Heavy metal and human health

Background Those metals with a specific gravity

of greater than 4.0.

Mainly produced from industrial

activities

most hazardous heavy metals are-

1. arsenic (As)

2. lead (Pb)

3. mercury (Hg)

4. cadmium (Cd)

Factors affecting

toxicity1. The total dose absorbed

2. The exposure either acute or

chronic.

3. Age of the person

E.G.-Young children are more

susceptible to lead

4- The route of exposure

E.g.- Elemental mercury is

inert in the gastrointestinal

tract and through intact skin,

but inhaled or injected

elemental mercury have

disastrous effects.

LEAD

Mode of Exposure 2nd most hazardous substance

Lead poisoning is the most

important chronic environmental

illness

In the environment lead is in

organic and inorganic

compounds.

Inorganic lead compounds are

less toxic

Occupational exposure

Battery makers

Cable makers

Glass makers/polishers

Gunshot/gun barrel makers

Jewelers

Lead burners

Painters

Pigment makers

Pipe cutters

Printers

Non-occupational exposure

Battery burning

Bullet retention

Cooking in leaden pots

Ingestion of paints

gasoline

cigarette smoke.

surface paints onthe toys.

stagnant water inpipes.

Absorption1. GI tract

Children are at greater risk for lead absorption(adults:11%-16%,children : 40% - 50%)

Absorption increased with fe, ca, zndeficiency

2. Lungs

50% - 70% if < 1 μm

3. Skin

Inorganic lead is non-absorbable

Organic lead is readily absorbed

DistributionExchanged in 3 compartments:

1. Blood

2. Soft tissue (liver, kidneys, lungs,

brain, spleen, muscles, and heart)

3. Mineralizing tissues (bones and

teeth). In bone it is stored for

several years. Redistribution

occurs in pregnancy

Crosses the placenta

Exists in breast milk.

Malnutrition and iron

deficiency-higher lead

absorption in the mother.

Pathophysiology Lead inhibit enzyme with sulfhydryl

groups Delta amino levulinic acid dehydratase

(formation of porphyrin ring) and ferrochelatase (incorporation of iron into porphyrin ring) inhibited, decrease in heme production

Basophilic stippling of erythrocytes

Pb2+ disturbs intracellular ca2+

homeostasis(calmodulin, protein

kinase C, ca2+ -dependent K+

channels and neurotransmitter

release disturbed)

The burton line or gingival lead line

in gums

CNS- Children are most succeptible

Symptoms Acute toxicity-

vomiting, constipation, ataxia,

somnolence

Lead nephropathy

Elevated intracranial pressure

(icp)-lead encephalopathy.

Chronic toxicity (plumbism)

Low-level exposure over a long

time

• Early symptoms-

- Muscle weakness, and

paresthesias

- Confusion/ irritability

- Metallic taste in mouth

Late complication-

Diminished libido

Anemia

Peripheral neuropathy inextensor surfaces k/a wristdrop and/or foot drop (mostcommon in adults)

Burton

line

Wrist drop

• In children-• Permanent learning disability

and behavior disorders.

• Hearing loss, aggression

• Delayed growth.

DIAGNOSIS Blood lead level (BLL)(> 9 μg/dl )

CBC- basophilic stippling of red

rbcs,anemia(microcytic,hypochoch

romic)

Lead in bones (x-ray fluorescence,

XRF)

Acute poisoning- radiographic

examination of the abdomen

Free erythrocyte

protoporphyrin level (FEP)

High blood lead lead but FEP

normal- acute

Both are high- chronic

Regulatory limits

EPA –

15 ppb in drinking water,

OSHA- 0.15 µg/cu.m in air for 8 hrs work

MERCURY

Sources 3rd on the top hazardous

substances.

Naturally-degassing of the earth's

crust and volcanic eruption.

Mining, smelting, and industrial

discharges

Atmospheric mercury comes to the

earth in rain

Paint, fungicide .

Thermometers, thermostats,

fluorescent light bulbs, amalgams

Antiseptics (mercurochrome and

merthiolate),

Vaccines (flu vaccines contain

thiomersal)

Mode of Exposure three forms Elemental◦ Inhalation(main source)

◦ Poorly through GI tract, Skin contact

Inorganic◦ Poorly through GI tract(7-15%).

◦ Dermal exposure causes toxicity

Organic◦ Lipid soluble

◦ well absorbed via GI (90-100%); lungs and skin

◦ Cross BBB and affects CNS

◦ Can cross placenta and into breast milk

Pathophysiology Binds to sulfhydryl of enzymes

(cellular stress response, protein

repair, and oxidative damage

prevention.)

Methylmercury inactivates Na+/K+-

ATPase(membrane depolarization

eventual cell death)

Industrial mercury-inorganic form

aquatic organisms and vegetation

convert it to methylmercury.

