Heavy Metal Toxicity

METALS AND DRUGS (CHELATORS) TO CONSIDER

METAL CHELATING AGENTS (DRUGS)

Lead Ethylenediamine-tetraacetic acid (EDTA)

2,3-dimercatosuccinic acid (Succimer)
2,3-dimercatopropanol (BAL, Dimercaprol)
Penicillamine

Cadmium Ethylenediamine-tetraacetic acid (EDTA)

Mercury N-acetyl-penicillamine (NAP)

Penicillamine
2,3-dimercatopropanol (BAL, Dimercaprol)
2,3-dimercatosuccinic acid (Succimer)

Arsenic N-acetyl-penicillamine (NAP)

Antimony Ethylenediamine-tetraacetic acid (EDTA)

Iron Deferoxamine
Metabolism after exposure to metals via skin absorption, inhalation, and ingestion
Environmental Factors That Influence Lead Toxicity

1. Pollution from air line industry- major cities like Atlanta,

Chicago, New York

2. Pottery related lead toxicity – associated with travelling

3. School Children Projects-associated with handling clay

4. Consumption of illicitly distilled liquor

5. Old lead pipes corrode and contaminate drinking water

6. Lead contamination associated with painting

7. Gasoline tank cleaning associated organic lead toxicity

8. Recent recalls on “toys” (Made in China) due to excessive lead

contamination
 Lead Toxicity Interferes With Heme Biosynthesis

Hemoglobin RBC function

Heme Myoglobin Muscle function

Cytochromes Mitochondrial Respiration

 MECHANISM OF LEAD TOXICITY

Heme Biosynthesis

Succinyl CoA + Glycine

Pb δ-Aminolevulinate synthase
Increased
in plasma and δ-Aminolevulinate
urine Pb δ-Aminolevulinate dehydratase

Porphobilinogen
Porphobilinogen deminase

Uroporphyrinogen III cosynthase

Uroporphyrinogen III

Uroporphyrinogen decarboxylase

Coproporphyrinogen III

Pb Coproporphyrinogen oxidase
Increased
in plasma Protoporphyrin IX
and urine
Pb Ferrochelatase + Fe2+

Heme
 Lead

Absorption
a. Skin- alkyl lead compounds (because of lipid solubility)
b. Inhalation- up to 90% depending particle size
c. GI- adults 5 to 10%, children 40%

Distribution: Initially carried in RBC and distributed to soft tissues

(kidney and liver); redistributed to bone, teeth, and hair

Source of exposure:
a. GI- paint, pottery, moonshine
b. Inhalation- metal fumes
c. Skin- tetraethyl lead in gasoline

Mechanism of Toxicity:
a. Inhibits heme biosynthesis
b. Binds to sulfhydryl groups (-SH groups) of proteins

Diagnosis:
a. History of exposure
b. Whole blood lead level
1. Children: >25 μg/dl treatments
2. Adults: >50 μg/dl candidates for treatment
c. Protoporphyrin levels in erythrocytes are usually elevated
with lead levels> 40 μg/dl
d. Urinary lead excretion >80 μg/dl
e. Urinary δ aminolevulonic acid
Clinical Symptoms

Acute: nausea, vomiting, thirst, diarrhea/constipation, abdominal pain

hemoglobinuria, oliguria leading to hypovolemic shock

Chronic: GI- lead colic (nausea, vomiting, abdominal pain)

NMJ- lead palsy (weakness, fatigue, wrist-drop)
CNS- lead encephalopathy (headache, vertigo, irritation, insomnia
CNS edema)

Treatment

a. Remove from exposure

b. CaNa2EDTA
c. 2,3-dimercaptopropanol (Dimercaprol, BAL)
d. 2,3-dimercaptosuccinic acid (Succimer)
e. D-penicillamine
 Cadmium (Cd++)
Absorption:
a. Inhalation 10 to 40%
b. GI 1.5 to 5%
Source of Exposure:
a. GI-pigments, polishes, antique toys
Environmental- electroplating, galvanization, plastics, batteries
c. Inhalation industrial, metal fumes, tobacco- 1 – 2 μg/pack

Mechanism of toxicity:
a. Inhalation: lung – local irritation and inhibition of α1-antitrypsin
associated with emphysema

b. Renal:
Mechanism of cadmium-induced renal toxicity

Bile Plasma Tubular

Fluid
GSH damage
Cd-GSH Cd (200 μg/g) Cd-MT
MT Cd
Cd-GSH Cd Cd-Alb

Cd Cd
MT Lysosome

Cd-MT Cd-MT Cd-MT Cd-MT

aa
Liver Cell to urine Renal Cell
Glomerular
membrane

Diagnosis:
a, History of exposure
b, Blood cadmium level >80 μg/dl
Clinical Symptoms

