Heavy metal poisoning

Question 1

What are the four heavy metals that pose a serious threat to human organism ?

Answer 1

1. Arsenic
2. Cadmium
3. Lead
4. Mercury

Question 2

What are main sources of arsenic ?

Answer 2

1. Smelting and microelectronics industries;
2. Wood preservatives, pesticides, herbicides, fungicides;
3. Contaminant of deep-water wells;
4. Folk remedies;
5. Coal;
6. Incineration of these products

Question 3

What are the most important facts on metabolism of arsenic ?

Answer 3

• organic arsenic - arsenobetaine and arsenocholine - is ingested in seafood and fish, it is excreted rapidly and can be considered nontoxic;
• inorganic arsenic is readily absorbed through the GI tract and lungs => sequestered in liver, spleen, kindeys, lungs and GI tract;
• residues of inorganic arsenic persist in skin, hair, nails;
• biomethylation results in detoxification, but this process saturates;

Question 4

What are the results of acute arsenic poisoning ?

Answer 4

1. Necrosis of intestinal mucosa => hemorrhagic gastroenteritis, fluid loss, hypotension;
2. Delayed cardiomyopathy;
3. Acute tubular necrosis;
4. Hemolysis;

Question 5

What are the results of chronic arsenic poisoning ?

Answer 5

1. Skin lesions : hyperpigmentation, hypopigmentation, hyperkeratoses, scaling - palms and soles, maculopapular eruptions, Bowen’s disease, skin carcinomas - multiple SCCs;
2. Diabetes mellitus type II;
3. Vasospasm, peripheral vascular insufficiency and gangrene => “Blackfoot disease”;
4. Symmetric sensorymotor polyneuropathy;
5. Cancer of the skin, lungs, liver - angiosarcoma, bladder, kidney;
6. Cardiovascular : arrythmias, hypertension;

Question 6

What signs, symptoms and diagnostic findings support arsenic poisoning diagnosis ?

Answer 6

1. Nausea, vomiting, diarrhea, abdominal pain
2. Delirium, coma, seizures (acute encephalopathy)
3. Garlicky odor on breath
4. Hyperkeratosis, hyperpigmentation, exfoliative dermatitis, patchy alopecia, herpetic like ulcers in mouth, diffuse, pruritic macular rash, Mees’ lines - transverse leukonychia
5. Sensory and motor polyneuritis
6. Distal weakness
7. Radiopaque sign on abdominal XR
8. ECG : QRS broadening, QT prolongation (risk of torsade de pointes), ST depression, T-wave flattening
9. Renal injury => hematuria, proteinuria, acute tubular necrosis, anuria
10. Hepatitis
11. Pancytopenia
12. 24-h urinary arsenic >67 umol/d or 50 ug/d
13. High arsenic in hair or nails

Question 7

Outline treatment of arsenic poisoning ?

Answer 7

1. If acute ingestion => decontamination of the skin and GI tract => ipecac to induce vomiting, gastric lavage, activated charcoal with a cathartic.
2. Supportive care in ICU : administration of fluids (with good urine output), cardiac monitoring.
3. Dimercaprol (BAL) 3–5 mg/kg IM q4h × 2 days; q6h × 1 day, then q12h × 10 days; alternative: oral succimer (DMSA = DiMercaptoSuccinic Acid).

Question 8

What are the sources of cadmium ?

Answer 8

1. Metal-plating, smelting, battery and plastics industries;
2. Tobacco - smoking cigarettes;
3. Incineration of these products;
4. Ingestion of food that concentrates cadmium - grains, cereals, vegetables !

Question 9

What is the metabolism of cadmium ?

Answer 9

• absorbed through ingestion (10% of oral intake) and/or inhalation (25% of inhaled);
• transported to the liver and bound to metallothionein (detoxyfing protein produced in the liver) => being a small particle it is filtered at the glomerulous, but reabsorbed at the proximal convoluted tubules via pinocytosis => in lysosomes free cadmium ions are released => poorly excreted;
• renal tubular cells have a considerable capacity to synthesize metallothionein => binds toxic cadmium ions => kidneys’ detoxifying capacity is surpassed => free cadmium causes tubular damage, interstitial inflammation => fibrosis and glomerular injury;
• binds cellular sulfhydryl groups, competes with zinc and calcium for binding sites;
• concentrates in liver and kidneys;

Question 10

What are the results of acute and chronic cadmium toxicity ?

