Heavy Metal Toxicity and Lead Poisoning

Heavy Metal Toxicity

• Heavy metals, including lead, arsenic, mercury, and iron, induce toxicity in humans.
• Chelators are commonly used to mitigate toxic effects from heavy metal exposure.
• Chelators are organic compounds forming stable bonds with cationic metal atoms, acting as chemical antagonists and antidotes.

Lead Poisoning: Environmental Hazards

• Poses a significant environmental hazard due to its presence in air and water.
• Exposure risk is elevated in older homes built before 1978 with chipped paint, especially for children, and in workplaces for adults.
• Lead inhibits ferrochelatase and ALA dehydratase, reducing heme synthesis and RBC protoporphyrin.
• Lead inhibits rRNA degradation, causing RBCs to retain rRNA aggregates, resulting in basophilic stippling.

Types of Lead Toxicity

• Acute lead poisoning can occur from industrial exposure via dust inhalation, or in children ingesting chips/flakes from lead-painted surfaces in old houses.
• Acute lead poisoning symptoms inlcude acute abdominal colic and CNS changes.
• Acute lead poisoning causes acute encephalopathy in children and has a high mortality rate.
• Chronic lead poisoning (plumbism) can cause peripheral neuropathy (wrist-drop), anorexia, anemia, tremor, weight loss, and GI symptoms.
• Chronic lead poisoning (plumbism) can cause neurocognitive deficits, and developmental delay in children.
• Succimer is used in chronic lead poisoning cases.

Lead Poisoning: Organic Lead Poisoning

• Organic lead poisoning is rare and due to tetraethyl or tetramethyl lead, formerly included in gasoline additives.
• Organic lead poisoning is absorbed through the skin and lungs.
• Organic lead poisoning causes hallucinations, headache, irritability, convulsions, and coma.

Lead Poisoning: Clinical Findings

• Elevated free erythrocyte protoporphyrin (FEP) levels occur due to inhibition of enzymes involved in hemoglobin synthesis in lead poisoning.
• Serum iron and ferritin levels are increased.

Lead Poisoning: Symptoms

• Symptoms of LLEEAAD poisoning include Lead Lines on gingivae (Burton lines) and on metaphyses of long bones on X-ray.
• Symptoms of LLEEAAD poisoning include Encephalopathy and Erythrocyte basophilic stippling.
• Symptoms of LLEEAAD poisoning include Abdominal colic and sideroblastic Anemia.
• Symptoms of LLEEAAD poisoning include Drops—wrist and foot drop.

Lead Poisoning: Complications and Treatment

• Lead poisoning can cause developmental delay and lead encephalopathy in children.
• Treatment involves chelation therapy when blood lead levels are ≥ 45 µg/dL.
• First-line treatment includes succimer, and second-line is penicillamine.
• For severe disease or lead encephalopathy, dimercaprol plus EDTA is used, as it crosses the blood-brain barrier.

Arsenic Poisoning: General Information

• Arsenic is used in industrial processes, found in soils, and released during coal burning.
• Arsenic disrupts cellular metabolism by binding to sulfhydryl groups on lipoic acid, a cofactor for pyruvate dehydrogenase complex, and interferes with ATP production.
• It causes severe GI discomfort, vomiting, "rice-water" stools, and capillary damage leading to dehydration and shock.
• A sweet, garlicky odor may be detected in breath and stools.
• Treatment includes supportive therapy for water and electrolyte replacement, with chelation therapy using dimercaprol.

Arsenic Poisoning: Chronic and Clinical Findings

• Causes skin changes, hair loss, bone marrow depression, anemia, chronic nausea, and GI disturbances.
• Arsenic is a known carcinogen that affects the liver, lungs, and skin.
• Imagine a vampire (pigmentary skin changes, skin cancer), vomiting and having diarrhea, running away from a cutie (QT prolongation) with garlic breath.

Arsenic Poisoning: Arsine Gas

• Arsine gas is an occupational hazard in metal refinement and semiconductor industries.
• Arsine gas toxicity is characterized by massive hemolysis.
• Pigment overload from erythrocyte breakdown can cause renal failure.
• Arsine gas poisoning treatment is supportive.

Mercury Poisoning: Exposure and Effects

• Inorganic mercury exposure is a toxic hazard in dental labs and manufacturing (batteries, insecticides).
• Organic mercury, used in agriculture as a fungicide, is lipid-soluble and can cross cellular membranes.
• Mercury's toxic effects result from protein precipitation, enzyme inhibition, and corrosive action.
• Mercury binds to sulfhydryl, phosphoryl, carboxyl, amide, and amine groups on proteins, rendering them inactive.

