Toxicity of Heavy Metals

Definition:
The term ‘Heavy metal’ refers to
any metallic chemical element that has
a relatively high density or high
relative atomic weight and is toxic at
low concentrations.
 1- Arsenic (As) toxicity
Forms:
• Inorganic arsenic
Trivalent (As3+)
e.g., arsenic trioxide and sodium arsenite
Pentavalent (As5+)
e.g., arsenic pentoxide and calcium arsenate
• Organic arsenic
e.g., methyl arsenite and methyl arsenate
• Arsine gas (AsH3)
Pentavalent arsenic is less toxic than the trivalent form
Sources of poisoning:
• Arsenic is found in rocks and soils, foods
(especially shelfish), industry such as
herbicides, fungicides and wood
preservatives.
• Human sources include combustion of coal,
metal smelting, and burning of agricultural
wastes.
• The routes of exposure to arsenic include
inhalation, ingestion, and through the skin.
Mechanism of toxicity:
1- Arsenite inhibits sulfhydryl enzymes such as
pyruvate dehydrogenase which converts pyruvate
to acetyl CoA and CO2 during tissue respiration.
This enzyme inhibition hinders Kreb's cycle,
impaired energy production and causes
accumulation of pyruvic acid leading to metabolic
acidosis.
2- It causes uncoupling of oxidative phosphorylation
by competitive substitution of arsenate for
phosphate and formation of an unstable adenosine
diphosphate-arsenate complex that is rapidly
hydrlyzed (Arsenolysis process)

Phosphate is chemically similar to arsenate

3- Arsenic also inhibits the production of glutathione
(GSH), resulting in increased cellular oxidative
damage with subsequent injury to multiple organs
Clinical Presentation:
1- Acute toxicity
• GIT: Nausea, vomiting, colic and diarrhea (rice-
water stools)
• CVS: Rapid and irregular pulse, and collapse
• Kidneys: Nephritis, hematuria, proteinurea,
oliguria and tubular necrosis
• Hematologic: Anemia, thrombocytopenia and
leukopenia
• Liver: Ascites and jaundice
• Skin: Hyperkeratosis and exfoliative dermatitis
• CNS: Convulsion and coma
2- Chronic toxicity
• The chronic poisoning of arsenic is characterized
by loss of weight, garlic odor in breath,
hyperpigmentation, loss of hair (alopecia),
peripheral neuritis, nephritis and liver damage.
• Transverse white lines (Mees' lines) on the
fingernails are suggestive of nail growth arrest.
• Long-term exposure to arsenic may cause
carcinoma of the skin and teratogenesis.
Management:
1- GI decontamination
• Gastric lavage is recommended for patients with
recent ingestion
• Emesis is not recommended, as arsenic may cause
seizures and coma within a short time
• Activated charcoal does not significantly adsorb
arsenic
2- Elimination enhancement
• Haemodialysis
• Exchange transfusion
3- Chelation therapy
Chelating agents are indicated in symptomatic
patients and those with urine arsenic >200 mg/L
• British anti-Lewisite (BAL, Dimercaprol)
• Dimercaptosuccinic acid (DMSA, succimer)
• Penicillamine
4- Supportive measures:
• Intravenous fluids for dehydration
• Dopamine for hypotension
Lewisite is an arsenical compound that
was used in world war I
Why is arsenic known as the king of poisons?
• It is cheap
• Easily obtained Arsenic
• No smell trioxide
• No taste
• Small quantity is required to cause death
• Can be easily administered with food or drink
• Onset of symptoms is gradual
• Symptoms simulate those of Cholera
 2- Lead (Pb) toxicity
Forms:
• Inorganic lead
e.g., lead sulfide, lead acetate and lead silicate
• Organic lead
e.g., tetramethyl lead and tetraethyl lead

