This document discusses heavy metals and their antagonists. It notes that heavy metals are naturally occurring elements that are at least 5 times denser than water. The metals of greatest environmental concern are lead, mercury, arsenic, and cadmium. Chelating agents can be used to treat heavy metal poisoning by binding to the metals and promoting their excretion. Common chelating agents include dimercaprol, penicillamine, DMSA, DMPS, and EDTA. Lead exposure remains a significant risk for children in the US and can cause neurological and behavioral issues that are sometimes misdiagnosed.

1. HEAVY METALS AND HEAVY METAL ANTAGONISTS www.freelivedoctor.com

2. INTRODUCTION Heavy metals are chemical elements that have a specific gravity (a measure of density) at least five times that of water. www.freelivedoctor.com

3. Metals - major fraction of Periodic Table generally interpreted to include those metals from periodic table groups IIA through VIA Heavy metals are natural constituents of the Earth's crust and are present in varying concentrations in all ecosystems Metals differ from other toxic substances in that they are neither created nor destroyed by humans. Therefore, they tend to accumulate in the soils, seawater, freshwater, and sediments. www.freelivedoctor.com

4. Metals are probably the oldest toxins known to humans. Lead usage may have begun prior to 2000 BC in the smelting of silver. Arsenic was obtained during the melting of copper and tin, and an early use was for decoration in Egyptian tombs/ www.freelivedoctor.com

5. The environmental metals of greatest concern are lead, mercury, arsenic, and cadmium.. www.freelivedoctor.com

6. In the past lead paint was available for use in homes, and lead pipes and/or lead solder. As a result people can be exposed to lead on a daily basis; this exposure is a major pediatric concern www.freelivedoctor.com

7. Mercury is a contaminant of our water ways. Humans are exposed to mercury in the fish they eat as well as in the amalgam fillings in their teeth. Arsenic is found naturally in high concentration in drinking water in various parts of the world. Cadmium has been classified as a known human carcinogen. www.freelivedoctor.com

8. CHEMICAL AND PHYSICAL PROPERTIES CHEMICAL AND PHYSICAL PROPERTIES 1. Physical states - solids, liquids, gases aerosols 2. Elements - indestructible 3. Electrophyllic cations - react with ligands reversible complexes molecular mimicry 4. Oxidation States affects toxicity 5. Organometallic compounds differ from inorganic 6. Essential versus non-essential www.freelivedoctor.com

9. Heavy metals (HM) exert their toxic effects by combining with one or more reactive groups (ligands) essential for normal physiological functions. Heavy metal antagonists (HMA) - chelating agents are designed specifically to compete with these groups for the metals, and thereby prevent or reverse toxic effects and enhance excretion of metals. www.freelivedoctor.com

10. Nearly all organ systems are involved in heavy metal toxicity; however, the most commonly involved organ systems include the CNS, PNS, GI, hematopoietic, renal, and cardiovascular (CV). To a lesser extent, lead toxicity involves the musculoskeletal and reproductive systems. The organ systems affected and the severity of the toxicity vary with the particular heavy metal involved, the age of the individual, and the level of toxicity. www.freelivedoctor.com

11. c helation Treatment of Metal Poisoning Chelaters (Greek = claw) bind directly with metal ions to form stable complexes that remove the metal from competition with the body's cells. Because a chelated metal is water soluble, it can be excreted readily by the kidney. www.freelivedoctor.com

12. By definition, Chelation is the formation of a metal ion complex in which the metal ion is associated with a charged or uncharged electron donor, referred to as a ligand. A chelate is a cyclic complex formed between a metal and a compound that contains two or more ligands (binding sites). The most stable chelates are those with a five or six membered ring. www.freelivedoctor.com

13. Ideal chelating agents Water soluble Resistant to biotransformation Able to reach sites of metal storage Capable of forming nontoxic complexes with toxic metals Be excreted from the body Have a low affinity for essential metals www.freelivedoctor.com

14. Chelating Agents An agent frequently used in chelation therapy is dimercaprol (also known as BAL or British Anti-Lewisite). Oral chelating agents used as alternatives to BAL are 2,3-demercaptosuccinic acid (DMSA), dimercaptopropanesulfonate (DMPS), D-penicillamine Deferoxamine, is often used to chelate iron. Ethylenediamintetraacetic acid (ETDA) also has an affinity for lead and was one of the first chelators developed. www.freelivedoctor.com

15. Dimercaprol - BAL (British Antilewisite) BAL clinically useful for treating acute and chronic poisoning by organic or inorganic arsenals and for protecting against mercury-induced renal damage. Not effective in treating mercury-induced neurological conditions or CNS damage. Not useful to chelate cadmium because it can partially dissociate in urine and enhance renal damage. Also true for iron and selenium. www.freelivedoctor.com