Answer 10

• Acute poisoning :
  
  • via inhalation : pneumonitis after 4-24 hours;
  • via ingestion : gastroenteritis;
• Chronic poisoning :
  
  1. anosmia
  2. yellowing of the teeth
  3. emphysema
  4. minor LFTs elevations
  5. microcytic hypochromic anemia unresponsive to iron therapy
  6. proteinuria, increased urinary B2-microglobulin, calcinuria, chronic renal failure
  7. osteomalacia, fractures
  8. possible risk of cardiovascular disease and cancer

Question 11

What are the clinical findings with cadmium poisoning ?

Answer 11

1. inhalation : pleuritic chest pain, dyspnea, cyanosis, fever, tachycardia, nausea, noncardiogenic pulmonary edema;
2. ingestrion : nausea, vomiting, cramps, diarrhea;
3. osteomalacia, bone pain, fractures;
4. increased urinary and serum cadmium concentration;
5. increased beta2-microglobulin excretion => isolated tubular defect;

Question 12

What is the treatment of cadmium poisoning ?

Answer 12

• No effective treatment for cadmium poisoning => chelation not useful; dimercaprol can exacerbate nephrotoxicity;
• Avoidance of further exposure;
• Supportive therapy, vitamin D for osteomalacia.

Question 13

What are the sources of lead ?

Answer 13

1. Manufacturing of auto batteries, lead crystal, ceramics, fishing weights, etc.;
2. Demolition or sanding of lead-painted houses, bridges;
3. Stained glass–making, plumbing, soldering;
4. Environmental exposure to paint chips, house dust (in homes built <1975), firing ranges (from bullet dust), food or water from improperly glazed ceramics, lead pipes;
5. Contaminated herbal remedies, candies;
6. Exposure to the combustion of leaded fuels.

Question 14

What is the metabolism of lead ?

Answer 14

• absorbed through ingestion and inhalation; organic lead also absorbed dermally;
• in blood in 95-99% of lead is sequestered within RBC’s => measure lead content in whole blood;
• distributed widely in soft tissues => t1/2 : 30 days;
• 15% of lead sequestered in bone => t1/2 : >20yrs;
• excreted mostly in urine, appears in other body fluids like breast milk;
• interferes with : mitochondrial oxidative phosphorylation, ATPases, calcium dependent messengers; enhances oxidation and cell apoptosis;
  
  • Pb is electropositive => affinity to negative sulfhydryl groups => binds and inhibits sulfhydryl-dependent enzymes : delta-ALAD and ferrochelatase (heme synthesis) => production of free erythrocyte protoporphyrins (measurable);
  • inhibition of pyrimidine 5’ nucleotidase => rRNA degradation in RBCs => basophilic stippling;
  • divalent Pb competes with Ca => interference with Ca dependent processes;
  • Pb alters the permeability of BBB => accumulates in astroglia;
  • PB affects cell membranes, interferes with various energy and transport systems => shortened RBC survival time, hemolysis, renal toxicity;
  • Pb promotes generation of superoxide and hydrogen peroxide in human endothelial cells and vascular smooth muscle cells;

Question 15

What are the results of acute lead exposure ?

Answer 15

• BPb >60–80 μg/dL :
  
  1. impaired neurotransmission and neuronal cell death (central and peripheral nervous system effects);
  2. impaired hematopoiesis;
  3. renal tubular dysfunction;
• BPb >80–120 μg/dL :
  
  1. acute encephalopathy with convulsions, coma, and death;

Question 16

What are the results of chronic lead exposure in children and in adults ?

Answer 16

• Subclinical exposures in children (BPb 25–60 μg/dL):
  
  1. anemia,
  2. mental retardation,
  3. deficits in language, motor function, balance, hearing, behavior, school performance;
• Chronic subclinical exposures in adults (BPb >40 μg/dL) :
  
  1. anemia,
  2. demyelinating peripheral neuropathy,
  3. impairments of reaction time and hearing,
  4. accelerated declines in cognition,
  5. hypertension,
  6. ECG conduction delays,
  7. higher risk of cardiovascular disease and death,
  8. interstitial nephritis and chronic renal failure,
  9. diminished sperm counts, spontaneous abortions;

Question 17

What are the clinical features of acute lead poisoning in children and in adults ?

Answer 17

• Children when BPb >80 μg/dL :
  
  1. Abdominal pain - lead colic, constipation,
  2. Irritability, lethargy, anorexia,
  3. Anemia,
  4. Fanconi’s syndrome,
  5. Pyuria, azotemia;
  6. Epiphyseal plate “lead lines”,
  7. Convulsions, coma at BPb >120 μg/dL,
  8. Neurodevelopmental delays at BPb of 40–80 μg/dL;
• Adults - similar to childen plus :
  
  1. Headaches, depression, impaired short-term memory,
  2. Loss of libido,
  3. Arthralgias, myalgias,
  4. “Lead line” at the gingiva-tooth border,
  5. Pallor,
  6. Wrist/ankle drop,
  7. Cognitive dysfunction (e.g., declines on the mini-mental state exam);
  8. Normocytic, normochromic anemia, basophilic stippling, elevated blood protoporphyrin level (free erythrocyte or zinc),
  9. Motor delays on nerve conduction;

Question 18

What is the treatment to lead poisoning ?

