Heavy Metal Toxicity

Dr Tajdar Husain Khan

Mercury

Arsenic

Lead

Definitions ‘Metals’ originally included only gold, silver,

copper, iron, lead, and tin. Dense, malleable, lustrous Conduct heat and electricity, cations

Many other elements since added to the list with some of these characteristics

‘Metalloids’ are elements with features intermediate between metals and non-metals. Example: arsenic

‘Heavy metal’ A metal having an atomic weight

greater than sodium, a density greater than 5 g/cm3

Some notion of toxicity Usually includes lead, cadmium

and mercury Many others may variably be

added to list

Lead

Soft blue-gray metal Found in the

natural environment Was added to paint

and gasoline in past Still used in

consumer products

What is Lead?What is Lead?

the natural ore galena

How Does Lead Get Into the Environment?How Does Lead Get Into the Environment?

Deterioration of lead-based paint

Leaded gasoline Businesses that

involve lead Lead mines or

smelters 

How Are People Exposed to Lead?How Are People Exposed to Lead?

Dust, paint, and/or soil Contaminated food,

water, or alcohol Some imported home

remedies and cosmetics

Endogenous exposure

Lead in Ethnic ProductsLead in Ethnic Products

Mexican: azarcon,greta, liga, Maria Luisa, alarcon, coral, rueda

Asian: chuifong, tokuwan, ghasard, bali goli, kandu,surma, ba-baw-san

Middle Eastern: alkohl, saoott, cebagin

For more examples, see Appendix 1 of: http://www.cdc.gov/nceh/lead/CaseManagement

Azarcon

Azarcon is a folk remedy that contains 85-96% lead tetroxide

Other lead containing remedies include Greta.

Pb Toxicity to Plants, Animals From air, soil, lead shot Dependent on species

Ex: barley sensitive Ex: goldfish insensitive

May inhibit seed germination Paralyzes bird gizzard starvation,

death Impt: ingestion by animals further up

food chain

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Lead Poisoning

Lead has no known biological function. There is no proven safe lower limit for lead. Lead Pb++, competes with Ca++, Fe++

It is cheap, useful,easy to mine, therefore Lead is ubiquitous- in air, food, water, soil,

ceilings etc. Leaded petrol means that all environmental

dusts are high in lead-contaminating ceiling dust, topsoil, window wells etc.

Biologic FateBiologic Fate

Most lead is excreted Children and pregnant

women absorb morelead than others

Exchanged betweenblood, soft tissues,and mineralizingtissues

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Distribution of Lead 95% long bones. Binds into matrix. Released during

osteolysis. 4% brain,liver,

kidneys. 1% blood. Crosses placenta,

foetal BBB is open

Neurologic Effects of LeadNeurologic Effects of Lead

Neurologic effects onchildren documentedat levels below 10 mcg/dL

Low exposure effects:lowered IQ, attention deficits,and impaired hearing

High exposure effects:irritability, convulsions, coma, or death

Similar effects in adults at higherexposure levels

Renal Effects of LeadRenal Effects of Lead

Acute exposure: reversible effects

Chronic exposure: nephropathy (chronic interstitial nephritis)

Childhood exposures → adult renal disease

Hematologic Effects of LeadHematologic Effects of Lead

Interferes with production of hemoglobin

Can induce two kinds of anemia: Acute exposure → hemolytic Chronic exposure → synthetic

Threshold for adults: 50 mcg/dL Threshold for children: 40 mcg/dL

Pb Toxicity within Cells

Not fully known Highly reactive to –SH grps

Mercaptide R—S—Pb—S—R

Can inactivate enz’s, other prot’s Book ex: adenyl cylase (brain

transmission) Book ex: aminotransferase (aa metab)

Similar to Ca, competes At presyn. receptor

Now decr’d Ca avail Bone

Interacts w/ nucleic acids Decr’s protein synth

Decr’d binding tRNA to ribosomes OR may increase protine synth

Nucleus

Ex: Pb best studied Renal tubule DNA, RNA, prot syntheses

stim’d So biochem changes in nuclear structure,

function Karyomegaly Can renal adenocarcinoma w/ high dose

Ex: Methyl-Hg, Cd inhibit nucleic acid synth w/ acute exposure

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Toxicology of Lead 1

Lead disrupts the main structural components of the

blood-brain barrier by primary injury to astrocytes

with a secondary damage to the endothelial

microvasculature. Within the brain, lead-induced

damage occurs preferentially in the prefrontal

cerebral cortex, hippocampus and cerebellum.