Organic lead is extremely dangerous as it

can be absorbed through the skin and is
much more toxic to the brain and CNS
than inorganic lead
Sources of poisoning:
• Children may ingest leaded paints or other
articles containing lead such as newspapers,
toys, pencils and plasters.
• Inhalation of lead is hazard in battery
industry, leaded gasoline, miners and smelters.
• Toxicity may occur in addicts using
methamphetamine by IV injection since lead
acetate is used as reagent during the
manufacture of this drug.
• Organic lead compounds (e.g., tetraethyl lead)
may be absorbed through intact skin.
Mechanism of toxicity:
1- Lead interferes with antioxidant activities by
inhibiting functional SH groups in several
enzymes such as superoxide dismutase (SOD),
catalase (CAT) and glutathione peroxidase (GPx).
It increases free radicals and decreases availability
of endogenous anti-oxidant reserves (GSH, GPx,
SOD, CAT), involved in scavenging the reactive
oxygen species (ROS) generated in the lead-
exposed individuals.
Lead-induced oxidative stress
2- Lead also interferes with enzymes of heme
synthesis for hemoglobin production [delta-
aminolevulinic acid (ALA) dehydratase and
coproporphyrinogen decarboxylase]. This
interference can result in anemia. Delta-
ALA and coproporphyrin accumulate in the
urine where they serve as markers for lead
intoxication.
3- Lead also causes high blood pressure through two
mechanisms:
First, it inhibits the Na+/K+-ATPase enzyme
activity in vascular smooth muscle and stimulates
the Na+/Ca++ exchange pump. This will increase
intracellular Ca++ concentration.
Second, exposure to lead results in the release of
rennin from the kidneys. Rennin converts
angiotensinogen to angiotensin I which is
converted in turn to angiotensin II, a powerful
vasopressor.
Clinical Presentation:
1- Symptoms of acute toxicity:
• GIT: Burning sensation in mouth, esophagus and
stomach followed by severe abdominal pain. Loss
of appetite, metallic taste, colic, vomiting and
constipation
• CNS: Restlessness, convulsions, and coma
• Blood: Anemia and hemolysis
• Kidney and liver functions are impaired with the
presence of blood in urine
Diagnostically, blood lead levels > 60 mg/dl
corresponds with acute poisoning
2- Symptoms of chronic toxicity (Plumbism):
• GIT: Anorexia, loss of weight, abdominal pain and
constipation. Chronic toxicity of lead is
characterized by the presence of black line on the
gum near the border of the teeth (Burton line).

• Lead encephalopathy: Irritability, insomnia,

headache, loss of memory, convulsions and coma.
• Lead palsy: Peripheral neuritis, paralysis, wrist
and foot drop.

