2. Metals:
The oldest toxicants known.
In common use for over 4000 years.
Discovery of new and more toxic metals (e.g cadmium
discovered in 1817)
About 90 of the 116 elements in the periodic table are
metals of
which only <30 are reported to be toxic to human at
conventional toxic exposures.
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2
Introduction
Metals
3. Introduction
Metals are classified as
Essential metals:
Cobalt, copper, iron, magnesium, manganese, zinc, selenium and
molybdenum
Excess exposure-toxic to humans.
Non-essential metals:
Haven’t known/little physiologic role.
Toxicology concern
Arsenic (As), lead (Pb), mercury(Hg), and cadmium (Cd)
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Metals
4. Introduction
4
Pathophysiological actions
Exert their toxic effects by combining with one or more
reactive groups (ligands) essential for normal physiological
functions.
React in the body with ligands containing
Oxygen (-OH, - COO-, - OPO3H-, >CO),
Sulfur (- SH, - S-S-) and
Nitrogen (-NH2, >NH) by forming stable co-ordination
complex.
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Metals
5. Introduction
Substituting essential elements in enzymes, neurotransmission,
structural components.
Reacting covalently or non covalently with enzymes,
membrane, DNA.
Stimulate production of reactive oxygen species.
5
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Metals
6. Introduction
6
Risk factors for poisoning
Working in agriculture
Pharmaceutical manufacturing and
Industrial work
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Metals
7. Sites to measure exposure or dose of metals
7
Blood, urine, and hair are the most accessible
Blood and urine conc. usually reflect recent exposure
Correlate best with acute effects
For most metals, hair is not a reliable tissue for
measuring exposure
Contribution of external contamination.
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Metals
8. Factors affecting determining toxic effects of metals
– Interaction with essential nutrients
• Influence on a common homeostatic mechanism ( Pb,
Ca, Fe
• Vitamine C increases Fe absorption and decreases Cd
and Pb absorption
• Pb affects Ca2+ induced NT releases
– Formation of metal-protein complex
– Age and develpment
• The young and the old are more suceptible
– Life style
• Drinking and smoking increase metal toxicity
• Chemical form/ species of the metal
• Immune status of the individual
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Metals
8
9. Protection/detoxification of heavy metals
Epidermis – external defense
Sequestration – HMs can be sequestered in
tissues or protein..
Protein complex formation
Metallothioneins
Transferrin
Ferritin
Ceruloplasmin
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Metals
9
10. Protection/detoxification of HM Cont’d...
Metallothioneins
Have low MWt and rich in thiol ligands.
Essential metal homeostasis and
protection against metal toxicity
Have high affinity binding of essential and non essential
metals such as
Hg, Cd, Cu, Ag and Zn
Are inducible by number of metals
Important in regulation of Cu and particularly Zn
metabolism.
Their induction is highly stimulated by Zn;
Cd is strong inducer
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Metals
10
11. Protection/detoxification of HM Cont’d...
Transferrin
Glycoprotein that binds most of ferric iron in
plasma
Transport of iron across cell membranes occurs
by receptor-mediated endocytosis of ferric transferrin
complex
This protein also transports Al3+ and Mn2+.
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Metals
11
12. Protection/detoxification of HM Cont’d...
Ferritin
A primarily storage protein for iron in the reticulo-
endothelial cells of liver, spleen, and bone.
Ferritin may serve as a general metal detoxicant.
Binds a variety of toxic metals.
Cd, Zn, and Al
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Metals
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13. Protection/detoxification of HM Cont’d...
Ceruloplasmin
A copper-containing glycoprotein oxidase in
plasma that converts ferrous to ferric iron,
which then binds to transferrin.
This protein also stimulates iron uptake
by a transferrin independent mechanism.
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Metals
13
15. Complexation & Chelation
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Measures taken after reduction and/or
prevention of further exposure
» Complexation
Combination of a metal with a charged or
uncharged electron donating ligand (mono,
bi or multidentate binding).
» Chelation
Combination of a bidentate lignad
containing –OH, -COOH, -SH, -NH2, -NH,
forming ring-structure (claw) with
coordinate bonds to metals.
