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)Penicillamine2,3-dimercatopropanol (BAL, Dimercaprol)2,3-dimercatosuccinic acid (Succimer)

Arsenic N-acetyl-penicillamine (NAP)

Antimony Ethylenediamine-tetraacetic acid (EDTA)

Iron Deferoxamine

Heavy Metal Toxicity

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

Heme

Hemoglobin RBC function

Myoglobin Muscle function

Cytochromes Mitochondrial Respiration

MECHANISM OF LEAD TOXICITY

Heme Biosynthesis

Succinyl CoA + Glycine

δ-Aminolevulinate synthasePb

δ-Aminolevulinate

δ-Aminolevulinate dehydratasePb

Porphobilinogen

Porphobilinogen deminase

Uroporphyrinogen III cosynthase

Uroporphyrinogen III

Uroporphyrinogen decarboxylase

Coproporphyrinogen III

Coproporphyrinogen oxidase

Protoporphyrin IX

Ferrochelatase + Fe2+Pb

Pb

Increasedin plasmaand urine

Increased in plasma and

urine

Heme

Lead

Absorptiona. Skin- alkyl lead compounds (because of lipid solubility)b. Inhalation- up to 90% depending particle sizec. 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, moonshineb. Inhalation- metal fumesc. Skin- tetraethyl lead in gasoline

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

Diagnosis:a. History of exposureb. Whole blood lead level

1. Children: >25 μg/dl treatments2. 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 exposureb. CaNa2EDTAc. 2,3-dimercaptopropanol (Dimercaprol, BAL)d. 2,3-dimercaptosuccinic acid (Succimer)e. D-penicillamine

Liver Cell

Cd-MT

Lysosome

Renal Cell

aa

Cd

MT Cd

Cd-MTdamageCd (200 μg/g)

Cd-MT

CdMT

Cd

Cd-GSH GSH

TubularFluid

Glomerular membrane

Plasma

Cd-Alb

Cd-MT Cd-MT

Cd-GSH

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, batteriesc. 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 exposureb. 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 industryb. 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 membranesb. necrosis of proximal tubular epitheliumc. inhibition of sulfhydryl (-SH) group containing enzymes

Diagnosis:a. history of exposureb. blood mercury

Treatment: a. remove from exposureb. Hg and Hg salts > 4 μg/dl: 2,3 dimercaptopropanol (BAL),

penicillamine, N-acetyl-penicillamine (most effective)

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 enzymesc. 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 exposureb. 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)

CH2CH CH2

OHSH SH

CH2 CH CH2

OHS S

Hg

CH2 CH CH2

OHS S

Hg

S S

CH2 CH CH2

OH

Chelators

2, 3-dimercaptopropanol (dimercaprol) or BAL

Structure Complex with Hg

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

H3C C

CH3

SH

CH

NH2

COOH H3C C

CH3

S

CH

NH

COOH

H3C C

CH3

SH

CH

N

COOH H3C C

CH3

S

CH

N

C

Hg

CO

CH3

OHO

C CH3

OHg

Penicillamine

N-acetyl penicillamine

Penicillamine-Hg complex

N-acetyl penicillamine-Hg complex

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)Penicillamine2,3-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)•