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Definition
• ‘Metals’ originally included only gold,
silver, copper, iron, lead, and tin.

• Many other elements since added to the

Toxicity of metals / metaloids list with some of these characteristics

• ‘Metalloids’ are elements with features

intermediate between metals and non-
metals

Metals in workplace
• Metals are extensively used in industrial operation thus resulting in a high risk of
exposure to workers and environment
– Welding METALS/metaloids for which medical
– Grinding
– Soldering surveillance must be performed
– Painting
– Smelting
1. Arsenic and any of its compound
– Storage battery 2. Beryllium
– Recycling
• Industries with high potential of lead exposures include construction work, most
3. Cadmium
smelter operations, radiator repair shops, and firing ranges. 4. Chromium
• Cadmium is found in industrial workplaces, particularly where any ore is being
processed or smelted. 5. Lead
• Common sources of mercury exposure include mining, production, and transportation 6. Manganese
of mercury, oil and gas industry as well as mining and refining of gold and silver ores.
7. Mercury

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Absorption
• Respiratory Absorption • Gastrointestinal Absorption
– Metal may be inhaled as vapor or
aerosol (fume or dust particulate)
• Fume or vapor of some metals & compound
are readily absorbed in from alveolar space
(cadmium, mercury, tetraethyl lead)
– Large particles trapped in upper
respiratory tract, cleared by mucociliary
transport to pharynx and swallowed
(equivalent to oral exposure)
• Small particles may reach alveolar/gas
exchange. Water soluble metal aerosols are
rapidly absorbed from alveoli into the blood
Absorption
– Metal may introduce into GI tract through food,
water, mucociliary clearance
– Metal are absorbed into the cells lining the intestinal
tract by:
• Passive or facilitated diffusion
• Specific transport process
• Pinocytosis
– Depends on many factors
• Solubility of metal in fluids of the intestinal tract
• Chemical forms of metal (lipid soluble methyl mercury is completely
absorbed compare to inorganic mercury – poorly absorbed)
• Presence and composition of other materials in GI tract
• Composition for absorption sites between similar metals (zinc & cadmium
or calcium & lead)
• Physiological state of the person exposed (Vitamin D enhance the
absorption of lead)

Excretion
Excretion
• Kidney - Important route of excretion
– Metals in blood plasma are bound to plasma proteins and amino acids • Enterohepatic Circulation
– Metals bound to low molecular weight proteins and amino acids are
filtered in glomerulous into fluid of the renal tubule
– Absorbed metal may also excreted into intestinal
tract in bile, pancreatic secretion or saliva
– Some metals (Cd & Zn) are effectively resorbed by tubular epithelia
before they reach the urinary bladder where very little resorption occur • Minor Pathways
– Hair (Hg, Zn, Cu and As)
– Nails
– Saliva
– Perspiration
– Exhaled air
– Lactation
– Exfoliation of skin

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Acute Toxicity of Metal Chronic Toxicity

• Organs and tissue affected are those involved in
the absorption and elimination
Result of the accumulation of high, critical concentrations of metal that
at these sites with little opportunity to detoxify, eliminated or adapted
to metal
• Toxicity of acute metal intoxication is design to :
– Enhance the elimination of the metal through neutralization
– Prevent irreversible damage to organs and tissue
– Treat the symptoms of acute toxicity
• Duration of initial exposure to the onset of
signs and symptoms months to years
– Diagnosis of chronic metal intoxication is more
difficult than acute intoxication
• Diagnosis – presence of excessive metals in
blood and urine
• Organ system not involve in absorption or
elimination of metal such as hematopoetic or
immune system may be affected

● The only metal that is

liquid at room temperature.

Hg Toxicity
● Heavy! 1 teaspoon weighs approx. 70g!

● derived from the Greek word “hydraqrgyros”

meaning “watersilver.”

