Heavy Metals Lecture Notes PDF

Shady Allam 3th year,2nd semester 5th lecture Heavy Metal Poisoning By Shady Naguib Allam; PhD  Arsenic “the silent killer” Shady Allam “The King of Poisons” “The Poison of Kings”...

Shady Allam 3th year,2nd semester 5th lecture Heavy Metal Poisoning By Shady Naguib Allam; PhD  Arsenic “the silent killer” Shady Allam “The King of Poisons” “The Poison of Kings”  Discovered by Albertus Magnus, 1250 Used for strengthening metals: copper and lead – Automotive batteries – Semiconductor in electronic devices Used in production of pesticides: – To treat wood products – Also herbicides and insecticides In painting pigments: – As2S3 and As4S4 Also used in medicine as antibiotic (past) Agency for Toxic Substances and Disease Registry (ATSDR) Priority list of hazardous substances 2017 Rank Substance Name Total Points CAS RN 1 ARSENIC 1674 2-38-7440 2 LEAD 1531 1-92-7439 3 MERCURY 1458 6-97-7439 4 VINYL CHLORIDE 1358 4-01-75 5 POLYCHLORINATED BIPHENYLS 1345 3-36-1336 6 BENZENE 1329 2-43-71 7 CADMIUM 1320 9-43-7440 8 BENZO(A)PYRENE 1306 8-32-50 POLYCYCLIC AROMATIC 9 1279 2-29-130498 HYDROCARBONS 10 BENZO(B)FLUORANTHENE 1251 2-99-205 11 CHLOROFORM 1203 3-66-67 12 AROCLOR 1260 1191 5-82-11096 13 DDT, P,P’- 1183 3-29-50 14 AROCLOR 1254 1172 1-69-11097 15 DIBENZO(A,H)ANTHRACENE 1156 3-70-53 16 TRICHLOROETHYLENE 1155 6-01-79 17 CHROMIUM, HEXAVALENT 1148 9-29-18540 18 DIELDRIN 1144 1-57-60 19 PHOSPHORUS, WHITE 1141 0-14-7723 20 HEXACHLOROBUTADIENE 1130 3-68-87 21 DDE, P,P’- 1127 9-55-72 22 CHLORDANE 1126 9-74-57 23 AROCLOR 1242 1126 9-21-53469 24 COAL TAR CREOSOTE 1124 9-58-8001 25 ALDRIN 1116 2-00-309 26 DDD, P,P’- 1114 8-54-72 27 AROCLOR 1248 1105 6-29-12672 28 HEPTACHLOR 1102 8-44-76 29 AROCLOR 1101 2-79-12767  Metalloid: both metal and nonmetal properties Grey Yellow Black Solid & semiconductor Soft & waxy Glossy and brittle Volatile & toxic Low conductivity Naturally occurring in earth’s crust > 200 mineral species soil ~ 3-4 ppm water ~ 1 ppb (> 1000 ppb)  Forms Inorganic Organic Most prevalent in human toxicity Less toxic Arsenite Arsenate Soil, (As+3) As2O3 (As+5) – As2O5 pesticides, greater absorption, most marine organisms toxic  Arsenic is common in the environment Sources - Poisoning occurs due to contaminated drinking water Groundwater Shady Allam Arsenic containing mineral ores Industrial processes Semiconductor manufacturing (gallium arsenide) Fossil fuels Wood treated with arsenic preservatives Metallurgy Smelting (copper, zinc, lead) and refining of metals and ores Glass manufacturing Commercial products Food Wood preservatives Seafood and fish Pesticides Others Herbicides Antiparasitic drugs Fungicides Folk remedies Pica behavior Pica is a psychological disorder characterized by a compulsive appetite for non-nutritive substances: Ice (pagophagia); Hair (trichophagia) Paper (xylophagia) Drywall or paint and chalk. Metal (metallophagia) Stones (lithophagia) Soil (geophagia) Glass (hyalophagia) Feces (coprophagia);  Metal (metallophagia) Stones (lithophagia) Soil (geophagia)  Ice (pagophagia); Hair (trichophagia) Paper (xylophagia)  Glass (hyalophagia) Feces (coprophagia); Drywall or paint and chalk. Soil Pica behavior Shady Allam Children ingest large amounts of soil at a time (e.g. up to 1 teaspoon or 5,000mg) Children 1 to 2 years old have strongest soil pica behavior, which may occur as part of their normal exploratory behavior Preschool children also purposely eat soil for unknown reasons Some cultures promote eating soil, specifically clay, as part of a cultural practice Pathophysiology Shady Allam Trivalent forms (main toxic form): Bind to sulfhydryl groups → inhibition of enzymatic systems → disturbance in cell function e.g. inhibit pyruvate DH → accumulation of Pyruvic a → acidosis Inhibit the