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Toxicity of Heavy Metals
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Toxicity of Heavy Metals

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Toxicity of Heavy Metals Presentation Transcript

  • 1. ‫د‬.‫عبدالعزيز‬ ‫الطاهر‬ tsoleman@yahoo.com
  • 2. GENERAL CHARACTERS • Most common heavy metals toxicity: lead (Pb), mercury (Hg), cadmium (Cd) and arsenic (As) • They are mainly produced by industrial activities, and deposit slowly in the surrounding water and soil
  • 3. • Toxicity may occur through ingestion, inhalation or dermal exposure • Toxicity is either acute or chronic • Metallic taste if ingested except arsenic which is tasteless • Can cause both local & systemic effects • Most metals cause diarrhea except lead which causes constipation • The antidotes are called chelators
  • 4. • The most common metallic poison. • Occurs in organic and inorganic forms. • Absorption of ingested lead in children is much more than in adults (50% children& 10% in adults). • Probably the most important chronic environmental illness affecting children. • In children, probably no organ system is immune to the effects of lead poisoning. • Developing brain is the most risky organ to be affected.
  • 5. 1- Occupational: More than 900 occupations. Parents may bring lead dust. 2- Some cosmetics and folk remedies. 3- Water & Food contamination: lead pipes or storage tanks, and eating contaminated food. 4- Foreign body ingestion: several reports have documented cases of childhood lead poisoning resulting from the ingestion of lead-based foreign bodies. 5- Retained bullet 6- Illegally manufactured alcohols 7- Inhalation of lead from motor vehicle
  • 6. NEWS headlines! Lead laced Marijuana producing sociopaths? Leaded turmericLeaded kohl eye make-up LEAD AS A COLORANT OR TO ADD WEIGHT TO FOOD
  • 7. • Lead has a high affinity for SH groups. It is therefore particularly toxic to multiple enzyme systems. • Many of lead’s toxic effects also result from its inhibition of cellular function requiring calcium. • Lead binds to calcium-activated proteins 105 times than Ca2+ • Pb2+ and Ca2+ compete at the plasma membrane for transport systems, which affect their entry or exit (ie, Ca2+ channels and the Ca2+ pump.) • Intracellular Ca2+ is buffered by proteins, endoplasmic reticulum, and mitochondria; Pb2+ disturbs this intracellular Ca2+ homeostasis. • Pb2+ interacts with a number of Ca2+ -dependent effector mechanisms, such as calmodulin (a Ca2+ receptor protein, which couples to several enzymes, eg, phosphodiesterase, protein kinases).
  • 8. A-HEMATOLOGICAL EFFECTS Lead-induced anemia: •Hypochromic Microcytic •More in children Mechanisms: •Inhibition of heme synthesis: •a) Inhibits conversion of DALA to porphobilinogen. •b) Inhibits conversion of coproporphyrinogen III to protoporphyrin. •c) Blocks incorporation of iron into protoporphyrin to form heme. Protoporphyrin accumulates in RBCs and chelate zinc. EP reflects chronic lead exposure.
  • 9. ENZYMES INVOLVED IN THE INHIBITION OF HEME SYNTHESIS
  • 10. • Increase of RBC fragility • Erythropoietin deficiency: from the toxic effects of lead on renal tubules. • Inhibition of 5-pyrimidine nucleotidase: aggregation of ribosomes, appearing as basophilic stippling of RBCs (not specific to lead toxicity).
  • 11. Basophilic Stippling Inhibition of 5- pyrimidine nucleotidase: aggregation of ribosomes, appearing as basophilic stippling of RBCs (not specific to lead toxicity)
  • 12. • Acute toxicity may cause renal colic. • Acute toxicity may cause direct tubular damage (Fanconi-like syndrome) • Chronic toxicity may cause chronic interstitial nephritis. • Alters rennin-angiotensin system and may cause hypertension. • Alters uric acid excretion resulting in hyperuricemia and gout
  • 13. • Direct effect on CNS causing lead encephalopathy especially in children. • Delayed or reversed development, permanent learning disabilities. • Children below 3 Y are at the greatest risk (brains are rapidly developing). • DALA is thought to be neurotoxic by interfering with GABA. • Chronic lead exposure affects peripheral nerves mainly the motor (radial nerve)
  • 14. D- Reproductive System Effects • Abortion, stillbirth, neurodevelopmental problems. • May cause decreased sperm count, and increased number of abnormal sperms. E- Bone Effects • Triggers hypermineralization (reflected in metaphyseal & growth plate densities (lead lines). • They reflect bone growth arrest and not deposition. Their width is related to the duration of exposure. • Lead inhibits the conversion of vitamin D into its active form.