Then mercury becomes

biomagnified in the fish. (Fish

protein binds about 90% of the

consumed methyl mercury )

Even by cooking it cannot be

removed

Minamata disease-(Minamata Bay)

After eating methyl mercury containing fish neurologic damage such as visual loss, extremity numbness, hearing loss, and ataxia

Babies exposed in utero and also exposed after birth through breast milk

Infants with mental retardation, blindness, deafness, and seizures

Elemental

MercuryAcute-

Acute necrotizing bronchitis(vapor

inhalation)

Pneumonitis

Skin, and nose irritation

Long term exposure affects CNS.

◦Early: insomnia, impaired memory, mild tremor

◦Late: erethism (red palms, emotional lability (irritability and nervousness), ◦ renal toxicity (proteinuria, or nephrotic syndrome)

Mercurial erethism

Inorganic Mercury Gastrointestinal ulceration and hemorrhage

Proximal tubular necrosis and anurea

Acrodynia (pink disease, erythroedema, or

feer’s disease) in dermal exposure

◦ Maculopapular rash(fingertips, toes )

◦ Pus-filled skin eruptions

◦ Swollen and painful extremities

Acrodynia /Pink disease

Organic Mercury Methylmercury, dimethylmercury and

ethylmercury

effects the CNS ( Minamata disease)

Teratogen with large chronic exposure

◦ Asymptomatic mother

◦ congenital Manimata disease in infants

Diagnosis Elemental and inorganic mercury-

urine collection

organic mercury- whole-blood (s’d

be < 6 μg/L)

Hair analysis is more reliable

Regulatory limits EPA – 2 ppb in drinking water

FDA – 1 part of methylmercury in

a million parts of seafood.

OSHA – 0.1 mg of organic

mercury per cubic meter of

workplace air for 8 hrs

Arsenic toxicity

Source Most common cause of acute heavy

metal poisoning in adults

Number 1 on the top hazardous

substances.

Smelting process

Galvanization

Manufacturing of pesticides that contain arsenic. (Arsine gas )

Paints, pesticides

Tobacco smoke

Organic arsenic- seafood

Mode of Exposure Three forms, organic and

inorganic arsenic compounds,

arsine gas.

Inorganic arsenic is more harmfull

Inorganic arsenic- reduced (trivalent

as (iii)) and oxidized (pentavalent

as(v))

Toxicocokinetics Inorganic arsenic are readily

absorbed through the GI tract

Then accumulate in tissues and

body fluids.

Also readily deposited in the hair

and nails

PharmacokineticsA. Pentoxide

Trioxide increases its toxicity and bioavailability

B. Trioxide

( Monomethylarsonous acid (mma(iii), dimethylarsinous acid (dma(iii))

Methylation decreases toxicity and increases excretion

trioxideGSH

MMA(III)+

DMA(III)

Arsenate methyl

transferase

liver

Mechanism of

actionAs+3 :

◦ inhibit SH- containing enzymes (glutathione reductase and thioredoxinreductase)

◦ Inhibit the Krebs cycle (inhibit pyruvatedehydrogenase) and oxidative phosporylation.

As+5

◦Replace the phosphate ester bond in ATP (arsenic ester stable bond )

• High carcinogenic(inhibition of DNA repair due to interaction of arsenic with –SH group)

Irritant effect

Endothelial damage, loss of capillary integrity

Arsenic trioxide-

Prolongation of cardiac action

potential duration

Induce atherosclerosis

Platelet aggregation

Reducing fibrinolysis

Symptoms of

toxicityAcute toxicity:

Hematemesis, abdominal pain

rice-water diarrhoea

Garlic-like breath

Thirst and metalic taste

Contact dermatitis

Arsine gas exposure- acute hemolytic

anemia and striking chills.

Chronic toxicity: Multiple organ dysfunctions problems

Neuronal :peripheral neuropathy, encephalopathy, dementia, cognitive impairment, hearing loss

CVS: hypertension, myocardial infarction, anemia and leukopenia

Respiratory: pharyngitits, laryngitis

GIT: severe abrominal cramping and hematemesis.

kidney and liver damage

Skin abnormalities:

darkening of the skin

appearance of small "corns" or

"wart" on the palms, soles ( palmar

keratosis).

whitish lines (Mees lines) found on

the fingernails.

Mees line

Palmar keratosis

Reproductive system:

spontaneous abortion

lower birth weights

Carcinogenic: cancers of the

skin, liver, respiratory tract,

kidney, bladder and

gastrointestinal tract

Diagnosis1. Urine analysis

2. whole blood arsenic

measurements

3. hair and fingernails

Acute hemolytic anemia in arsine

exposure

Regulatory limits EPA - 0.01 ppm in drinking water.

