration
4. Industrial processes
Exposure of Arsenic
• Ingestion
Arsenic containing foods like: meat, fish, seafood – Drinking well water – Drugs
• Inhalation
Burning of fossil fuel containing arsenic – Cotton gins – Emission from industrial
operations – Smelters – Pesticides – Tobacco smoke.
• Dermal
Preserved wood products – Clothes using dyes.
Exposure of Arsenic
• High exposures from smelting operations and from well water
derived from rock strata with a high arsenic content are associated
with:
• Arsenical keratoses (premalignant lesions)
• Blackfoot disease (a circulatory disorder reflecting endothelial cell
damage)
• Squamous cell carcinoma of the skin.
• Several other organs (bladder, lung, and liver).
Arsenic Toxicity
• Acute Poisoning: Ingestion of large doses (70 to 180 mg) of inorganic
arsenic can be fatal. Symptoms of acute intoxication include fever,
anorexia, hepatomegaly, melanosis, cardiac arrhythmia, and, in fatal
cases, terminal cardiac failure.
• Chronic Toxicity: Chronic exposure to arsenic induces a series of
characteristic changes in skin epithelium. Diffuse or spotted
hyperpigmentation and, alternatively, hypopigmentation can first
appear between 6 months and 3 years with chronic exposure to
inorganic arsenic. Palmar-plantar hyperkeratosis usually follows the
initial appearance of arsenic-induced pigmentation changes within a
period of years.
Arsenic Toxicity
• Arsenic is a known human carcinogen. It can cause cell injury and
death by multiple mechanisms. Toxicity may vary by the forms:
1. Metalloid arsenic is generally regarded as nonpoisonous due to its
insolubility in water and body fluids.
2. Trivalent, methylated, and relatively less ionizable arsenic
metabolites may be capable of interacting with cellular targets
such as proteins and even DNA.
3. The half life of inorganic arsenic in humans is about 10 hours.
4. After inhalation, arsine gas rapidly binds to red blood cells,
producing irreversible cell membrane damage.
5. At low levels, arsine is a potent hemolysin, causing dose dependent
Mechanism of Toxicity
• The trivalent compounds of arsenic are thiol-reactive, and thereby
activate or inhibit enzymes or alter protein structure by reacting with
proteinaceous thiol groups.
• Pentavalent arsenate mimics phosphate and can inhibit phosphotransfer
reactions, such as mitochondrial oxidative phosphorylation. such as
mitochondrial oxidative phosphorylation, when present in concentrations
that are stoichiometrically competitive. Arsine gas is formed by the
reaction of hydrogen with arsenic, and is a potent hemolytic agent.
• Arsenic and its metabolites stimulate oxidant production through
activation of NADPH oxidases and inference with mitochondrial
respiration.
Arsenic Carcinogenicity
• The carcinogenic potential of arsenic was recognized over 110 years
ago by Hutchinson.
• Unlike many carcinogens, arsenic is not a mutagen in bacteria and
acts weakly in mammalian cells, but can induce chromosomal
abnormalities, aneuploidy, and micronuclei formation.
• It is clear that inorganic arsenic and its metabolites are not directly
genotoxic, as arsenic does not react directly with DNA. Instead,
reaction with thiols in critical proteins produces transcriptional and
epigenetic changes that promote cancers and tumor growth.
Diagnosis
• There are tests to measure high levels of arsenic in the body via the:
1. Blood
2. Fingernails
3. Hair
4. Urine
• Urine tests are most commonly used in cases of acute exposure that has
happened within a few days.
• At least 6 months exposure to arsenic levels of greater than 50 mg / L or
exposure of high arsenic level from food and air.
• Arsenic level in hair and nail above 1 mg / kg and 1.08 mg / kg respectively
and / or arsenic level in urine, above 50 mg / L (without any history of taking
seafood).
Signs and Symptoms
• Vomiting
• Abdominal Pain
• Diarrhea
• Dark urine (termed black water urine)
• Hemolysis (destruction of red blood cells)
• Vertigo
• Delirium
• Shock
• Death
Treatment
• Gastric Lavage
• Whole Bowel Irrigation with polyethylene glycol
• Chelation Therapy (Antidotes for Arsenic) should be instituted
promptly (Minutes to hours).
1. BAL (British Anti-Lewisite) – IM
2. Succimer (DMSA) – PO
3. DMPS – PO, IV
4. D-Penicillamine – Less effective
Treatment
• For acute arsenic poisoning, treatment is symptomatic, with
particular attention to fluid volume replacement and support of blood
pressure. The oral chelator penicillamine or succimer (2,3
dimercaptosuccinic acid [DMSA]) is effective in removing arsenic
from the body.
• Dimercaptopropanesulfonic acid (DMPS) has also been used for
acute arsenic poisoning with fewer side effects, However, for
chronic poisoning, chelator therapy has not proved effective in
relieving symptoms.
• Vitamin E and Selenium supplements have been used as
alternative remedies to limit the effects of arsenic exposure.
Fatality
• Fatal Dose: 100 – 300 mg
• Fatal Period: 1 To 2 Days
• Initial Deposit: Liver> Kidney > Spleen
Real Case
• A 42 year-old male was brought to the emergency department 90
minutes after intentionally ingesting the contents of arsenic-
containing ant bait. Upon arrival, the patient complained of
abdominal pain and was vomiting profusely. He was also lethargic,
with tachycardia and hypotension. Intravenous fluid resuscitation
was initiated, followed by intramuscular dimercaprol (BAL)
administered every 6 hours. Over the next 12 hours, the patient’s
symptoms improved and hemodynamic stability returned. A spot
urine arsenic level was measured at 1141 mcg/L. On hospital day
three, the patient was in stable condition, and was switched to oral
succimer (DMSA) for additional chelation therapy and discharged. At
follow-up six weeks later, the patient remained asymptomatic.
The Largest Mass Poisoning in
History
• Up to 77 million people in Bangladesh are being exposed to toxic
levels of arsenic , potentially taking years or decades of their lives.
• it takes 20 years for the negative morbidity effects of arsenic
poisoning to dissipate , even after they stopped using contaminated
wells .
References
• Curtis D. Klaassen, Mary O. Amdur, John Doull - Casarett &
Doull’s Toxicology The Basic Science Of Poisons-McGraw-Hill;
Chapter 23; Page 1115.
• Whalen Lippincott Illustrated Reviews Pharmacology; Unit 8;
Chapter 48; Page 637.
• Andrew AS, Karagas MR, Hamilton JW. Decreased DNA repair gene
expression among individuals exposed to arsenic in United States
drinking water. Int J Cancer. 2003;104:263–268.
• Agency for Toxic Substances and Disease Registry (2007)ToxGuide for
Arsenic, USA: Centers for Disease Control and Prevention.
• WHO (2000) Air Quality Guidelines, 2 edn., Copenhagen, Denmark:
WHO Regional Office for Europe.