• Cardiovascular: Hypertension may occur with

chronic exposure.
• Kidney: Fanconi-like syndrome (proteinuria,
hematuria, amino-aciduria and phosphaturia)
may occur, ultimately leading to chronic
interstitial nephritis and renal failure.
• Reproductive: Abnormal sperm production,
miscarriages and low birth weight.
Management:
1- GI decontamination
• Whole bowel irrigation with PEG should be
considered if lead is seen on radiograph.
• Surgical removal may be necessary for lead
foreign bodies.
2- Chelation therapy
• BAL chelates lead both intra- and extra-cellularly.
In the presence of renal impairment, BAL was
once the chelator of choice because its main route
of excretion is in the bile.
• Calcium disodium ethylenediamine tetra-acetic
acid (CaNa2 EDTA) removes lead from the
extracellular compartment and increases the
urinary excretion 20-50 fold.
• DMSA is an orally active water-soluble chelator. It
may remove lead from the bone and soft tissues. It
does not deplete essential metals as do BAL and
CaNa2 EDTA.
3- Supportive measures
• Hemodialysis in patients with renal failure.
• Liver and kidney function tests should be carried
out.
 3- Mercury (Hg) toxicity
Sources of poisoning:
Elemental mercury
• It is the only elemental metal that is a liquid at
room temperature. It is used in glass
thermometers, sphygmomanometers, amalgams,
fluorescent lamps and paints.
• Spilled mercury vaporizes readily and can be
inhaled, where it is rapidly absorbed in the lungs.
• Elemental mercury is poorly absorbed in the
gastrointestinal tract and toxicity is rare.
Inorganic mercury
• It is present in divalent form (Hg2+, mercuric) or
monovalent (Hg, mercurous).
• Mercuric salts (e.g., mercuric chloride and
mercuric nitrate) have been used as antiseptic and
in other industrial processes.
• Mercurous chloride is used as a teething powder
and laxative.
• Ingestion and dermal contamination are the main
routes of absorption of inorganic mercury.
Organic mercury
• Methyl and ethyl mercury are environmental
contaminants of fish.
• Industrial discharge of contaminated wastes into
Minamata Bay in Japan in 1950s led to episodes of
neurological and congenital diseases by eating
contaminated fish.
• Ingestion is the main route of absorption of
organic mercury.
• Organic mercury compounds are used as
fungicides, herbicides and topical antiseptics.
Minamata disease:
• Minamata disease is a neurological
syndrome caused by sever mercury
poisoning.
• Signs and symptoms include ataxia,
numbness in the hands and feet, general
muscle weakness, and damage to hearing
and speech.
• In extreme cases, paralysis, coma, and death
may occur.
Mechanism of toxicity:
• Mercury produces inhibition of sulfhydryl enzyme
systems and interfering with cellular metabolism
and function.
• Mercury also reacts with phosphoryl, carboxyl
and amide groups, resulting in widespread
dysfunction of enzymes, transport mechanisms,
membranes and structural proteins.
• Because they are more soluble in water, mercuric
salts are usually more acutely toxic than
mercurous salts.
Signs and symptoms:
A- Inhalation:
• Elemental mercury vapors cause bronchitis, fever,
dyspnea, pulmonary edema and lung fibrosis.
• CNS damage is manifested as tremors, depression
and insomnia.

B- Ingestion:
• GIT: Gingivitis, stomatitis, esophageal erosions,
hematemesis and severe abdominal cramping.
• Circulation: Rapid irregular pulse, low blood
pressure, collapse and myocardial damage.
• Renal: Both inorganic salts and elemental
mercury cause proteinuria, glucosuria,
aminoaciduria, tubular necrosis and acute renal
failure within 24 hours of toxicity.
Chronic poisoning:
• Chronic exposure yields a classic triad of gingivitis
and salivation, tremor, and neuropsychiatric
changes.
• Acrodynia (Pink disease) is associated with the use
of calomel (mercurous chloride) in children and
manifests as color changes in the tips fingers, toes
and ankles.
Management:
1- Decontamination
• Removal of patient from further exposure.
• Emesis should not be induced except if patient is
alert and not vomiting.
• Gastric lavage and activated charcoal are not
recommended in elementary mercury poisoning.
However, they may be used after organic salt
ingestion within 1 hour.
• Whole bowel irrigation may be useful.
2- Chelation therapy
• Oral DMSA (succimer), a chelating agent enhances renal
excretion of mercury.
• Immediate intramuscular administration of BAL may
prevent renal toxicity of inorganic salts.

BAL is contraindicated for chelation of methyl mercury

because BAL redistributes methyl mercury to the brain
from other tissue sites, resulting in increased neurotoxicity.

• Penicillamine for symptomatic acute mercury exposure.

3- Supportive measures
• Treatment of pulmonary oedema.
• Controlling of seizures with intravenous diazepam.
 4- Cadmium (Cd) toxicity
Forms:
Soluble compounds (Cadmium chloride, cadmium
carbonate) are more toxic than insoluble ones
(Cadmium sulfide).
Sources of poisoning:
• Cadmium is used in industries and for plating of
equipments.
• It is also used in pigments and paints, in plastics
such as polyvinyl chloride and in fungicides.
• Cigarette smoking increases the level of cadmium
in blood.
Mechanism of toxicity:
1) Cadmium binds to cystein-rich protein such as
metallothionein (MT). Cd-MT complexes are
concentrated in proximal tubular cells inducing
necrosis.
2) It decreases the level of α1-antitrypsin leading to
pulmonary symptoms such as emphysema and
chronic obstructive pulmonary disease (COPD).

