This document summarizes heavy metal toxicity in animals. It discusses various heavy metal contaminations across India including from lead in water, arsenic contamination of groundwater in West Bengal and Bangladesh, and various industrial sites contaminated with heavy metals. It also outlines the clinical signs and target organ toxicity of several heavy metals including lead, mercury, cadmium, and arsenic as well as methods for managing heavy metal toxicity.

1. HEAVY METALS TOXICITY IN ANIMALS
Dr. V.K. GUPTA
Senior Scientist
Division of Medicine
Indian Veterinary Research Institute,
Izatnagar,

2. Itai-itai disease :Toyama, Japan, starting around
1912
Mitsui Mining & Smelting Co., Ltd, Jinzu
river

3. Minamata (1953--60) & Niigata(1964--65) disease in Japan

4. Chandigarh in early 1978, West Bengal in 1984

5. AREA AFFECTED WITH ARSENIC
Fifty districts of Bangladesh and 9 districts in West Bengal, India have
arsenic levels in groundwater above the maximum permissible limit of 50
μg/L . ( WHO )

6. ARSENIC TOXICITY AREA IN WEST BENGAL

7. CITITES AT RISK IN INDIA
LEAD CONTENT IN WATER
Alarming High Medium Low
Kolkata Delhi Chennai Bengaluru
Kochi Coimbatore Ludhiana Ahmedabad
Mumbai Madurai Surat Hyderabad
Pune Bhubaneswar Ghaziabad Indore
Nagpur Jamshedpur Bhopal
Nashik Chandigarh
Guwahati Lucknow
Mangalore
Mysore

8. Pb Hg Cd As
Ratlam
(M.P.)
Kodaikanal
(T.N.)
Kamrup,
Dhemaji
(Assam)
Tuticorin
(T.N.)
Bandalamottu Mines
(A.P.)
Ganjam
(orissa)
Pathanamthitta
(Kerala)
West Bengal
Vadodara
(Gujrat)
Singrauli
(M.P.)
Ballia
(U.P.)
Korba
(Chattisgarh)
HEAVY METALS CONTAMINATED AREA IN INDIA
Gautam SP, CPCB, New Delhi, Ram Murty, Indian Institute of Toxilogy Research
Buragohain et al.,2013, Shakhila et al.,2014

9. INTRODUCTION
 All living creatures requires minerals
 Naturally metals are distributed in environment during earth's
origin.
 Rapid industrialization
 Overgrowing urbanization
 Environmental manipulation
(Jarup L, 2003; Waldron and Ediing,1997)
Threshold
level
Deficiency disease
Normal healthy life
Toxicity

10. Heavy Metals
Non essential
Ba, Li, Zr
Less toxic
Sn, Al
Highly toxic
Pb, Hg, Cd
Essential
Cu, Zn, Co,
Cr, Mn, Fe
On health effects basis
Metal having atomic weight greater than sodium (23) and specific
gravity (density) > 5gm/cm3 (Hollemen and Wiverd,1985)
(Mukesh K. Raikwar et al.,2008)

12. Primary sources of Heavy metals
Pb Battery plant, Refinery, Smelter, Fuel combustion, Leaded
gasoline, Lead-based paints, Lead-soldered food cans,
Lead plumbing pipes & automobile exhaust
(Tetraethyl lead) (McGraw-Hill, 2006)
Cd Tannery, smelter, battery crushing unit, mining,
Electroplating, Pigments (Cd yellow) and plastics
(McGraw-Hill, 2006)
As Pesticides, Wood preservative, Glass/Copper smelters, Coal
combustion & Uranium mining.
(H.S.Sandhu, 2nd ed, 2012)
Hg Refinery, Plastic, Paints, Antiseptic, Scientific instruments,
Photography, Fuel combustion. (H.S.Sandhu,2nd ed, 2012)

13. Secondary sources of heavy metals
 Most of the animals affected
 Industrial & Domestic wastage directly/indirectly release in water
(Pb, Hg, Cd, As) (Bell et al., 2001)

14. Contd...
Agriculture soil contaminated by Heavy metals through…
 Long-term use of phosphatic fertilizers (Cd)
 Sewage/sludge application (Hg, Cd)
 Dust from smelters, industrial waste (Pb, Hg, Cd, As)
 Bad watering practices in agricultural lands (Pb, Hg, Cd, As)
(Bell et al., 2001)
Plants are contaminated by Heavy metals through…
 Excessive use of fertilizers/pesticides/insecticides
 Plants growing in soil contaminated area
 Irrigation of crop by contaminated water

