heavy metals& antagonists

HEAVY METALS AND HEAVY METAL ANTAGONISTS

wwwfreelivedoctorcom

INTRODUCTION Heavy metals are chemical

elements that have a specific gravity (a measure of density) at least five times that of water


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 Earths 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


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


The environmental metals of greatest concern are lead mercury arsenic and cadmium


In the past lead paint was available for use in homes and lead pipes andor lead solder As a result people can be exposed to lead on a daily basis this exposure is a major pediatric concern


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


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


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


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


chelation Treatment of Metal Poisoning Chelaters (Greek = claw) bind directly with

metal ions to form stable complexes that remove the metal from competition with the bodys cells

Because a chelated metal is water soluble it can be excreted readily by the kidney


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


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


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 23-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


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


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 21 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


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

conjunctivitisrhinorrhoea tingling of the hands and other extremities a feeling of constriction in the chest and throat sweating of the forehead and hands


Calcium Disodium Edetate ndash 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


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 (ie CaNa2EDTA - lead BAL - mercury) Pen is not universally recognized as the first-choice antidote


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


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


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


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


The following table summarizes chelating agents the heavy metals they are used to treat their route of administration and their brand name

Chelating Agent

Toxin Route Drug

Dimercaprol (BAL)ArsenicLeadMercury (inorganic)

imDimercaptolInjection BPBAL in Oil

Dimercaptosiccinic acid (DMSA Succimer)

ArsenicLeadMercury

po Chemet

Dimercaptopropane- sulfonate (DMPS) Arsenic po

im

Bulk form(for compounding by pharmacists)

D-pencillamineArsenicMercuryLead

po

MetalcaptasePencillamineCuprimineDepen

Ethylenediamintetra- acetic acid (EDTA) (Edetate disodium)

Lead IV Chealamide Versenate

Not methylmercury poisoning Under supervision of a physician im intramuscular po 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 USNMLNIH Drug Information 2001a 2001b 2001c 2001d


An estimated 17 million children are currently affected by lead toxicity in United States and almost 900000 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 US 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 doctors 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 guidelineswwwfreelivedoctorcom

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


Occupational 1 Smelters (air concentration may exceed

1000gm3) 2 Storage battery manufacture (50 total

US consumption) 3 Welding and cutting lead-painted

structures 4 Automobile radiator repair 5 Production of lead-based paints (6 total

US consumption) 6 Frequent use of firearms


LEAD Distribution


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






Treatment Chelation therapy with DMSA(succimer) for

children with blood lead levels of greater than 45 mcgdL 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


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


MercuryMAJOR PHYSICAL AND CHEMICAL FORMS OF

MERCURY INORGANIC

Hg Hg2++ Hg++ Metallic Mercurous Mercuric

ORGANIC C6H5Hg+ CH3Hg+ Phenyl Mercuric Methyl Mercuric


Human Exposure Mercury Vapor

Environmental - unimportant Occupational - main source

Electrical equipment paints thermometers laboratory

Dental Amalgam fillings - main source of

background exposure


ORGANIC

1 Methylmercury important a Environmental - main source is fish Biomethylation - Hg (all forms) --gt Hg++ --gt

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)wwwfreelivedoctorcom

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


DiagnosisMercury vapor symptoms history of exposure urine Hg concentration-normal

less than 20 mgl Tremors gt 500 mgl Methylmercury neurological signs and symptoms early diagnosis difficult dietary history blood normal less than 20 mgl symptoms 200

mgl hair normal about 1 mgg (adult) symptoms 50 mgg (adult) Inorganic salts signs and symptoms history elevated urine concentration


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


lsquoThe Mad Hatterrsquo 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 hatters shakes other symptoms included distorted vision and confused speech Advanced cases developed hallucinations and other psychotic symptoms


Therapy Dimercaprol (British Anti-Lewisite 23dimercaptopropanol) 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 effectsDimercaptosuccinic acid (DMSA) given orally probably effective for CH3Hg+ Hg Hg++ low toxicity Polythiol resion (experimental) CH3Hg+ only


Cadmium Cadmium is a natural element in the earths

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



Cadmium Cadmium accumulates especially in the kidneys leading

to dysfunction of the kidney with increased secretion of eg 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


Long-term exposure to cadmium at levels around 01 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


The EPA has set a limit of 5 parts of cadmium per billion parts of drinking water (5 ppb) EPA doesnt 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 microgmsup3) as cadmium fumes and 200 microg cadmiummsup3 as cadmium dust


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


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


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



INTRODUCTION

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chelation Treatment of Metal Poisoning