● Can be found as
– the free metal,
– inorganic salt, or
– organic mercury

Forms are interchangeable

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Toxicity of mercury
Mercury Chemistry • Three forms of Hg with very different
toxicities
• Mercury exists in
three oxidation • Elemental mercury:
states: – Sphygmomanometers (blood pressure meter
– Hg0 (elemental
mercury). ), thermometers, barometers
– Hg22+ (mercurous). – Liquid at room temp – volatilises easily
– Hg2+ (mercuric). • Inorganic mercury:
• Mercurous and
mercuric form – Traditional remedies (ayurvedic, chinese)
numerous inorganic – Used in gold extraction, caustic soda
and organic chemical manufacturing
compounds.
– Organic forms of – Pesticides
mercury, especially • Organic mercury:
methyl mercury,
CH3Hg(II)X, where “X” – Fungicides, seed dressings
is -a ligand- (typically
Cl or OH ) are the – Methylmercury in fish …
most toxic forms.

Mercury - Absorption

• Inhalation : 60-80%
Sources
• Dermal : 3-15%

• GI Tract : Metallic <0.2%

Inorganic 15%

Organic 90+%

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Mercury in the Environment

• Upwards of 70% of the
mercury in the environment
comes from anthropogenic
sources, including:
– Metal processing, waste
incineration, agro-
industrial processes and
coal-powered plants.
• Natural sources include
volcanoes, natural mercury
deposits, hot springs and
volatilization from the
ocean.

• Estimates are that human

sources have nearly doubled
or tripled the amount of
mercury in the atmosphere.

Point Source Pollution

Sewage

• Causes disease outbreaks

• Contributes to
eutrophication

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TOXIC EFFECTS OF MERCURY COMPOUNDS

• NEUROTOXICITY
– DEVELOPMENTAL EFFECTS (NRC, WHO)
Impacts – ADULTS MAY BE AS SENSITIVE
• NEPHROTOXICITY
• DERMATOTOXICITY
• IMMUNOTOXICITY?

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• Hg is immunotoxic, affecting host response to A CONCEPTUAL MODEL FOR Hg AND

infections, susceptibility to autoimmune disease, and AUTOIMMUNITY (Step 1 + 2 = 3)
acting on immune mechanisms in target organ disease
• The immunotoxic effects of Hg in animals are the
lowest dose/effects yet described (0.4 μg/kg)…
• There may be genetic susceptibility factors for Hg
immunotoxicity
• Hg may play a contributing role in the incidence and
severity of autoimmune disease
• DO WE NEED TO RE-ASSESS THE RISKS OF MERCURY,
ESP FOR ADULTS?

Small (Artisanal) scale mining: major

exposures to elemental, inorganic, and
MERCURY IN THE ENVIRONMENT
methyl mercury

• INCREASINGLY RECOGNIZED AS A GLOBAL POLLUTANT • World wide activity – 2 to 6 million persons

(UNEP, WHO)
• Women and children
• MAJOR ENVIRONMENTAL RISK TO CHILDREN’S HEALTH
(EPA, WHO, CEC) • Hazardous conditions
• CRITICAL EFFECT - DEVELOPMENTAL NEUROTOXICITY • Toxic chemicals
(WHO, NAS)
• FISH CONSUMPTION MAJOR ROUTE OF HUMAN • Illegal, unregulated
EXPOSURE TO MeHg • Regional, national impacts
• AIRBORNE Hg EXPOSURES?
• MERCURY EXPOSURES CONTINUE IN WORKPLACES

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BURNING THE AMALGAM

• Inhaled (lipid soluble) ----- bloodstream/red blood cells. Types of Exposure

Converted to inorganic divalent (mercuric). Small
amounts of non-oxidized elemental mercury still exist
and readily cross blood/brain barrier into CNS = toxic • Acute • Chronic
effects! – Short term usually very – Long term (days weeks,
high levels years)
• ACUTE EXPOSURE : bronchitis & pneumonia due to lung
damage. Fever, chills, confusion, vomiting. – Can have – Repeated contact
• Immediate effects – Relatively low amounts.
• Delayed effects
• CHRONIC EXPOSURE – In many cases chronic
– Full effect may not be effects are much
known for years different than acute.
• WARNING : Women chronically exposed to metallic
mercury vapor show a higher frequency of menstrual
disturbances, spontaneous abortions, and complications
of pregnancy.
© 2002 Ron Pristera 32