15. Grazing in
contaminated
area
Crops growing
in contaminated
soil

16. Drinking
Contaminated
water
Toxicological
compounds

17. Excessive use fertilizers
& chemicals
Use of some drugs that
predispose Metal toxicity

18. HEAVY METALS IN AYURVEDIC MEDICINES
 Karela tablets, produced by Shriji Herbal Products, India
 Karela capsules, produced by Himalaya Drug Co, India
 Karela capsules, produced by Charantia, UK (specifically batch #12011)
 Maha Sudarshan Churna powder, produced by Zandu Pharmaceuticals,
Mumbai, India
 Maha Sudarshan Churna powder, D & K Pharmacy, Bhavnagar, India
 Maha Sudarshan Churna powder, produced by Chhatrisha, Lalpur, India
 Maha Sudarshan Churna powder, produced by Dabur India Ltd, New
Delhi, India
 SAFI liquid, produced by Hamdard-WAKF-Pakistan
 SAFI liquid, produced by Hamdard-WAKF-India
 Yograj Guggul tablets, produced by Zandu Pharmaceuticals, Mumbai,
India
 Sudarshan tablets, produced by Zandu Pharmaceuticals, Mumbai, India
 Shilajit capsules, produced by Dabur India Ltd, New Delhi, India
(WHO Drug Information Vol. 19, No. 3, 2005).

20. E-WASTE

22. Pollutants Occurrence
Arsenic Semiconductors, diodes, microwaves, LEDs (Light-
emitting diodes), solar cells
Cadmium Batteries, pigments, solder, alloys, circuit boards,
computer batteries, monitor cathode ray tubes
(CRTs)
Lead Lead rechargeable batteries, solar, transistors,
lithium batteries, PVC (polyvinyl chloride)
stabilizers, lasers, LEDs, thermoelectric elements,
circuit boards
Mercury Components in copper machines and steam irons;
batteries in clocks and pocket calculators, switches,
LCDs
Pollutants and their occurrence in waste electrical and electronic equipment
(P. Srisudha, ‘Tackling e-waste’, The Hindu, 28 June, 2009)

24. Soil WaterAir
Primary source
Plants
Domestic animals
(Brady, 1994))

25. Metal Livestock's
drinking
Water
(µg/ml)
Irrigation
water
(µg/ml)
Soil
(µg/gm)
Plant
(µg/gm)
Pb 0.10 0.06 100 0.30
Hg 0.01 0.01 30 0.O3
Cd 0.05 0.01 3 0.10
As 0.2 0.01 20 0.1
Indian standards (Awashthi, 2000) & WHO, 1999, 2011, FAO, Chiroma et al; 2014,
Schütze and Throl (2000)
Maximum permissible limits of heavy metals

26. How its affecting food chain: bioaccumulation &
biomagnification

28. Lead
 Cattle, Horse, Dog more susceptible
 Pig & Cat rare (H.S.Sandhu 2nd ed, 2012)
 Younger Vs. old
 Ruminants Vs. Non ruminants (Neathery, 1984)
 Pb-acetate
 Pb-oxide
 Pb-carbonate (H.S.Sandhu 2nd ed, 2012)
 Ubiquitous environmental contaminant.
(H.S.Sandhu 2nd ed, 2012)

29. Affected organs/system
Pb
Neuro
-T
GIT-
T
Hepat
o-T
Nephr
o-T
Endocrin
e-T
Reproducti
ve-T

31. Mechanism underlying the development of
oxidative stress in a cell on lead exposure
(Gagan flora at al.,2012)
Under normal physiological conditions, there is a
balance between free radicals and antioxidants and
any deviation from it can cause oxidative stress
leading to cell death. (Gagan flora at

32. Cattle : show
head pressing
behaviour.
LEAD POISONING: CLINICAL
SIGNS
Cattle: advanced stages of lead poisoning,
become frenzied, bellow, stagger and crash
into obstacles
 Gastrointestinal signs include colic, constipation for several days followed by
diarrhoea.
 Abortion(mid or late gestation), opisthotonos, salivation, lacrimation and
paralysis may also be observed.
 Death may occur within several hours or days. (O.M.Radostits et al. 10th
Ed.)