Krebs cycle and oxidative phosporylation → inhibition of ATP production Pentavalent forms (less effect on enzymes) can replace the stable phosphate ester bond in ATP and produce an arsenic ester stable bond which is not a high energy bond Endothelial damage, loss of capillary integrity, capillary leakage, volume loss, shock Clinical picture of acute toxicity Shady Allam Gastrointestinal Clinical picture Garlic or metallic taste Burning mucosa Cholera-like vomiting (persist for hours at a time.) Severe diarrhea (rice watery, bloody) Abdominal pain Hematemesis Hematochezia, melena  Skin Erythema, hyperpigmentation & hyperkeratosis Shady Allam Chronic exposure→ Black foot disease, a vaso- occulusive disease that leads to gangrene Clinical picture Liver Hepatitis, necrosis, fibrosis CNS Delirium, hypoxic convulsions, coma and death Pulmonary Pulmonary edema and respiratory failure  Circulation Shady Allam Tachycardia, dehydration and hypovolemic shock Clinical picture kidney Proteinuria, Hematuria, oliguria, ATN and Acute renal failure Hematologic BM depression → anemia, thrombocytopenia or aplastic anemia Arsine gas inhalation → acute hemolytic anemia & hemaglobinuria  Treatment of acute poisoning Shady Allam Emesis is not recommended Gastric lavage Activated charcoal does not bind well inorganic arsenic Whole bowel irrigation with polyethylene glycol Skin decontamination in dermal exposure Supportive care Chelation therapy should be instituted promptly (minutes to hours) Succimer (DMSA, ) The best BAL (British anti-Lewisite)- IM D-Penicillamine- less effective Shady Allam  Shady Allam Lead (Pb) Inorganic Organic Lead arsenate — insecticide (antiknock gasoline additives) Lead azide — bullet primers Tetraethyl lead: gasoline additive Lead carbonate — white (light) paints until 1978. Lead chromate — yellow (pastel) paints Tetramethyl lead: gasoline additive until 1978. Sources of Lead Exposure Shady Allam Paints: cracking and peeling off; Water: Lead pipes and solder in pre-1980 buildings; lead glazed crystal, cooking utensils, pots, water coolers. Air: 500 tons released/year from battery and radiator recycling. Food: 1% of cans and containers may contain lead , lead-soldered cans, acidic juices releasing lead in ceramic glassware.  Pathophysiology Shady Allam Primary Effects: Neurologic Hematologic Renal Reproductive Secondary Effects: Endocrine Skeletal Gastrointestinal Cardiac A. Primary effects Shady Allam CNS 1. Lead Neurotoxicity Peripheral nervous system  ❖Central Nervous System (targeted in children) Shady Allam The developing nervous system of the child makes it more sensitive pathophysiology to lead-induced impairment Inhibits Ach, dopamine, NE and GABA neurotransmission →  nerve conduction Hearing, cognition, IQ (intelligence quotient), developmental, motor, and coordination disorders Targets cortex, cerebellum, & occipital lobes Acute encephalopathy: Increased intracranial pressure.  ❖Peripheral Nervous System (targeted in adults) Shady Allam rarely seen in children except for those with sickle cell disease involving the extensor muscles, with minimal sensory loss Schwann cell necrosis & demyelination (adults): ↓ peripheral nerve conduction amplitude and velocity Motor > sensory neuropathy Wrist drop > foot drop  Shady Allam pathophysiology 2. Lead Hemotoxicity Shady Allam ↑ RBC membrane fragility pathophysiology ↓ Red blood cell (RBC) survival.  Hb Synthesis. Erythropoietin deficiency: as a result of toxic effect of lead on renal tubules Basophilic stippling of RBCs Anemia.  3. Lead Nephropathy Adults > children. Fanconi’s syndrome: Aminoaciduria, glucosuria, and phosphaturia (Rickets), Bicarb. (Acidosis) (reversible). Chronic renal failure (CRF) secondary to tubular atrophy and fibrosis (irreversible). Renovascular Hypertension secondary to renin.  