8

Toxicity of Hg
• 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, fine motor
trembling in lips and hands, depression,
excessive shyness withdrawal from society)
Where are Minamata and Niigata?
Niigata
Minamata
1/13/2016
What is Minamata Disease?
• The most massive pollution problem to
strike Japan in the post WWII period.
• A neurological syndrome caused by methyl
mercury in the industrial wastewater.
• Continued from 1932 to 1968 (36 years)
• 2 cities (Minamata and Niigata were
affected in Japan)
Source of Methyl Mercury
• Minamata City: The Nippon Chisso
Corporation's Minamata Chemical Factory
• Niigata City: The Showa-Denko’s Niigata
Chemical Factory
Photo obtained from U Department of Agriculture
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The discovery of Minamata The difficulty of in determining

Disease its cause
• In 1956: official • It was taboo to speak of the Chisso’s
discovery wastewater in the Chisso castle town
– Eight patients
suffering from a yet • The engineering dept. of Kumamoto
unheard-of disease University was predisposed not to co-
were brought to the
Chisso Corporation’s operate with the medical research group of
factory hospital the same university in this regard
– 40 patients had been
discovered in a year

Mechanism of toxicity Consequences

• 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 and over time inorganic
Hg is formed
• Hg metal may also form inorganic Hg and it
also can penetrate many strauctures
• 2,955 victims have been officially recognized
(2,009 of whom have died) as of March 2006
• Over 10,000 have received financial
compensation from the Chisso co.
• Over 2 million people may have eaten fish
contaminated with methyl mercury from the
Chisso factory

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Methyl Mercury Methyl Mercury

• Volatile and very lipidsoluble
• Readily and completely absorbed by
gastrointestinal tract
• Found complexed with free cysteine and with
CH３Hg proteins and peptides containing that amino
acid
• Recognized by amino acid transporting
proteins as methionine

Methyl Mercury Methyl Mercury

H OH
I /
H3N-C-C
H
I /
OH H
I /
OH • Mimicry of Methionine
I \\ → H3N-C-C H3N-C-C
CH2 O
|
I \\
CH2 O
I \\
CH2 O ↓
| |
SH S
|
CH２
| • Across the blood-brain barrier and placenta
Hg S

Cystein
|
CH3
|
CH3 • Strong binding to proteins
e
+
↓
CH3Hg+ • Easy to become a part of body
Methionine
Methyl Mercury • Not readily eliminated (less than 1% of load)

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Methyl Mercury Conclusion

• Inhibits acetylcholine synthesis • Mercury intoxication ≒ Minamata disease
– Fatigue, memory loss, mood change, tremors, pallor, weakness and – The difficulty of in determining its cause
loss of vision or taste – Spreading out of the disease
• Impairs • Lipid soluble, strong binding to protein, high
– glycolysis affinity for -SH
– nucleic acid biosynthesis – Readily and completely absorbed
– Not readily eliminated
– aerobic respiration
– protein synthesis • Highly Toxic with small amount
– neurotransmitter release • We can find anything when we know what there
• Oxidative injury, altered calcium homeostasis is, but it is very difficult to determine the cause of
– The injured neurons eventually die yet unheard disease.

