1. 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)
Arsenic N-acetyl-penicillamine (NAP)
Antimony Ethylenediamine-tetraacetic acid (EDTA)
Iron Deferoxamine

2. Heavy Metal Toxicity
Metabolism after exposure to metals via skin absorption, inhalation, and ingestion

3. Environmental Factors That Influence Lead Toxicity
Pollution from air line industry- major cities like Atlanta, Chicago, New York
Pottery related lead toxicity – associated with travelling
School Children Projects-associated with handling clay
Consumption of illicitly distilled liquor
5. Old lead pipes corrode and contaminate drinking water
Lead contamination associated with painting
Gasoline tank cleaning associated organic lead toxicity
Recent recalls on “toys” (Made in China) due to excessive lead contamination

4. Lead Toxicity Interferes With Heme Biosynthesis
Hemoglobin
RBC function
Myoglobin
Muscle function
Cytochromes
Mitochondrial Respiration

5. MECHANISM OF LEAD TOXICITY
Heme Biosynthesis
Succinyl CoA + Glycine
δ-Aminolevulinate synthase Pb
δ-Aminolevulinate
δ-Aminolevulinate dehydratase
Porphobilinogen
Porphobilinogen deminase
Uroporphyrinogen III cosynthase
Uroporphyrinogen III
Uroporphyrinogen decarboxylase
Coproporphyrinogen III
Coproporphyrinogen oxidase
Protoporphyrin IX
Ferrochelatase + Fe2+
Increased
in plasma
and urine
in plasma and
urine
Heme

6. Lead
Absorption
a. Skin- alkyl lead compounds (because of lipid solubility)
b. Inhalation- up to 90% depending particle size
c. GI- adults 5 t0 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
Treatment:
a. Remove from exposure
b. CaNa2EDTA
c. 2,3-dimercaptopropanol (Dimercaprol, BAL)
d. 2,3-dimercaptosuccinic acid (Succimer)
e. D-penicillamine

7. Cadmium (Cd++) Liver Cell Cd-MT Lysosome Renal Cell aa Cd MT damage
Cd (200 μg/g)
Cd-GSH
GSH
Tubular
Fluid
Glomerular
membrane
Plasma
Cd-Alb
Bile
to urine
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
Treatment:
a. Remove from exposure
b. CaNa2 EDTA
(2,3 dimercaptopropanol (BAL) Cadmium complex extremely
nephrotoxic and therefore is not used)

8. 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
Treatment:
a. remove from exposure
b. Hg and Hg salts > 4 μg/dl: 2,3 dimercaptopropanol (BAL), penicillamine, N-acetyl-penicillamine (most effective)
Minamata disease:

9. 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)
Symptoms:
a. Acute – damage to mucosa, sloughing, diarrhea (rice-water stools), hypovolemic shock, fever, etc.
b. Chronic- weakness, GI irritation, hepatomegaly, melanosis, arrhythmias, peripheral neuropathy, perivascular disease (blackfoot disease)
c. 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)

10. Chelators Structure CH OH SH S Hg
2, 3-dimercaptopropanol (dimercaprol) or BAL
Structure
Complex with Hg
IM-administration in peanut oil
Use-arsenic, mercury, antimony, lead

11. 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

12. H3C C
CH3 SH CH
NH2
COOH S NH N Hg O OH
Penicillamine
N-acetyl penicillamine
Penicillamine-Hg complex
N-acetyl penicillamine-Hg complex
Given orally
Uses: 1. lead, mercury, arsenic
2. copper- Wilson’s disease

14. 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)
Arsenic N-acetyl-penicillamine (NAP)
Antimony Ethylenediamine-tetraacetic acid (EDTA)
Iron Deferoxamine

15. 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)
N-acetyl-penicillamine (Oral)
Arsenic: N-acetyl-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)