Metals
16. The ideal chelating agent
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• Water-soluble,
• Resistant to biotransformation,
• Able to reach sites of metal storage,
• Capable of forming nontoxic complexes with
toxic metals, and
• Capable of being excreted from the body
• Have a low affinity for essential metals,
particularly calcium and zinc
• Challenge to produce a safe and effective
chelating agent with all the above properties.
Metals
17. Common chelating agents
1. Dimercaprol (2,3-dimercapropropanol,British Anti-
Lewisite (BAL))
2,3-dimercapropropanol, discovered in WWII against
poisoning Arsenical war gases.
Form of chelation complexes between its sulfhydryl groups
and metals.
17
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Metals
18. Chelating agents Cont’d,...
Dimercaprol is much more effective when given as soon as
possible after exposure to the metal
because it is more effective in preventing inhibition of
sulfhydryl enzymes than in reactinating them.
Because aqueous solutions of dimecaprol are unstable and
oxidizes readily,
it is dispensed in peanut oil and
must be administered by intramuscular injection.
18
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Metals
19. Chelating agents Cont’d,...
Antagonizes the biological actions of metals that
form mercaptides with essential cellular sulfhydryl
groups,
principally arsenic, gold, and mercury and
also in the treatment of severe lead poisoning (esp.
encephalopathy) when used in conjunction with edetate
calcium disodium.
19
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Metals
20. Chelating agents Cont’d,...
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2. DMPS (2,3-dimercapto-1-propanesulfonic
acid)
Oral derivative of BAL
Less toxic than the first BAL compound (dimercaprol)
Reduce blood Pb levels in children
Better than ethylene diamine tetraacetic acid (EDTA) in
that it is administered orally and
does not appear to have toxic side effects.
Metals
21. Chelating agents Cont’d,...
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3. Ethylene diamine tetraacetic acid (EDTA)
Na2EDTA (high affinity for Ca2+) results in life-threatening
depletion of calcium;
May cause hypocalcemic as the Na salt has more
affinity to body calcium.
to prevent this the drug should only be administered as the
calcium disodium salt.
CaNa2EDTA
used for treatment of poisoning by metals that have higher
affinity for the chelating agent than does Ca2+
Form chelates with divalent and trivalent metals in the
body.
Metals
22. Chelating agents Cont’d,...
Zn, Mn, Fe
higher affinity for CaNa2EDTA than Ca2+
chelated, mobilized, and usually excreted
Main therapeutic use of CaNa2EDTA
Treatment of lead intoxication
Lead to displace calcium from the chelate
Also used in poisoning by
zn, Mn, and certain heavy radionuclides.
22
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Metals
23. Chelating agents Cont’d,...
Mercury poisoning
does not respond to the drug
despite the fact that mercury displaces calcium from
CaNa2EDTA in vitro
Mercury is unavailable to the chelate perhaps because
It is too tightly bound sulfhydryl group or
Sequestered in body compartments that are not penetrated by
CaNa2EDTA
23
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Metals
24. Chelating agents Cont’d,...
The highly polar ionic character of EDTA limits its oral
absorption – IV route
Renal toxicity …potential ADEs
Combination therapy of EDTA with other chelating agents,
such as BAL and DMSA, has been used to reduce the risk of
side effects.
24
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Metals
25. Chelating agents Cont’d,...
4. DMSA (2,3-dimercaptosuccinic acid)
Aka succimer
Orally available
More specific than EDTA, doesn’t increase
excretion of essential metals (Ca and Zn).
25
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Metals
26. Chelating agents Cont’d,...
Desirable feature of succimer
Does not significantly mobilize essential metals
- safer than EDTA.
Unlike EDTA, succimer
can be given orally and
has greater specificity for lead.
26
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Metals
27. Chelating agents Cont’d,...
It is effective chelator of lead, arsenic, cadmium, mercury,
and other metals.
Approved for the treatment of children with blood lead
concentrations greater than 45 µg/Dl.
