Mercury & its toxicity

Metal poisoning – mercury, lead, cadmium

Lecture No. 9

Copyright © Mgr. Zuzana Široká, PhD.

Mercury - Hg• Only metal which is liquid at room temperature• Vapours are much more dangerous• Both organic and inorganic compounds, all toxic• Sources: earth’s crust and industry• Cummulation in water environment • Water microorganisms transform pure mercury into

methylmercury – most common source of poisonings – incorporation into food chain (fish)

• Other cases of intoxication usually occupational, mistakes – Iraq (wheat seed with antifungal mercury compound – exchanged for food), Minamata disease (fishermen)

Inorganic mercury compounds:• HgCl2, Hg(CN)2, Hg(NO3)2 • Transported bound to blood peptides• Mercury binds with covalent bond to -SH, -COOH and – His• This influences function of many enzymes

and cell processes• Water soluble salts moreover coagulate

peptides and are corrosive• They damage kidney tubules and GIT mucosa

Organic mercury compounds:• Methoxyethylmercury and arylmercury compounds – release

mercuric ions – act like inorganic compounds• Methyl- and ethylmercury – firm bond, whole compound toxic• Bind with –Cys and –SH, block enzymes, destroy

haematoencephalic (blood-brain) barrier, increase permeability• Don't have corrosive effect on mucosas• In blood transported bound to erythrocytes• They have high affinity to neural tissue• Cummulate also in liver and kidney• Cross the placenta and have fetotoxic effect Excretion to

faeces, urine, milk, sweat, saliva• Deposition in hair and skin, excretion very slow

• Clinical signs: - in dogs, cats and young cattle – stimulation of CNS - in cattle, pigs and poultry – depression of CNS in dogs: blindness, involuntary chewing in cats: weakness, ataxia, rigidity of hind limbs, convulsions, glass-

like gaze, miaowing, hypersalivation in calves: ataxia, limping, stumbling, clonuses of eyelids and ears,

hypersensitivity, malfunction of swallowing, disturbance of vision, convulsions, opistotonus, coma, death

in cattle: anorexia, loss of weight, weakness, loss of coordination, salivation, lacrimation, diarrhoea and colic, loss of teeth, swollen lymphatic nodes, disturbances in EKG, cough, dyspnoe, eczema, hyperkeratosis. Convulsions very rare

in pigs: inappetence, colic, diarrhoea, hypermotility, tremors, loss of coordination, they are hunched, paralysis of hind limbs

in poultry: ataxia, loss of coordination, pale cere and lobes

Acute intoxication: more often in inorganic poisoning, mainly GIT signs, oliguria, uraemia, typical mercury bluish gum line, decrease of blood pressure, CNS disturbances

Chronic intoxication: typical for methylmercury, not GIT signs, damage of CNS, kidneys, again bluish margin on gingiva, loss of teeth, tremor

• Pathoanatomical examination: - reduction of cerebellum, leptomeningitis in cats,

congestion and haemorhagia in brain, stomatitis, enteritis, petechias

- histology – swollen axons, demyelinisation, vacuolisation on neurons, hyperplasia of epithelium

• Treatment: chelate agents – penicilamin (not dimercaprol or EDTA!), vitamin E and Se – antioxidants, spironolacton – blocks binding of organic mercury compounds to erythrocytes in acute poisoning

Lead - Pb• Soft, grey metal• Known since ancient times• Absolutely abiogenic to organisms• Used in pipes, tetraethyl-lead as a petrol

additive, red-lead (minium) primer paintings• Most poisonings in cattle (lead paintings,

batteries in silage)• Both inorganic and organic compounds – like in

mercury, different characteristics

• Absorption and elimination:- Inorganic lead: toxic after digestion- Organic lead: toxic after skin contact, digestion, inhalation- Resorption is promoted by calcium, iron and fats in food,

higher in young animals- Transported bound to erythrocytes (90 %)- High deposition in tissues – first in liver, then redistributed

to bones (inorg.), kidneys, muscles and hair- Bone-lead becomes mobilized through pregnancy or

fracture healing - Excretion via bile to faeces, also to urine and milk- Inorganic compounds acummulate more and elimination is

very slow, organic compounds excreted much quicker- Normal blood level of lead cca 0,1 mg/kg, above 0,4 it is

considered as toxic

• Mechanism of action:- Inorganic lead: - Disturbs saccharide metabolism, metabolism of haem -

inhibits Ala-D (Delta-aminolevulinic acid dehydratase) – increased concentration of aminolevulinic acid in urine

- The toxicity comes from its ability to mimic other biologically important metals - calcium, iron and zinc and to interact with proteins

- Organic lead: - interferes with excitatory neurotransmission by

glutamate - it is a potent inhibitor of the NMDA receptor, a

protein playing an important role in brain development and cognition (also in development of schizophrenia)

- doesn't influence synthesis of haem much

• Clinical signs of intoxication:- Acute intoxication: - from 12 – 92 hours after absorption - apathy, atonia of rumen, anorexia, CNS disturbances –

tremor of head, neck, loss of coordination, salivation, gnashing of teeth, aggressiveness, convulsions, blindness, death due to respiration collapse

- Subacute intoxication: - similar symptoms, but more severe GIT damage,

changing of constipation and severe diarrhoea, strong colic pains, mydriasis, opistotonus

- Chronic intoxication: - inappetence, anorexia, paresis, paralysis of n. recurens

in horse – whistling, typical grey gum line, CNS disturbances

• Pathological examination:- Typical smell from cadaver, petechias- Green-grey colour of muscles- Corrosive changes on GIT mucosa- Dystrophic kidneys

• Diagnostics:- Samples of blood, urine, muscle, liver etc.- Assessment of lead in these samples + assessment of

aminolevulinic acid in blood and urine

• Treatment:- Usually only in pets- Gastrolavage, administration of activated charcoal, laxatives –

MgSO4

- Chelating agents – EDTA, penicilamin

Cadmium - Cd• No constructive purpose in the body • Extremely toxic even in low concentrations, accumulates in organisms and ecosystems• Chemical properties similar to zinc – exchange in an

organism (also can replace Cu, Fe, Ca)• Sources: earth crust, fossil fuels, plastic materials

industry, electronic industry, tobacco fume• Absorption after digestion or less by inhalation (but

here better bioavailability)• The first documented case of mass cadmium poisoning

in the world - in Toyama Prefecture, Japan in 1950 – Itai-Itai disease (river polluted with waste from factory, water used on rice fields – poisoning from rice)

- In blood transported bound to proteins (formation of complexes), in higher concentrations bound to erythrocytes

- Deposition in liver, kidneys and gonads

• Mechanism of action:- Inhibition of many enzymes, antagonist to many

metals – Zn, Cu, Ca, Fe- Disturbance of cholecalciferol production, thus

influences Ca metabolism- Inhibition of specific hydrolase in testis – affects

activity of gonads- Formation of complexes, which are digested in

kidney –release of Cd – damage- Xenoestrogennic effect

• Clinical signs:- Acute exposure: - Cadmium fumes may cause flu like symptoms

including chills, fever, and muscle ache - More severe exposures can cause tracheo-

bronchitis, pneumonitis, and pulmonary oedema. Symptoms of inflammation may start hours after the exposure and include cough, dryness and irritation of the nose and throat, headache, dizziness, weakness, fever, chills, and chest pain.

- Ingestion of any significant amount of cadmium causes immediate poisoning and damage to the liver and the kidneys. Also CNS disturbances occur and changes in blood count

- Chronic exposure: - Osteomalacia, osteoporosis – disturbance of vitamin

D and calcium metabolism - Pain in the joints and the back, and also increases

the risk of fractures. In extreme cases of cadmium poisoning, the mere body weight causes a fracture

- The kidneys lose their function to remove acids from the blood. The kidney damage inflicted by cadmium poisoning is irreversible and does not heal over time.

- Gout, a form of arthritis due to the accumulation of uric acid crystals in the joints (hyperuricemia).