Increased serum uric acid. Shady Allam Uric acid crystal deposition in : joints (gouty arthropathy), kidneys (urolithiasis), skin (tophi). 4. Lead Reproductive Toxicity Shady Allam Females: Infertility, Stillbirths , Prematurity , Possible birth defects. Males: Infertility from: * Sperm motility and counts *Abnormal sperm morphology  B. Secondary effects 1. Lead Endocrinopathy Shady Allam Adults: Hypothyroidism Children:  GH secretion →short stature  2. Lead Skeletal Effects (children) Shady Allam Reduced osteoblast and osteoclast function. Lead lines at pediatric metaphyses, long bones ↓bone growth --→ short extremities & stature in children.  Shady Allam Metaphysis Part of the bone between the epiphysis and the diaphysis; it contains the connecting cartilage enabling the bone to grow, and disappears at adulthood.  3. Lead Cardiac Effects (adults) Systolic Hypertension. Shady Allam Dysrhythmias. 4. Lead GIT Effects Metallic taste in mouth. Lead colic: Abdominal pain, vomiting, constipation (mechanism: colonic autonomic neuropathy). Acute exposure: Hepatitis and pancreatitis, especially in adults.  Clinical picture of acute toxicity Uncommon and results from accidental or suicidal Shady Allam ingestion of lead oxides. GIT: metallic taste, vomiting, colic, constipation. CNS: lead encephalopathy, behavioral changes, lethargy, fatigue, seizures and coma.  Clinical picture of chronic toxicity (Plumbism) Shady Allam Non specific vague body aches. Anorexia Constipation & abdominal colic Blue line on the gums caused by bacterial action on blood lead at these sites precipitating lead sulfide. Peripheral neuritis: wrist drop, foot drop, optic neuritis. Cognitive disturbances, headache Anemia Renal impairment Bone aches & gouty arthritis Myocarditis.  DEFINITION OF LEAD POISONING Shady Allam Centers for Disease Control and Prevention statement concerning lead poisoning defined elevated blood lead levels: in young children as those ≥10 µg/dl and recommended a new set of guidelines for treatment of lead levels ≥15 µg/dl. In Adults at 20 µg/dl. Investigations 1. Laboratory Studies Shady Allam anemia. Basophilic stippling of RBCs. U/A: Increased protein and glucose. Biomarkers: blood lead level > 20 µg/dl 2. Radiographic Images: Long bones (children): Metaphyseal lead lines of increased calcification at wrists (radius), hips (femur), and knees (tibia). Radiopaque ingestions of metal foreign bodies, paint chips, adynamic ileus with dilated bowel. 3. CT: Cerebral edema, reduced gray-white matter demarcation. 4. MRI: Cortical atrophy, cerebral infarcts.  Treatment 1. For children with lead levels of 15 to 19 µg/dl, the pediatrician Shady Allam should take a careful history of the environment. 2. Reduce Lead Exposures: Reduce pre-exposures risks: Children and pregnant > adults; Nutritional interventions include iron and calcium supplementation, a reduced-fat diet, and frequent meals, as all these measures are associated with reduced gastrointestinal absorption of ingested lead Change work clothes; increased ventilation and dust reduction Individualized case management, which includes a detailed medical history, nutritional assessment, physical examination, environmental investigation, and hazard reduction, begins at a blood lead levels of ≥20 µg/dl. 3. Chelation therapy may be considered, but is not routinely recommended at blood lead levels of 45ug/dl. N.B: Shady Allam 1. In adults, reducing lead exposure is the first key step in treatment for all cases of excessive lead absorption 2. Tendency to recommend chelation therapy for: individuals with blood lead levels greater than 45 µg/dl, individuals with blood lead levels between 40 and 60 µg/dl if they show continuing symptoms and elevated lead levels two weeks after