1. Toxicology of Heavy Metals

2. Toxicology Of Heavy Metals:
1-General Concepts.
2-Arsenic
3-Lead.
4-Mercury.
5-Chelating Therapy.

3. General Concepts:
-Metals are neither Created nor Destroyed by the human body.
-They are the oldest toxins known to humans.
-Hippocrates 370 B.C. described abdominal colic as a symptom of lead poisoning.

4. Bioconcentration in plant and animals play important role, thus entering the food cycle.
Human industrial activity is important e.g. lead was added to gasoline in 1920s.

5. Biomarkers of heavy metal poisoning:
-Blood level (Concentration).
-Urine level.
-Hair Concentration is useful.
Other markers e.g. DNA–protein complexes

6. Complexation and chelation therapy is specific treatment
Complexation and chelation therapy is specific treatment. 1- BAL (British anti-lewisite). 2-DMSA. 3-DMPS. 4-EDTA. 5-DTPA. 6-Desferrioxamine. 7-Penicillamine.

7. Arsenic poisoning:
-Is a medical condition caused by elevated levels of arsenic in the body.
-The dominant basis of arsenic poisoning is from ground water that naturally contains high concentrations of arsenic.
In one study it was found that over 137 million people in more than 70 countries are probably affected by arsenic poisoning from drinking water.

8. -Symptoms of arsenic poisoning begin with headaches, confusion, severe diarrhea, and drowsiness. -As the poisoning develops, convulsions and death could result. -The organs of the body that are usually affected by arsenic poisoning are the lungs, skin, kidneys, and liver. -The final result of arsenic poisoning is coma to death.

9. -The Acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200 mg or 1 mg/kg/day -World Health Organization recommends a limit of 0.01 mg/L (10ppb) of arsenic in drinking water.

10. Arsenic became a favorite murder weapon of the Middle Ages and Renaissance. Because the symptoms are similar to those of cholera, which was common at the time, arsenic poisoning often went undetected!

11. Pathophysiology:
Arsenic interferes with cellular function by inhibition of an essential metabolic enzyme:
Pyruvate Dehydrogenase (PDH) complex, which catalyzes the oxidation of pyruvate to acetyl-CoA.
With the enzyme inhibited, the energy system of the cell is disrupted resulting in a cellular apoptosis.

12. Diagnosis:
Arsenic may be measured in blood or urine to monitor excessive environmental or occupational exposure, confirm a diagnosis of poisoning in hospitalized victims or to assist in the forensic investigation in a case of fatal over dosage.

13. Treatment: -Chelation:
Dimercaprol and Dimercaptosuccinic acid (DMSA) are chelating agents which sequester the arsenic away from blood proteins and are used in treating acute arsenic poisoning.
The most important side effect is hypertension.

14. 2-Lead poisoning:
(also known as Plumbism, or Painter's colic) is a medical condition caused by increased levels of the heavy metal lead in the body.

15. Lead interferes with a variety of body processes and is toxic to many organs and tissues including the heart, bones, intestines, kidneys, and reproductive and nervous systems. It interferes with the development of the nervous system and is therefore particularly toxic to children, causing potentially permanent learning and behavior disorders. Symptoms include abdominal pain, confusion, headache, anemia, irritability, and in severe cases seizures, coma, and death.

16. Routes of exposure to lead include contaminated air, water, soil, food, and consumer products. Occupational exposure is a common cause of lead poisoning in adults.

17. -Elevated lead in the body can be detected by the presence of changes in blood cells visible with a microscope and dense lines in the bones of children seen on X-ray. -However, the main tool for diagnosis is measurement of the blood lead level or a urine test. -When blood lead levels are recorded, the results indicate how much lead is circulating within the blood stream, not the amount being stored in the body!

18. (Basophilic stippling)
(Lead Line in the Gum)
(Basophilic stippling)

19. The Centers for Disease Control has set the standard elevated blood lead level for adults to be 25 (µg/dl) of the whole blood. For children however, the number is set much lower at 5 (µg/dl)

20. Children are especially prone to the health effects of lead and as a result, blood lead levels must be set lower and closely monitored if contamination is possible. The major treatments are removal of the source of lead and chelation therapy = (administration of agents that bind lead so it can be excreted).

21. Signs and symptoms:
Lead poisoning can cause a variety of symptoms and signs which vary depending on the individual and the duration of lead exposure.
Symptoms are nonspecific and may be subtle, and someone with elevated lead levels may have no symptoms.

22. Symptoms from exposure to organic lead, which is probably more toxic than inorganic lead due to its lipid solubility, occur rapidly. Poisoning by Organic lead compounds has symptoms predominantly in the central nervous system, such as insomnia, delirium, cognitive deficits, tremor, hallucinations, and convulsions.