- Some patients may lose their sense of smell (anosmia)

- Damage of gonads, suspected carcinogen – tumours of testes

• Pathological examination:- gastritis, enteritis, nephritis, stomatitis,

degeneration of liver, necrosis on testes

• Treatment : - Chelating agents – EDTA –only partially effective - Administration of calcium

More info:http://www.ilo.org/encyclopedia/?doc&nd=857200247&nh=0http://enhs.umn.edu/hazards/hazardssite/mercury/merchealtheffects.htmlhttp://www.niehs.nih.gov/http://www.ra.mahidol.ac.th/journal/index.php?command=preview&selvol=27&selno=1&selids=156http://www.nsc.org/library/facts/lead.htmhttp://www.calpoison.org/public/lead.htmlhttp://www.lead.org.au/au.htmlhttp://www.atsdr.cdc.gov/toxprofiles/tp5.pdfhttp://www.portfolio.mvm.ed.ac.uk/studentwebs/

session2/group29/introtox.htm

Introduction

• Liquid metal• Used in dentistry – Dental amalgam• Acc to ADA > 100 million silver fillings/ year

History • > 2000 years in preparations such as diuretics,

anti-bacterial ointments, laxatives and skin ointments.

• original amalgamation process was demonstrated by a chemist in France

Toxic Effects of Mercury Exposure

• Mercury poisoning, also known as mercurialism, is the phenomenon of toxication by contact with mercury.

Pure elemental mercury is a cumulative heavy-metal poison

moderately absorbed through the skin, rather poorly absorbed through the

gastrointestinal tractreadily absorbed as vapor through the lungs.

2 Biggest Hg poisonings

• “Mad Hatter”- during the industrial revolution, hat-makers used mercury nitrate to soften fur used as lining in hats. Toxic effected brains causing mental instability.

• Japan - 1952, chemical co. dumped Hg into Minamata harbor; residents of local fishing villages contaminated; 100s affected and 68 died

Hazardous!!• DANGER! CORROSIVE. CAUSES BURNS TO

SKIN, EYES, AND RESPIRATORY TRACT. MAY BE FATAL IF SWALLOWED OR INHALED. HARMFUL IF ABSORBED THROUGH SKIN. AFFECTS THE KIDNEYS AND CENTRAL NERVOUS SYSTEM. MAY CAUSE ALLERGIC SKIN REACTION. (MSDS 2008)

Toxicity• Compounds of mercury

tend to be much more toxic than the element itself, and organic compounds of mercury are often extremely toxic.

• Dimethylmercury, for example, is a potent neurotoxin that is lethal in amounts of a fraction of a milliliter.

• Mercury damages the central nervous system, endocrine system, kidneys, and other organs, mouth, gums, and teeth.

• Exposure over long periods of time or heavy exposure to mercury vapor can result in brain damage and death. Mercury and its compounds are particularly toxic to fetuses and infants.

Is it reversible?• Some of the toxic effects of mercury are reversible,

either through specific therapy or through natural elimination of the metal after exposure has been discontinued.

• However, heavy or prolonged exposure can do irreversible damage, particularly in fetuses, infants, and young children. Exposure to certain highly toxic compounds of mercury such as dimethylmercury can be fatal within hours or less.

Case Studies

• From 1932 to 1968 methyl mercury was released into the sea around the city of Minamata, Japan.

• The toxin bioaccumulated in fish, which when eaten by the local population caused the largest case of mercury poisoning known

• Minamata disease caused the deaths of over 1000 people and permanently disabled a great many more.

• Another case of widespread mercury poisoning occurred in rural Iraq in 1971-1972, when grain treated with a methylmercury-based fungicide was used by the rural population to make bread.

Case Studies

• In December 1997, a chemistry professor, Karen Wetterhahn, at Dartmouth College was contaminated with dimethylmercury when she spilled a drop on her latex glove.

• China's first emperor of unified China, Qin Shi Huang Di, was driven insane and killed by mercury pills intended to give him eternal life.

Symptoms

1. Psychological disturbances 2. Oral Cavity problems 3. Digestive tract problems 4. Cardiovascular problems 5. Respiratory problems 6. Neurological Problems

History • In 1833, two English Entrepreneurs, The

Crawcour Brothers

History • Tin-mercury dental restorations in China 600

AD• First amalgam War• 1980 controversy –Huggins, a Practicing

Dentist in Colorado publicly condemned amalgam

History • Multiple sclerosis, Alzheimers Disease - no

basis• In Japan 1952, mercury was dumped in

Minamata Bay by a local chemical plant (Chisso Corporation

Physical & chemical properties

• ADA Specification No. 6• Mercury exists in 3 chemical forms

• Half life of mercury – 55 days• Half life of methyl mercury – 70 days

http:www.mercury.wikipedia.org.com

Uses of mercuryElemental mercury:

Sphygmomanometers, thermometers, barometersLiquid at room temp – volatilises easily

Inorganic mercury:Traditional remedies (ayurvedic, chinese)Used in gold extraction, caustic soda manufacturingRodenticides

Organic mercury: Fungicides, seed dressingsMethylmercury in fish …

Source of mercury • 2,700 and 6,000 tons of mercury are released

annually from the oceans and the Earth’s crust• The greatest source - mercury vapor released

during volcanic eruptions

Uses/Applications

• Used in thermometers, barometers, electrical switches, mercury vapor lamps, fluorescent lamps, paints, fungicides/insecticides/antiseptics

• Dental amalgams, battery manufacturing

• 2,000 to 3,000 tons are released from human activities, primarily burning household and industrial waste

• Swordfish and tuna - 1000 g/kg of mass

• 160 mg/kg in cattle and 25 mg/kg in humans• Methyl mercury compounds are routinely

used as fungicides and herbicides to coat seeds used to plant farm fields.

• Dental fillings are composed of mercury, silver, tin, copper, and zinc. The approximate percentages are as follows: ±50% mercury, 33-37% silver, 12.5-13.5% tin 0-3% copper 0-1% zinc

• Mercury is 1 of 2 elements (bromine• is the other)the other) that are liquid at room temperature.• Its elemental symbol is Hg, derived• from the Greek word hydrargyrias,• meaning “water silver.” This is a fitting• term, since elemental mercury does resemble• liquid silver. The greatest source of• mercury happens to be natural. Outgassing• of granite rock accounts for more than• 80% of the mercury found in the atmosphere• and on the earth’s surface.3 Mercury• is found in many industries, such as battery,• thermometer, and barometer manufacturing.• Some consumer products that• contain mercury include automotive equipment• with halide relay switches, fluorescent• and high-intensity discharge lamps,• and fungicides. Before 1990, paints contained• mercury as an anti-mildew agent. In• medicine, mercury is used in dental amalgams,• as a preservative in vaccines, and in• various antiseptic agents. It

Uses of mercury & its effects

• Calomel (mercurous chloride) was used for the treatment of syphilis.

• Inorganic mercury - electrical applications, chlorine production and dental restorations

• Thimerosol as medicine in Hepatitis B, Diptheria, Pertussis and Tetanus vaccines

• Mercury in vaccines have caused death of infants - diapers

• Acrodynia and kawasaki disease – teething powder

Gerald T. Charbenue; Principles and Practices of Operative Dentistry

Biotransformation

• Mercury from dental amalgam is released in two forms

• Mercury vapors• Mercuric ions

• Inhalation is the major route of entry into the human body. Metallic mercury is poorly absorbed to the skin or via the gastro intestinal tract.

• Under normal circumstances, mercury is biochemically processed and excreted

• Mercury ions (Hg0) circulate readily in the blood but pass the membrane barriers of the brain and placenta with difficulty

• Non-ionized mercury (Hg°) is capable of crossing through lipid layers barriers and if subsequently oxidized within these tissues – neuromuscular problems

Mercury• Mercury was an important constituent of drugs for centuries

as an ingredient in many diuretics, antibacterials, antiseptics, skin ointments, and laxatives.

• More specific, effective, and safer modes of therapy now have replaced the mercurials, and drug-induced mercury poisoning has become rare.

• However, mercury has a number of important industrial uses, and poisoning from occupational exposure and environmental pollution continues to be an area of concern.

• Chloralkali (e.g., bleach),Electrical equipment, Paints, Thermometers, Dental amalgams and Laboratory chemicals.