Slide 12

Ideal chelating agents

Chelating Agents


Slide 16

Adverse effects


Penicillamine

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Deferoxamine

Slide 23

Slide 24

Slide 25

Sources of Lead - environmental

Occupational

Slide 28

Absorption

Slide 30

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Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury

lsquoThe Mad Hatterrsquo

Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment

INTRODUCTION Heavy metals are chemical

elements that have a specific gravity (a measure of density) at least five times that of water














































































Chelating Agent

Toxin Route Drug




ArsenicLeadMercury

po Chemet


im



po








Needleman HL 1990


Lead Toxicity











LEAD Distribution




















MERCURY INORGANIC








background exposure


ORGANIC





















































Treatment




INTRODUCTION

Slide 3

Slide 4

Slide 5

Slide 6

Slide 7


Slide 9

Slide 10


Slide 12


Chelating Agents


Slide 16

Adverse effects


Penicillamine

Slide 20


Deferoxamine

Slide 23

Slide 24

Slide 25


Occupational

Slide 28

Absorption

Slide 30

Slide 31

Slide 32

Slide 33

Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury


Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment













































































Chelating Agent

Toxin Route Drug




ArsenicLeadMercury

po Chemet


im



po








Needleman HL 1990


Lead Toxicity











LEAD Distribution




















MERCURY INORGANIC








background exposure


ORGANIC





















































Treatment




INTRODUCTION

Slide 3

Slide 4

Slide 5

Slide 6

Slide 7


Slide 9

Slide 10


Slide 12


Chelating Agents


Slide 16

Adverse effects


Penicillamine

Slide 20


Deferoxamine

Slide 23

Slide 24

Slide 25


Occupational

Slide 28

Absorption

Slide 30

Slide 31

Slide 32

Slide 33

Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury


Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment


Needleman HL 1990


Lead Toxicity











LEAD Distribution




















MERCURY INORGANIC








background exposure


ORGANIC





















































Treatment




INTRODUCTION

Slide 3

Slide 4

Slide 5

Slide 6

Slide 7


Slide 9

Slide 10


Slide 12


Chelating Agents


Slide 16

Adverse effects


Penicillamine

Slide 20


Deferoxamine

Slide 23

Slide 24

Slide 25


Occupational

Slide 28

Absorption

Slide 30

Slide 31

Slide 32

Slide 33

Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury


Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment










LEAD Distribution




















MERCURY INORGANIC








background exposure


ORGANIC





















































Treatment




INTRODUCTION

Slide 3

Slide 4

Slide 5

Slide 6

Slide 7


Slide 9

Slide 10


Slide 12


Chelating Agents


Slide 16

Adverse effects


Penicillamine

Slide 20


Deferoxamine

Slide 23

Slide 24

Slide 25


Occupational

Slide 28

Absorption

Slide 30

Slide 31

Slide 32

Slide 33

Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury


Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment



















MERCURY INORGANIC








background exposure


ORGANIC





















































Treatment




INTRODUCTION

Slide 3

Slide 4

Slide 5

Slide 6

Slide 7


Slide 9

Slide 10


Slide 12


Chelating Agents


Slide 16

Adverse effects


Penicillamine

Slide 20


Deferoxamine

Slide 23

Slide 24

Slide 25


Occupational

Slide 28

Absorption

Slide 30

Slide 31

Slide 32

Slide 33

Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury


Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment





background exposure


ORGANIC





















































Treatment




INTRODUCTION

Slide 3

Slide 4

Slide 5

Slide 6

Slide 7


Slide 9

Slide 10


Slide 12


Chelating Agents


Slide 16

Adverse effects


Penicillamine

Slide 20


Deferoxamine

Slide 23

Slide 24

Slide 25


Occupational

Slide 28

Absorption

Slide 30

Slide 31

Slide 32

Slide 33

Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury


Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment

ORGANIC





















































Treatment




INTRODUCTION

Slide 3

Slide 4

Slide 5

Slide 6

Slide 7


Slide 9

Slide 10


Slide 12


Chelating Agents


Slide 16

Adverse effects


Penicillamine

Slide 20


Deferoxamine

Slide 23

Slide 24

Slide 25


Occupational

Slide 28

Absorption

Slide 30

Slide 31

Slide 32

Slide 33

Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury


Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment


















































Treatment




INTRODUCTION

Slide 3

Slide 4

Slide 5

Slide 6

Slide 7


Slide 9

Slide 10


Slide 12


Chelating Agents


Slide 16

Adverse effects


Penicillamine

Slide 20


Deferoxamine

Slide 23

Slide 24

Slide 25


Occupational

Slide 28

Absorption

Slide 30

Slide 31

Slide 32

Slide 33

Treatment

Mercury

Slide 36

Human Exposure

ORGANIC


Diagnosis

Methylmercury


Therapy

Cadmium

Slide 45

Slide 46

Slide 47

Slide 48

Cancer Risk

itai-itai disease

Treatment

heavy metals& antagonists

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