Heavy Metals in Toxicology PDF

HEAVY METALS DR. HANAA ASHOUR Lead [Pb]  Lead Sources of poisoning: ▪ Inorganic lead compounds are used as pigments in paints, dyes, Ceramic food containers and leaded-glazed dishes (acidic food like tomato juice and fruit juice dissolve Pb) Lead-containing pai...

HEAVY METALS DR. HANAA ASHOUR Lead [Pb]  Lead Sources of poisoning: ▪ Inorganic lead compounds are used as pigments in paints, dyes, Ceramic food containers and leaded-glazed dishes (acidic food like tomato juice and fruit juice dissolve Pb) Lead-containing paint is a primary source of lead exposure in children due to hand-to-mouth transfer of lead containing paint chips or dust from floors of older housing ▪ Lead are used in batteries, water pipes, 70 % of current lead use occurs in storage batteries (rechargeable batteries e.g. car batteries) ▪ Organolead compounds were used as additives in gasoline  Lead Toxicokinetics: ❖Absorption ▪ Alkyl lead compounds, because of lipid solubility (methyl and tetraethyl lead) are well absorped via Skin, lung & GIT ❖Distribution ▪ Initially carried in red cells and distributed to soft tissues (kidney and liver); redistributed to bone, teeth and hair mostly as a phosphate salt. high PO4, increases lead storage in bone ▪ Lead readily crosses the placental barrier. Breast milk from heavily exposed mothers is a potential source of lead  Lead Mechanism of toxicity: ▪ Lead can inhibit enzymes by reacting with the thiol groups Lead interfers with several enzymatic steps in the heme pathway, the most sensitive are δ-aminolevulinic acid dehydratase (ALAD) and ferrochelatase -Inhibition of ALAD results in accumulation of ALA , thus, excretion of ALA in urine is a biochemical indicator of lead exposure - Ferrochelatase catalyzes the formation of heme by insertion of iron into the protoporphyrin ring ▪ Inhibition of Na+,K+-ATPase pump ▪ Lead is chemically similar to calcium and interferes with numerous metabolic pathways, particularly in mitochondria regulating cellular energy metabolism  Lead Symptoms of toxicity: CNS: The nervous system is an important target tissue for lead toxicity, especially in infants and young children in whom the nervous system is still developing Lead damages the arterioles and capillaries, resulting in cerebral edema and neuronal degeneration Lead affects virtually every neurotransmitter system in the brain, including glutamatergic, dopaminergic, and cholinergic systems Clinical feature of Pb enecephalopathy include headache, drowsiness, inco- ordination, ataxia, convulsion and coma.  Lead Symptoms of toxicity: CNS: ▪ In children, up to 80% of children with encephalopathy develop permanent neurologic damage. Clinical feature include hyperactivity, decreased attention, slight lowering IQ score. ▪Recovery is often accompanied by sequelae including epilepsy, in some cases, optic neuropathy , blindness & mental retardation  Lead Symptoms of toxicity: ❖ PNS: Peripheral neuropathy is a classic manifestation of lead toxicity in adults. The motor axons responsible for muscle contraction are primarily affected. The neurons undergo demylination and axonal degeneration leading to lead pulsy (Motor nerve dysfunction,) showing as wrist drop (cannot extend the wrist) and foot drop and muscle weakness. ❖ GIT: Nausea, vomiting, constipation, cramps and abdominal pain, Chronic toxicity is characterized by Burton’s line which is a thin, grey-blue line visible along the margin of the gums, at the base of the teeth due to precipitation of pb sulfide  Lead Symptoms of toxicity: ❖ Cardiovascular: Hypertension upon chronic lead exposure ❖ Blood: Anemia ❖ Kidney: Renal tubular degeneration ❖ Bones: 95% of Pb is deposited in the bone leading to osteoporosis, dental caries and delays in fracture repair ❖ Reproductive: spontaneous abortion and oligospermia  Lead Biomarkers of toxicity ❑ Whole blood lead level ❑Protoporphyrin levels in erythrocytes are usually elevated ❑ Urinary delta aminolevulonic acid (ALA) Treatment of toxicity: Lead Decontamination Whole bowel irrigation (WBI) for inorganic lead compounds Activated charcoal after ingestion of organolead compounds surgical or endoscopic removal of lead objects in GIT not removed by WBI, or in other locations, and with evidence of ongoing lead absorption. Supportive care Normalize elevated intracranial pressure secondary to cerebral edema (e.g. by the diuretic mannitol ) Transfusion of packed red blood cells Treat seizures (diazepam or Phenobarbital ) Referral to physical therapy and/or cognitive rehabilitative therapy for treatment of significant neurotoxic sequelae Mercury [Hg]  Mercury Mercury is the only metal in a liquid state at room temperature Mercury exists in the environment in three main chemical forms: Elemental mercury (HgO), Inorganic mercurous (Hg+) and mercuric (Hg2+) salts, Organic methylmercury and dimethylmercury compounds  Mercury Elemental Hg (liquid) glass Organic Hg Methyl & ethyl thermometer, dental amalgams, mercury Used as antiseptic and electrical equipment, batteries & paints fungicides Inorganic Hg Monovalent e.g. mercurous chloride It was used as teething powder and antibacterial Divalent e.g. mercuric chloride It was used as disinfectant.  