α1-antitrypsin is produced in the liver and

released into the blood, ultimately to protect
the lungs from attack by an enzyme called
neutrophil elastase
3) Cadmium competes with the cellular uptake of
copper & zinc (Cu & Zn) which are essential for
many cellular biochemical reactions and cellular
defense functions.
4) Cadmium inhibits the activity of SH-containing
enzymes and it can also produce uncoupling of
oxidative phosphorylation in mitochondria.
Clinical presentation:
1- Acute toxicity
Inhalation:
If the dust is inhaled, it produces cough and
dyspnea that develop 4 to 12 h after exposure and
may be followed by fever, chest pain and
pulmonary edema.
Ingestion:
If cadmium is ingested, it causes gastritis,
weakness, abdominal pain, vomiting, and
diarrhea.
2- Chronic toxicity
Kidneys: Fanconi-like syndrome (proteinuria,
aminoaciduria) may occur, ultimately leading to
chronic interstitial nephritis and renal failure.
Lungs: Pneumonitis, emphysema and lung cancer

Emphysema is a lung condition

that causes shortness of breath.
In people with emphysema, the
air sacs in the lungs (alveoli)
are damaged
Itai-itai disease:
• Itai-itai disease is the most severe form of
chronic Cd poisoning
• It is caused by eating rice contaminated
with cadmium in Japan
• This disease is characterized by
osteomalacia, osteoporosis with severe bone
pain and is associated with renal tubular
dysfunction.
 Mechanism of bone effects of
cadmium
1) Interference with parathyroid hormone (PTH)
stimulation of vitamin D production in kidney
cells
2) Reduced activity of kidney enzymes activating
vitamin D
3) Increased excretion of calcium in urine
4) Reduced absorption of calcium from intestines
5) Direct interference with calcium incorporation
into bone cells
6) Direct interference with collagen production in
bone cells
Management:
1- Gut Decontamination
• Gastric lavage can be applied to prevent further
cadmium absorption.
• Whole bowel irrigation can be applied effectively.
• Activated charcoal can't adsorb cadmium.
• Emesis should be avoided due to hemorrhagic
gastroenteritis.
2- Chelation therapy
• The chelator of choice is CaNa2 EDTA
• Chelation is not effective in chronic cadmium
toxicity.
• BAL should be avoided as it complexes with Cd
causing nephrotoxicity.
3- Supportive measures
• Osteomalcia and osteoporosis can be treated with
calcium and vitamin D supplements to reduce
bone pain.
• Obstructive lung disease can be treated using
inhaled bronchodilators and corticosteroids.
 Metal chelators
• Chelating agents are organic compounds with two
or more electronegative groups that can form
stable covalent bonds with cationic metal ions.
• These stable complexes are non-toxic and easily
excreted in urine.
• The most useful chelators for clinical purposes are
dimercaprol (BAL), succimer, penicillamine,
edetate (EDTA) and deferoxamine.
1- Dimeraprol
• Dimercaprol is typically formulated as a
suspension in peanut oil.
• It is administered by a deep intramuscular (IM)
injection.
• Common side effects include hypertension,
tachycardia, headache, pain at the site of the
injection, vomiting and fever.
2- Succimer
• Succimer is a water soluble analogue of dimercaprol
with reasonable oral bioavailability.
• Adverse effects include GIT disturbances, CNS effects,
skin rash and elevation of liver enzymes.
3- Penicillamine
• Penicillamine, a derivative of penicillin, is effective
chelator of copper
• It is water-soluble, well absorbed from the GIT
and excreted unchanged.
• Common side effects include proteinuria and
autoimmune dysfunction, including lupus
erythematosis and hemolytic anemia.
4- EDTA
• EDTA is usually given parenterally.
• To prevent dangerous of hypocalcaemia, EDTA is
given as the calcium disodium salt.
• The most important adverse effect of the agent is
nephrotoxicity.
5- Deferoxamine
• Deferoxamine is used parenterally in the
treatment of acute iron intoxication.
• Rapid intravenous administration may cause
histamine release and hypotensive shock.