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Mercury…• Three major chemical forms of the metal must be

distinguished: mercury vapor (elemental mercury), salts of mercury, and organic mercurials.

• Mercury readily forms covalent bonds with sulfur, and it is this property that accounts for most of the biological properties of the metal.

• Even in low concentrations, mercurials are capable of inactivating sulfhydryl groups of enzymes and thus interfering with cellular metabolism and function.

• The affinity of mercury for thiols provides the basis for treatment of mercury poisoning with such agents as dimercaprol and penicillamine. Mercury also combines with phosphoryl, carboxyl, amide, and amine groups.

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Mercury…• Elemental mercury is not particularly toxic when

ingested because of very low absorption from the GI tract. However, inhaled mercury vapor is completely absorbed by the lung and then is oxidized to the divalent mercuric cation by catalase in the erythrocytes.

• CNS toxicity is more prominent after exposure to mercury vapor than to divalent forms of the metal.

• The soluble inorganic mercuric salts (Hg2+) gain access to the circulation when taken orally. GI absorption is approximately 10% to 15%. Insoluble inorganic mercurous compounds, such as calomel (Hg2Cl2), may undergo some oxidation to soluble compounds that are more readily absorbed. Inorganic mercury has a markedly nonuniform distribution after absorption.

52

Mercury…• The highest concentration of Hg2+ is found in the

kidneys, where the metal is retained longer than in other tissues.

• Inorganic mercurials do not readily pass across the BBB or the placenta. The metal is excreted in the urine and feces with a half-life of about 60 days.

• More than 90% of Organic mercurials/methylmercury is absorbed from the human GI tract. The organic mercurials cross the BBB and the placenta and thus produce more neurological and teratogenic effects than do the inorganic salts.

• Methylmercury in humans is excreted mainly in the feces in the form of a glutathione conjugate. The half-life of methylmercury in the blood of humans is between 40 and 105 days

53

Mercury vapor toxicity• Short-term exposure: weakness, chills, metallic taste, nausea,

vomiting, diarrhea, dyspnea, cough, and a feeling of tightness in the chest.

• Pulmonary toxicity may progress to an interstitial pneumonitis with severe compromise of respiratory function.

• Recovery, although usually complete, may be complicated by residual interstitial fibrosis.

• Chronic exposure: asthenic (physically weak) vegetative syndrome( neurasthenic symptoms ,goiter, increased uptake of radioiodine by the thyroid, tachycardia, labile pulse, gingivitis, dermographia (a skin condition in which red, itchy lines appear when a person scratches his or her skin), and increased mercury in the urine.

54

Mercury vapor toxicity…• With continued exposure to mercury vapor, tremor

becomes noticeable, and psychological changes consist of depression, irritability, excessive shyness, insomnia, reduced self-confidence, emotional instability, forgetfulness, confusion, impatience, and vasomotor disturbances (such as excessive perspiration and uncontrolled blushing, which together are referred to as erethism = abnormal physical sensitivity).

• Common features of intoxication from mercury vapor are severe salivation and gingivitis.

• Renal dysfunction also has been reported to result from long-term industrial exposure to mercury vapor.

55

Inorganic mercury toxicity• Precipitation of mucous membrane proteins by mercuric

salts (e.g., mercuric chloride) results in an ashen-gray appearance of the mucosa of the mouth, pharynx, and intestine and also causes intense pain and vomiting.

• The local corrosive effect on the GI mucosa results in severe hematochezia(passing of fresh blood in a stool) with evidence of mucosal sloughing in the stool. Hypovolemic shock and death can occur in the absence of proper treatment.

• Systemic toxicity: a strong metallic taste is followed by stomatitis (mouth inflammation) with gingival irritation, foul breath, and loosening of the teeth.

56

Inorganic mercury toxicity…• The most serious and frequent systemic effect of

inorganic mercury is renal toxicity(oliguria or anuria). Renal injury also follows long-term exposure, where glomerular injury predominates.

• The symptom complex of acrodynia also commonly follows chronic exposure.

• Acrodynia: mercury poisoning in young children; mercury poisoning caused by powders formerly prescribed for teething, resulting in pinkness and itching of the hands and feet, excessive sweating, low blood pressure, limpness, and insomnia

57

Organic Mercurials toxicity• Symptoms of exposure to methylmercury are mainly

neurological and consist of visual disturbance (scotoma and visual-field constriction), ataxia, paresthesias, neurasthenia (chronic fatigue), hearing loss, dysarthria (difficulty in speech articulation), mental deterioration, muscle tremor, movement disorders, and with severe exposure, paralysis and death.

• Effects of methylmercury on the fetus can occur even when the mother is asymptomatic; mental retardation and neuromuscular deficits have been observed.

58

Treatment of Mercury Poisoning• Therapeutic measures include immediate termination

of exposure and close monitoring of pulmonary status. Short-term respiratory support may be necessary.

• Inorganic: Prompt attention to fluid and electrolyte balance and hematological status is of critical importance in moderate-to-severe oral exposures. Emesis can be induced if the patient is awake and alert, although emesis should not be induced where there is corrosive injury.

59

Treatment of Mercury Poisoning…• Chelation therapy with dimercaprol (for high-level

exposures or symptomatic patients) or penicillamine (for low-level exposures or asymptomatic patients) is used routinely to treat poisoning with either inorganic or elemental mercury.

• Recommended treatment includes dimercaprol 5 mg/kg intramuscularly initially, followed by 2.5 mg/kg intramuscularly every 12 to 24 hours for 10 days. Penicillamine (250 mg orally every 6 hours) may be used alone or following treatment with dimercaprol.

• The orally effective chelator succimer appears to be an effective chelator for mercury, although it has not been approved by the FDA for this purpose.

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Treatment of Mercury Poisoning…• The dimercaprol-mercury chelate is excreted into both

bile and urine, whereas the penicillamine-mercury chelate is excreted only into urine.

• The short-chain organic mercurials, especially methylmercury, are the most difficult forms of mercury to mobilize from the body presumably because of their poor reactivity with chelating agents.

• Dimercaprol is contraindicated in methylmercury poisoning because it increases brain concentrations of methylmercury in experimental animals.

• Methylmercury compounds undergo extensive enterohepatic recirculation in experimental animals.

61

Treatment of Mercury Poisoning…• A nonabsorbable mercury-binding substance into the

intestinal tract should facilitate their removal from the body.

• A polythiol resin has been used for this purpose in humans and appears to be effective.

• The resin has certain advantages over penicillamine. It does not cause redistribution of mercury in the body with a subsequent increase in the concentration of mercury in blood, and it has fewer adverse effects than do sulfhydryl agents that are absorbed.

• Conventional hemodialysis is of little value in the treatment of methylmercury poisoning because methylmercury concentrates in erythrocytes, and little is contained in the plasma.

62

Treatment of Mercury Poisoning…• However, it has been shown that L -cysteine can be

infused into the arterial blood entering the dialyzer to convert methylmercury into a diffusible form.

• Both free cysteine and the methylmercury-cysteine complex form in the blood and then diffuse across the membrane into the dialysate. This method has been shown to be effective in humans .

• Studies in animals indicate that succimer may be more effective than cysteine in this regard.

63

Mercuralism • Acute toxicity• Chronic toxicity (Hydrargyrism) –

Erethism

• Neurological • Renal – increase plasma creatine level• Immunological • Reproductive • Cardiac • Blood • Liver • Nervous system• Oral manifestations• Thyroid

William. G.Shafer, M.K. Hine; A Text book of Oral Pathology

• PINKS disease, Acrodynia, Swift disease - 6 P’s hands & feet: puffy, pink, painful, peeling, parasthetia, perspiring

• Mercury ions produce toxic effects by• protein precipitation, enzyme inhibition,• and generalized corrosive action. Mercury• not only binds to sulfhydryl groups but• also to phosphoryl, carboxyl, amide, and• amine groups. Proteins (including• enzymes) with such groups readily available• are susceptible to reaction with mercury.• Once bound to mercury, most• proteins are rendered inactive. Toxicity is• in part related to the oxidative state and to• the chemical form (organic versus inorganic).