23. The main symptoms in adults are headache, abdominal pain, memory loss, kidney failure, reproductive problems, pain, or tingling in the extremities.

24. In adults, symptoms can occur at levels above 40 μg/dL, but are more likely to occur only above 50–60 μg/dL. Symptoms begin to appear in children generally at around 60 μg/dL.

25. Signs that occur in adults at blood lead levels exceeding 100 μg/dL include wrist drop and foot drop, and signs of encephalopathy, delirium, coma, seizures, and headache. For both adults and children, it is rare to be asymptomatic if blood lead levels exceed 100 μg/dL

26. Acute poisoning:
In acute poisoning, typical neurological signs are pain, muscle weakness, paraesthesia, and, rarely, symptoms associated with encephalitis.
Gastrointestinal problems, such as constipation, diarrhea, poor appetite, or weight loss, are common in acute poisoning.

27. Chronic poisoning:
Chronic poisoning usually presents with symptoms affecting multiple systems, but is associated with three main types of symptoms:
1-gastrointestinal, 2-neuromuscular, and 3-neurological.
Features of chronic exposure include loss of short-term memory or concentration, depression, nausea, abdominal pain, loss of coordination, and numbness and tingling in the extremities.

28. A blue line along the gum is another indication of chronic lead poisoning.
Children with chronic poisoning may refuse to play or may have hyperkinetic or aggressive behavior disorders.

29. Enzymes:
The primary cause of lead's toxicity is its interference with a variety of enzymes because it binds to sulfhydryl groups found on many enzymes.
Part of lead's toxicity results from its ability to mimic other metals that take part in biological processes, which act as cofactors in many enzymatic reactions, displacing them at the enzymes on which they act.

30. Peripheral nervous system effects are more prominent in adults and central nervous system effects are more prominent in children.

31. Lead exposure in young children has been linked to learning disabilities. Increased blood lead level in children has been correlated with decreases in intelligence.

32. Diagnosis:
Diagnosis includes determining the clinical signs and the medical history, with inquiry into possible routes of exposure.
The main tool in diagnosing and assessing the severity of lead poisoning is laboratory analysis of the blood lead level (BLL).

33. Lead in bones can be measured by X-ray fluorescence; this may be the best measure of cumulative exposure and total body burden.

34. (Lead Poisoning in a Child)

35. kits are commercially available for detecting lead
kits are commercially available for detecting lead. These swabs, when wiped on a surface, turn red in the presence of lead.

36. The mainstays of treatment are:
1- Removal from the source of lead and, for people who have significantly high blood lead levels.
2-Chelation therapy.

37. Blood lead level (μg/dL): -10–14 Education, repeat screening
Blood lead level (μg/dL): -10–14 Education, repeat screening. -15–19 Repeat screening. -20–44 Medical evaluation. -45–69 Medical evaluation, Chelation. >69 Hospitalization, immediate Chelation.

38. Prognosis:
Effects of lead on the physiology of the kidneys and blood are generally reversible; its effects on the central nervous system are not.
While peripheral effects in adults often go away when lead exposure ceases, evidence suggests that most of lead's effects on a child's central nervous system are irreversible.

39. Lead encephalopathy:
Is a medical emergency and causes permanent brain damage in 70–80% of patients ….

40. Mercury poisoning:
Is a disease caused by exposure to mercury or its compounds.
Its zero oxidation state Hg0 exists as vapor or as liquid metal,
its mercurous state Hg21+ exists as inorganic salts,
and its mercuric state Hg2+ may form either inorganic salts or organomercury compounds

41. Signs and symptoms:
Common symptoms of mercury poisoning include peripheral neuropathy (presenting as paresthesia or itching, burning or pain), swelling, and desquamation (shedding of skin).
Mercury irreversibly inhibits selenium-dependent enzymes and may also inactivate S-adenosyl-methionine, which is necessary for catecholamine catabolism by catechol-o- methyl transferase.

42. Due to the body's inability to degrade catecholamines (e. g
Due to the body's inability to degrade catecholamines (e.g. epinephrine), a person suffering from mercury poisoning may experience:
1- Profuse sweating.
2-Tachycardia.
3-Salivation.
4-Hypertension.

43. Causes:
The consumption of Fish is by far the most significant source of ingestion-related mercury exposure.
Although plants and livestock also contain mercury due to bioaccumulation of mercury from soil, water and atmosphere.

44. (Mercury in Food Chain)

45. Mechanism:
Mercury is highly reactive with selenium, an essential dietary element required by about 25 genetically distinct enzyme types (selenoenzymes).
Among their numerous functions, Selenoenzymes prevent and reverse oxidative damage in the brain and endocrine organs.