Less toxicity as compared to dimercaprol
• May be -- it is relatively lower lipid solubility which minimizes
its uptake into cells
27
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Metals
28. Chelating agents Cont’d,...
5. Pencillamine (β, β-Dimethylcysteine)
Hydrolysis product of penicilline
Bind and remove Cu, in Wilson’s disease
Can also remove Hg, Pb, Fe
May cause loss of physiological Zn, Co, Mn
Risk of hypersensitivity.
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Metals
29. Chelating agents Cont’d,...
Wilson's disease is characterized by the excessive
accumulation of copper in the liver, brain, kidneys, and
corneas.
Penicillamine is the drug of choice
For treatment of Wilson's disease.
Rationale for the use of penicillamine in cystinuria
It reacts with the poorly soluble cysteine in a thiol-disulfide
exchange reaction and
forms a relatively water-soluble cysteine-penicillamine
mixed disulfide.
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Metals
30. Chelating agents Cont’d,...
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6 . Diethylene-triamine-penta-acetic acid
(DTPA)
Must be used as calcium salt (CaNa2DTPA)
because of DTPA’s high affinity for calcium.
Binds metals in the actinide series like
plutonium.
Metals
31. Chelating agents Cont’d,...
31
7. Desferrioxamine/Defferoxamine/Desferal
It is a hydroxylamine isolated as
the iron chelate from Streptomyces pilosus
and
is used clinically in the metal-free form.
Very high affinity for Fe3+ ,
low affinity to Ca++
Competes effectively with ferritin and
not with heme or heme-containing enzymes (e.g.
cytochromes) .
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Metals
32. Chelating agents Cont’d,...
Used parentrally [poor GI absorption]
– IM, IV
It removes iron from hemosiderin and ferritin
and,
to a lesser extent from transferrin.
ADRs limiting the use of Deferoxamine
Hypotention
Rash
Cataracts
32
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Metals
33. Chelating agents Cont’d,...
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8. DTC (Dithiocarbamate)
Oral DTC => for mild nickel poisoning.
Parentral DTC =>for sever Nickel poisoning
Sodium, N-(4-methoxybenzyl)-glucamine
dithiocarbamate
is among the most effective in removing cadmium from
tissues.
Metals
34. 34
Chelating agent Metals reported to be chelated
Calcium disodium EDTA Beryllium, cadmium, cobalt,
copper, iron, lead, manganese,
nickel, zinc
Deferoxamine Iron
Dimercaprol Arsenic, lead, mercury
Penicillamine Copper, lead, mercury, zinc
Succimer Lead
Table: Use of chelating agent
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Metals
36. . Arsenic (As)
Used
In the production of herbicides and agricultural chemicals
As chemotherapeutic agent even though declining.
Chemical forms:
» Arsine ( AsH3)
• Most toxic of all As cpds
» Trivalent (As3+ , arsenites)
• Organic (alkyl arsenates),
• Inorganic (arsenic trioxide and sodium arsenite)
• More toxic than petavalent cpds b//c they high
lipophillicity.
» Pentavalent (As5+)
• Organic As (Alkyl arsenates).
• Inorganic (sodium arsenate, arsenic pentoxide, and
arsenic acid).
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Metals
37. Arsenic cont’d,...
Toxicity increased in the sequence of
Organic arsenicals (dimethyl As < methyl As)
< As5+ < As3+ < arsine (AsH3).
The toxicity is related to the
rate of clearance from the body
degree of accumulation in tissue.
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Metals
38. Arsenic cont’d,...
Sources of As poisoning
– Homicide using tasteless and colorless As
trioxides
– Accidental ingestion
– Occupational exposure in metal smelters
– Water, fish, soil
– Household chemicals like ant and roach killers
– As-containing pharmaceuticals
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Metals
39. Arsenic cont’d,...
• After absorption As is stored in
– Liver
– Kidneys
– GIT wall
– Spleen
– Lungs
– Nail beds, fine hairs … may persist for many years
• Indicators of As exposure
– Urine
– Blood
– Hair samples 4/23/2021
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Metals
41. Arsenic cont’d,...
Signs and symptoms: As toxicity
•Ingestion of 5-50 mg
• causes acute toxicity in 30-60 minutes
•70-120 mg As
• causes rapid circulatory collapse, intense gasritis,
perispiration.