• As mentioned, elemental mercury• vapor is highly lipid soluble which allows• it to readily cross cellular membranes. It• can also be oxidized to the mercuric state.• Since mercuric salts form more soluble• divalent compounds, these forms are more• toxic than the mercurous salts that form• monovalent mercury compounds. Thus,• when ingested they will be more rapidly• absorbed and produce greater toxicity.• Only about 10% of an inorganic salt (regardless• of the oxidative state) is absorbed• compared to 90% absorption via the GI• track of the organic forms. This means the• inorganic forms are available within the GI• track to exert corrosive effects on the gastrointestinal• mucosa.

• The organomercurial compounds are• further classified according to chemical• structure and relative toxicity. These• groups are the long-chained arylmercury• compounds and short-chained alkylmercury• compounds. The group that poses the• greater hazard is the short-chained alkyl• compounds, such as methymercury. These• are also most completely absorbed from• the GI tract, distributed to the brain, liver,• and kidney. Excretion is primarily in the• feces. The aryl mercury compounds are• excreted as mercuric ions.

• Women who are exposed to mercury in pregnancy have given birth to children with serious birth defects due to mercury poisoning.

• In utero mercury exposure can lead to Minamata disease

• Allergy

• Others - White cell reaction, reaction to N2O, hyperventilation, reaction to diet pills, gall bladder, painful menstruation, hepatitis, severe complexion problems

Treatment

Supportive treatment DMPSDMPS Chelation (2,3-Dimercapto-1-

propanesulphonate) Chelation therapy of choice for mercury For both acute and chronic mercury

poisoning. Urinary excretion of mercury two hours

after DMPS administration

• Discontinuance of exposure to mercury .• The administration of BAL (British Anti-

lewisite) pencillamine

• Acute mercurialism - Sodium ascorbate•

• Dr. Olympio Pinto of Rio de Janeiro – “remove amalgams when the WBC remained over 11,000 for three months without visible medical cause”

The dental Amalgam Contraversy:A ReviewJCC,1996

• N-Acetyl-Cysteine (NAC) For Mercury Detoxification

• NAC is produced in living organisms from the amino acid cysteine. Thus

NAC is a natural sulfur-containing amino acid derivative found naturally in foods and is a powerful

antioxidantThe dental Amalgam Contraversy:A ReviewJCC,1996

Normal levels

Intake of mercury vapor - 0.4 to 4.4 ug/day depending on number of amalgam fillings.

Mercury concentration in urine - 15 ug/lt4 nanograms in blood1 micro gram/ m3 in air

Tolerable daily intake (TDI) of .014 μg Hg0/kg-day (Richardson, 1996)

Richardson, GM; Allan, M. A Monte Carlo assessment of mercury exposure and risks from dental amalgam. Human and Ecol Risk Assess

Mercury exposure in dental office

• Incorrect storage of mercury or waste amalgam

• Spillage of mercury or waste amalgam• Mishandling at any stage would result in

mercury splashing on the bench or floor causing it to be scattered widely as small droplets.

Strudevent’s Art and Science of Operative Dentistry; T.M. Robers

How would you clean up the mercury?1. Spill on a non-porous surface:

lift the mercury with card or paper (remove gold rings and wear gloves)

place in a sealed container & dispose in general waste

2. Spill on a carpet:Use a sulphur based (calcium polysulfide) powder

mercuric sulphide & then can vacuum up

Strudevent’s Art and Science of Operative Dentistry; T.M. Robers

Monitoring mercury levels

• Detection meter – mercury sniffer• Paper discs impregnated with palladium

chloride

Mercury vapour analyzer

• A badge system - mercury is adsorbed on gold foil

• Mercury in vapor and dust form - absorbing system and then quantifying the absorbed mercury

Mercury monitoring system

Precautions

• Mercury-containing products should not be stored in the open, but rather in closets or cabinets

• Reusable capsules and precapsulated designs - vacuum aspirator

• During trituration• Sprinkling sulfur powder • Scrap amalgam from condensation procedures• Strudevent’s Art and Science of Operative Dentistry; T.M. Robers

Canadian Dental Association, 1996

Recommendations Avoid using mercury to restore children's

teeth. Avoid placing or removing amalgam in the

teeth of pregnant women. Avoid using dental amalgams in patients

suffering from kidney ailments. Use methods and equipment to reduce the

risks of exposure to mercury vapor

"The Safety of Dental Amalgam:” Health Canada, Dept. of Supply and Services

Avoid using amalgams in patients who risk suffering from allergic hypersensitivity.

Remove amalgams from a patient who has become sensitive.

Avoid placing amalgam in contact with other metal appliances in the mouth

Fully inform patients of the risks and benefits involved. Recognize the patient's right to refuse treatment using

a “specific material.”

The Safety of Dental Amalgam:” Health Canada, Dept. of Supply and Services

Mercury hygiene • Minimize the contamination• Drain, vacuum cuspidor or sink is fitted with a

filter, strainer or trap • Spilled mercury - dusting with sulfur powder

or spraying with a solution of sodium thiosulfate

• Mercury spillage kit -->

Strudevent’s Art and Science of Operative Dentistry; T.M. Robers

• Office personnel should also be monitored

• Pre-capsulated alloys should be used

• Skin contact with mercury should be avoided

• Change masks after removing amalgam restorations

• Strudevent’s Art and Science of Operative Dentistry; T.M. Robers

• Mercury contaminated items should be deposited in sealed bags

• Spilled mercury should be cleaned with trap bottles, taps or fresh mixes of amalgam

• The removal of the defective mercury with air turbine

• Strudevent’s Art and Science of Operative Dentistry; T.M. Robers

Mercury poisoning

Mercury poisoning

- elemental

- inorganic

- organic

• Each has a different toxicological profile

• There are 3 different forms of mercury

Sources of mercury• Elemental mercury:

– Sphygmomanometers, thermometers, barometers– Liquid at room temp – volatilises easily

• Inorganic mercury:– Traditional remedies (ayurvedic, chinese)– Used in gold extraction, caustic soda manufacturing– Rodenticides

• Organic mercury: – Fungicides, seed dressings– Methylmercury in fish …

Mercury - Absorption

• Inhalation : 60-80%

• Dermal : 3-15%

• GI Tract : Metallic <0.2% Inorganic 15% Organic 90+%

Organic mercury poisoning: Rare … but severe

• Exposure: ingestion, topical or inhalation

• CNS Toxicity:• poor concentration, fatigue, ataxia, tremor, constricted

visual fields, • coma & convulsions

• BM suppression

• Renal toxicity - dealkylation to inorganic form

• Poorer response to treatment

Inorganic mercury poisoning

• Gastrointestinal phase: Hg2+ is a potent GI irritant

– gingivitis, stomatitis- oesophageal, gastric, small and large bowel erosions- haematemesis, bloody diarrhoea, CVS collapse

• Systemic toxicity: Hg2+ inhibits sulphydryl enzymes

– hypotension, lactic acidosis

• Nephrotoxicity: Hg2+ deposits in the tubules ATN

– acute renal failure - potentially leads to CRF in survivors

Elemental Mercury

Case 1: A 4 yr old boy has bitten the top of a mercury thermometer and his mother thinks he

may have swallowed it.

• Little or no risk of toxicity from oral elemental mercury:- Faecal excretion precedes slow oxidation

• What would your advice be?

Case 2: A man rings A&E because he has dropped a mercury thermometer in his

son’s bedroom.

– elemental mercury is volatile

– if on a heated surface it may volatalise & be inhaled

– once inhaled ~ 80% absorption

• What is the risk of toxicity?

