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HEAVY METAL TOXICITYProf. DR. Sri Agus Sudjarwo

Knowledge ObjectivesThe student should understand and know:1. metabolism, absorption, distribution, excretion and

mechanism of toxicity for each of the metals.2. characteristics of a good biological chelating agent.3. uses of chelating agents in terms of:

a. route of administrationb. mechanism of actionc. specificityd. stability of the heavy metal -chelator complexe. toxicity of chelator and the complex

In Utero ExposureIn Utero Exposure

Heavy Metals that bioconcentrate in Heavy Metals that bioconcentrate in placental tissue:placental tissue:MercuryMercuryLeadLeadCadmiumCadmiumArsenicArsenic

Hazard + Exposure = Risk

Individual Susceptibility

Dose / Response

Sources:› 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

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

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

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

synthesis induced by Cd in kidney Elimination: urine

› half-life in humans is 20 - 30 years

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

associated with beta2-macroglobulin

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

Toxicity Lung toxicity:

› edema and emphysema by killing lung macrophages and inhibition alpha 1 antitrypsin

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

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

Sources:› smelting of gold, silver, copper, lead and zinc

ores› combustion of fossil fuels› agricultural uses as herbicides and

fungicides› cigarette smoke

Environmental fate:› accumulates in plants › bioaccumulates in aquatic ecosystems (so

fish consumption is a source)

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

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

reduced oxidative phosphorylation

-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.

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)

› Diabetes Melitus

skin disease:› keratosis of palms and soles, and hyperpigmentation

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

Leaded gasoline, paint, pb pipes Pb affects nervous system, Heam

biosynthesis and Kidney Children are at high risk

› Poor blood brain barrier› Absorb 30-40% of ingested Pb

( Pb&Ca)› Decreased iq tests at very low levels

of Pb 10-20ug/dL

DistributionInitially carried in red cells and distributed to soft tissues (kidney and liver); redistributed to bone, teeth and hair mostly as a phosphate salt. Rates of absorption and distribution are greatly influenced by dietary intake and body stores of phosphate, calcium and iron relative to lead# high PO4, Pb storage in bone# high Vitamin D, Pb storage in soft tissue# low PO4, Pb sequestered in soft tissue# high Ca++, Pb sequestered in soft tissueHalf life in blood 30-60 days, bone 20-30 years

Lead binds to enzymes that have functional sulfhydryl groups, rendering them nonfunctional and further contributing to impairment in oxidative balance, leading to:

Autoimmunity

Depletion of glutathione

Increased levels of free radicals in tissue

Adult have well developed BB barrier absorb 7% of ingested Pb and it affects primarily the periferal nervous system

Destroys myelin coating on nerves ( insulation like a wire) affects the conduction velocity of nerves( segmental demyelination, widening of nodes of ranvier)

“ Blood lead concentrations as low as 2.07 µg/dL likely represent a public health hazard.”

In NHANES 1999 to 2000, 38% of US adults had a blood lead level above this threshold.

Circulation 2006;114:1347-1349

42% of cataracts are related to bone leadJAMA. 2004;292:2750-2754

Pregnancy and lactation Lead mobilization during pregnancy is

hazardous to the fetus Lead passes across the placenta almost

without hindrance. Blood lead levels in mother and fetus Elderly with osteoporosis

Environ Health Perspect 1996;104(Suppl 1)

Inorganic Pb goes to the CNS and decreases IQ test scores

Children absorb more Pb because of Ca and growth phase

Most important effects on CNS and they occur at low levels in children ( why Pb was banned from gasoline)

ALA dehydratase is the rate Limiting enzyme in the biosynthesis of Haem

Enzyme has Fe binding site and it is very sensitive to inhibition by Pb

Inhibition by Pb results in porphyrin buildup in the blood and in the urine ( depending upon the degree of inhibition urine may be brown or black)

Inhibition of ALA dehydatase may be used as a biomarker of Pb exposure

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Usually in adults results in a fanconi syndrome and leakage of phosphate and other nutrients in the urine

Effects are reversible if stop Pb exposure as are the effects of Pb on nerve conduction and Heam biosynthesis

WOMEN• lead crosses the placenta • low infant birth weight• retarded mental development• miscarriages• premature birth