Some characteristic clinical features of lead

poisoning may be attributed to this specific

anatomical pattern.

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Toxicology of Lead contd Although the molecular targets for lead are unknown, a vast

amount of evidence accumulated over many years has shown

that lead disrupts processes that are regulated by calcium.

Picomolar concentrations of lead can replace micromolar

concentrations of calcium in a protein kinase C enzyme assay.

Furthermore, lead activates protein kinase C in intact cells and

induces the expression of new genes by a mechanism dependent

on protein kinase C. We propose that the learning deficits caused

by lead are due to events regulated by protein kinase C that most

likely occur at the synapse.

Bressler J, Kim KA, Chakraborti T, Goldstein GMolecular

mechanisms of lead neurotoxicity. Neurochem Res 1999

Apr;24(4):595-600

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Toxicology of Lead 3

The cellular, intracellular and molecular mechanisms of

lead neurotoxicity are numerous, as lead impacts

many biological activities at different levels of

control: at the voltage-gated channels and on the

first, second and third messenger systems. These

effects could be related to lead's ability to interfere

with the regulatory action of calcium in cell functions.

Finkelstein Y, Markowitz ME, Rosen JF Low-

level lead-induced neurotoxicity in children: an

update on central nervous system effects Brain

Res Brain Res Rev 1998 Jul;27(2):168-76

Pharmacokinetics and Pharmacoynamics

Distributed extensively throughout tissues: bone, teeth, liver, lung, kidney, brain, and spleen Body lead storage: bones- can constitute a source of

remobilization and continued toxicity after the exposure has ceased

Lead crosses the BBB and concentrates in the gray matter Lead crosses the placenta Excretion:

Kidneys. The excretion increases with increasing body stores (30g-200 g/day)

Feces

Signs and SymptomsSigns and Symptoms

Patient may appear asymptomatic Impaired abilities may include

Decreased learning and memory Lowered IQ Decreased verbal ability Impaired speech and hearing functions Early signs of hyperactivity or ADHD

Symptoms vary by exposure level

Signs and Symptoms: Low ToxicitySigns and Symptoms: Low Toxicity

Myalgia or paresthesia Mild fatigue Irritability Lethargy Occasional abdominal discomfort

Signs and Symptoms: Moderate ToxicitySigns and Symptoms: Moderate Toxicity

Arthralgia General fatigue Difficulty concentrating/Muscular

exhaustibility Tremor Headache Diffuse abdominal pain Vomiting Weight loss Constipation

Signs and Symptoms: Severe ToxicitySigns and Symptoms: Severe Toxicity

Paresis or paralysis Encephalopathy—may abruptly

lead to seizures, changes in consciousness, coma, and death

Lead line (blue-black) on gingival tissue

Colic (intermittent, severe abdominal cramps)

Long bone radiographsLong bone radiographs

Lead Lines

Lead Lines

“Lead Lines” in five year old male with radiological growth retardation and blood lead level of 37.7µg/dl

(Photo courtesy of Dr. Celsa López Campos, Clinical Epidemiologic Research Unit, IMSS, Torreón, México)

Clinical ManagementClinical Management Most important step is removal of

lead exposure Referral to health department Environmental Investigations Other potential sources of lead Education about prevention

Chelation TherapyChelation Therapy

At very high blood lead levels (over 40 mcg/dL for children), chelation may be indicated

Consult with physicians or medical centers with chelation therapy experience

Instructions to PatientsInstructions to Patients

• Reduce source(s) of lead exposure• Maintain a diet high in calcium and

iron• Continue to monitor blood lead levels• If workplace exposure suspected,

contact: Workplace health and safety officer Occupational Safety and Health

Administration (OSHA)

SummarySummary

Primary sources: deteriorated paint, contaminated dust or soil, and some products