NEVER FORGET: MINAMATA DISEASE

Their Repercussions – JAPAN

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Arsenic Facts

ARSENIC

“The King of Poisons”

“The Poison of Kings”

ARSENIC
Arsenic Facts Very common in most geological environments, igneous,
metamorphic and sedimentary

Chalcophile, oxyanionic or metalloid element often

associated with sulphide ores

Crustal abundance: ranging from 0.1 to several hundred

ppm.
Major source of anthropogenic arsenic mobilization is
weathering of mine waste rock and tailings as gold is
often associated with arsenopyrite
Also common in reduced environment of coal deposits

Arsenopyrite Orpiment

Realgar

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• Arsenic is common in the environment

• Sources
Arsenic Chemistry
– Groundwater Several oxidation states:
As-1 in sulphide minerals,
– Arsenic containing mineral ores As0, metal, only stable in very reduced conditions but can be reduced to As -
3 in the most toxic form of arsine gas (AsH )
3
– Industrial processes As3+ As5+ are common in oxidizing conditions and soluble at all values of Eh
and pH
• Semiconductor manufacturing (gallium arsenide)
Oxidation of As3+ to less toxic As5+ is slow so usually both are
• Fossil fuels present in oxidized environments like mine tailings.
• Wood treated with arsenic preservatives
• Metallurgy Arsenic can be removed from mine water by the addition of a
• Smelting (copper, zinc, lead) and refining of metals and solution containing FeSO4.
ores Fe2+ is oxidized to Fe3+ and precipitates as FEOOH
• Glass manufacturing Arsenate is strongly absorbed by FeOOH and precipitated
Used as a poison for political assassinations; speculated that Napoleon
was poisoned with arsenic

• Commercial products Arsenic Exposure

– Wood preservatives
– Pesticides
– Herbicides
– Fungicides

• Food
– Seafood and fish
• Others
– Antiparasitic drugs
Inhalation Absorption through Ingestion
– Folk remedies
skin

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Arsenic Toxicity
Mechanism of action:
• Inhibition of sulfhydryl group-containing cellular enzymes
and the replacement of phosphate molecules in “high
energy” compounds
• Trivalent arsenic is a carcinogen (lung and skin cancer) and
is the most toxic form
• 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
Overview
• Endothelial damage, loss of capillary of
integrity, capillary leakage, volume loss,
shock Glycolysis
• Toxic dose ranges from 1 mg to 10 grams
• Can be recovered from the hair, nails and
skin
Pelicano, H., et al.
(2006)

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Chemical Structure of Step 6 in Glycolysis

Phosphate and PO32-
Pi
Arsenate
G3P 1, 3 BPG

AsO4
3- AsO3
2-
Enzyme: glyceraldehyde-3-phosphate
dehydrogenase (G3PD)
Phosphate Arsenate

Step 7 in Glycolysis Significance

PO32- 2, 3 BPG production
ADP
ATP
Biphosphoglycerate
1, 3 BPG
Mutase

1, 3 Biphosphoglycerate 2, 3 Biphosphoglycerate
(1,3 BPG) (2,3 BPG)
AsO3
2-

ATP
ADP Hemolytic anemia

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Citric Acid Cycle Citric Acid Cycle

 Pyruvate Dehydrogenase
conversion to acetyl CoA via Complex (PDC)
pyruvate dehydrogenase complex

Inactivation of Acute Poisoning

Dihydrolipoamide • Ingestion of large doses (70 –180 mg) of inorganic

arsenic can be fatal
 formation of • Symptoms of acute intoxication include:
arsenite chelate Fever
Anorexia
Hepatomegaly
Melanosis
cardiac arrhythmia
in fatal cases, eventual cardiac failure

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Acute Poisoning
• Acute arsenic ingestion can damage:
mucous membranes of the gastrointestinal tract
Sensory loss in the peripheral nervous system is the most
common neurologic effect
Anemia and leucopenia(granulocytopenia ), (few days
following high-dose arsenic )
Acute exposure to a single high dose can produce
encephalopathy, with signs and symptoms of
headache, lethargy, mental confusion, hallucination,
seizures, and even coma
Acute Poisoning
Arsine gas(ASH3), generated by electrolytic or metallic
reduction of arsenic in nonferrous metal production.
It is a potent hemolytic agent, producing
acute symptoms of nausea, vomiting, shortness of breath,
and headache accompanying the hemolytic reaction.
Exposure to arsine is fatal in up to 25% of the reported
human cases.

