Toxicity of Heavy Metals

1. HEAVY METALTOXICITY

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. LEAD TOXICITY

5. General Characters • 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.

6. Methods of Exposure 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

7. Lead as a colorant or to add weight to food Leaded turmeric Leaded kohl eye make-up NEWS headlines! Lead laced Marijuana producing sociopaths?

9. Pathophysiology • 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 (Ca2+ binding protein, which couples to several enzymes, eg, phosphodiesterase, protein kinases).

10. A-Hematological Effects

11. ENZYMES INVOLVED IN THE INHIBITION OF HEME SYNTHESIS

12. 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).

13. Basophilic Stippling Inhibition of 5-pyrimidine nucleotidase: aggregation of ribosomes, appearing as basophilic stippling of RBCs (not specific to lead toxicity)

15. B-Renal Effects • 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

16. C-Nervous Effects • 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)

17. D- Reproductive System Effects • Abortion, stillbirth, neurodevelopmentalproblems. • 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.

18. CLINICAL FEATURES 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.

19. 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

20. Gingival Lead Line

21. BONE LEAD LINE (bone growth arrest)

22. Wrist Drop (RADIAL NERVE)

23. Carcinogenicity • 2B. Agent is possibly carcinogenic to humans • Human epidemiology data weak • Animal data positive

24. !!!!!!!!!!!!!!!!!!!!!NOTE!!!!!!!!!!!!!!!!!! ABSENT (NOAEL) No Observable Adverse Effect Level

25. INVESTIGATIONS 1- 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

26. BLLs in Different European Countries (WHO)

27. Recommended Blood Lead Levels 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.

28. Centers of Disease Control & Prevention (USA) 2012 • 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

29. 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

30. TREATMENT

33. Postmortem Appearance • Depends on whether acute or chronic poisoning according to clinical manifestations

34. MERCURY TOXICITY

35. 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: • Elemental (metallic) mercury (Hg0) • Organic • Inorganic

36. 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.

37. 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, Haemophilusinfluenzae, and hepatitis B.

38. 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

39. Elemental Mercury In January 2008, Norway and Sweden totally banned mercury fillings. In April 2008, Denmark banned mercury fillings Ingested Elemental Hg

40. 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

41. Organic mercury Minamata Disease (1940) Iraq Grain Disaster (1971)

42. 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.

43. AUTISM & THIMEROSAL ?????????????????????????????

44. 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)

45. Mechanism of Toxicity • Mercury reacts with sulfhydryl (SH) groups, resulting in enzyme inhibition and pathologic alteration of cellular membranes. • Elemental and methylmercuryare 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.

46. CLINICAL FEATURES 1- Acute inhalation elemental mercury: • Dyspnea and pleuritic chest pain. • Lethargy, confusion. • Fatal ARDS has been reported following elemental mercury inhalation.

47. 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

48. 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.

49. 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.

50. 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