16. Must be given parentally. BAL blood concentration are best achieved and maintained by giving repeated doses within the first 4 hours after poisoning. Excessive large doses should be avoided because of possible side effects. Dosage of BAL is designed to assure the formation of a 2:1 complex (2 molecules of BAL: 1 molecule of metal). Contraindications to using BAL are preexisting kidney disease, pregnancy, hypertension, and current use of medicinal iron. www.freelivedoctor.com

17. Adverse effects Tachycardia, hypertension, anxiety, nausea, vomiting, abdominal pain, headache, agitation, salivation, lacrymation, Dental and muscle pains Pain at the site of injection. Burning sensation of the lips, mouth, throat and eyes, conjunctivitis,rhinorrhoea, tingling of the hands and other extremities, a feeling of constriction in the chest and throat, sweating of the forehead and hands. www.freelivedoctor.com

18. Calcium Disodium Edetate – CaNa2 - EDTA will chelate any metal that has a higher binding affinity than Ca (lead, iron, zinc, manganese, beryllium and copper) CaNa2EDTA does not enter host cells but relies on excretion of lead into blood from bone. Lead chelates with EDTA to form a complex that is much greater than that of the Ca complex. Toxicity to EDTA partly restricts its usage. After IV administration, severe proximal nephron degeneration may occur. Other symptoms include fever, nasal congestion, and dermatitis. www.freelivedoctor.com

19. Penicillamine Penicillamine is formed from hydrolysis of penicillin. It forms tight chelates with copper, lead, mercury, and zinc. An advantage of this chelator is that it is well absorbed from the GI tract after oral administration. Penicillamine is often given for long-term treatment of chronic metal poisoning, after the patient has been removed from immediate danger. (i.e. CaNa2EDTA - lead; BAL - mercury). * Pen is not universally recognized as the first-choice antidote. www.freelivedoctor.com

20. Added advantage of pen is that it facilitates removal of methyl mercury and enhances urinary mercury excretion after inhalation of mercury vapor. Pen may cause acute allergy-like reactions, particularly in individuals who are allergic to penicillin; must be carefully given to those individuals. www.freelivedoctor.com

21. Succimer, Dimercaptosiccinic acid (DMSA) Succimer is chemically similar to dimercaprol (BAL) but is more water soluble, has a high therapeutic index, and is absorbed well from the GI tract. (It is given orally). It produces a lead diuresis comparable to that of CaNa2-EDTA and reverses the biochemical toxicity of lead, as indicated by normalization of circulatory delta-aminolevulinic acid dehydratase (an enzyme necessary for heme synthesis). The most common adverse effects include nausea, vomiting, diarrhea and anorexia. www.freelivedoctor.com

22. Deferoxamine Deferoxamine possesses high affinity for both ferrous and ferric iron; especially in acute iron poisoning in small children. It is also used to chelate aluminum. It is given parenterally(IV), since less than 15% is absorbed from the GI tract www.freelivedoctor.com

23. Adverse effects Common side effects are blurred vision, wheezing, rapid heartbeat, seizures, itching, skin rash, bluish skin, and redness and pain at the injection site. Gastrointestinal discomfort, fever, cramping, and bruising are less common. Contraindications are allergies to certain foods or dyes, other medicines currently being taken, pregnancy or breast feeding, and kidney disease Toxicity - includes allergy reactions related to histamine release. Pain at the site of injection, rash, itching, anaphylactic reactions, hypotension, tachycardia. www.freelivedoctor.com

24. The following table summarizes chelating agents, the heavy metals they are used to treat, their route of administration, and their brand name . www.freelivedoctor.com Chelating Agent Toxin Route** Drug Dimercaprol (BAL) Arsenic Lead Mercury (inorganic)* i.m. Dimercaptol Injection B.P. BAL in Oil Dimercaptosiccinic acid (DMSA, Succimer ) Arsenic Lead Mercury p.o. Chemet Dimercaptopropane- sulfonate (DMPS) Arsenic p.o. i.m. Bulk form (for compounding by pharmacists) D-pencillamine Arsenic Mercury Lead p.o. Metalcaptase Pencillamine Cuprimine Depen Ethylenediamintetra- acetic acid (EDTA) (Edetate disodium) Lead IV Chealamide Versenate *Not methylmercury poisoning. **Under supervision of a physician: i.m., intramuscular; p.o., peroral or by mouth; IV, intravenous. Source: Data from Beers et al. 1999; Micromedex 1999; Roberts 1999; Wentz 2000; Anon. 2001; Ferner 2001; Marcus 2001; USNML/NIH Drug Information 2001a; 2001b; 2001c; 2001d.