Chronic Toxicity Chronic Toxicity

Skin Liver
• major target organ in chronic inorganic arsenic exposure
• Diffuse or spotted hyperpigmentation and, alternatively, • Characteristic of long-term or chronic arsenic
hypopigmentation can first appear between 6 months to 3
years with chronic exposure to inorganic arsenic exposure, manifests :
jaundice
abdominal pain
Palmar-plantar hyperkeratosis usually Hepatomegaly
follows the initial appearance of
arsenic-induced pigmentation changes progress to cirrhosis and ascites
within a period of years
even to hepatocellular carcinoma
 Skin cancer is common with
protracted high-level arsenical exposure

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Chronic Toxicity
Chronic Toxicity
cardiovascular disease
Peripheral neurophathy • Peripheral vascular disease has been
• Repeated exposure to low levels of inorganic arsenic observed in persons with chronic exposure to
can produce
• This neuropathy usually begins with : inorganic
sensory changes • It is manifested :
numbness in the hands and feet painful “pins
and needles” sensation acrocyanosis
motor nerves be affected Raynaud’s phenomenon
muscle tenderness
weaknes  progressing from proximal to distal (Blackfoot disease).
muscle groupss
• Effects are dose-related

Palmer Keratosis
Black Foot Disease
• skin disease:
– keratosis of hands and feet, and
hyperpigmentation

Blisters

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Carcinogenicity
• The carcinogenic potential of arsenic was
recognized over 110 years ago
• Arsenic has been classified as a known human
carcinogen, associated with tumors of the skin,
lung, and urinary bladder, and possibly kidney,
liver, and prostate

TREATMENT

Chelating agents
Chelating Agents
• Chelating agents form a ring around the metal  making it more
Keratosis treatment water soluble for excretion
• Examples: Dimercaperol and Succimer (Dimercaptosuccinic acid)
• Only form of treatment

Supporting treatment

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Chelating Agents Toxicology

Dimercaperol Succimer • As(III) compounds arsine (AsH3) and trimethylarsince

(As(CH3)3) are most toxic

Toxicokinetics Toxicokinetics
• T1/2 of inorganic arsenic in the blood is 10 hrs • Inorganic arsenic is converted to organic arsenic
(biomethylation to monomethyl arsonic- MMA or DMA) in the
and of organic arsenic is around 30 hours liver. This may represent a process of detoxification

• 2-4 weeks after the exposure ceases, most of • Renally excreted (30-50% of inorganic arsenic is excreted in
about 3 days). Both forms are excreted depend on the
the remaining arsenic in the body is found in acuteness of the exposure and dose
keratin-rich tissues (nails, hair, skin)

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Arsenic Problems: Bangladesh Toxic Hazards Associated with Poultry Litter

• Arsenic is found in groundwater of many countries: particularly Incineration
South East Asia and Bangladesh What Goes In, Must Come
Out
“One of the most basic
• As leached from underground sources into village wells of 1 million people, principles of incineration is that
levels of 1000 ppb what goes in, must come out.
– 62% of wells tested exceeded WHO standard There is no alchemy going on,
– ~ 35 million people exposed above US EPA standard so if there are toxic heavy
metals like lead, mercury or
arsenic going in one end, they
• 200,000 people suffering from As-induced skin lesions must come out in the form of
• problem may have been exacerbated by large scale withdraw of toxic ash and toxic air
groundwater for irrigation or by extensive use of fertilizers emissions.” Arsenic Use in Chicken & Turkey Feed
Roxarsone, or 3-nitro-4-hydroxyphenylarsonic acid, is
currently the most commonly used arsenical compound in
poultry feed in the United States, with a usage of 23 to 45
grams of chemical per ton of feed for broiler chickens for
increased weight gain, feed efficiency, improved
pigmentation, and prevention of arasites. Roxarsone is used
in turkeys as well as chickens. By design, most of the
chemical is excreted in the manure.