Acute: Oral- vomiting, diarrhea, abdominal cramps

Inhalation- chest pains, nausea, dizziness, diarrhea, pulmonary edema

Chronic: Oral- nephrotoxicity

Inhalation- emphysema-like syndrome and nephrotoxicity

Treatment

a. Remove from exposure

b. CaNa2 EDTA
(2,3 dimercaptopropanol (BAL) Cadmium complex extremely
nephrotoxic and therefore is not used)
 Mercury (Hg)

Source of exposure:
a. environmental from electronics and plastic industry
b. seed fungicide treatment, dentistry (dental amalgam fillings), wood
preservatives, herbicides and insecticides, thermometers, batteries, and other
products

Absorption:
a. GI- inorganic salts are variably absorbed (10%) but may be converted to
organic mercury (methyl and ethyl in the gut by bacteria); organic
compounds are well absorbed >90%
b. Inhalation- elemental Hg completely absorbed

Mechanisms of toxicity:
a. dissociation of salts precipitates proteins and destroys mucosal
membranes
b. necrosis of proximal tubular epithelium
c. inhibition of sulfhydryl (-SH) group containing enzymes

Diagnosis:
a. history of exposure
b. blood mercury >4 µg/dl
Clinical Symptoms

Acute:
1, (inorganic salts) degradation of mucosa- GI pain, vomiting, diuresis,
anemia, hypovolemic shock, renal toxicity.

2, (organic) CNS involvement- vision, depression, irritability, blushing,

intention tremors, insomnia, fatigue, diuresis

Chronic: CNS symptoms similar to acute organic poisoning with gingivitis,

tachycardia, goiter, increased urinary Hg

Treatment

a. remove from exposure

b. Hg and Hg salts > 4 μg/dl: 2,3 dimercaptopropanol (BAL), penicillamine,
N-acetyl-penicillamine (most effective)
c. Methyl Hg- supportive treatment (non absorbable thiol resins can be given
orally to reduce Hg level in the gut)

Minamata disease:
 Arsenic, As3+, As5+
Sources of exposure:
a. GI – well water, food
b. Inhalation- fumes and dust from smelting

Environmental: byproducts of smelting ore, AsGa in semiconductors,

herbicides and pesticides

Absorption:
a. GI-inorganic: trivalent (arsenites) and pentavalent (arsenates) salts >90%
organic: also bound as tri and pentavalent >90%

Distribution: accumulates in lung, heart, kidney, liver, muscle and neural tissue.
Concentrates in skin, nails and hair. Half life is 7 to 10 hours

Mechanism of toxicity:

a. Membranes: protein damage of capillary endothelium increased vascular

permeability leading to vasodilation and vascular collapse

b. Inhibition of sulfhydryl group containing enzymes

c. Inhibition of anaerobic and oxidative phosphorylation (substitutes for

inorganic phosphate in synthesis of high-energy phosphates)
Clinical Symptoms

Acute: damage to mucosa, sloughing, diarrhea (rice-water stools),

hypovolemic shock, fever, GI discomport/pain, anorexia.

Chronic: weakness, GI irritation, hepatomegaly, melanosis, arrhythmias,

peripheral neuropathy, perivascular disease (blackfoot disease)

Carcinogenicity: epidemilogic evidence; liver angiosarcoma, skin and lung cancer

Treatment

a. Remove from exposure

b. Acute: supportive therapy- fluid, electrolyte replacement, blood pressure
support (dopamine)
c. Chronic: penicillamine w/o dialysis
Arsine gas (AsH3) acts as hemolytic agent with secondary to
renal failure. Supportive therapy: transfusion (chelators have not
been shown to be beneficial)
 Chelators

2, 3-dimercaptopropanol (dimercaprol) or BAL

Structure Complex with Hg

CH2 CH CH2 CH2 CH CH2 CH2 CH CH2

SH SH OH S S OH S S OH
Hg Hg

S S OH

CH2 CH CH2
IM-administration in peanut oil

Use-arsenic, mercury, antimony, lead

 Ethylene diamine-tetraacetic acid (EDTA)

EDTA disodium salt

EDTA calcium disodium salt

Pb-EDTA complex

Given IV as calcium disodium salt.