Case 2: Mercury thermometer broken in a bedroom

• How would you advise him to clean up the mercury?1. Spill on a non-porous surface:

– lift the mercury with card or paper (remove gold rings and wear gloves)

– place in a sealed container & dispose in general waste

2. Spill on a carpet:– DON’T USE a hoover !– Use a sulphur based (calcium polysulfide) powder mercuric

sulphide & then can vacuum up … – Large spills: involve environmental health

Inhaled Elemental Mercury (1)ACUTE

• Irritant respiratory effects: - cough, dyspnoea- pulmonary oedema, ARDS

• Metal fume fever: - pyrexia, cough, malaise, flu-like symptoms

• CNS features: - confusion, emotional lability, psychoses- convulsions, CNS depression & coma

• Renal effects: - rarely ARF (oxidation to Hg2+)

• ‘Erethism’ TREMOR, dysarthria peripheral neuropathy, sweating personality change

• Stomatitis, gingivitis

• Chronic renal impairment

Inhaled Elemental Mercury (2)CHRONIC

AcrodyniaAcrodynia• Mercury syndrome in children

– Usually related to elemental mercury exposure, 2 reports secondary to inorganic exposure

• 6 P’s hands & feet: puffy, pink, painful, peeling, paraesthetic, perspiring

• Associated with weight loss, anorexia, irritability, behavioural changes

• Hypertension – can mimic phaeochromocytoma– Mercury inhibits COMT (catecholamine-o-

methyltransferase) … NAdr / Adr accumulateTorres AD Torres AD Pediatrics Pediatrics 20002000

IV/IM Elemental Mercury

• Results in:

- local complications- embolic complications- mercuralism

IV/IM Elemental Mercury Local Complications

• Thrombophlebitis• Infection• Granuloma formation

Excise large s/c deposits ? prevents local & systemic effects

IV/IM Elemental Mercury Embolic Complications

• Pulmonary - usually asymptomatic - may cause chest pain, SOB- normal spirometry, decreased transfer factor

• Systemic - ? mercury through pulmonary capillary bed- widespread eg. abdomen, intracerebral- asymptomatic

IV/IM Elemental Mercury Mercuralism

• Slow oxidation of metallic Hg mercuric ions (Hg2+)

Chronic renal impairment ?? CNS toxicity

• Consider chelation therapy:- guided by blood mercury- may require long-term chelation

Diagnosis of Mercury poisoning• Blood mercury:

– only really useful acutely normal <10µg/l symptoms with blood mercury >150-200µg/l

• Urine mercury– probably the most reliable indicator normal <10µg/l symptoms with urine mercury >100-150µg/l

• U&E

• Radiology: for elemental ingestion/aspiration/injection

• Remove from source

• Supportive care– particularly important with inhalation

• DMPSDMPS Chelation (2,3-Dimercapto-1-propanesulphonate) Chelation therapy of choice for mercury For both acute and chronic mercury poisoning For all forms of Hg (inorganic > metallic >> organic)

- Indications: symptomatic patients blood/urine mercury persistently > 100 - 150g/l

Treatment of Mercury poisoning

Mercury - Hg• Only metal which is liquid at room temperature• Vapours are much more dangerous• Both organic and inorganic compounds, all toxic• Sources: earth’s crust and industry• Cummulation in water environment • Water microorganisms transform pure mercury into

methylmercury – most common source of poisonings – incorporation into food chain (fish)

• Other cases of intoxication usually occupational, mistakes – Iraq (wheat seed with antifungal mercury compound – exchanged for food), Minamata disease (fishermen)

Inorganic mercury compounds:• HgCl2, Hg(CN)2, Hg(NO3)2 • Transported bound to blood peptides• Mercury binds with covalent bond to -SH, -COOH and – His• This influences function of many enzymes

and cell processes• Water soluble salts moreover coagulate

peptides and are corrosive• They damage kidney tubules and GIT mucosa

Organic mercury compounds:• Methoxyethylmercury and arylmercury compounds – release

mercuric ions – act like inorganic compounds• Methyl- and ethylmercury – firm bond, whole compound toxic• Bind with –Cys and –SH, block enzymes, destroy

haematoencephalic (blood-brain) barrier, increase permeability• Don't have corrosive effect on mucosas• In blood transported bound to erythrocytes• They have high affinity to neural tissue• Cummulate also in liver and kidney• Cross the placenta and have fetotoxic effect Excretion to

faeces, urine, milk, sweat, saliva• Deposition in hair and skin, excretion very slow

• Clinical signs: - in dogs, cats and young cattle – stimulation of CNS - in cattle, pigs and poultry – depression of CNS in dogs: blindness, involuntary chewing in cats: weakness, ataxia, rigidity of hind limbs, convulsions, glass-

like gaze, miaowing, hypersalivation in calves: ataxia, limping, stumbling, clonuses of eyelids and ears,

hypersensitivity, malfunction of swallowing, disturbance of vision, convulsions, opistotonus, coma, death

in cattle: anorexia, loss of weight, weakness, loss of coordination, salivation, lacrimation, diarrhoea and colic, loss of teeth, swollen lymphatic nodes, disturbances in EKG, cough, dyspnoe, eczema, hyperkeratosis. Convulsions very rare

in pigs: inappetence, colic, diarrhoea, hypermotility, tremors, loss of coordination, they are hunched, paralysis of hind limbs

in poultry: ataxia, loss of coordination, pale cere and lobes

Acute intoxication: more often in inorganic poisoning, mainly GIT signs, oliguria, uraemia, typical mercury bluish gum line, decrease of blood pressure, CNS disturbances

Chronic intoxication: typical for methylmercury, not GIT signs, damage of CNS, kidneys, again bluish margin on gingiva, loss of teeth, tremor

• Pathoanatomical examination: - reduction of cerebellum, leptomeningitis in cats,

congestion and haemorhagia in brain, stomatitis, enteritis, petechias

- histology – swollen axons, demyelinisation, vacuolisation on neurons, hyperplasia of epithelium

• Treatment: chelate agents – penicilamin (not dimercaprol or EDTA!), vitamin E and Se – antioxidants, spironolacton – blocks binding of organic mercury compounds to erythrocytes in acute poisoning

Lead• Through natural occurrence and its industrial use, lead is

ubiquitous(existing every where) in the environment.• The primary sources of environmental exposure to lead

are leaded paint and drinking water; most of the overt toxicity from lead results from environmental and industrial exposures.

• Occupational exposure to lead has decreased markedly because of appropriate regulations and programs of medical surveillance. Workers in lead smelters have the highest potential for exposure because fumes are generated, and dust containing lead oxide is deposited in their environment. Workers in storage-battery factories face similar risks.

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Lead… Dietary intake of lead has decreased since the 1940s

due largely to • decrease in the use of lead-soldered cans for food and

beverages; • decrease in the use of lead pipes and lead-soldered joints in

water distribution systems; • introduction of lead-free gasoline; • public awareness of the hazards of indoor leaded paint

The major routes of absorption of lead are from the GIT and the respiratory system.

Adults absorb approximately 10% of ingested lead, whereas children absorb up to 40%.

Approximately 90% of inhaled lead particles from ambient air are absorbed.

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Lead…• After absorption, about 99% of lead in the bloodstream

binds to hemoglobin in erythrocytes. Only 1% to 3% of the circulating blood lead is in the serum available to the tissues.

• Inorganic lead initially distributes in the soft tissues, particularly the tubular epithelium of the kidney and in the liver. In time, lead is redistributed and deposited in bone, teeth, and hair.

• About 95% of the body burden of lead eventually is found in bone. Only small quantities of inorganic lead accumulate in the brain, mostly in gray matter and the basal ganglia.

• Iron and Ca2+ may compete with lead transport.117

Lead…• After establishment of a steady state early in human life,

the daily intake of lead normally approximates the output, and concentrations of lead in soft tissues are relatively constant. However, the concentration of lead in bone apparently increases, and its half-life in bone is estimated to be 20 to 30 years.

• A daily intake of 2.5 mg lead requires nearly 4 years for the accumulation of a toxic burden, whereas a daily intake of 3.5 mg requires a few months because deposition in bone is too slow to protect the soft tissues during rapid accumulation.

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Acute Lead Poisoning• Acute lead poisoning is relatively infrequent(acid-soluble

lead compounds or inhalation of lead vapors). • Marked astringency, thirst, and a metallic taste. Nausea,

abdominal pain, and vomiting . Stools may be black from lead sulfide, and there may be diarrhea or constipation.

• If large amounts are absorbed rapidly, a shock syndrome may develop as the result of massive GI loss of fluid.

• Acute CNS symptoms include paresthesias, pain, and muscle weakness.

• An acute hemolytic crisis sometimes causes severe anemia and hemoglobinuria.

