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7/28/2019 BISC 313 - Heavy Metals
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Dr. Onkar S. Bains
BISC 313
SFU
Spring 2013
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Metals are probably the oldest toxins known to humans
Lead usage may have begun prior to 2000 BC in the smelting of silver
Arsenic was obtained during melting of copper and tin, and an early use was
for decoration in Egyptian tombs
The five main heavy metalsmercury (Hg), lead (Pb), cadmium
(Cd), chromium (Cr), and arsenic (As)present the greatest
environmental hazard due to their extensive use, their toxicity, andtheir widespread distribution
Introduction
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Heavy metals consist of both
essential and non-essential
Biological essential heavy metals
include copper (Cu), nickel (Ni),iron (Fe) and zinc (Zn)
Iron for instance forms an essential
part of hemoglobin, a protein in
our blood which transports oxygen
from the longs to other tissues.
Although necessary, essential
metals become toxic at high
concentrations.
Non-essential heavy metalsinclude lead (Pb), mercury (Hg),
cadmium (Cd) and tin (Sn)
They can be tolerated at low levels,
but become toxic as well at higher
concentrations
QUALITYOFHEALTH
DOSE OF METAL
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"Heavy metals" are chemical
elements with a specific gravity at
least 5 times that of water
The specific gravity of water is 1 g/cm3
at 4C (39F)
Some well-known toxic metals with a
specific gravity five or more times that
of water are arsenic (5.8), cadmium
(8.7), chromium (7.2), lead (11.3), and
mercury (13.5)
In small quantities, certain heavy
metals are nutritionally essential
for a healthy life
Some of these are trace elements (i.e.,iron, copper, manganese, and zinc)
These elements, or some form of them,
are commonly found naturally in
foodstuffs, fruits and vegetables, and in
commercially available multivitaminproducts
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Heavy metals become toxic whenthey are not metabolized by body
and accumulate in soft tissues
Heavy metals may enter humanbody via food, water, air, or
absorption through the skin in
agriculture, manufacturing,
pharmaceutical, industrial, orresidential settings
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Alter function of essential metals
Toxic metals may displace essential metals as co-factors for
enzymes
Lifestyle factors
Smoking contains toxic metals such as cadmium and
arsenic
Formation of metal complexes
Metallothioneins form complexes with cadmium, zinc,
copper and other metals by interacting with sulfhydrylgroups on cysteine residues
Captured metals are transported to
kidney for filtration and excretion
Factors affecting toxicity of metals
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Chemical form/speciation
The free metal ion is considered most bioavailable and hence
the most toxic
Example: Metal sorption by soil (organic matter, clay minerals) makes
metal ions less bioavailable
Example: High pH decreases bioavailability (metals predominantly
found an insoluble meta mineral phosphates and carbonates) while low
pH increases bioavailability (commonly found as free ionic species or as
soluble organometals)
Example: Under oxidizing or aerobic conditions, metals found as soluble
cationic forms (i.e., Cd2+ or Pb2+) while in areas rich in sulfur and sulfate-
reducing bacteria, the sulfide that is generated is available to form non-
toxic, insoluble sulfide deposits (i.e., CdS or PbS)
Lipid soluble and non-ionized pass membrane easily (i.e.,
tetraethyl lead and methylmercury)
Some metals are more toxic in one speciation state than
another (i.e., chromium VI is more toxic than chromium III)
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Age
Young children and elderly more susceptible
to metal toxicity
Major exposure of many toxic chemicals in children is food
(children consume more calories per pound of body weight
than adults)
Also, children have increased GI tract absorption with respect
to metals, particularly lead
Newborns have increase exposure of toxic metals from breast
milk contaminated with lipophilic metals
Immune status of host Metals shown to provoke immune reactions
(some examples of metals that can do this
are mercury, chromium, platinum beryllium
and nickel)
l h f
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Protein inactivation Can substitute in for essential metals that are involved in the binding of substrate
to active site of enzymes
Bind to sulfhydryl group (SH) found within proteins (thereby prevent disulfide
bridge formation)
Example: Microtubule function disruption (affect chromosomal separation during
cell division or affect cilia/flagella movement)
Oxidative stress Reflects an imbalance between systemic manifestation of reactive oxygen species
and a biological system's ability to readily detoxify reactive intermediates or to
repair resulting damage Heavy metals disturb redox homeostasis by stimulating formation of reactive
oxygen species such as superoxide anions and hydroxyl radicals
Interference with DNA transcription, translation and
repair
General mechanisms of toxicity
with heavy metals
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Mercury
Cadmium
Arsenic
Lead will mention at next lecture
Heavy metals to cover in course
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Mercury is found in many rocks
including coal
When coal is burned, mercury is released into
the environment
Mercury that was once in the Earths
crust could be released through a
volcanic eruption or other geologicalactivity
Mercury can also be released to
environment by human activities such
as metal smelting, iron and steelproduction, coal-fired electricity
generation, industrial boilers, cement
kilns, waste incineration, and use of
products such as electrical switches
and fluorescent lights
Mercury
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Elemental/metallic: Hg0
A metallic, silvery liquid (also referred to as quicksilver) that is processed from anore called cinnabar
Readily breaks into droplets and easily vaporizes at room
temperature into an odorless, colorless vapor that can easily be
inhaled
High absorption from lungs (~80%) but poorly absorbed from
GI tract (~20%)
Readily absorbed due to its lack of charge and is highly lipid
soluble