Ground Water
• Arsenic in ground water is largely the result of
minerals dissolving from weathered rocks and • LD50 values for some common
forms of As
soils.
– Arsenic concentrations in ground water generally
are highest in the West

• Several types of cancer have been linked to

arsenic in water
• 2001: EPA lowered the maximum level of As
permitted in drinking water 50 ug/L → 10 ug/L.
Meat and
Converted by bio-methylation → seafood
excreted

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Some formulae for the chemists in the audience. More formulae for the chemists in the audience.

arsenite arsenate monomethylarsonat

e

cacodylate trimethylarsine oxide tetramethylarsonium

dimethylarsinate trimethylarsine
oxide

Yet more formulae for the chemists

TETRA

arsenobetaine

arsenocholine
Seafood arsenic

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More on Methylation How much arsenic is considered safe?

How much inorganic arsenic is considered safe?
• Reduce arsenite (via purine
nucleoside phosphorylase) to
arsenate then methylation (via
Food: No US guideline value.
enzymatic transfer of the methyl Drinking water: US EPA 10 µg L-1 (ppb)
group from S-adenosylmethionine
(SAM) to arsenite to form
The limit for dietary inorganic arsenic exposure is:
monomethylarsonic acid (MMAV) )

3.0 µg per kg body weight per day

• Gene that codes for the enzyme
responsible for this reaction is just
like Cyt 19

How much inorganic arsenic is considered safe?

Biological Monitoring
Dietary: 3.0 µg per kg body weight per day.

• Ingestion of seafood may elevate urinary arsenic levels

Developmental Weight lbs Tolerable daily
stage 1 lb = 0.45 kg intake µg
• If urinary arsenic levels are high
Newborn 7 9 – Ask the patient whether he ingested seafood in the last 72 hours
1-year-old 22 30 – Speciation can be performed in several laboratories
5-year-old 42 57 – Methylated derivatives determination in the urine. These levels are
not influenced by the presence of organic arsenic from marine origin
teenager 140 (m) 117 (f) 191 (m) 160 (f)
young adult 155 (m) 127 (f) 211 (m) 173 (f)
Adult (US average) 191 (m) 164 (f) 260 (m) 224 (f)
football player 300 409
overweight your call > 400

Acute lethal dose (adult) 100 mg

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Removal of As from Water

• Pass over alumina (Al2O3)

• Anion exchange or reverse osmosis
• Precipitation
LEAD
In treatment facilities by precipitating it in the form of insoluble
arsanate, AsO43-
Fe3+ + AsO43- → FeAsO4(S)

GW As is usually reducing so As(III) must first be oxidized to As(V)

Lead Poisoning Uses and Sources of Lead:

Physical Properties • Lead paint:

• Lead (Pb) has been used by humans for at least 7000 years, because it Food containers(painted with
is widespread, easy to extract, and easy to work with. It is highly
lead-based paint or lead-containing glaze ,
malleable and ductile as well as easy
canned foods)
to smelt.

• Metallic lead (PbO) is resistant to corrosion • Petrol (tetraethyl lead)

and can combine other metals to form • Toys and Jewelry
various alloys(Lead alloys are used in batteries,
shields from radiation, water pipes, and ammunition) • Herbal remedies
from India, China, and other
• Inorganic Lead
parts of Asia may be potential
Organic Lead sources of lead exposure.
Lead has no known biological function.

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Uses and Sources of Lead: Lead Paint

• Soil: • The use of lead in residential paint was
Exposure to soil that contains particulate lead has been
shown to be significantly hazardous for children, who are banned in 1977
more commonly exposed by ingestion of house dust or soil
than by paint chips.
• Lead-containing pigments still are used for
• Water:
Drinking water is also a major source of lead outdoor paint products because of their bright
Exposure. colors and weather resistant properties

• Occupational sources:
Remodeling construction • Tetraethyl and tetramethyl lead are still used
Smelters as additives in gasoline in several countries
Battery factories
Ammunition