33. Mercury (Hg)
 Minamata(1953--60) & Niigata(1964--65) disease in Japan
(Mottet et al, 1985)
 Elemental-Hg – non toxic (orally), highly toxic(inhalation)
 Inorganic-Hg – less toxic (insoluble < soluble)
 Organic-Hg – more toxic (H.S.Sandhu,2nd ed,2012)
 Liquid forms at room temp
 Young ruminants more susceptible than Horse & Pig
(H.S.Sandhu,2nd ed,2012)
 Se & Vitamin E protects against toxicity (Parizek et al., 1974)
 Structural and functional disintegration of the enzymes
(–SH group) ( Roy Chowdhury A and Vachhzajani KD; 1987)

35. Mercury (Hg)
Hg
Lung
GIT
Skin
Absorption
Organic-Hg
Inorganic-
Hg Deposition
Bile &
Faeces
Urine
Hairs &
others
Elemental-
Hg
Faeces
Elimination

36. The intestinal uptake and subsequent distribution of organic mercurials, such as
methylmercury, throughout the body. a. Conjugation with glutathione (GSH), shown as
CH3—Hg—SG. b. Secretion of conjugate into bile. c. Reabsorption in gallbladder.
d. Remaining Hg enters intestinal tract.

37. The ability of organic mercurials to cross the blood–brain barrier and the placenta
contributes to their greater neurological and teratogenic effects when compared with
inorganic mercury salts. Note the structural similarity of the methylmercury complex to
methionine, CH3SCH2CH2—CH(NH3 +)COO–.

38. Affected organs/system
Hg
Neuro-
T
GIT-
T
--
SH
Nephro-
T
Endocrin
e
Repro-T

39. Mercurial
salts
stomatitis,pharyngitis,
vomiting,diarrhea
,dehydration, and shock.
Death may occur within
hours.
Oliguria and azotemia,
lasting for 1-2 days,
follow in animal animals
that survive acute
mercuric ion toxicosis
Alkyl mercurials(e.g.,methyl
mercury,ethyl mercury)
signs develop over a
period of 7-21 days.
Neurological signs
(depression,ataxia,Incoordination,
paresis, & blindness
Dermatologic
signs(e.g.,dermatitis,pustules, Ulcers)
Abnormal
postures,complete
blindness
Mercury Toxicity: Clinical
Signs
(O.M.Radostits et. al.,10th ed.

40.  Regulatory limit in agricultural soil is 100 mg/kg soil.
(Salt et al., 1995)
 Itai Itai disease
 > 5ppm toxic effect
 Most common in Ruminants (NRC,1980)
CADMIUM (Cd)

42.  Antagonistic activity against Cu, Zn, Se & Fe
(chemical similarities & competition for binding )
(Ammerman et al., 1973)
 Oxidative stress
Destroy the SOD (Cd replaces Zn2+ )
(Zn maintain the str. of SOD that scavenges the FR)
(Darbre, 2006)
 Inhibits the GSHB-Px
(catalyzed the destruction of H2O2 & LP & protects the lipids
membrane from peroxide damage)
Cd involved in Metal interaction

43. Affected organ/system

44. • Anemia
• Retarded growth
• Proteinuria
• Glycosuria,
• Hyperphosphatemia
• Testicular degeneration and necrosis
• Arthropathy and osteoporosis
• Vomition and diarrhoea in acute cases.
(O.M.Radostits et al. 10th Ed.)
Clinical Signs

45. More abundance in the Earth’s crust 1.5–3.0 mg/kg
(20th most abundant element)
(Mandal and Suzuki, 2002)
Used as first drug to cure syphilis by Paul Erlich
(Waxman and Anderson, 2001)
Most extensive exposure through drinking water
In Bangladesh 1980, arsenic-contaminated Artesian well water.
(Mandal and Suzuki, 2002)
Oxidative stress
Carcinogenicity
Arsenic

46. (Casarett and Douls,7th
ed.)

47. SUBACUTE:
Bloody diarrhoea & dehydration.
Weakness and hind limb
paralysis
Organic Arsenic: Blindness and incordination
mainly occur in overdosing of arsenilic acid.
In swine dog sitting posture
ARSENIC TOXICITY CLINICAL SIGNS
Chronic:
Low body weight &
sloughing of skin
(O.M.Radostits et al. 10th Ed.)