MEN• impotence• sterility• altered sperm-birth defects

Pb blood levels indicate relatively recent exposure ( range from 1-20 ug/dL, with >20 dangerous for children, >50 adult toxicity)

Pb redistributes to the bone and behaves Like Ca ( Ca and phosphate mobilization can mobilize Pb, results in episodes of toxicity)

Half life of Pb in bone maybe 10 years and can cause formation of pb lines in bones

Treat symptoms and try to lower Pb levels in blood and urine. Renal. Nueral and Haem effects are reversible

Chelating agents EDTA ( iv) DMCA ( oral)

Carcinogenic in rats at high doses induces renal cancers ( may be due to Pb inclusion bodies)

Slightly mutagenic Teratogenic

Three forms of Hg with very different toxicities ( Inorganic Hg, Organic Hg and Hg Metal)

Hg metal ( thermometers, electrodes for electrolysis)

Organic Hg ( Fungicide, chemical industry)

Inorganic Hg ( fur cutting, felt hat manufacture)

Most of the Environmental levels Of Hg come from natural sources ( valconos etc)› Swordfish accumulate Hg

Metallic Hg ( dental fillings) Methyl Hg ( Minimatta bay, IraQ)

Activity (mcg)/m³

Chewing Food 68 Tooth Brushing 272 Place Amalgam 2,000 Remove Amalgam 4,000 Polish Amalgam 4,000

Source Daily Intake

(mcg)• Amalgams 3.8 → 21

• Fish 3.0

• Other foods 3.6

Inorganic ( effects mainly the Kidney) Methyl Hg ( CNS effects sensory input

loss of hearing, periferal vision delayed onset of symptoms may be related to cellular conversion of Methy Hg to Inorganic Hg

Metallic Hg ( psychiatric effects, motor trembling in lips and hands, depression)

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Inorganic Hg binds to SH groups in cells and Inactivates enzymes ( inactivation of enzymes that protect the cell from oxidative stress SOD, Catalase)

Methyl Hg penetrates all cells in the body particularly the CNS

Hg metal may also form inorganic Hg and it also can penetrate many strauctures

Bal Or Pen for Inorganic Hg and methyl Hg

Methyl Hg delayed onset of symptoms can confirm exposure by Hair measurements

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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 the chelator-metal complex should be less

toxic than the metal alone

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2,3-dimercatopropanol (dimercaprol) also known as

British Anti Lewisite (BAL)- given IM in peanut oil

Use: arsenic, mercury, antimony, lead, gold, zinc,

bismuth.

Half life is less than onehour.

Toxicity:

i. CNS convulsions in high dose

ii. Increased Blood pressure due to tachycardia and

peripheral

constriction of arterioles.

iii. Renal toxicity can be reduced by alkalizing the

urine, which protects against

dissociation of the metal-BAL complex. Toxicity is

50%

+ Anxiety

+ increased blood pressure

+ nausea, vomiting and headache

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Ethylene diamine-tetraacetic acid (EDTA) given IV as the Calcium disodium salt.

Usesi. Disodium EDTA binds calcium in blood to prevent clotting- used in blood collection and storageii. chelator for leadiii. only chelates circulating metal because EDTA cannot enter inside the cell membraneiv. frequently used in combination with BAL or penicillamine for treatment of lead poisoning

Toxicityi. tubular destruction due to release of metal or the metal-EDTA complex in thekidney.ii. thrombophlebitis in some cases- too rapid infusion

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d-isomer of beta,beta-dimethylcysteine (Penicillamine) given orally

Usesi. lead, mercury, arsenicii. copper - Wilson’s disease

Toxicityi. l-isomer depletes pyridoxine (Vitamin B6), therefore d-isomer is used clinicallyii. fever, skin rashes, leukopenia, nausea, vomitingiii. anaphylactic reactions (do not use in the case of allergic to penicillin)

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DeferoxamineUses: iron (Fe3+) poisoning IM or slow IV. It has also been used orally to chelate iron poisoningToxicityi. skin rashii. histamine release with reduced blood pressure (shock)iii. Cataracts

Trientine (triethylenetetramine HCl) is a polydentate chelating agent. It chelates copper and less toxic than penicillamine, but it is teratogenic in long term use. It is used for treating wilson’s disease (hepatolenticular degeneration).

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