removal from exposure 4. Symptomatic treatment: Shady Allam Treatment of anemia Renal affection: hemodialysis. Splint & physiotherapy for wrist & foot affection. Shady Allam Mercury Shady Allam toxicity  Forms and Exposures of Mercury Shady Allam Elemental Inorganic Organic EX: “Quicksilver” Mercuric chloride Methyl mercury Dentists Antiseptics Seafood, Calibrated Disinfectants Grain and seed instruments Batteries fumigants (bl.pressure Insecticides gauges, Explosives Fungicides thermometer)  Pathophysiology Shady Allam Elemental Hg targets lungs (chemical pneumonitis), Inorganic Hg targets GIT & kidneys (hemorrhagic gastroenteritis, ATN), organic Hg targets CNS, especially fetal CNS. ingested elemental mercury is not absorbed at all; however, 90% of any methylmercury ingested is absorbed into the bloodstream from the GI tract.  Mechanism of toxicity irreversible inhibition of selenoenzymes, such as thioredoxin Shady Allam reductase. thioredoxin reductase restores vitamins C and E, as well as a number of other important antioxidant molecules, back into their reduced forms, enabling them to counteract oxidative damage. Since the rate of oxygen consumption is particularly high in brain tissues, production of reactive oxygen species (ROS) make them particularly vulnerable to oxidative damage and especially dependent upon the antioxidant protection provided by selenoenzymes. High mercury exposures deplete the amount of cellular selenium available for the biosynthesis of thioredoxin reductase and other selenoenzymes that prevent and reverse oxidative damage, which, if the depletion is severe and long lasting, results in brain cell dysfunctions that can ultimately cause death.  Clinical picture of acute toxicity Shady Allam Acute Elemental Hg Inhalation: Pulmonary: Cough, chills, fever, dyspnea, chemical pneumonitis, pulmonary edema, GIT: Metallic taste, nausea, vomiting, diarrhea, dysphagia. CNS: Headaches, weakness, visual disturbances. Shady Allam Acute Inorganic Ingestion Shady Allam GIT: Metallic taste, oral pain and burning, nausea, vomiting, diarrhea, abdominal pain, hemorrhagic gastroenteritis, dehydration → orthostatic hypotension. Renal: ATN.  Clinical picture of Chronic toxicity (Mercurialism) Shady Allam Elemental Mercury Pulmonary: Pulmonary fibrosis, restrictive lung disease. Renal: Fanconi’s syndrome Gastrointestinal: Relatively nontoxic due to negligible absorption  Acrodynia (Pink disease) Acrodynia is a condition of pain and dusky pink Shady Allam discoloration in the hands and feet most often seen in children chronically exposed to heavy metals, especially mercury Toxic form: Inorganic Hg salts — Calomel and similar inorganic Hg-containing creams used for infant eczema and as inorganic mercurial teething powders in the 1950s. Symptoms: Pink papular distal rash with pinkish-purple acrocyanosis skin discoloration (pink cheeks, fingertips and toes) that may be followed by hyperkeratoses on palms and soles, with later acral desquamation and possibly ulceration. N.B. Acro: extremities Dynia : pain Shady Allam  Shady Allam Minamata disease has devastating neurologic consequences as a primary outcome of methyl mercury intoxication; unfortunately, these are relatively resistant to treatment Complications include the following: Acute perioral and facial paresthesias Visual-field constriction Respiratory distress and nonspecific dermatitis Extremity numbness eventually appears, along with headache, fatigue, and tremor Ataxia and dysarthria can also be observed Shady Allam  Shady Allam Investigations CBC, renal function tests, blood Hg level. Treatment: Stop further exposure Chelation therapy: Penicillamine or DMSA (dimethylsuccinic acid) Renal affection: hemodialysis. Shady Allam Shady Allam Forms and toxic dose Iron is widely