25. An estimated 1.7 million children are currently affected by lead toxicity in United States, and almost 900,000 of all children affected are under the age of six. This statistic is very important because the symptoms of lead poisoning in children are strikingly similar to several psychiatric "diseases" that are on the rise in the U.S. Children with high lead levels can exhibit lower IQ scores, learning disabilities, hyperactivity , aggressive or disruptive behavior, and difficulty maintaining attention. A child exhibiting this type of behavior today would likely be sent to a doctor's office, diagnosed with attention deficit disorder, and promptly started on Ritalin or other psychoactive drugs. Needleman HL ,1990 Lead levels and Hyperactivity Lead Toxicity CDC guidelines www.freelivedoctor.com

26. Sources of Lead - environmental 1. Combustion of tetramethyl in gasoline 2. Persistent lead-based paint (children with Pica) 3. Improperly glazed earthenware 4. Lead piping (acid rain) 5. Solder in food containers 6. Moonshine whiskey 7. Automobile battery casing www.freelivedoctor.com

27. Occupational 1. Smelters (air concentration may exceed 1000g/m3) 2. Storage battery manufacture (50% total U.S. consumption) 3. Welding and cutting lead-painted structures 4. Automobile radiator repair 5. Production of lead-based paints (6% total U.S. consumption) 6. Frequent use of firearms www.freelivedoctor.com

28. LEAD Distribution www.freelivedoctor.com

29. Absorption Gastrointestinal Tract 8% absorbed (adult) 50% absorbed (children) Ca++, Fe++ decrease absorption Respiratory Tract - Particle size Chemical form Skin - Does occur at high exposures www.freelivedoctor.com

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34. Treatment Chelation therapy with DMSA(succimer) for children with blood lead levels of greater than 45 mcg/dL was approved in 1991 by the FDA. A major advantage of DMSA is that it can be given orally, which leads to better compliance by the patient. DMSA is relatively safe and significantly reduces blood levels of iron (Fournier et al. 1988). BAL, D-penicillamine, and EDTA are also used (Wentz 2000). Whole bowel irrigation is used if x-rays indicate the presence of lead (Ferner 2001). Follow-up blood testing is required because stored lead in bones may continue to release from the bones when the lead exposure has been long-term www.freelivedoctor.com

35. Mercury Throughout the centuries, several incidents of mercury toxicity have been reported. Mercury has been found in Egyptian tombs, indicating it was used as early as 1500 BC. In the late 18th century, antisyphilitic agents contained mercury. It was during the 1800s that the phrase "mad as a hatter" was coined because of the chronic mercury exposure that the felters faced because mercury was used in hat making. www.freelivedoctor.com

36. Mercury MAJOR PHYSICAL AND CHEMICAL FORMS OF MERCURY INORGANIC Hg, Hg2++ Hg++ Metallic Mercurous Mercuric ORGANIC C6H5Hg+, CH3Hg+, Phenyl Mercuric Methyl Mercuric www.freelivedoctor.com

37. Human Exposure Mercury Vapor Environmental - unimportant Occupational - main source Electrical equipment, paints, thermometers, laboratory Dental Amalgam fillings - main source of background exposure www.freelivedoctor.com

38. ORGANIC 1. Methylmercury important a. Environmental - main source is fish Biomethylation - Hg (all forms) --> Hg++ --> CH3Hg and CH3HgCH3 Bioaccumulation in aquatic food chains b. Industrial, agricultural * By-product of plastic industry * Fungicide in seed grain (also ethylHg) * Misuse of treated grain (developing countries) www.freelivedoctor.com

39. Signs and Symptoms of Poisoning Acute Mercury Poisoning Local Effects Oral ingestion (chiefly inorganic salts) gastrointestinal: pain, vomiting, diarrhea, hemorrhage Inhalation: Pneumonitis, metal fume fever (HgO) Systemic Effects Shock Kidney (inorganic salts) CNS: lethargy, (shock related effects) Metallic taste, sore gums, salivation www.freelivedoctor.com

40. Diagnosis Mercury vapor symptoms history of exposure urine Hg concentration-normal less than 20 mg/l, Tremors > 500 mg/l Methylmercury neurological signs and symptoms early diagnosis difficult dietary history blood normal less than 20 mg/l, symptoms 200 mg/l hair normal about 1 mg/g (adult) symptoms 50 mg/g (adult) Inorganic salts signs and symptoms history elevated urine concentration www.freelivedoctor.com

41. Methylmercury Methylmercury has a high affinity for sulfhydryl groups, which attributes to its effect on enzyme dysfunction. One enzyme that is inhibited is choline acetyl transferase, which is involved in the final step of acetylcholine production. This inhibition may lead to acetylcholine deficiency, contributing to the signs and symptoms of motor dysfunction. www.freelivedoctor.com