Lead is very dangerous to young children and the developing fetus

Certain workers may be exposed Focus on preventing exposure/removing

source

Arsenic

Introduction Arsenic is common in the environment Sources

Groundwater Arsenic containing mineral ores Industrial processes

Semiconductor manufacturing (gallium arsenide) Fossil fuels Wood treated with arsenic preservatives Metallurgy Smelting (copper, zinc, lead) and refining of metals and

ores Glass manufacturing

Introduction Commercial products

Wood preservatives Pesticides Herbicides Fungicides

Food Seafood and fish

Others Antiparasitic drugs Folk remedies

Soil Pica Soil pica behavior: when children ingest large

amounts of soil at a time (e.g. up to 1 teaspoon or 5,000mg)

Children 1 to 2 years old have strongest soil pica behavior, which may occur as part of their normal exploratory behavior

Preschool children also purposely eat soil for unknown reasons

Some cultures promote eating soil, specifically clay, as part of a cultural practice

What contains Arsenic?• Arsenic was detected in fruits, vegetables,

grain products, fast foods, dairy products, BUT mostly seafoods

– Arthropods (shrimp)– Fish– Bivalves (clams)– Algae

• Arsenic concentration for all seafoods in fast food sandwiches was 2.1 μg/g (dry weight). (Nielson et al. 1991)

• Average intake is about 10–50 µg/day (humans)

– More if seafood is consumed

Arsenic into the Body• Arsenite is more toxic than

arsenateArsenite (0) accumulation in cells is faster than arsenate (-).

It can pass through the cell membrane, but also actively transported into cells

Arsenite = aquaglycoporins 7 and 9 Which also transports water and glycerol

Arsenate = phosphate transporter

• Metabolized by methylationThen excreted in the urine. Methylation occurs in liver, kidney and lungs.

More on MethylationReduce arsenite (via purine nucleoside phosphorylase) to arsenate then methylation (via enzymatic transfer of the methyl group from S-adenosylmethionine (SAM) to arsenite to form monomethylarsonic acid (MMAV) )

Gene that codes for the enzyme responsible for this reaction is just like Cyt 19arsenite+SAM→MMAVMMAV+thiol→MMAIIIMMAIII+SAM→DMAVDMAV+thiol→DMAIIIDMA III = Dimethylarsinous Acid

• Most humans exposed to arsenic excrete 10–30% inorganic arsenic, 10–20% MMA(V+III) and 60–80% DMA(V+III),

Bound to red blood cellsDistributes to liver Binds to sulfhydryl containing

proteins - concentrates in the hair and fingernails (Mees’ Lines)

Distribution

As5+ (Arsenate)

As3+ (Arsenite)

Methylarsenite (in liver)

Dimethylarsenite

(readily eliminated – urine)

Metabolism

3-5 days Excreted: Urine (majority);Skin cells ;SweatT1/2 of inorganic arsenic in the blood is 10 hrs and of organic

arsenic is around 30 hours2-4 weeks after the exposure ceases, most of the remaining

arsenic in the body is found in keratin-rich tissues (nails, hair, skin)

Inorganic arsenic is converted to organic arsenic (biomethylation to monomethyl arsonic- MMA or DMA) in the liver. This may represent a process of detoxification

Renally excreted (30-50% of inorganic arsenic is excreted in about 3 days). Both forms are excreted depend on the acuteness of the exposure and dose

ToxicokineticsHALF-LIFE

Inorganic arsenic (arsenic trioxide) 70 to 180 mg can be fatal

Constriction of the throat with difficulty in swallowing

Sever intestinal pain Vomiting, diarrhea Muscle cramps Severe thirst Coma and death

Acute - Toxicity

Chronic exposure (drinking water)• Skin cancer (recognized 100 years ago)• Garlic odor on breath• Excessive perspiration • Muscle tenderness and weakness• Changes in skin pigmentation• Paresthesia in hands and feet • Peripheral vascular disease• Gangrene of feet – Blackfoot disease

Chronic - Toxicity

Pathophysiology Trivalent forms:

bind to sulfhydryl groups leading to inhibition of enzymatic systems

inhibit the Krebs cycle and oxidative phosporylation. These lead to inhibition of ATP production