Answer 18

• Identification and correction of exposure sources;
• In highly exposed individual with symptoms, chelation is recommended with oral DMSA (succimer);
• If acutely toxic, hospitalization and IV or IM chelation with ethylene-di-amine tetra-acetic acid calcium disodium (CaEDTA) may be required, with the addition of dimercaprol to prevent worsening of encephalopathy;
• Correction of dietary deficiencies in Fe, Ca, Mg, Zn will lower Pb absorption and may also improve toxicity.
• Vitamin C is a weak but natural chelating agent.
• Ca supplements (1200 mg at bedtime) have been shown to lower blood Pb levels in pregnant women.

Question 19

What are the sources of mercury ?

Answer 19

• There are : (1) metallic, (2) mercurous, (3) mercuric mercury (Hg, Hg+, Hg2+);

1. Chemical, metal-processing, electrical-equipment, automotive industries;
2. Thermometers, dental amalgams, batteries;
3. Dispersed by waste incineration
4. Environmental bacteria convert inorganic to organic mercury, which then bioconcentrates up the aquatic food chain to contaminate tuna, swordfish, and other pelagic fish.

Question 20

What is the matbolism of mercury ?

Answer 20

• Elemental mercury (Hg) not well absorbed; but it volatilizes into highly absorbable vapor.
• Inorganic mercury is absorbed through the gut and skin. Organic mercury is well absorbed through inhalation and ingestion.
• Elemental and organic mercury cross the blood-brain barrier and placenta.
• Mercury is excreted in urine and feces and has a half-life in blood of ~60 days; however, deposits will remain in the kidney and brain for years.
• Exposure to mercury stimulates the kidney to produce metallothionein, which provides some detoxification benefit.
• Mercury binds sulfhydryl groups and interferes with a wide variety of critical enzymatic processes.

Question 21

What are the results of acute and chronic mercury exposure ?

Answer 21

• Acute inhalation of Hg vapor causes intersticial pneumonitis and noncardiogenic pulmonary edema leading to death, CNS symptoms, polyneuropathy.
• Chronic high exposure causes CNS toxicity (mercurial erethism); lower exposures impair renal function, motor speed, memory, coordination.
• Acute ingestion of inorganic mercury causes gastroenteritis, the nephritic syndrome, or acute renal failure, hypertension, tachycardia, and cardiovascular collapse, with death at a dose of 10–42 mg/kg;
• Ingestion of organic mercury causes gastroenteritis, arrhythmias, and lesions in the basal ganglia, gray matter, and cerebellum at doses >1.7 mg/kg.
• High exposure during pregnancy causes derangement of fetal neuronal migration resulting in severe mental retardation.
• Mild exposures during pregnancy (from fish consumption) are associated with declines in neurobehavioral performance in offspring.
• Dimethylmercury, a compound only found in research labs, is “supertoxic”—a few drops of exposure via skin absorption or inhaled vapor can cause severe cerebellar degeneration and death.

Question 22

What are the clinical features of mercury poisoning ?

Answer 22

• Chronic exposure to metallic mercury vapor produces a characteristic intention tremor and mercurial erethism: excitability, memory loss, insomnia, timidity, and delirium (“mad as a hatter”).
• Children exposed to mercury in any form may develop acrodynia (“pink disease”): flushing, itching, swelling, tachycardia, hypertension, excessive salivation or perspiration, irritability, weakness, morbilliform rashes, desquamation of palms and soles.
• Organic mercury exposure is best measured by levels in blood (if recent) or hair (if chronic);

Question 23

How should one treat mercury poisoning ?

Answer 23

• Treat acute ingestion of mercuric salts with induced emesis or gastric lavage and polythiol resins (to bind mercury in the GI tract).
• Chelate with dimercaprol (up to 24 mg/kg per day IM in divided doses), DMSA (succimer), or penicillamine, with 5-day courses separated by several days of rest.
• If renal failure occurs, treat with peritoneal dialysis, hemodialysis, or extracorporeal regional complexing hemodialysis and succimer.
• Chronic inorganic mercury poisoning is best treated with N-acetyl penicillamine.