•Garlic-type odor in breath
• characteristic to As
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Metals
42. Arsenic cont’d,...
• In general
– Acute effects
• Usually GI ADRs , corrosion
• Loss of blood, capillary transudation,
hypotension
• Rice-water stools
• Uremia
• Arrythmias,
• convulsion
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Metals
43. Arsenic cont’d,...
Chronic symptoms
Milk and Roses complexion on the face
Skin pigmentation ,mottled spots
thick white bands on the lunulae of the
nails
Hyperkeratosis .. Thick palm and plantar
surfaces
Weight loss, anorexia, malaise, diarrhea
Peripheral neuropathy
Anemia, pancytopenia 4/23/2021
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Metals
44. Arsenic cont’d,...
Management of toxicity: As
• Supportive symtomatic care
• Gastric decontamination
– Ipecac
– Lavage
• Chelation
• Acute axposure:
• Dimercaprol 3 mg/kg IM every 4 hours) until symptoms
subside, followed by oral penicillamine
• Chronic exposure:
• similar combination of chelating agents
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Metals
45. 2. Cadmium (Cd)
Used in
electroplating or galvanizing
Zn, Pb, and Cu smelting ,welding ,
employed as pigment and stabilizers in paints, plastics and print
industries
cathode material for nickel-cadmium batteries
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Metals
46. Cadmium cont’d,...
PK:
bound to blood cells and albumin
distribute to liver and
then redistributes to the kidney as
Cd-metallothionein (Cd-MT) or cause renal
toxicity.
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Metals
47. Cadmium cont’d,...
Mechanism of toxicity
In the liver
induces synthesis of metallothionien
stored in the liver as Cd-MT complex or
transported via blood to the kidney,
where it may accumulate in lysosomes.
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Metals
48. Cadmium cont’d,...
Toxic effects of chronic exposure
COPD and emphysema
Chronic renal tubular disease
Affects CVs and
skeletal systems.
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Metals
51. Management of Cd poisoning
Currently there are no treatments for cadmium
poisoning.
Only the symptoms can be treated.
With minor exposure the symptoms and effects of
cadmium exposure usually subside within a few days.
Chelation and hemodialysis speed up the removal of
the excess cadmium, but
only effective for oral ingestion,
not effective to fume exposure.
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Metals
52. 3. Mercury (Hg)
Used
In pharmaceuticals: constituents of drugs as an
ingredient in many diuretics, antibacterials, antiseptics,
skin ointments, and laxatives.
These uses have largely been replaced by safer drugs.
also used in electrical meters, thermometer,
antimicrobial preservatives, in paints & cosmetics.
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Metals
53. Mercury cont’d,...
Chemical forms
Elemental Hg
Mercury vapour (Hg0)
Inorganic salts of Hg
Hg+ ,Hg++ and Hg+++
Organic Mercury
Aryl, alkyl alkoxyalkyl Hg
Order of toxicity
Elemental Hg < Inorganic Hg salts< Organic Hg
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Metals
54. Mercury cont’d,...
PK and mechanism of toxicity
About 80% of Hg0 is absorbed (inhalation)- poor GIT absorption
Hg2+ 10-15% GIT absorption: Hg+ less absorption
Organic mercury (methyl mercyry90%) >>> Hg2+ > Hg+ >>> Hg0
GIT absorption
After absorption
Hg0,Hg+,methyl mercury Hg2+(more toxic form)
Inorganic mercurials do not readly pass across the BBB/placenta
Organic mercurials: cross the BBB or the placenta
more neurotoxic and teratogenic
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Metals
55. Signs and symptoms of Hg poisoning
Depend of the
» Form of HG
» Amount of exposure
» Duration of exposure
» Susceptibility of the subject
• Chronic Vapour exposure
– Anorexia
– Weight loss
– Fatigue
– Muscle wekaness
– Fine tremores (eyes, tongue, fingers)
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55
56. Signs and symptoms of Hg poisoningcont’d,...
Erethism
• Abnormally high degree of irritability or sensitivity due to
CNS effects of Hg
• Sudden anger
• Memory loss
• Drowsiness
• Apathy, excessive shyness, social phobia
• HgCl2
• Ingestion results in
• Sever epigastric pain
• Profuse mucoid vomitting
• Bloody diarrhea
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Metals
56
58. The primary routes of exposure differ for d/t forms of Hg
and so do their major adverse effects.