Pentavalent forms can replace the stable phosphate ester bond in ATP

and produce an arsenic ester stable bond which is not a high energy bond

Endothelial damage, loss of capillary integrity, capillary leakage, volume loss, shock

Treatment of acute poisoning Supportive care Chelation therapy should be

instituted promptly (minutes to hours) BAL (British anti-Lewisite)- IM Succimer (DMSA)- PO DMPS – PO, IV D-Penicillamine- less effective

What is Cadmium? A metal most often encountered in earth’s crust combined

with chlorine (cadmium chloride), oxygen (cadmium oxide), or sulfur (cadmium sulfide)

Exists as small particles in air, result of smelting, soldering or other high temp. industrial processes

By-product of smelting of zinc, lead, copper ores Used mainly in metal plating, producing pigments, batteries, plastics and as a neutron absorbent in nuclear reactors

Cadmium is used in batteries

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 ingestion (1-5%) or by inhalation (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. Slow excretion (up to 10 years). Does not go to milk and to foetus.

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

many metals – Zn, Cu, Ca, Fe- Disturbance of cholecalciferol (vit. D)

production, thus influences Ca metabolism- Inhibition of a specific testis hydrolase –

affects activity of gonads- Xenoestrogennic element- Formation of complexes, which are digested

in kidney – release of Cd - damage

Exposure Sources – By Mouth Foods (only a small amount is absorbed) Itai Itai disease (cadmium contamination + diet low in calcium &

vitamin D) Cadmium a component of chuifong tokwan, sold illegally as a miracle

herb Tobacco smoke (a one pack a day smoker absorbs roughly

5 to 10 times the amount absorbed from the average daily diet)

Low levels are found in grains, cereals, leafy vegetables, and other basic foodstuffs

Biologic Fate Cadmium has no known beneficial function

in the human body Is transported in the blood bound to

metallothionein Greatest concentrations found in kidneys

& liver Urinary excretion is slow Biologic half-life may be up to 30 yrs.

Why Is Cadmium a Health Hazard?

Affects lungs & kidneys 2o effects on skeletal system Binds to sulfhydryl groups, displacing other

metals from metalloenzymes, disrupting those enzymes

Competes with calcium for binding sites on regulatory proteins

Lipid peroxidation has been demonstrated

High Affinity Metal Binding Proteins

In cytosol Intracellular “sinks”

Hold toxic metals away from Sensitive organelles Metabolic sites

Overwhelmed w/ very high metal exposure

Cd Toxicity within Cells Energy prod’n

Chloroplast photophosph’n Mitochondria ATP synth, NADH ox’n,

electron transport Enzyme inhib’n

Book ex: alkaline phosphatase, myosin ATPases

Binds –SH grps Competes w/, displaces Zn

Mitochondria Major intracell

target of many metals Rapid transport

metals across mitoch membr’s

Has high metab activity

Sensitive to disruption

Respiratory Effects Acute inhalation may mimic metal fume fever

Fever, chills & decreases in FVC and FEV1Initial symptoms: flu-like symptoms Later: chest pain, cough, dyspnea Bronchospasm and hemoptysis may occur

Chronic inhalation MAY result in impairment of pulmonary function with reduction in ventilatory capacity

Renal Effects May cause tubular and glomerular

damage with resultant proteinuria May follow chronic inhalation or

ingestion Latency period of ~10 yrs Nephropathy is progressive &

irreversible

Renal Effects Chronic exposure – progressive renal

tubular dysfunction Toxic effects are dose related Critical renal concentration Decreased GFR Chronic renal failure Kidney stones more common

Skeletal Effects Bone lesions occur late in severe

chronic poisoning Pseudofractures Other effects of osteomalacia and

osteoporosis Appear to be secondary to increased

urinary calcium and phosphorus losses

Signs and Symptoms - Acute

Food poisoning (ingestion) Bronchitis (inhalation) Interstitial pneumonitis (inhalation) Pulmonary edema (inhalation) A condition that mimics metal fume fever