OSHA - 10 µg per cubic meter for

8 hrs workplace air

Cadmium

Sources Soils and rocks

Coal and mineral fertilizers

Batteries,

Pigments

Metal coatings

Plastics

Electroplating.

Tobacco smoking largest source

Accumulates in leaves, fruits and

seeds.

Accumulates in animal milk and

fatty tissues

Seafood, such as molluscs and

crustaceans

Toxicity Acute-

Vomiting and diarrhoea.

Severe respiratory irritation

Chronic-

Kidneys damage mostly PCT(increased excretion of α 2, β 2, gamma globulins)

Lung damage(occupational exposure)

Fragile bones(loss of ca in urine)

Testicular degeneration

prostate cancer.

itai-itai disease syndrome-1. severe renal dysfunction

2. damage to bone structure.

3. elderly multiparous women mostly

affected

4. poor nutritional status

5. Chronic exposure

Itai itai disease

Regulatory limits

EPA – 5 ppb cadmium in drinking

water

FDA – concentration in bottled

drinking water should not exceed

0.005 ppm

OSHA – an average of 5 µg/cu.m. of

workplace air for an 8-hour workday

BariumSource-

Electrodes

Vacuum tubes

Oxygen-removing agent

Barium sulfide- fluorescent lamps

Barium sulfate-diagnostic medicine

Drilling muds, paint, bricks, ceramics,

glass, and rubber.

Health effects

● Short term exposure- vomiting,

diarrhoea, increased or decreased

blood pressure, muscle weakness.

● Large amounts - high blood pressure,

heart muscle paralysis, kidney damage,

respiratory failure

barium carbonate or chloride-

hypokalemia(adverse effect on heart)

Regulatory limits

EPA - 2.0 ppm in drinking water.

OSHA - 0.5 mg of soluble barium

compounds per cubic meter of

workplace air for 8 hour shifts

ChromiumSource Persistent in sediments in water

Stainless steel

Electroplating, magnetic tapes

Pigments for paints, cement, paper,

rubber, composition .

Wood preservatives.

Health effects

Chromium (VI) is human carcinogens

● Breathing- irritation to nose; nose ulcers; runny nose ,asthma

● Skin contact- skin ulcers, Allergic reactions

● Long term exposure- damage to liver, kidney ,circulatory and nerve tissues

chromium(III) in high conc. can lead to DNA damage

Haemolysis

Regulatory limits

EPA– 0.1 ppm (parts per million)

in drinking water.

FDA – should not exceed1 ppm in

bottled water.

OSHA – 0.0005 and1.0 milligram

per cubic meter of workplace air

for an 8-hour

Selenium Rocks and soils

Electronics industry

Glass industry , plastics, paints,

enamels, inks, and rubber

Pharmaceuticals, nutritional feed

additive for poultry and livestock

Pesticide formulations

Antidandruff shampoos

Fungicides

Health effects

Upper Intake Level is 400 µg/day.

● Short-term oral exposure -nausea,

vomiting, and diarrhea.

● Chronic oral exposure-produce

selenosis.(hair loss, nail brittleness,

neurological abnormalities.,discolouration

of skin)

● Brief aerosol exposures -irritation,

bronchitis, difficulty breathing

Longer-term exposure-respiratory

irritation, bronchial spasms

Discoloration of skin Baldness

SELENOSI

S

Regulatory limits

EPA – 50 ppb drinking water.

OSHA – 0.2 mg per cubic meter

of workroom air for an 8-hour

work shift.

Silver Jewelry, silverware,

Dental filling

Brazing alloys and solders

Mirrors

Photographic film

Disinfectants and antibacterial

agent.

Health effects Exposure to high levels for a long

period-argyria(blue-gray

discoloration of the skin and other

body tissues)

Aerosol exposure-breathing

problems, lung and throat irritation,

and stomach pains.

● Skin contact with-mild allergic

reactions

Argyria

EPA – drinking water not to

exceed 0.10ppb

OSHA – in workplace air 0.01

mg/m³ for an 8-hour workday

Tin Dinnerware and canned food

Food standards agency in UK set upper limits of 200 mg/kg.

Un-lacquered tin cans with food of a low ph(fruits and pickled vegetables) contain higher conc.

Interference with the iron and copper metabolism(heme and cytochrome P450)

Nausea, vomiting and diarrhea

Copper Called copperiedus

Eating acid foods cooked in uncoated copper cookware

Excess copper in drinking water

Free copper in blood generates ROS these damage proteins, lipids and DNA

Acute- vomiting, hematemesis, hypotension, melena, coma, jaundice, and haemolytic anaemia

Chronic- damage the liver and kidneys.

Kayser-fleischer ring(deposition of cupper in

descemet membrane of eye