46. Elemental mercury:
liquid metallic mercury is poorly absorbed by ingestion and skin contact. less than 0.01% of ingested mercury is absorbed through the intact gastrointestinal tract.
Cases of systemic toxicity from accidental swallowing are rare.
Some mercury vapor is absorbed dermally, but uptake by this route is only about 1% of that by inhalation.

47. Approximately 80% of inhaled mercury vapor is absorbed via the respiratory tract, where it enters the circulatory system and is distributed throughout the body.
Chronic exposure by inhalation, even at low concentrations has been shown to cause effects such as tremors, impaired cognitive skills, and sleep disturbance in workers.

48. The most prominent symptoms include:
Tremors
emotional lability
insomnia
memory loss,
Neuromuscular changes (weakness, muscle atrophy, muscle twitching)

49. Methylmercury: “Mercury in fish”
Methylmercury is the major source of organic mercury , it works its way up the food chain through bioaccumulation in the environment.
Larger species of fish, such as tuna or swordfish, are usually of greater concern than smaller species.

50. Diagnosis:
Diagnosis of elemental or inorganic mercury poisoning involves determining the history of exposure, physical findings, and an elevated body burden of mercury.
Chelation therapy can cause a transient elevation of urine mercury levels

51. Prevention:
Mercury poisoning can be prevented (or minimized) by eliminating or reducing exposure to mercury and mercury compounds.

52. Treatment:
Identifying and removing the source of the mercury is crucial.
Decontamination requires removal of clothes, washing skin with soap and water, and flushing the eyes with saline solution as needed.
Immediate chelation therapy is the standard of care for a patient showing symptoms of severe mercury poisoning or the laboratory evidence of a large total mercury load.

53. History:
Widespread mercury poisoning occurred in rural Iraq in , when grain treated with a methylmercury- based fungicide that was intended for planting only was used by the rural population to make bread, causing at least 6530 cases of mercury poisoning and at least 459 deaths.

54. Dental amalgam:
Dental amalgam, an alloy of about 50 percent elemental mercury, was first introduced in France.
Chosen for its cost-effective durability, this amalgam is a source of low-level exposure to mercury vapour, and an enormous amount of controversy.
Although the vast majority of patients with amalgam fillings are exposed to levels believed to be too low to pose any risk to health, many patients exhibit urine test results that are comparable to those at the maximum allowable legal limits for workplace (occupational) safety.

55. (Dental Amalgam)

56. (Dental Amalgam)

57. Cosmetics: The use of mercury in cosmetics is illegal.
Some skin whitening products contain the toxic chemical mercury chloride.
The use of mercury in cosmetics is illegal.
However, cosmetics containing mercury are often illegally imported.

58. Fluorescent lamps:
Fluorescent lamps contain mercury released when bulbs are broken.
Mercury in bulbs is typically present as either elemental mercury liquid, vapor, or both, since the liquid evaporates at ambient temperature.
When broken indoors, evacuating and airing out a room for at least 15 minutes.

61. Chelation therapy:
Chelation therapy is the administration of chelating agents to remove heavy metals from the body.
DMSA dimercaptosuccinic acid has been recommended for the treatment of lead poisoning in children by Poison Centers around the world.

64. Dimercaprol (INN) or British anti-Lewisite (abbreviated BAL), is a compound developed by British biochemists during World War II. It was developed secretly as an antidote for lewisite, the now-obsolete arsenic-based chemical warfare agent. Today, it is used in treatment of arsenic, mercury, and lead, poisoning. In addition, it has in the past been used for the treatment of Wilson's disease, a genetic disorder in which the body tends to retain copper.

65. Dimercaprol competes with the thiol groups for binding the metal ion, which is then excreted in the urine.
Dimercaprol is itself toxic, with a narrow therapeutic range and a tendency to concentrate arsenic in some organs.
Other drawbacks include the need to administer it by painful intramuscular injection.
Serious side effects include nephrotoxicity and hypertension.

66. =Chemet = Succimer Dimercaptosuccinic acid (DMSA):
This colorless solid contains two carboxylic acid and two thiol groups, the latter being responsible for its mildly unpleasant odor.

67. Clinical Use:
Dimercaptosuccinic acid (CHEMET) is indicated for the treatment of poisoning with lead and mercury.
Its elimination half-life is h.
Another application for DMSA is for provocation of tissue heavy metals in anticipation of a urine test.
This is sometimes called a "challenge“ heavy metals test.

68. DMSA should be taken under the supervision of a physician trained in chelation therapy.
Recommended Dosage: 1 capsule up to three times every other day on an empty stomach.
 Cautions: Not for use by pregnant or nursing women or by children, unless under supervision.