Elemental Hg
– Route: Inhalation
– Target: CNS [Erethism], kidney [tubular necrosis], Lung (Pneumonitis)
– Skin toxicity not common
– Biologic half-life: 10-15 days
– Chelation: Dimercaprol, Pencillamine
Inorganic Hg
– Route: Oral ingestion
– Target: Kidney (Tubular necrosis), skin [vesication, urticaria]
– CNS and Lung toxicity not common
– Biologic half-life: 65-70 days
– Chelation: N-acetylcysteine, Pencillamine
Organomercurials
– Oral, food chain
– Target CNS (Mercurialism), Liver (hepato-necrosis)
– Kidney, GI, Skin, Lung toxicity not common 4/23/2021
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Metals
59. • NB: CaNa2EDTA should not be used in cases of Hg
poisonong
– Increased renal toxicity
• Dimercaprol-Hg chelate may also increase Hg-
induce renal damage
– However Rx of choice in sever Hg salt
intoxication
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Metals
59
60. 4. Lead (Pb)
Ubiquitous toxic metal detectable
in all phases of the inert environment and
in all biological systems.
Used for
production of storage batteries, metal alloys, glass, plastics and
ceramics.
Lead exists;
Organic form
tetraethyl lead (TEL) (as a gasoline additive)
has specific affinity for lipoid and nerve tissues
resulting in rapid metabolism and toxicity of CNS.
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Metals
61. Lead cont’d,...
Rout of exposure:
organic lead –respiratory, GIT, skin
inorganic lead- respiratory and GIT
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Metals
62. Lead cont’d,...
PK:
Transported across the GIT mucosa
Using clacium transporter -competition
lead absorption is increased
low dietary calcium, iron deficiency and empty stomach.
binds to hemoglobin in erythrocytes (99%) then
initially distributes to soft tissues
bone marrow, brain, kidney, liver, muscle, and
gonads;
then to skeletal system (bone),teeth,hair
Crosses placenta
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Metals
63. Lead cont’d,...
The total body burden of lead may be divided into
two kinetic pools:
Skeletal pool
the largest and kinetically slowest pool
t1/2 of more than 20 yrs
lead in bone may contribute as much as 50%
of blood lead.
Soft tissue pool
– much more labile with a half-life of 1-2 months.
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Metals
64. Lead cont’d,...
Mechanism of toxicity:
Multiple modes of action including
Inhibition of enzymatic function
Interference with the action of essential cations,
particularly calcium, iron, and zinc
Disturbance of cellular redox status, and
Alteration of the structure of cell membranes
and receptors
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Metals
65. Lead cont’d,...
Toxic effects;
– Neurotoxicity (CNS effects )(both organic and inorganic
lead)
– mechanism:
– Interferes with NT function
– Disrupts calcium metabolism
Blocks voltage-dependent calcium membrane
channels
Substitutes for calcium in calcium-sodium ATP pump
Competes for uptake by mitochondria
Binds to 2nd messenger calcium receptors (eg.
calmodulin, protein kinas )
Damage to the membrane
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Metals
66. Lead cont’d,...
Hematotoxicity—induce anemia
The anemia results from two basic defects:
Shortened RBC life span (increased mechanical fragility of CM)
due to inhibition of Na+ and K+-dependent ATPase
Impairment of heme synthesis
Nephrotoxicity (Renal effects )-two forms:
– A reversible tubular disorder (after acute exposure) and
– An irreversible interstitial nephropathy (in long-term industrial lead
exposure)
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Metals
67. Signs and symptoms: Pb poisoning
GI inflammation
Black stool
Kidney damage
CV collapse at very high
doses
Sweet metallic taste,
vomiting
Salivation
• Hematologic dysregulation
• Abdominal obstruction
and intestinal spas
• Lead colic =abdominal
cramps
• Lead encephalopathy
• Neuromuscular (Lead
Palsy)
• Chronic nephritis
Acute (rare) Chronic (Plumbism)
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Metals
68. Management of Pb Poisoning
• Blood levels of Pb in µg/dl
• <9 …need no treatment
• > 10 …commence symptomatic treatment
• for neurologic toxicities.