48. Management of Heavy Metal
Toxicity

49. 1. Decontamination
• Removal of the patient from the source of exposure is critical to
limiting dose.
• Emetics, activated charcoal, gastric lavage employed if ingestion is
recent.
• Charcoal administered @1-4 mg/kg P/O.
2. Resuscitation
Good supportive care is critical.
3. Chelation
Basic principles of metal toxicity management :
(1) Prevention of further metal absorption into the system
(2) Elimination of metal from the circulation
(3) Inactivation of metal bioavailable in the system

50. • Chelation has its origin in the Greek word chele that means claw of a
lobster, thus depicting the concept of clinging or holding with a strong
grip.
• The term chelate was first applied by Sir Gilbert T. Morgan and H. D. K.
Drew in 1920.
They suggested the term for the caliper-like groups which function as two
associating units and fasten to a central atom so as to produce heterocyclic
rings
(T. Morgan et. al.,1920)
CHELATION

52. (Swaran J.S. Flora and Vidhu Pachauri ,

53. Edetate Calcium Disodium
Treatment of poisoning by metals that have
higher affinity for the chelating agent than does
ca2+.
EDTA is charged at physiological pH, it does not
significantly penetrate cells; its volume of
distribution approximates extracellular fluid space.
Lead Poisoning.
• Bone provides the primary source of lead that is chelated by CaNa2EDTA
• After such chelation, lead is redistributed from soft tissues to the skeleton
• Calcium versenate (Ca Na2 EDTA, Ca EDTA) @ 110-220 mg/kg BW IV infusion, 2
times a day (as 1-2% solution in 5% dextrose) for 4-5 days ( Large animals)
(CALCIUM DISODIUM VERSENATE)
• Mercury is unavailable to the chelate perhaps because it is too tightly bound
by sulfhydryl groups or sequestered in body compartments that are not
penetrated by CaNa2EDTA.
Toxicity: hypocalcemic tetany, hydropic vacuolization of the proximal tubule, loss of the brush
border, and eventually, degeneration of proximal tubular cells (Catsch and Harmuth- Hoene,

54. • Like EDTA, is a polycarboxylic acid chelator, but it has somewhat greater
affinity for most heavy metals.
Pentetic Acid (DTPA/ Di ethylene tri amine penta acetic acid)
• Limited access to intracellular sites of metal storage
• Because DTPA rapidly binds ca2+, CaNa3DTPA is employed
Heavy-metal poisoning that do not respond to EDTA, particularly poisoning by
radioactive metals like Uranium and Plutonium (N.L.Spoor, 1977)
Disadvantage of depleting zn from the system that may be overcome by supplementation
or using the zinc salt of the drug.
Teratogenic like CaNa2EDTA due to its Zn and Mn depletion effect

55. Developed during world war II as an antidote to lewisite, a
vesicant arsenical war gas, hence its alternative name,
british antilewisite (BAL).
Dimercaprol(2,3dimercaptopropanol)
Its instability in aqueous solutions, peanut oil is the solvent employed in
pharmaceutical preparations.
Arsenicals would form a very stable and relatively nontoxic
chelate ring with the dimercaprol
MOA: Formation of chelation complexes Between its sulfhydryl groups and metals
• Antagonizes the biological actions of metals that form mercaptides with essential
cellular sulfhydryl groups, principally arsenic, gold, and mercury.
The sulfur–metal bond may be labile in the acidic tubular urine, which may increase
Delivery of metal to renal tissue and increase toxicity.
Maintain a concentration of dimercaprol in plasma adequate to favor the continuous
formation of the more stable 2:1 (BAL–metal) complex and its rapid excretion

56. More effective in preventing inhibition of sulfhydryl enzymes than in reactivating them.
Used in combination with CaNa2EDTA to treat lead poisoning, especially when
evidence of lead encephalopathy exists.
Dimercaprol cannot be administered orally; it is given by deep intramuscular injection
as a 100 mg/ml solution in peanut oil,
Toxicity: rise in systolic and diastolic arterial pressures, accompanied by tachycardia
Arsenic toxicity: BAL(British Anti-lewisite)/Dimecaprol:@4-7mg/kg I/M
t.i.d×3days.