available at home Shady Allam in an attractive colored sugar coated vitamins and nutrient supplements preparations (over the counter drug). Iron supplements are in the form of iron salts as ferrous sulfate Acute toxicity Shady Allam Mode of poisoning Iron intoxication a remains common and serious problem of accidental poisoning in children  Pathophysiology It has local corrosive action on the GI mucosa Shady Allam via the direct oxidative damage After absorption iron is bound to the circulating transferrin protein. Once this protein is saturated, the free iron promotes its oxidative damaging process organ systems. Excess free iron is a mitochondrial toxin leading to disturbances in energy metabolism. It disrupts the mitochondrial oxidative phosphorylation reaction, leads to liberation of hydrogen and development of Acidosis.  Clinical Picture It passes into 5 stages : Shady Allam Stage I : Onset : 1-6 hours. GIT irritation due to direct corrosive action on mucosal surfaces with nausea, vomiting, abdominal pain, GIT bleeding (which may be severe), diarrhea and shock. Necrosis may be severe and lead to perforation and peritonitis. In severe cases, CNS depression may occur at this stage leading to lethargy and coma. Stage II (Quiescent phase) : Onset : up to 24 hours from ingestion Shady Allam Apparent (false) improvement in most cases. Stage III : Onset : 12-48 hours. Metabolic acidosis : hydrogen is released in the conversion of ferrous iron to ferric iron in the blood or interference with Kreb's cycle with accumulation of organic acids, Fever and leucocytosis (due to invasion of the damaged intestinal mucosa by bacteria). G.R. Fever one day post iron overdose Coma and cardiovascular collapse. Stage IV : Hepatic necrosis, liver cell failure (jaundice, Shady Allam hypoglycemia and coagulation defect). It occur 2-3 days after ingestion. Renal failure (all due to deposition of excess iron exceeding total iron binding capacity in soft tissues ). Stage V : Onset : 2 – 8 weeks. Intestinal scarring with or without obstruction. Investigations Serum iron level (normal serum level ranges Shady Allam between 80-180 ug /dl – its peak level occur 2-6 hours post ingestion.: Level between 300-500 µg /dl usually correlates with significant GIT toxicity. Level between 500-1000 µg /dl are associated with pronounced systemic toxicity. Level> 1000 µg /dl are associated with significant morbidity and mortality. Renal function tests e.g. BUN and creatinine. ABGs. Hepatic profile : transaminases higher levels with severe toxicity, bilirubin and coagulation profiles. X-Ray abdomen to detect radiopaque tablets  Treatment I. Emergency measures (ABC). Shady Allam II. Elimination : Gastric lavage. Whole Bowel irrigation. Follow up by X ray films to evaluate the efficacy of GL or WBI and determine if there is need for endoscopy for removal of iron remnants stuck on GIT wall. G.R. Importance of follow up X-ray films in iron overdose N.B. Activated charcoal can not adsorb iron, so it is not used. III Antidote : Deferoxamine (Desferal ®) Shady Allam It is iron chelating agent, it is excreted as iron-deferoxamine complex in the urine. It does not bind iron in hemoglobin, myoglobin, or other iron carrying proteins. Indications for treatment by deferoxamine : Serum Fe > 500 ug / dl or estimated dose > 60 mg / kg of elemental iron. Shock. Altered mental status. Persistent GI symptoms. Metabolic acidosis. Serum iron level is not available with presence of symptoms.  IV. Symptomatic treatment : fluids Shady Allam liver support correction of acidosis  Chronic iron toxicity Hemochromatosis Shady Allam Causes Chronic blood transfusion in hemolytic anemias → deposition of iron in tissues → deposition of iron in the pancreas → diabetes "bronze diabetes“ Shady Allam Shady Allam