• The kidneys are damaged, and oliguria and urinary changes are evident. Death may occur in 1 or 2 days.

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Chronic Lead Poisoning• The medical term for lead poisoning is plumbism.• GIT: Anorexia, muscle discomfort, malaise, headache

and Constipation. Severe abdominal pain (lead colic), is the most distressing feature of the advanced abdominal syndrome.

• In cases where colic is not severe, removal of the patient from the environment of exposure may be sufficient for relief of symptoms.

• Calcium gluconate administered IV is recommended for relief of pain and usually is more effective than morphine

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Chronic Lead Poisoning• Lead palsy occurs with repeated lead exposure: Muscle

weakness and easy fatigue.• lead encephalopathy, is the most serious manifestation

of lead poisoning and is much more common in children than in adults.

• The early signs of the syndrome include clumsiness, vertigo, ataxia, falling, headache, insomnia, restlessness, and irritability. As the encephalopathy develops, the patient may first become excited and confused; delirium with repetitive tonic-clonic convulsions or lethargy and coma follow. Visual disturbances also are present.

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Chronic lead toxicity…• CDC considers a blood lead concentration of 10 mg/dl

or greater to indicate excessive absorption of lead in children and to constitute grounds for environmental assessment, cleanup, and/or intervention.

• Chelation therapy should be considered when blood lead concentrations exceed 25 mg/dl.

• Hypochromic microcytic anemia, which is observed more frequently in children and is morphologically similar to that resulting from iron deficiency.

• Ferrochelatase is the enzyme responsible for incorporating the ferrous ion into protoporphyrin to form heme. When ferrochelatase is inhibited by lead, excess protoporphyrin takes the place of heme in the hemoglobin molecule.

122

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Chronic Lead Poisoning…• Renal toxicity occurs in two forms: a reversible tubular

disorder (usually seen after acute exposure of children to lead) and an irreversible interstitial nephropathy (observed more commonly in long-term industrial lead exposure).

• Ashen color of the face and pallor of the lips; retinal stippling; appearance of "premature aging," with stooped posture, poor muscle tone, and emaciation; and a black, grayish, or blue-black "lead line" along the gingival margin.

• There is a relationship between the concentration of lead in blood and blood pressure. Lead also interferes with vitamin D metabolism.

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Organic Lead toxicity• Tetraethyl lead and tetramethyl lead are lipid-soluble

compounds that are absorbed readily from the skin, GI tract, and lungs.

• The toxicity of tetraethyl lead is believed to be due to its metabolic conversion to triethyl lead and inorganic lead.

• The major symptoms of intoxication with tetraethyl lead are referable to the CNS: insomnia, nightmares, anorexia, nausea and vomiting, diarrhea, headache, muscular weakness, and emotional instability.

• Subjective CNS symptoms such as irritability, restlessness, and anxiety are next evident, usually accompanied by hypothermia, bradycardia, and hypotension.

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Treatment of Lead Poisoning• Prevention of further exposure is important. • Seizures are treated with diazepam or phenytoin , fluid and

electrolyte balances must be maintained, and cerebral edema is treated with mannitol and dexamethasone or controlled hyperventilation.

• The concentration of lead in blood should be determined prior to initiation of chelation therapy.

• Chelation therapy is indicated in symptomatic patients or in patients with a blood lead concentration in excess of 50 to 60 mg/dl.

• A chelate is a complex formed between a metal and a compound that contains two or more potential ligands.

• The stability of chelates varies with the metal and the ligand atoms. 126

Treatment of Lead Poisoning…• Four chelators are employed: edetate calcium disodium

(CaNa2EDTA), dimercaprol [British antilewisite (BAL)], D- penicillamine, and succimer [2,3-dimercaptosuccinic acid (DMSA). CaNa2EDTA and dimercaprol usually are used in combination for lead encephalopathy.

• CaNa2EDTA is initiated at a dose of 30 to 50 mg/kg per day in two divided doses either by deep IM injection or slow IV infusion for up to 5 consecutive days.

• Dimercaprol is given IM at a dose of 4 mg/kg every 4 hours for 48 hours, then every 6 hours for 48 hours, and finally, every 6 to 12 hours for an additional 7 days.

127

Treatment of Lead Poisoning…• Penicillamine is effective orally and may be included in

the regimen at a dosage of 250 mg given four times daily for 5 days. During chronic therapy with penicillamine, the dose should not exceed 40 mg/kg per day.

• Succimer is the first orally active lead chelator available for children, with a safety and efficacy profile that surpasses that of D-penicillamine. Succimer usually is given every 8 hours (10 mg/kg) for 5 days and then every 12 hours for an additional 2 weeks.

• In any chelation regimen, the blood lead concentration should be reassessed 2 weeks after the regimen has been completed; an additional course of therapy may be indicated if blood lead concentrations rebound.

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Chelator• The stability of chelates varies with the metal and the ligand

atoms. For example, lead and mercury have greater affinities for sulfur and nitrogen than for oxygen ligands; calcium, however, has a greater affinity for oxygen than for sulfur and nitrogen. These differences in affinity serve as the basis of selectivity of action of a chelating agent in the body.

• An ideal chelating agent would have the following properties: high solubility in water, resistance to biotransformation, ability to reach sites of metal storage, capacity to form nontoxic complexes with toxic metals, ability to retain chelating activity at the pH of body fluids, and ready excretion of the chelate .

129

Chelators…• A low affinity for Ca2+ also is desirable because Ca2+ in

plasma is readily available for chelation, and a drug might produce hypocalcemia despite high affinity for heavy metals.

• The most important property of a therapeutic chelating agent is greater affinity for the metal than that of the endogenous ligands. The large number of ligands in the body is a formidable barrier to the effectiveness of a chelating agent.

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Arsenic• The foundations of many modern concepts of

chemotherapy derive from Ehrlich's early work with organic arsenicals, and such drugs once were a mainstay of chemotherapy.

• Arsenic is found in soil, water, and air as a common environmental toxicant.

• The major source of occupational exposure to arsenic-containing compounds is from the manufacture of arsenical herbicides and pesticides.

• In the manufacture of both computer chips and semiconductors, metallic arsenic also may be used or produced as a by-product of the reaction chambers.

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Arsenic…• In general, toxicity increases in the sequence of organic

arsenicals < As5+ < As3+ < arsine (AsH3).• The organic arsenicals contain arsenic covalently linked

to a carbon atom, where arsenic exists in the trivalent or pentavalent state. The organic arsenicals usually are excreted more rapidly than are the inorganic forms.

• The pentavalent arsenicals have very low affinity for thiol groups, in contrast to the trivalent compounds, and are much less toxic.

• Arsine (AsH3) is a gaseous hydride of trivalent arsenic; it produces toxic effects that are distinct from those of the other arsenic compounds.

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Arsenic…

• Arsenate (pentavalent) uncouples mitochondrial oxidative phosphorylation. The mechanism is thought to be related to competitive substitution of arsenate for inorganic phosphate in the formation of ATP.

• Trivalent arsenicals, including inorganic arsenite, are regarded primarily as sulfhydryl reagents. As such, trivalent arsenicals inhibit many enzymes by reacting with biological ligands containing available -SH groups.

• The arsenite salts are more soluble in water and are better absorbed than the oxide. Experimental evidence has shown a high degree of GI absorption (80% to 90%) of both trivalent and pentavalent forms of arsenic.

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Arsenic…• Arsenic is stored mainly in liver, kidney, heart, and lung.

Much smaller amounts are found in muscle and neural tissue.

• Because of its chemical similarity to phosphorus, it is deposited in bone and teeth and is retained there for long periods.

• Arsenic readily crosses the placenta, and fetal damage has been reported.

• Arsenic is eliminated by many routes (e.g., feces, urine, sweat, milk, hair, skin, and lungs), although most is excreted in urine in humans. The half-life for the urinary excretion of arsenic is 3 to 5 days, much shorter than those of the other metals discussed.

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Toxicity of arsenic• Acute and subacute doses of inorganic arsenic induce

mild vasodilation. Serious CV effects include hypotension, CHF, and cardiac arrhythmias.