Children who eat dirt (pica behavior) are at risk

Signs & Symptoms - Chronic

Chronic exposure may result in renal dysfunction and bone disease

Mild anemia, anosmia & yellow discoloration of the teeth may occur

Chronic exposure may effect the sense of smell

Evaluation Inhalation

Chest radiograph Chronic exposure

Renal tests Serum electrolytes, BUN, serum and urinary

creatinine, serum creatinine, cadmium in blood & urine, urinary protein

Other tests – CBC & LFTs

Biologic Indicators 24 hour urine cadmium – reflects exposure over time an total body burdenBlood cadmiumCadmium in hair – not reliableUrinary ß2-microglobulin – evaluate urine levels > 300 g/g creatinine Urinary RBPUrinary metallothionein (MT)

No quantitative relationship between hair cadmium levels and body burden

Direct

Indirect

Treatment & Management

Acute Exposure No proven treatment

Supportive treatment includes fluid replacement, oxygen, mechanical ventilation. With ingestion, gastric decontamination by emesis or gastric lavage soon after exposure. Activated charcoal not proven effective

Chronic – Prevent further exposure

Mercury

Mercury Occurs in three forms (elemental, inorganic

salts, and organic compounds)

Contamination results from mining, smelting, and industrial discharges. Mercury in water can be converted by bacteria to organic mercury (more toxic) in fish.

Can also be found in thermometers, dental amalgams, fluorescent light bulbs, disc batteries, electrical switches, folk remedies, chemistry sets and vaccines.

Mercury - Exposure Elemental

liquid at room temperature that volatizes readily

rapid distribution in body by vapor, poor in GI tract

Inorganic poorly absorbed in GI tract, but can be caustic dermal exposure has resulted in toxicity

Organic lipid soluble and well absorbed via GI, lungs

and skin can cross placenta and into breast milk

Elemental Mercury At high concentrations, vapor inhalation produces

acute necrotizing bronchitis, pneumonitis, and death.

Long term exposure affects CNS. Early: insomnia, forgetfulness, anorexia, mild

tremor Late: progressive tremor and erethism (red palms,

emotional lability, and memory impairment) Salivation, excessive sweating, renal toxicity

(proteinuria, or nephrotic syndrome)

Dental amalgams do not pose a health risk.

Inorganic Mercury Gastrointestinal ulceration or

perforation and hemorrhage are rapidly produced, followed by circulatory collapse.

Breakdown of mucosal barriers leads to increased absorption and distribution to kidneys (proximal tubular necrosis and anuria).

Acrodynia (Pink disease) usually from dermal exposure maculopapular rash, swollen and

painful extremities, peripheral neuropathy, hypertension, and renal tubular dysfunction.

Organic Mercury Toxicity occurs with long term exposure and

effects the CNS. Signs progress from paresthesias to

ataxia, followed by generalized weakness, visual and hearing impairment, tremor and muscle spasticity, and then coma and death.

Teratogen with large chronic exposure Asymptomatic mothers with severely

affected infants Infants appeared normal at birth, but

psychomotor retardation, blindness, deafness, and seizures developed over time.

Hg Toxicity within Cells Inhib’n enzymes

Selective affinity to –SH grps R—SH + CH3Hg R—S—Hg—CH3 +

H+ Incr’s permeability Na+, K+

Inhibits active transport mech’s Disrupts fluid/electrolyte balance

Affects chromosomes, mitosis mutagenesis

Protection against Hg Toxicity Metallothionein

Kidney damage when metallothionein saturated

Se Mech unknown, but Se binds cysteine

more tightly than Hg Vitamin E

Mech unknown

Cellular Injuries

Dependent on individual physiological factors Developmental stage Sex Nutritional status Toxicant dose Toxicant combination

Diagnosis and Treatment

Dx made by history and physical and lab analysis. Inorganic mercury can be measured in 24 hour urine collection; organic mercury is measured in whole blood.

The most important and effective treatment is to identify the source and end the exposure

Chelating agents (DMSA) may enhance inorganic mercury elimination. Dimercaprol may increase mercury concentration in the brain.

Mercury - Prevention Controlling mercury compounds in market Elemental mercury spills:

Roll onto a sheet of paper and place in airtight container

Use of a vacuum cleaner should be avoided because it causes mercury to vaporize (unless it is a Hg Vac)

Consultation with environmental cleaning company is advised with large spills.

State advisories on public limit or avoid consumption of certain fish from specific bodies of water.