  • 15. ACUTE TOXICITY • More commonly on top of chronic exposure. 1- GIT: anorexia, abdominal pain, constipation, vomiting. 2- CNS: encephalopathy, behavioral changes, lethargy, fatigue, seizures & coma.
  • 16. CHRONIC TOXICITY (PLUMBISM) • Nonspecific: vague body aches, anorexia, constipation and abdominal colic. • Blue lines on the gums and around anal marginsdue to bacterial action precipitating lead sulfide. • Neuropathy: wrist drop and foot drop. Optic neuropathy may occur. • CNS: cognitive disturbances, headache and encephalopathy • Anemia, reticulocytosis and hemolysis. • Renal impairment. • Bony aches and gouty arthritis. • Myocarditis
  • 17. GINGIVAL LEAD LINE
  • 18. BONE LEAD LINE (BONE GROWTH ARREST)
  • 19. WRIST DROP (RADIAL NERVE)
  • 20. CARCINOGENICITY 2B. Agent is possibly carcinogenic to humans •Human epidemiology data weak •Animal data positive
  • 21. !!!!!!!!!!!!!!!!!!!!!NOTE!!!!!!!!!!!!!!!!!! ABSENT (NOAEL) NO OBSERVABLE ADVERSE EFFECT LEVEL NOAEL: An exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its control. NOAEL is absent in Lead toxicity
  • 22. INVESTIGATIONS1- Blood Lead level • less than 5 µg/dL for children (before 2012 as 10 (µg/dl). • less than 25 µg/dL for adults • biological exposure index (a level that should not be exceeded) for lead-exposed workers in the U.S. is 30 µg/dL in a random blood specimen. 2- Blood zinc protoporphyrin (ZPP) (Free erythrocyte Protoporphyrin FEP) • The normal range for ZPP is 0-35 • Its gives clue about duration of toxicity • can be used as screening test 3- Urine DALA • 1 - 8 years: 2.3-6.2 mg/g creat • 9 - 17 years : 1.5-5.3 mg/g creat • ≥ 18 years: • Females : <5.4 mg/g creat • Males : <1.8 mg/g creat
  • 23. BLLS IN DIFFERENT EUROPEAN COUNTRIES (WHO)
  • 24. All Australians should have BLL below 10 µg/dL • “It was never intended that this goal of 10 µg/dL be interpreted as a ‘safe’ level of exposure or a ‘level of concern’”, rather, it is the level at which sources of exposure to lead should be investigated. • This is currently under review and the outcomes should be available to the public in late 2013/early 2014 RECOMMENDED BLOOD LEAD LEVELS
  • 25. • Update on BLLs in Children • Reference BLLin children below 6 Ys is 5 µg/dL • This new level is based on the U.S. population of children ages 1-5 years who are in the highest 2.5% of children when tested for lead in their blood. • The new recommendation does not change the guidance that chelation therapy be considered when a child has a blood lead test result greater than or equal to 45 µg/dL CENTERS OF DISEASE CONTROL & PREVENTION (USA) 2012
  • 26. 2- A baseline hemogram Typical pattern of iron-deficiency anemia with hypochromia and microcytosis. 3- A chemistry profile including: RFT, LFT & uric acid. • Adults may have elevated uric avid level because of the disturbance of enzymatic amino hydrolases
  • 27. TREATMENT Dimercaprol (BAL) Removes intracellular & extracellular lead. It is a lipid-soluble drug and must be administered IM only as IV may cause fat embolism. It is the first chelator used in encephalopathic individuals. Rapidly crosses the BBB.