• Long-term exposure results in peripheral vascular disease , more specifically gangrene of the extremities, especially of the feet, blackfoot disease.

• Myocardial damage and hypotension may become evident after more prolonged exposure to arsenic.

• Acute or subacute exposure to arsenic can produce GI disturbances that range from mild abdominal cramping and diarrhea to severe hemorrhagic gastroenteritis associated with shock. With chronic exposure to arsenic, GI effects usually are not observed.

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Toxicity of arsenic…• Kidney: Initially, the glomeruli are affected, and

proteinuria results. Varying degrees of tubular necrosis and degeneration occur later. Oliguria with proteinuria, hematuria, and casts frequently results.

• Diffuse or spotted hyperpigmentation over the trunk and extremities, cutaneous vasodilation and a "milk and roses" complexion and eventually, skin cancer.

• High-dose acute or subacute exposure to arsenic can cause encephalopathy; however, the most common arsenic-induced neurological lesion is a peripheral neuropathy with a stocking/glove distribution of dysesthesia (constant burning sensation).

• This is followed by muscular weakness in the extremities.136

Toxicity of arsenic…• Serious, irreversible blood and bone marrow

disturbances(rare with organic arsenicals).• Fatty infiltration, central necrosis, and cirrhosis.• Skin, bladder ,lung, kidney, and liver cancer.• Chronic exposure to arsenic has been associated with

increased prevalence of diabetes mellitus, goiter, hepatomegaly, and respiratory system dysfunctions

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Treatment of Arsenic Poisoning• Routine measures are taken to stabilize the patient and

prevent further absorption of the poison.• Hypotension requires fluid replacement and may

necessitate pharmacological support with pressor agents such as dopamine.

• Chelation therapy often is begun with dimercaprol (3 to 4 mg/kg IM every 4 to 12 hours) until abdominal symptoms subside and charcoal (if given initially) is passed in the feces.

• Oral treatment with penicillamine then may be substituted for dimercaprol and continued for 4 days.

• Succimer is efficacious in the treatment of arsenic poisoning.

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Treatment of Arsenic Poisoning…• After long-term exposure to arsenic, treatment with

dimercaprol and penicillamine also may be used, but oral penicillamine alone usually is sufficient.

• Dialysis may become necessary with severe arsenic-induced nephropathy.

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Arsenic (As)• Chemistry:

– extremely complex because it can exist in metallic form, can be in trivalent and pentavalent state (charge of 3+ or 5+), and can be organic or inorganic

– widely distributed in nature (variety of forms)

• Sources:– smelting of gold, silver, copper, lead and zinc ores– combustion of fossil fuels– agricultural uses as herbicides and fungicides– cigarette smoke– occupational: largest source is manufacture of pesticides and herbicides

• Environmental fate:– found in surface and groundwater through runoff– accumulates in plants if soil conditions are right– bioaccumulates in aquatic ecosystems (so fish consumption is a source)

From: Klaassen et al., Chap. 19, Philp, Chap. 6

Sources of As• Eating food, drinking water, or breathing air containing arsenic.

– Herbal medicines (India/Pakistan Ayurvedic” remedies• Breathing contaminated workplace air. • Breathing sawdust or burning smoke from wood treated with arsenic. • Living near uncontrolled hazardous waste sites containing arsenic. • Living in areas with unusually high natural levels of arsenic in rock.

Arsenic: the poison of choice

• Napoleon and Paris Green

Arsenic (As)• pharmacokinetics and dynamics:

– absorbed via inhalation, ingestion and dermal exposure– mimics phosphate in terms of uptake by cells– Detoxified by methylation: decreased rates lead to

increased toxicity (individual susceptibility)– Can cross placenta– accumulates in liver, kidney, heart and lung - later in

bones, teeth, hair, etc.– half-life is 10 hr, excretion via kidneys

From: Klaassen et al., Chap. 19, Philp, Chap. 6

Arsenic Toxicity Mechanisms• binds to sulfhydryl groups (and disulfide

groups), disrupts sulfhydryl-containing enzymes (As (III))– inhibits pyruvate and succinate oxidation

pathways and the tricarboxylic acid cycle, causing impaired gluconeogenesis, and redu ced oxidative phosphorylation

• targets ubiquitous enzyme reactions, so affects nearly all organ systems

• substitution for phosphorus in biochemical reactions– Replacing the stable phosphorus anion in

phosphate with the less stable As(V) anion leads to rapid hydrolysis of high-energy bonds in compounds such as ATP. That leads to loss of high-energy phosphate bonds and effectively "uncouples" oxidative phosphorylation.

Arsenic Toxicity

• organic arsenicals>inorganic arsenicals>metallic forms

• trivalent>pentavalent• acute: severe abdominal pain, fever, cardiac

arrhythmia • chronic: muscle weakness and pain, gross

edema, gastrointestinal disturbances, liver and kidney damage, swelling of peripheral nerves (neuritis), paralysis– liver injury: jaundice– peripheral vascular disease - blackfoot

disease• chronic drinking water exposure in

Taiwan and Chile– cancer (skin, lung. Maybe other organs)

Arsenic Toxicity• skin disease:

– keratosis of palms and soles, and hyperpigmentation

Medical uses: Chemotherapy

• Causes cancer but also cures it?– Perhaps 2 mechanisms?

• Arsenic trioxide approved for acute promyelocytic leukemia (APL)– Used to be used 100 years ago as chemo

agent, dropped when others were invented

• New interest based on Chinese therapies– 70% remission rate– Causes cancer cells to puff up and die– Mechanism: supression of hTERT gene,

which codes for building blocks of telomerase, which keeps the end parts of chromosomes intact

• Result: chromosomes fuse end-to endCase study

Arsenic detection and treatment

• What would cause you to suspect As toxicity?

• What tests could you do to detect exposure or effects?– Mee's lines: white lines on fingernails

can be used to determine chronology of exposure

• What could you prescribe for treatment?– Gastric lavage, activated charcoal– Hemodialysis– BAL chelation

• WWII

Arsenic Problems: Bangladesh• As leached from underground sources into village wells of 1 million people

– 62% of wells tested exceeded WHO standard– ~ 35 million people exposed above US EPA standard

• 200,000 people suffering from As-induced skin lesions• problem may have been exacerbated by large scale withdraw of groundwater for irrigation

or by extensive use of fertilizers

From: Klaassen et al., Chap. 19, Philp, Chap. 6

Arsenic in Drinking Water in the US

• Setting the Standard• 1992: California toxicologist

argues that US EPA standard for As in drinking water would constitute a 1:100 risk of cancer for lifetime consumption

• EPA standard not originally based on cancer as an endpoint

• achieving a 1:1,000,000 risk would require dropping standard from 50 ppb to 2 ppt

• EPA revising standard to from 50 to 10 ppb in 2006

– consider cost to small communities

Arsenic On the Playground

• Pressure treated wood• CCA: 22 percent pure arsenic • A 12-foot section of pressure-treated

lumber contains about an ounce of arsenic, or enough to kill 250 people.

• "In less than two weeks, an average five-year-old playing on an arsenic-treated playset would exceed the lifetime cancer risk considered acceptable under federal pesticide law."

• EPA, 2004, banned from residential use

Poisoned Playgrounds: EWG

Iron• Iron is an essential component of myoglobin; heme

enzymes such as the cytochromes, catalase, and peroxidase; and the metalloflavoprotein enzymes, including xanthine oxidase and the mitochondrial enzyme a-glycerophosphate oxidase.

• Iron exists in the environment largely as ferric oxide or hydroxide or as polymers. In this state, its biological availability is limited unless solubilized by acid or chelating agents.

• The body store of iron is divided between essential iron-containing compounds and excess iron, which is held in storage.

• Ferritin is a protein-iron storage complex that exists as individual molecules or as aggregates.

152

Iron…• Internal exchange of iron is accomplished by the

plasma protein transferrin.• Adult men require only 13 mg/kg per day (about 1 mg),

whereas menstruating women require about 21 mg/kg per day (about 1.4 mg). In the last two trimesters of pregnancy, requirements increase to about 80 mg/kg per day (5 to 6 mg), and infants have similar requirements due to their rapid growth.