EDTA is not cell permeable
 Penicillamine Penicillamine-Hg complex

CH3 CH3

H3C C CH COOH C
H3C CH COOH
SH NH2 S NH

Hg

N-acetyl penicillamine N-acetyl penicillamine-Hg complex

CH3 CH3
O
C H3C C CH C OH
H3C CH COOH

SH N C CH3 S N C CH3
O Hg O

Given orally
Uses: 1. lead, mercury, arsenic
2. copper- Wilson’s disease
 METALS AND DRUGS (CHELATORS) TO CONSIDER

METAL CHELATING AGENTS (DRUGS)

Lead Ethylenediamine-tetraacetic acid (EDTA)

2,3-dimercatosuccinic acid (Succimer)
2,3-dimercatopropanol (BAL, Dimercaprol)
Penicillamine

Cadmium Ethylenediamine-tetraacetic acid (EDTA)

Mercury N-acetyl-penicillamine (NAP)

Penicillamine
2,3-dimercatopropanol (BAL, Dimercaprol)
2,3-dimercatosuccinic acid (Succimer)

Arsenic N-acetyl-penicillamine (NAP)

Antimony Ethylenediamine-tetraacetic acid (EDTA)

Iron Deferoxamine
• Study Aid For Heavy Metal Toxicity

• Know specific chelating agents for each metals and route of administration.
• Lead: Calcium disodium EDTA (IV)
• 2, 3-dimercaptosuccinic acid (Succimer) (Oral)
• 2, 3-dimercaptoproponol (BAL, Dimercaprol) (IM)
• Penicillamine (Oral)
• Cadmium: Calcium disodium EDTA (IV)
• Mercury: 2, 3-dimercaptosuccinic acid (Succimer) (Oral)
• 2, 3-dimercaptoproponol (BAL, Dimercaprol) (IM)
• Penicillamine (Oral)
• N-acetyl-penicillamine (Oral)
• Arsenic: N-acetyl-penicillamine (Oral)
• Penicillamine (Oral)
• Arsine gas (AsH3) (hemolytic agent): transfusion
• Iron: Defroxamine (IM, slow IV, Oral-under rare circumstance)
• Know the mechanism of absorption.
• Skin, Inhalation, GI
• Know the mechanisms of toxicity
• Lead: Inhibits Heme Biosynthesis- -aminolevulonic acid and Protoporphyrin IX increases in
plasma and urine (Diagnosis); Children ingested large quantities of paint containing lead is
called “Pica”
• Cadmium: Inhibits 1-antitrypsin –(emphysema), nephrotoxicity
• Mercury: Mercury salts precipitates proteins, necrosis, inhibits sulfhydryl (-SH) group
containing enzymes; plastic industry-Minamata disease
• Arsenic: Increases vascular permeability, Inhibits anaerobic and oxidative phosphorylation;
(semiconductors, herbicides, pesticides, water contamination)
• Know why EDTA given IV.
• EDTA cannot cross the cell membrane.
• Know why EDTA given as Calcium disodium salt.
• To balance the calcium level
• Know how to treat copper poison (Wilson’s disease)
• Penicillamine; N-acetyl-penicillamine
• Allergic to penicilline – Trientine (triethylenetetramine HCl)
•
1. Effects commonly associated with acute or sub-acute lead poisoning include all of the
following EXCEPT
A) Abdominal pain
B) Headache
C) Lead “lines” (deposits) in the gums
D) Encephalopathy
E) Anemia

Directions: (items 2-5): The group of items in this section consists of lettered headings
followed by numbered phrases. For each phrase select the ONE letter heading that is
most closely associated with it.

A) Arsenic
B) Methyl-Mercury (organic-Hg)
C) Penicillamine
D) dimercaptoproponol

2. Produced in seawater by the action of bacteria and algae; synthesized for use as a fungicide

3. Used in the treatment of Wilsons’s disease and in copper, arsenic, and lead poisoning

4. Causes severe diarrhea, abdominal pain, and bone marrow depression

5. An oily chelator with high lipid solubility that readily enters cells

6. A 46-year-old man suffering from insomnia, memory loss, irritability, depression, shyness,
and tremor, visits a primary care clinic. Additional findings include mild symptoms of
gingivitis, stomatitis, and excess salivation. Chronic exposure of to which of the
following metals is most likely responsible for these findings in this patient?
A) Arsenic
B) Cadmium
C) Lead
D) Mercury
E) Thallium

Answers:
1. C; 2. B; 3. C; 4. A; 5. D; 6. D.