– Body lead storage: bones- can constitute a source of Toxicokinetics

remobilization and continued toxicity after the • Absorption of Lead:
exposure has ceased • GI:
Children absorb lead well orally (~50%)
adults poorly (~10%).
• Lead crosses the BBB and concentrates in the Lead absorption is enhanced if diet is
poor in iron or calcium.
gray matter High fat intake and inadequate calories
have also been associated with enhanced
• Lead crosses the placenta lead absorption.
• Respiratory:
• Excretion: Inorganic lead
– Kidneys. The excretion increases with increasing body • Skin:
stores (30g-200 g/day) Organic lead

– Feces

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Toxicokinetics Toxicokinetics

• Half-life Of Lead
• 25 DAYS -- BLOOD
• 40 DAYS -- SOFT TISSUE
• 20 YEARS -- BONE
• Hepatic Metabolism/Excretion
• Inorganic lead is not metabolized but is excreted unchanged.
• Organic or alkyl-lead,(leaded gasoline, also identified as tetraethyl-
and tetramethyl-lead) undergoes oxidative dealkylation to the highly
neurotoxin metabolites, triethyl- and trimethyl-lead.
• The major route of excretion of absorbed lead is the
kidney.
Urine: %65
Bile: %35
Children excrete less of their daily uptake than adults, with
an average retention in adults of %1-4 versus %33 in
children.

Toxicokinetics Toxic Effects of Lead

• Nervous System
Distribution: Neurological, Neurobehavioral, and Developmental Effects
• 95% in bone in Children
• Clinically lead encephalopathy may occur in children with high
(%70 in children) exposure to lead, probably at BLL of 70 μg/dL or higher.
• Symptoms of lead encephalopathy:
• 4% in soft tissue Lethargy
(brain, liver, kidneys, bone marrow) Vomiting
Irritability
• 1% blood Loss of appetite
• Lead readily crosses the placenta Dizziness
Progressing to obvious ataxia, and a reduced level of consciousness,
which may progress to coma and death

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Toxic Effects of Lead Toxic Effects of Lead

Neurological, Neurobehavioral, and Developmental Effects in
• Neurotoxic Effects in Adults
Children
• CNS :
Fatigue, irritability, lethargy, insomnia, headache, difficulty
• The pathological findings at autopsy are severe edema of the brain due to
concentrating, memory loss and tremor.
extravasations of fluid from capillaries in the brain. This is accompanied by
the loss of neuronal cells and an increase in glial cells. Sever lead intoxication can result in an encephalopathy
characterized by depressed consciousness, seizure, and
• Recovery is often accompanied by sequelae including epilepsy, mental coma, in association with cerebral edema.
retardation, and, in some cases, optic neuropathy and blindness. • PNS:
More than a half-century ago, foot drop and wrist drop characterized the
• Most studies report a 2- to 4-point IQ deficit for each house painter and other workers with excessive occupational exposure
μg/dL increase in BLL within the range of 5–35 μg/dL. to lead.
Axonopathy motor disturbance
Upper extremities, extensor

Toxic Effects of Lead

• Hematologic Effects
Lead has multiple hematologic effects, ranging from increased urinary
porphyrins, coproporphyrins, δ-aminolevulinic acid (ALA), and zinc-
protoporphyrin to anemia.
Toxic Effects of Lead
• Renal Toxicity
Acute lead nephrotoxicity consists of proximal
tubular dysfunction and can be reversed by treatment
with chelating agents.
Chronic lead nephrotoxicity consists of interstitial
fibrosis and progressive nephron loss and renal failure.

• Fanconlike syndrome; Fanconi syndrome is a

disorder of the kidney tubes in which certain substances
normally absorbed into the bloodstream by the kidneys
are released into the urine instead.