  • 28. Calcium disodium edentate (Ca Na2 EDTA) Allows extracellular lead to be renally eliminated. Once started CaNa2EDTA should be given in full 5-day course. The first dose begins removing lead from extracellular fluid in bone, if not followed by next doses free lead neurotoxicity. In cases of lead encephalopathy, BAL should be given first to avoid redistribution of lead mobilized by CaNa2EDTA to CNS.
  • 29. D-Penicillamine • orally and has few adverse effects. • Can chelate lead even in low blood levels. • Effective in children with levels 20-40 µg/100ml. Dimercaptosuccinic acid (Succimer or DMSA): 5- Dimerval (DMPS): Has become antidote for most heavy metal intoxications. It is available in the oral form and in a water-based parenteral form.
  • 30. POSTMORTEM APPEARANCE • Depends on whether acute or chronic poisoning according to clinical manifestations
  • 31. MERCURY TOXICITY
  • 32. • The only metal that is liquid at room temperature. • Elemental symbol is Hg: Greek word hydrargyrias “water silver.” • Found in 3 forms but all are toxic: 1) Elemental (metallic) mercury (Hg0) 2) Organic 3) Inorganic
  • 33. METHODS OF EXPOSURE 1- Elemental mercury: barometers, batteries, dental amalgams, electroplating, fingerprinting products, fluorescent and mercury lamps, infrared detectors, jewelry industry, manometers, neon lamps, paints, photography, silver and gold production, thermometers. 2- Organic mercury: antiseptics, bactericidals, fungicides, insecticidal products, laundry products, diaper products, paper manufacturing, seed preservation, and wood preservatives.
  • 34. 3- Inorganic mercury: Cosmetics, disinfectants, explosives, ink manufacturing, mirror silvering, perfume industry, photography, spermicidal jellies, tattooing inks, and wood preservation. 4-Thimerosal: Vaccine preservative to prevent bacterial contamination. Most commonly vaccines that contain Thimerosal are DTP, Haemophilus influenzae, and hepatitis B.
  • 35. ELEMENTAL MERCURY  Toxicity by inhalation exposure  Poorly absorbed from GIT (eg, thermometers) .  Once inhaled, it is mostly converted to inorganic Hg (limited permeability to BBB).  Acute toxicity might result in: • Fever, fatigue, and clinical signs of pneumonitis.  Chronic exposure results in • neurologic, dermatologic, and renal manifestations. • Signs and symptoms might include: • neuropsychiatric disturbances (e.g., memory loss, irritability, or depression) • Tremor • Paresthesias • Gingivostomatitis • flushing, discoloration and desquamation of the hands and feet • hypertension
  • 36. ELEMENTAL MERCURY In January 2008, Norway and Sweden totally banned mercury fillings. In April 2008, Denmark banned mercury fillings Ingested Elemental Hg
  • 37. ORGANIC MERCURY • Ingestion is the main route of ingestion • Largest outbreaks are related to organic mercury (fungicide, seed dressing, contaminated fish) • Marine animals convert elemental to organic mercury in their tissues • Minamata (1940) Japan • Iraq (1974) • Toxicity is mainly neurologic • Visual field defects • Hearing loss • Tremor • Dysarthria • Mental deteriration
  • 38. ORGANIC MERCURY Minamata Disease (1940) Iraq Grain Disaster (1971)
  • 39. INORGANIC MERCURY • Main absorption by ingestion and skin • Can be corrosive to mucosal membranes • Poor lipid solubility: • causes a non-uniform distribution with kidney accumulation, causing renal damage. • Limit CNS penetration, but chronic exposure allow for CNS accumulation & toxicity.
  • 40. AUTISM & THIMEROSAL ??????????????? ??????????????
  • 41. TOTAL AMOUNT OF MERCURY (µG) RECEIVED BY LIBYAN CHILDREN FROM VACCINES IN FIRST 2 YEARS OF LIFE ACCORDING TO OLD AND NEW IMMUNIZATION SCHEDULES (2007) Vaccine LIBYA USA Old Schedule New Schedule 1999 2004 BCG Polio HB DTP Hib MMR 0 0 0 37.5 --- 0 0 0 0 37.5 75 ? 0 100 37.5 100 <1.2 < 1.5 0 Total 37.5 µg 112.5 µg ? 237.5 µg < 2.7 µg
  • 42. • Mercury reacts with sulfhydryl (SH) groups, resulting in enzyme inhibition and pathologic alteration of cellular membranes. • Elemental and methylmercury are particularly toxic to the CNS. Metallic mercury vapor is also a pulmonary irritant. • Methylmercury is teratogenic. • Inorganic mercuric salts are corrosive to the skin, eyes, and gastrointestinal tract, and are nephrotoxic. • An immune mechanism is attributed to membranous glomerulonephritis and acrodynia.