42. ‘ The Mad Hatter’ The chemicals used in hat-making included mercurous nitrate, used in curing felt. Prolonged exposure to the mercury vapors caused mercury poisoning. Victims developed severe and uncontrollable muscular tremors and twitching limbs, called "hatter's shakes"; other symptoms included distorted vision and confused speech. Advanced cases developed hallucinations and other psychotic symptoms. www.freelivedoctor.com

43. Therapy Dimercaprol (British Anti-Lewisite, 2,3dimercaptopropanol) BAL is widely used for inorganic mercury; effective for protection of kidney (Hg++) ineffective from protection of brain (CH3Hg+) cannot be given orally, side effects Pencillamine given orally effective for Hg, less so for CH3Hg+ some side effects Dimercaptosuccinic acid (DMSA) given orally probably effective for CH3Hg+, Hg, Hg++ low toxicity Polythiol resion (experimental) CH3Hg+ only www.freelivedoctor.com

44. Cadmium Cadmium is a natural element in the earth's crust. It is usually found as a mineral combined with other elements such as oxygen (cadmium oxide), chlorine (cadmium chloride), or sulfur (cadmium sulfate, cadmium sulfide). All soils and rocks, including coal and mineral fertilizers, contain some cadmium. Most cadmium used in the United States is extracted during the production of other metals like zinc, lead, and copper. Cadmium does not corrode easily and has many uses, including batteries, pigments, metal coatings, and plastics. www.freelivedoctor.com

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46. Cadmium Cadmium accumulates especially in the kidneys leading to dysfunction of the kidney with increased secretion of e.g. proteins in urine (proteinuri) and other effects. The proximal renal tubular dysfunction creates low phosphate levels in the blood hypophosphatemia , causing muscle weaknesses and coma. The dysfunction also causes Gout , a form of arthritis due to the accumulation of sodium urate crystals in the joints because of high blood levels of uric acid ( hyperuricemia ). Another side effect are increased levels of chloride in the blood ( hyperchloremia ). The kidneys can also shrink up to 30%. The liver will also be affected by cadmium poisoning. Cadmium health effects www.freelivedoctor.com

47. Long-term exposure to cadmium at levels around 0.1 milligrams per cubic meter of air may cause kidney stones and lung damage, and have been linked to lung cancer and high blood pressure. Short-term exposure at ten times that level may irritate the lungs. Our everyday diet, however, only gives one-tenth the amount that could possibly affect long-term health, but if you eat large amounts of shellfish, liver and kidneys, or if you smoke, you may consume more cadmium than you should. www.freelivedoctor.com

48. The EPA has set a limit of 5 parts of cadmium per billion parts of drinking water (5 ppb). EPA doesn't allow cadmium in pesticides. The Food and Drug Administration (FDA) limits the amount of cadmium in food colors to 15 parts per million (15 ppm). The Occupational Safety and Health Administration (OSHA) limits workplace air to 100 micrograms cadmium per cubic meter (100 µg/m³) as cadmium fumes and 200 µg cadmium/m³ as cadmium dust. www.freelivedoctor.com

49. Cancer Risk: Several occupational studies have reported an excess risk of lung cancer in humans from exposure to inhaled cadmium. However, the evidence is limited rather than conclusive due to confounding factors. Animal studies have reported cancer resulting from inhalation exposure to several forms of cadmium, while animal ingestion studies have not demonstrated cancer resulting from exposure to cadmium compounds. EPA considers cadmium to be a probable human carcinogen (cancer-causing agent) and has classified it as a Group B1 carcinogen www.freelivedoctor.com

50. itai-itai disease The itai-itai disease (Japanese: イタイイタイ病 , literally: ouch-ouch-disease) From 1939 to 1954, some two hundred people near Fuchu, Japan suffered from a condition termed 'Itai-itai' There are a number of symptoms associated with cadmium poisoning. The two main organs affected are the bones and the kidneys. The bones get soft ( osteomalacia ) and lose bone mass and become weaker ( Osteoporosis ). This causes the pain in the joints and the back, and also increases the risk of fractures. In extreme cases of cadmium poisoning the body weight alone might cause a fracture. The second affected organ is the kidney, which loses its function to remove acids from the blood, a so called proximal renal tubular dysfunction . The kidney damage due to cadmium poisoning is irreversible and does not heal over time, and the victims of the itai-itai disease still have this disorder. www.freelivedoctor.com

51. Treatment At present, there is no effective treatment for cadmium intoxication, and patients are given supportive treatment according to their symptoms. However, it is thought that some of new chelating agents may be effective www.freelivedoctor.com