Mercury Poisoning: Acute vs Chronic

• Acute mercury poisoning is caused by inhalation of inorganic elemental mercury.
• Symptoms include chest pain, shortness of breath, nausea, vomiting, kidney damage, gastroenteritis, and CNS damage.
• Treatment includes intensive supportive care with prompt chelation using oral succimer or intramuscular dimercaprol.
• Chronic mercury poisoning from mercury vapor inhalation presents a diffuse set of symptoms that involves the gums and teeth, GI disturbances, and neurologic and behavioral changes (erethism).

Mercury Poisoning: Organic

• Organic mercury poisoning was first recognized during an epidemic in Minimata, Japan in the 1950s.
• Organic mercury poisoning came from consumption of fish with high levels of methylmercury.
• Epidemics have been reported from consumption of grain treated with organic mercury compounds.

Iron Poisoning

• Acute poisoning often occurs in children from ingesting ferrous sulfate tablets.
• Iron causes cell death by forming free radicals and peroxidation of membrane lipids.
• Symptoms include abdominal pain, vomiting, and GI bleeding.
• Iron poisoning may progress to anion gap metabolic acidosis and multiorgan failure, potentially leading to GI obstruction.
• Deferoxamine and deferasirox are the chelating agents of choice.

Chelators in Heavy Metal Toxicity

• Chelators are the primary treatment for heavy metal toxicity.
• Chelators form complexes with metal ions, making them less toxic and easier to eliminate via urine.
• Some chelating agents are highly specific for their target metal, while others chelate multiple metals.
• Specificity is crucial for safety, because chelation of other metals or minerals can cause side effects, such as lowering calcium or phosphate levels with EDTA.

Dimercaprol (BAL - British Anti-Lewisite)

• Dimercaprol is a bidentate chelator that forms two bonds, preventing metal from binding to tissue proteins, allowing rapid excretion.
• Dimercaprol is used in acute arsenic and mercury poisoning and, combined with EDTA, for lead poisoning.
• It is highly lipophilic and readily enters cells.
• Toxicity includes transient hypertension, tachycardia, headache, nausea, vomiting, paresthesia, and fever, especially in children.
• Long-term use is associated with thrombocytopenia and increased prothrombin time.

Succimer (DMSA)

• Succimer is a water-soluble bidentate chelator.
• Succimer is used for oral treatment of lead toxicity in children and adults.
• It is effective in arsenic and mercury poisoning if given within a few hours of exposure.
• While less toxic than dimercaprol, toxicity can include GI distress, CNS effects, skin rash, and elevated liver enzymes.

Unithiol

• Unithiol is a water-soluble derivative of dimercaprol that can be administered orally or intravenously.
• Intravenous unithiol is used for initial treatment of severe acute poisoning from inorganic mercury or arsenic.
• Oral unithiol serves as an alternative to succimer in treating lead intoxication.
• Toxicity includes mild dermatological reactions.

Penicillamine

• Penicillamine, a derivative of penicillin, serves as another bidentate chelator.
• Penicillamine is used in copper poisoning and Wilson disease.
• It is water-soluble, well-absorbed from the GI tract, and excreted unchanged.
• Penicillamine toxicity includes nephrotoxicity with proteinuria, pancytopenia, and autoimmune dysfunction, like lupus erythematosus and hemolytic anemia.

Ethylenediaminetetraacetic Acid (EDTA)

• EDTA is a polydentate chelator that binds to many divalent (including calcium) and trivalent cations.
• The primary use of EDTA is for lead poisoning treatment.
• To prevent hypocalcemia, EDTA is administered with the calcium disodium salt (CaNa₂EDTA).
• Toxicity includes nephrotoxicity (renal tubular necrosis).
• Adequate hydration and restricting treatment to less than 5 days reduces the risk of Calcium disodium salt EDTA.

Deferoxamine, Deferasirox, and Deferiprone

• Deferoxamine, Deferasirox, and Deferiprone have a selective affinity for iron.
• These are mainly used parenterally to treat acute iron intoxication and iron overload from blood transfusions in conditions like thalassemia or myelodysplastic syndrome.
• Toxicity includes skin reactions like flushing, erythema, and urticaria.
• Long-term use can cause neurotoxicity, and hepatic and renal dysfunction.