  • 43. CLINICAL FEATURES 1- Acute inhalation elemental mercury: • Dyspnea and pleuritic chest pain. • Lethargy, confusion. • Fatal ARDS has been reported following elemental mercury inhalation.
  • 44. 2- Acute ingestion of inorganic mercury & mercuric salts: Its corrosive properties account for most of the acute signs and symptoms. The presentation can include a) Gray mucous membranes. b) Vomiting, severe abdominal pain, hematemesis, and hypovolemic shock. c) Systemic effects usually begin several hours postingestion and may last several days
  • 45. 3- Acute ingestion of organic mercury (Methyl mercury): • Contaminated food. • Organic mercury targets specific sites in the brain, including the cerebral cortex (especially visual cortex), motor and sensory centers , auditory center, and cerebellum. • Onset of symptoms usually is delayed (days-weeks). Depletion of enzymes must occur before the onset of symptoms. • Symptoms are typically neurological: • visual (eg, scotomata), ataxia, paresthesias, hearing loss, dysarthria, mental deterioration, muscle tremor, movement disorders.
  • 46. 4- Chronic toxicity Triad: Tremors, Gingivitis, Erethism GIT: metallic taste, gingivostomatitis, hypersalivation. • Neurologic: Neurasthenia & Erethism. • Neurasthenia: impaired interpersonal relations, fatigue, depression, hypersensitivity to stimuli, loss of concentration. • Erethism: insomnia, shyness, memory loss, emotional instability, depression, anorexia, vasomotor disturbance, uncontrolled perspiration.
  • 47. Acrodynia (Pink disease): • considered to be a mercury allergy • erythema of the palms and soles • edema of the hands and feet • desquamating rash • hair loss • Pruritis • Diaphoresis • tachycardia, hypertension, • Photophobia • irritability • anorexia • Insomnia • poor muscle tone • constipation or diarrhea
  • 48. MERCURY WAS ADDITIVE FOR TEETHING POWDER UNTIL 1950
  • 49. • All forms are toxic to the fetus, but methylmercury most readily passes through the placenta. • Even with an asymptomatic patient, maternal exposure can lead to spontaneous abortion or retardation.
  • 50. Country No. of Subjects Mean level µg/L Level range µg/L References Belgium 474 15 1.1-103 Lauwerys et al. (1978) Italy 80 20 0-46 Pallotti et al. (1979) Japan 11 6.6 2 – 16.4 Suzuki et al. (1984 b) Norway 103 11.3 0.6 – 24 Lie et al. (1982) Poland 270 11.3 2.5-24 Szucki & Kurys (1982) USA 25 1709 3.4 1.02 0.82 0-7 0,85-1.2 Kuhnert et al. (1981) Schober et al. (2003) Jones et al. (2010) South Korea 293 8.63 1.48 – 45.71 Eun-mi Jo (2010) Canada 492 16 0.8 – 112 * Dewailly E et al. (2001) Sweden 106 3.4 0.4 – 16 Johansson N et al. (2002)
  • 51. 1- Blood levels less than 2 µg/L in unexposed individual (exceptions individuals with a high dietary intake of fish). 2- Urine mercury levels less than 10-20 µg/L. 3- Hg can be found in hair because high SH group • False-positive results secondary to environmental exposure. • Do not use hair analysis solely to confirm mercury toxicity.
  • 52. ABCs. Removal of contaminated clothing and skin irrigation Do not induce emesis if the compound ingested is caustic inorganic form. Gastric lavage is recommended for organic ingestion, especially if the compound is observed on the abdominal x-ray series. Whole bowel irrigation may be used until rectal effluent is clear and void of any radiopaque material. Use chelating agents if the patient is symptomatic or if increased blood or urine levels.