• Large amounts of ferrous salts are toxic, but fatalities are rare in adults. Most deaths occur in children, particularly between the ages of 12 and 24 months. As little as 1 to 2 g of iron may cause death, but 2 to 10 g usually is ingested in fatal cases.

153

Iron…• Signs and symptoms of severe poisoning may occur

within 30 minutes after ingestion or may be delayed for several hours.

• They include abdominal pain, diarrhea, or vomiting of brown or bloody stomach contents containing pills. Of particular concern are pallor or cyanosis, lassitude (tiredness and apathy), drowsiness, hyperventilation due to acidosis, and cardiovascular collapse.

• The corrosive injury to the stomach may result in pyloric stenosis or gastric scarring. Hemorrhagic gastroenteritis and hepatic damage are prominent findings at autopsy.

154

Treatment• Emesis• Deferoxamine is poorly absorbed after oral

administration, and parenteral administration is required in most cases. The drug is administered at 10 to 15 mg/kg per hour by constant infusion. For chronic iron intoxication , an intramuscular dose of 0.5 to 1.0 g/day is recommended.

• An orally effective iron chelator now under clinical investigation is deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one),

• Shock, dehydration, and acid-base abnormalities should be treated in the conventional manner.

155

Deferoxamine:deferoxamine mesylate• Isolated as iron chelate from Streptomyces pilosus and is

treated chemically to obtain the metal-free ligand.• Has desirable properties of a remarkably high affinity for

ferric iron coupled with a very low affinity for Ca.• Poorly absorbed after oral administration, and

parenteral administration is required in most cases. For severe iron toxicity (serum iron levels greater than 500 mg/dl), the IV is preferred. The drug is administered at 10 to 15 mg/kg per hour by constant infusion. Rapid boluses usually are associated with hypotension.

• For chronic iron intoxication (e.g., thalassemia), an intramuscular dose of 0.5 to 1.0 g/day is recommended.

156

Deferoxamine…• Causes a number of allergic reactions, including

pruritus, wheals, rash, and anaphylaxis. Other adverse effects include dysuria, abdominal discomfort, diarrhea, fever, leg cramps, and tachycardia.

• May cause neurotoxicity during long-term, high-dose therapy for transfusion-dependent thalassemia major; both visual and auditory changes have been described.

• A "pulmonary syndrome" has been associated with high-dose (10 to 25 mg/kg per hour) deferoxamine therapy; tachypnea, hypoxemia, fever, and eosinophilia are prominent symptoms.

• Contraindications: renal insufficiency and anuria; during pregnancy, the drug should be used only if clearly indicated.

157

Cadmium

Cadmium (Cd)• Relatively new metal in terms of humans• Sources:

– natural rock weathering– copper, lead and zinc smelting auto exhaust– cigarette smoke (a cigarette contains 1-2 ug

Cd)• Uses:

– metal plating – nickel-cadmium batteries– solders– paint pigments (blue)– plastic stabilizers– photographic chemicals– fungicides

• readily absorbed and accumulated in plants• Food as most common route of exposure

for general population

From: Klaassen et al., Chap. 19, Philp, Chap. 6

Cadmium (Cd)pharmacokinetics:• inhalation:

– smelters, cigarette smoke– 15-50% absorbed

• ingestion:• main source is liver and kidney of meats• 6% absorbed, greater if deficient in calcium,

zinc or iron Shenyang Copper Smelter

Cadmium (Cd)pharmacokinetics:• distribution:

– bound to albumin in plasma and red blood cells

– transported to liver, pancreas, prostate and kidney, with eventual transfer to kidney

• 50-75% of total body Cd is found in liver and kidney

• Metallothionein: protein rich in cysteine – traps Cd esp. in kidney

• synthesis induced by Cd• Elimination: urine

– half-life in humans is 20 - 30 years

Metallothionein

Cadmium (Cd)Toxicity• mechanisms:

– binding to –SH groups – competing with Zn and Se for inclusion into

metalloenzymes– competing with calcium for binding sites

(calmodulin)• Kidney toxicity:

– free Cd binds to kidney glomerulus– proximal tubule dysfunction

From: Klaassen et al., Chap. 19, Philp, Chap. 6

Cadmium (Cd)Toxicity• Lung toxicity:

– edema and emphysema by killing lung macrophages

• Skeletal effects:– Osteoporosis and osteomalacia

(pseudofractures)• Cancer:

– carcinogenic in animal studies– ~8% of lung cancers may be

attributable to Cd

From: Klaassen et al., Chap. 19, Philp, Chap. 6

Cadmium detection and treatment

• What would cause you to suspect Cd toxicity?• What tests could you do to detect exposure or

effects?– detected via increased excretion of

proteins, amino acids and calcium

• What could you prescribe for treatment?– Acute inhalation: fluid replacement,

mechanical ventilation– Acute ingestion: emesis and gastric lavage– Chronic:

• chelation therapy is ineffective so only treatment is to remove source

Cadmium (Cd)Epidemics/case studies

Japan (1940s)• effluent (outflow) from a lead-

processing plant washed over adjacent rice paddies for many years

– rice accumulated high level of Cd– community was poor (and

therefore malnourished with respect to calcium)

– acute toxicity: renal failure,anemia, severe muscle pain

• named "Itai-Itai" disease ("ouch, ouch")

From: Klaassen et al., Chap. 19, Philp, Chap. 6

Itai-itai victim

Cadmium (Cd)Epidemics/case studies

Sewage waste disposal

• contains high levels of N and P, and organic matter, so makes sense to use as fertilizer on fields

• also can contain Cd, which is readily accumulated in plants

• livestock grazing on fields can accumulate Cd in liver and kidney– 6-8x as much as sheep grazing

on clean fields

From: Klaassen et al., Chap. 19, Philp, Chap. 6

Land application

Cadmium - Cd• No constructive purpose in the body • Extremely toxic even in low concentrations, accumulates in organisms and ecosystems• Chemical properties similar to zinc – exchange in an

organism (also can replace Cu, Fe, Ca)• Sources: earth crust, fossil fuels, plastic materials

industry, electronic industry, tobacco fume• Absorption after digestion or less by inhalation (but

here better bioavailability)• The first documented case of mass cadmium poisoning

in the world - in Toyama Prefecture, Japan in 1950 – Itai-Itai disease (river polluted with waste from factory, water used on rice fields – poisoning from rice)

- In blood transported bound to proteins (formation of complexes), in higher concentrations bound to erythrocytes

- Deposition in liver, kidneys and gonads

• Mechanism of action:- Inhibition of many enzymes, antagonist to many

metals – Zn, Cu, Ca, Fe- Disturbance of cholecalciferol production, thus

influences Ca metabolism- Inhibition of specific hydrolase in testis – affects

activity of gonads- Formation of complexes, which are digested in

kidney –release of Cd – damage- Xenoestrogennic effect

• Clinical signs:- Acute exposure: - Cadmium fumes may cause flu like symptoms

including chills, fever, and muscle ache - More severe exposures can cause tracheo-

bronchitis, pneumonitis, and pulmonary oedema. Symptoms of inflammation may start hours after the exposure and include cough, dryness and irritation of the nose and throat, headache, dizziness, weakness, fever, chills, and chest pain.

- Ingestion of any significant amount of cadmium causes immediate poisoning and damage to the liver and the kidneys. Also CNS disturbances occur and changes in blood count

- Chronic exposure: - Osteomalacia, osteoporosis – disturbance of vitamin

D and calcium metabolism - Pain in the joints and the back, and also increases

the risk of fractures. In extreme cases of cadmium poisoning, the mere body weight causes a fracture

- The kidneys lose their function to remove acids from the blood. The kidney damage inflicted by cadmium poisoning is irreversible and does not heal over time.

- Gout, a form of arthritis due to the accumulation of uric acid crystals in the joints (hyperuricemia).

- Some patients may lose their sense of smell (anosmia)

- Damage of gonads, suspected carcinogen – tumours of testes

• Pathological examination:- gastritis, enteritis, nephritis, stomatitis,

degeneration of liver, necrosis on testes

• Treatment : - Chelating agents – EDTA –only partially effective - Administration of calcium