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

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

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

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

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

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

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)

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:

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)

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

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 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

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

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)