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Toxic Effects of Lead

Toxic Effects of Lead
• Effects on Cardiovascular System
The most important manifestation of lead toxicity on the cardiovascular
system is hypertension. • Reproductive system
• The pathogenesis of lead-induced hypertension is multifactorial including: Impairment of both male and female reproductive function
(1) Inactivation of endogenous nitric oxide and cGMP , possibly through Gastrointestinal
lead-induced reactive oxygen species.
Lead colic is a major gastrointestinal symptom of severe lead poisoning, and is
(2) Changes in the rennin–angiotensin–aldosterone characterized by abdominal pain, nausea, vomiting, constipation, and
system, and increases in sympathetic activity, important humoral cramps.
components of hypertension.
(3) Alterations in calcium-activated functions of vascular smooth
muscle cells including contractility by decreasing Na+/K+-ATPase activity
and stimulation of the Na+/Ca++ exchange pump.
(4) Possible rise in endothelin and thromboxane.

Carcinogenicity
Toxic Effects of Lead
• Bone Effects
Lead has an extremely long half-life in bone,
accounting for over 90 % of the body lead in adults.
Lead can affect bone by interfering with metabolic and
homeostatic mechanisms including parathyroid hormone, calcitonin,
vitamin D, and other hormones that influence
calcium metabolism.
Lead substitutes for calcium in bone.
Lead is known to affect osteoblasts, osteoclasts, and chrondrocytes and has
been associated with osteoporosis and delays in fracture repair.
•Human epidemiology data weak
In children exposed to lead, a higher bone mineral density 2B. Agent is possibly carcinogenic to •Animal data positive
humans
(BMD) was observed.

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Recommended Lead level

<0.48 (10µg/dl)
• < 0.48µmol/l (10µg/dl)
= NHMRC Goal.

• >0.48µmol/l (10µg/dl)
= elevated.

• >0.72µmol/l (15µg/dl)
=substantially elevated. Cd
Notifiable level.

• >1.20µmol/l (25µg/dl) >2.20µmol/l (45µg/dl)=

= dangerously elevated. Symptomatic

Cadmium and Smelters/Mine Sites Pharmacokinetics

• Cadmium is a by-product of pharmacokinetics:

• inhalation:
smelters – smelters, cigarette smoke
– 15-50% absorbed
• ingestion:
Shenyang Copper Smelter
• main source is liver
and kidney of meats
• 6% absorbed,
greater if deficient in
calcium, zinc or iron

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Exposure Sources - Tobacco Toxicity Mechanisms

• Mechanisms
– binding to –SH groups
• Tobacco smoke (a one pack a day – competing with Zn and Se for
inclusion into metalloenzymes
smoker absorbs roughly 5 to 10 – competing with calcium for
times the amount absorbed from binding sites (calmodulin)
• Kidney toxicity
the average daily diet) • Lung toxicity
• Skeletal effects
– Osteoporosis and
osteomalacia
Tobacco smoke • Cancer
is an important – carcinogenic in animal studies
source of – ~8% of lung cancers may be
cadmium attributable to Cd
exposure

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) Itai-itai victim
– acute toxicity: renal
failure,anemia, severe muscle
pain
• named "Itai-Itai" disease ("ouch,
ouch")

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Exposure Sources – By Mouth Respiratory Effects

• 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
Low levels are found in grains, cereals, leafy vegetables,
and other basic foodstuffs
• Acute inhalation may mimic metal fume fever
– Fever, chills & decreases in FVC and FEV1
Initial 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 Renal Effects

• May cause tubular and • Chronic exposure – progressive
glomerular damage with resultant renal tubular dysfunction
proteinuria
• Toxic effects are dose related
• May follow chronic inhalation or
ingestion • Critical renal concentration
• Latency period of ~10 yrs • Decreased GFR
• Nephropathy is progressive & • Chronic renal failure
irreversible • Kidney stones more common

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Skeletal Effects Direct Biologic Indicators

• Bone lesions occur late in severe

chronic poisoning • 24 hour urine cadmium –
reflects exposure over time
– Pseudofractures
an total body burden
– Other effects of osteomalacia and
osteoporosis • Blood cadmium
– Appear to be secondary to • Cadmium in hair
increased urinary calcium and
phosphorus losses

Indirect Biologic Indicators

• Urinary ß2-microglobulin – evaluate

urine levels > 300 g/g creatinine
• Urinary RBP
• Urinary metallothionein (MT)

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