  • 53. 1. Metallic (elemental) mercury: In acute or chronic poisoning, • Oral DMSA may enhance urinary Hg excretion. • Penicillamine is an alternative oral treatment. 2. Inorganic mercury salts: • BAL if begun within minutes to a few hours after ingestion, may reduce severe renal injury. • Oral DMSA is also effective. 3. Organic mercury: • Oral DMSA may be effective in decreasing Hg in tissues, including brain.  BAL should not be used in metallic or organic mercury as it redistribute mercury to the brain from other tissue sites.  CaNa2EDTA is contraindicated. It makes with Hg a nephrotoxic complex.
  • 54. • Hemodialysis is used in severe cases of toxicity when renal function has declined. • Neostigmine may help motor function in methylmercury toxicity. This toxicity often leads to acetylcholine deficiency.
  • 55. POSTMORTEM APPEARANCE • Grayish corrosion of GIT • Ulceration of large intestine • Congestion of kidneys
  • 56. ARSENIC TOXICITY
  • 57. • Homicidal agent • Signs & symptoms mimic natural diseases • Ease of administration; odorless, tasteless • Foods: daily human intake of arsenic contained in food 0.5-1 mg, with the greatest mainly from fish • Water: A 2007 study found that over 137 million people in more than 70 countries are probably affected by arsenic poisoning from drinking water. WHO recommends a limit of 0.01 mg/L of arsenic in drinking water • Industry: herbicide, fungicide, wood preservative.
  • 58. FORMS OF ARSENIC • Arsenic exists in: 1- Inorganic (arsenite) 2- Organic (arsine) 3- Elemental form
  • 59. PATHOPHYSIOLOGY 1. Arsenic distributes rapidly to erythrocytes and binds to the globin portion of hemoglobin 2. Redistribution occurs within 24 hours to the liver, spleen, kidney & GIT 3. Arsenic impairs cellular respiration by inhibiting mitochondrial enzymes and oxidative phosphorylation 4. Blocks pyruvate dehydrogenase in Kreb’s cycle 5. Over a period of weeks, deposits may be found in skin, hair, nails, bone.
  • 60. Arsenic produces cellular damage by: • binding to enzyme SH groups. • Massive fluid transudation into the bowel. • Arsenic blocks the conversion of pyruvate to acetyl coenzyme A and inhibits gluconeogenesis. • Long-term exposure results in nerve damage and may lead to lung, skin, or liver cancer. • Once inhaled, arsine gas combines with hemoglobin severe hemolysis and anemia.
  • 61. CLINICAL MANIFESTATIONS OF ACUTE TOXICITY • GIT: nausea, vomiting, abdominal pain, and profuse watery or bloody diarrhea. • Rice-water or cholera-like stools • Garlic odor • CVS: myocardial depression, hypotension, shock. • Renal: acute tubular necrosis, hematuria,, within few hours dark urine may be seen. • Liver: Jaundice in 1-2 days • CNS: encephalopathy, toxic delirium. • Blood: anemia due to hemolysis and GIT hemorrhage.
  • 62. CHRONIC TOXICITY • Peripheral Neuropathy: it affects sensory part more than the motor one, often present with the complaint of painful paresthesias. • Black Foot Disease: peripheral vascular disease due to peripheral vascular obliteration appearing with acrocyanosis, Raynaud’s phenomenon. • Dermatologic Effects: alopecia, hypo- or hyperpigmentation, palmoplantar keratosis. • Mee’s lines: transverse white lines in the nails appear several weeks after mercury exposure.
  • 63. INVESTIGATIONS • Blood and urine arsenic levels • Normal blood arsenic level is < 7 µg/dl • Ideal urine test is 24-hour urine collection • Hair & Nails • Arsenic is normally found in higher concentrations in human hair and nails than in other parts of the body. This has been explained by the high content of keratin in these tissues .
  • 64. TREATMENT • BAL (British Antilewisite) •Lewisite is arsenic- containing vesicant gas • DMSA (Succimer)
  • 65. POSTMORTEM APPEARANCE 1. Pigmentation of skin 2. Mees lines in finger nails 3. Garlic odor of gastric contents 4. Subendocardial hemorrhage 5. Fatty degeneration of liver