57. An orally effective chelator that is chemically similar to dimercaprol but contains two
carboxylic acids that modify both the distribution and chelating spectrum of the drug.
Succimer (2,3-dimercaptosuccinic acid, CHEMET)
After Absorption
Effective as a chelator of arsenic, cadmium, mercury, and other metals
(Aposhian and Aposhian, 1990)
Toxicity : less than that with dimercaprol perhaps because its relatively lower lipid
solubility minimizes its uptake into cells
A desirable feature : it does not significantly mobilize essential metals such as zinc,
copper, or iron.

58. First isolated in 1953 from the urine of patients with liver
disease who were receiving penicillin
Penicillamine (D-β,β-dimethylcysteine)
Effective chelator of copper, mercury, zinc, and lead and
promotes the excretion of these metals in the urine.
Absorbed (40% to 70%) from the GI tract
N-Acetylpenicillamine is more effective than penicillamine in protecting against the
toxic effects of mercury presumably because it is even more resistant to metabolism.
Toxicity. With long-term use, induces several cutaneous lesions, including urticaria,
macular or papular reactions, pemphigoid lesions, lupus erythematosus,
dermatomyositis, adverse effects on collagen,

59. Chelation
Monotherapy
Combination
Therapy
Antioxidents
Micronutrients
Phytochemicals
Acute Metal Exposure
Soft Tissues
Cellular Manifestation
Pro – vs antioxident imbalance
Metabolic pathway interfered
(haem synthetic pathway)
Tissue Damage & Organ
dysfunction
Cellular Manifestation
Oxidative Stress, Pro- or Anti-
apoptotic manifestations
(Mitochondrial dysfunction, DNA
damage, etc)
Systemic Manifestations
Disease induction or promotions
(Diabetes,Cancer, DVD, etc)
Soft & Hard Tissues
Chronic Metal Exposure
Excretion (Urinary / Biliary)

60. (Swaran J.S. Flora and Vidhu Pachauri ,

61. • Greater Affinity, Low Toxicity
•Ability to compete with natural chelators
•Ability to penetrate cell membranes
•Rapid elimination of the toxic metal
•High water solubility
•Capacity to form non-toxic complexes
•Same distribution as the metal
(Swaran J.S. Flora and Vidhu Pachauri ,
IDEAL CHELATER

62. Benefits
• Effective against
acute poisoning
• Form non-toxic
complexes
• Remove metal from
soft tissues
• Oral therapy is
available
Drawbacks
• Redistribution of toxic metal
• Essential metal loss
• No removal of metal from
intracellular sites
• Hepatotoxicity and
nephrotoxicity
• Poor clinical recovery
• Pro-oxidant effects (DTPA)
• Headache, nausea, increased
blood pressure
CHELATION

63. PREVENTION AND
CONTROL

64. BIOREMEDIATION
Use of different biological systems to destroy or reduce concentrations of
contaminants from polluted sites.
Microbes and plants have a natural capability to attenuate or reduce: Mass,Toxicity,
Volume, Concentration of pollutants
Aerobic bacteria:
Examples include: Pseudomonas, Alcaligenes, Sphingomonas, Rhodococcus, and
Mycobacterium.
Fungi:
Able to degrade a diverse range of persistent or toxic environmental pollutants
(Bodishbaugh, D.F., 2006)
Phytoremediation is the use of living green plants for in situ risk reduction and/or
removal of contaminants from contaminated soil, water, sediments, and air
Hyper accumulator plant species are used on many sites due to their tolerance of
relatively extreme levels of pollution.
Avena sp. , Brassica sp.

67. BIOREMEDIATION
Use of different biological systems to destroy or reduce concentrations of
contaminants from polluted sites.
Microbes and plants have a natural capability to attenuate or reduce: Mass,Toxicity,
Volume, Concentration of pollutants
Aerobic bacteria:
Examples include: Pseudomonas, Alcaligenes, Sphingomonas, Rhodococcus, and
Mycobacterium.
Fungi:
Able to degrade a diverse range of persistent or toxic environmental pollutants
(Bodishbaugh, D.F., 2006)
Phytoremediation is the use of living green plants for in situ risk reduction and/or
removal of contaminants from contaminated soil, water, sediments, and air
Hyper accumulator plant species are used on many sites due to their tolerance of
relatively extreme levels of pollution.
Avena sp. , Brassica sp.

68. Phytoextraction
1
Phytovolatilization
2
Phytostabilization
3
Rhizodegradation
Rhizofiltration
4
5
5 mechanisms based on the fate of contaminants
68