Mercury Mechanism of toxicity: Hg inactivates SH-enzymes causing interfering with cellular function Toxicokinetics: ▪ Elemental Hg (vapor) crosses membranes well and rapidly moves from the lung to the CNS. ▪ Organic salts (lipid soluble) are evenly distributed, intestinal (intracellular)-fecal elimination. ▪ Inorganic salts concentrate in blood, plasma and kidney (renal elimination) & can’t cross BBB.  Mercury Symptoms of toxicity: Elemental Mercury CNS: tremor , increased excitability, insomnia and depression Lung: corrosive bronchitis and pneumonitis and even result in respiratory failure. Kidney: Proteinuria Others: Acrodynia (pain and swelling of the extremities) & gingivitis  Mercury Symptoms of toxicity: Inorganic Mercury GIT: corrosive: Vomiting ,Hematemesis , Abdominal pain , Intestinal perforation& colitis Kidney: Acute renal failure CVS: cardiovascular collapse is the primary cause of death Symptoms of toxicity: Mercury Organic Mercury Neurotoxicity is the major human health effect from exposure to methylmercury the etiologic agent for Minamata disease Minamata disease is an example of organic toxicity. In Minamata Bay, a factory discharged inorganic mercury into the water. The mercury was methylated by bacteria and subsequently ingested by fish. Local villagers ate the fish and began to exhibit signs of neurologic damage, such as visual loss, extremity numbness, hearing loss, and ataxia. Babies exposed to the methylmercury in utero were the most severely affected. Furthermore, because mercury was also discovered in the breast milk of the mothers, the babies' exposure continued after birth Symptoms of toxicity: Mercury Organic Mercury Clinical manifestations of neurotoxicity include: Paresthesia: numbness and tingling sensation Ataxia: lack of voluntary coordination of muscle movements Neurasthenia: generalized sensation of weakness Spasticity: tendency to spasm Vision and hearing loss Tremors Prenatal exposure to methyl mercury causes congenital abnormalities such as micrognathia (undersized jaw) and neuroencephalopathyincluding microcephaly (smallness of head), mental retardation, blindness  Mercury Treatment of toxicity: Decontamination Lavage with a small orogastric or nasogastric tube (within 2 hr) for ingestion of inorganic and organic mercury, consider adding milk or egg white (sources of sulfhydryl groups ) in the lavage fluid whole bowel irrigation when mercury is identifiable in the abdominal radiograph Supportive treatment Chelation therapy Arsenic [As]  Arsenic Types: It occurs in both organic & inorganicsalts e.g. arsenic dioxide, arsenic trioxide, lead arsenate and arsine gas (the most toxic form) Sources of poisoning: Arsenicals may contaminate water, soil & food (seafood). Arsenicals are used as herbicides, pesticides, rodenticides & preservatives. Arsenicals may cause toxicity in workers of metallurgy, glass manufactures & pigment production. Arsenic trioxide is odorless & tasteless (criminal).  Arsenic (As) Mechanism of toxicity: The trivalent compounds of arsenic are SH-reactive, and thereby inhibit enzymes or alter proteins by reacting with the thiol groups (arsenic inhibits the conversion of pyruvate to acetyl coenzyme A and thus blocks the Krebs cycle) Arsenate (pentavalent) is an uncoupler of mitochondrial oxidative phosphorylation, by a mechanism likely related to competitive substitution of arsenate for inorganic phosphate in the formation of adenosine triphosphate. Arsine gas is formed by the reaction of hydrogen with arsenic, and is a  Arsenic Symptoms of Toxicity: “Acute” GIT: Arsenic is a direct gastrointestinal irritant causing necrosis and ulceration , burning severe esophageal & abdominal pain, nausea, vomiting & bloody & watery diarrhea (rice-water stool) Kidney: Renal damage, oliguria, proteinurea, hematourea & casts Skin: Necrosis & sloughing CVS : Hypotension , excessive bleeding and dehydration CNS: Convulsion, coma & death  Arsenic Symptoms of Toxicity: “Chronic” GIT: Anorexia & loss of weight, garlic odor in breath and stool & GIT ulceration. Liver: Hepatitis, necrosis & cirrhosis. Blood: Anemia due to bone marrow damage. Skin: Hyperpigmentation, hyperkeratosis & of low gangarene extremities (black foot disease). Nails: Horizontal white lines in the nails called Mees lines Carcinogenesis: Lung carcinogen. Chelation therapy  Chelation therapy ❑ BAL (British antilewisite, Dimercaprol): ▪ BAL is a dithiol compound with two sulfur atoms on adjacent carbon atoms that compete with critical binding sites involved in metal toxicity ▪ Route: IM Contraindications: ▪ Liver failure as it is excreted primarily in bile ▪ Concurrent administration of iron due to high toxicity of BAL-Fe chelate  Chelation therapy ❑ DMSA (2,3-dimercaptosuccinic acid, succimer): DMSA can be substituted for BAL when patient can tolerate an oral chelator ❑ Penicillamine ▪ Route: orally ▪ Should not be used unless DMSA is unavailable due to the superior efficacy of DMSA ▪ It is not used for patient with penicillin allergy.  Chelation therapy ❑ EDTA: Route: IM It formsstable chelate metal complex extracellularly that is excreted by kidney. Contraindication: Renal failure, so serum BUN and creatinine should be monitored during therapy. Thank You