• > 45 …. Start chelation therapy
• Chelation therapy for lead
• BAL
• CaNa2-EDTA
• Pencillamine
• Succimer
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Metals
69. 5.Iron (Fe)
Essential metals with potential toxic effects.
Iron toxicity is usually due to Fe overload secondary to
Idiopahtic hemochromatosis
Blood transfusion
Excess dietry intake
Fe absorption is dependent on
Rate of erythrocyte production
Bioavailability of iron
Amount of storage iron
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Metals
70. Iron cont’d
Ascorbic acid enhances GI absorption of Fe
Fe absorption is
enhanced in periods of high iron demand
Iron is absorbed in
its ferrous form in to GI mucosal cells
Mucosal cells release it in to the plasma
Fe2+ is bound to Transferrin
…direct Fe to target tissues
In the plamsa Fe2+ is converted to Fe3+
by ferroxidase and ceruloplasmin enzymes
Fe3+ is then bound to ferritin and stored 4/23/2021
Metals
70
71. Iron cont’d
• Total body Fe = 3 to 5 g
– 65% is bound to hemoglobin,
– 10 %in myoglobin and iron-containing enzymes,
– 25% is bound to ferritin and hemosiderin [storage
proteins ]
• Toxic effects are manifested when
– Serum Fe level exceeds the binding capacity of
transferrin.
– Ingestion of 20-60 mg/kg
– Mild-moderate toxicity.
– >60 mg/kg serious toxicity
• Minimum lethal dose for Fe = 200-300 mg/kg
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Metals
72. Causes of Iron overload
Hemochromatosis
Abnormally high GI absorption of Fe
Inherited abnormality
Excessive dietary intake of iron
Ingestion of excess iron with pharmaceuticals
Severe toxicity occurs after the ingestion of more
than 0.5 g of iron or 2.5 g of ferrous sulfate
Toxicity becomes manifest with vomiting 1 to 6 h
after ingestion
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Metals
73. Fe Toxicity
• Hepatic accumulation of Fe by Kupffer’s cells
– Hepatotoxicity
– Mitochondrial toxicity
– Formation of free radicals
– Lipid peroxidation = alteration of membrane
permeability
– Disruption of aerobic respiratory system
– Metabolic acidosis
– Cellular necrosis
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Metals
74. Signs and symptoms of Fe poisoning
Occur in 5 phases from the 1st 30’s to 4 weeks after
acute ingestion of Fe
Phase I [30’-2hrs]
– Irritability
– Seizures
– Restlessness
– Abdominal pain
– N/V, Bloody diarrhea
– Tachypnea
– Tachycardia 4/23/2021
Metals
74
75. Signs and symptoms of Fe poisoning cont’d,...
Phase II [post phase I]
• Period of apparent recovery
• Patients will appear quiescent (tranquil)
Phase III [12-48 hrs after phase I]
• GI necrosis, hemorrhage
• Abrupt shock
• Metabolic acidosis
• Hyperventilation
• Hypoglycemia
• Lethargy
• Cyanosis
• Fever & Coma 4/23/2021
Metals
75
76. Signs and symptoms of Fe poisoning cont’d,...
Phase IV [2-4 days]
• Hepatic phase
• Jaundice
• Continuing hypoglycemia
• Coagulopathy
Phase V [2-4 wks]
• GI obstruction
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76
77. Management of Fe poisoning
• Prevention of further GI absorption
• GI decontamination
– Emesis {Ipecac}
– Gastric lavage
• Chelation therapy
– Desferoxamine
– Phosphates
– Bicarbonates
• Dihydrogenphosphate
• May reduce absorption by converting ferrous to ferric
form.
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Metals