It easily crosses cell membranes and barriers (i.e., blood-brain, placental), and
becomes trapped in cells when it is reduced to Hg1+ or Hg2+
Inorganic salts: Divalent or mercuric (Hg2+), Monovalent or
mercurous (Hg1+)
Includes complexes: examples include HgX2, HgX3-, HgX4
2- (X=OH-, Cl-, Br-)
Low absorption because these positively charged ions do not readily transverse cell
membranes
Chemical forms of mercury
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Organic: CH3Hg+, CH3CH2Hg
+, (CH3)2Hg
Alkyl groups added to mercury can be dimethyl, ethyl, or methyl substituents High absorption from GI tract (~90-95%)...also readily absorbed through skin
Absorption due to being highly lipid soluble
Can cross blood brain and placental barrier using methionine transport system
(molecular mimicry)
When methyl-Hg bind toSH group on cysteine, the molecule looks similar to methionineand takes its place in the membrane transport system which normally moves methionine
into the brain or fetus
Able to easily bioaccumulate in organisms and biomagnify up a food chain
Chemical forms of mercury
methionine
cysteine
+
methylmercury
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Biomagnification of methylmercury
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Hg2+(major dissolved form in
freshwater), HgCl42-
(majordissolved form in seawater
Environmental cycling of mercury
and
biomagnification
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Biomethylation Process whereby living organisms produce a direct linkage of a methyl
group to a metal, thus forming metal-carbon bonds
Organisms involved are as follows: Sulphate-reducing bacteria found in anoxic waters and sediments
Some aerobic and facultatively anaerobic bacteria
Fungi and lower algae
Plants, animals and humans
Demethylation
Process whereby methyl group is removed from a molecule
Example: bacterial enzymes efficiently transform the most toxic forms ofmercury to less toxic states
Methylmercury lyase (MerB) acts on methylmercury to release less toxic ionic mercury
Hg2+
Mercury reductase (MerA) acts on Hg2+ to less toxic volatile metallic Hg0
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Chronic mercury poisoning amonghatmakers whose felting work
involved prolonged exposure tomercury
Mercury was commonly used in themanufacture of felt hats, especiallyin the 19th century
Once the fur has been rolled, beaten,and treated with mercury, it is calledfelt
Victims developed severe anduncontrollable muscular tremorsand twitching limbs, called "hatter'sshakes"; other symptoms includeddistorted vision and confusedspeech
Advanced cases developedhallucinations and other psychotic
symptoms
Mad hatter syndrome
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Minamata Bay region on the islandof Kyushu, Japan
The Chisso Corporation was oncea fertilizer company, and graduallyadvanced to a petrochemical andplastic-maker company
From 1932 to 1968, an estimated
27 tons of mercury compoundswas dumped into Minamata Bay
Mercury accumulated in seacreatures, leading eventually tomercury poisoning in humanpopulation Fish and shellfish consumption resulted in exposure to high levels of
methylmercury
Microorganisms biotransformed mercury into methylmercury
In 1952, the first incidents of mercury poisoning appear in thepopulation of Minamata Bay in Japan, caused by consumption of
fish polluted with mercury, bringing nearly 1000 fatalities
Case: Minamata Bay poisoning
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Hundreds of people exhibited serious neurological problemssuch as: Difficulty walking, swallowing, speaking, and hearing
Post mortem brain analysis revealed that many had a marked loss ofbrain weight and volume (brain atrophy)
Children born to exposed mothers had a high rate of birth defects,including severe brain damage, mental impairment, and delayeddevelopment
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Mass methylmercury poisoning incident that
began in late 1971
Iraq was rocked by a severe drought in 1971which led to ubiquitous food shortages
Excess grain in the United States and Mexico,
which had been treated with a methylmercury
fungicide, was shipped as aid Grain had distinctive orange-pink color
People suffered from parathesia (numbness of
skin), ataxia (lack of coordination of muscle
movements) and loss of vision, symptomssimilar to those seen when Minamata disease
affected Japan
The recorded death toll was 650 people, but
figures at least ten times greater have beensuggested
Case: Iraq poison grain disaster
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Occurs in nature primarily in association
with lead and zinc ores and is releasednear mines and smelters processing
these ores
Industrially cadmium is used as a
pigment in paints and plastics, inelectroplating, and in making alloys and
alkali storage batteries (e.g., nickel-
cadmium batteries)
Environmental exposure to cadmium ismainly from contamination of
groundwater from smelting and
industrial uses as well as the use of
sewage sludge as a food-crop fertilizer
Cadmium
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McDonald's recalls cadmium-tainted Shrek glasses In June 2010
12 million collectibles recalled after tests reveal cadmium in paint
Cadmium is a known carcinogen that research shows also can cause bonesoftening and severe kidney problems
Potential danger would be long-term exposure to low levels of cadmium,
which could leach from paint onto child's hand, then enter the body via oral
route of administration if hands are left unwashed
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Cadmium is present in circulatory system
bound primarily to metallothioneins,
produced in the liver Cadmium + metallothionein = CdMT
Main organ of damage following long-
term exposure is the kidney, with the
proximal tubules being primary site ofaction
Following glomerular filtration in kidney,
CdMT is re-absorbed efficiently by
proximal tubule cells, where itaccumulates within lysosomes
Subsequent degradation of the CdMT
complex releases Cd2+, which inhibits
lysosomal function, resulting in tubulecell injury
Cadmium toxicity
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Kidneys lose their function to remove
acids from the blood in proximal renal
tubular dysfunction
Decreased H+ secretion into renal filtrate
This dysfunction causes gout, a form of
arthritis due to the accumulation of uric
acid crystals in joints because of highacidity of blood (hyperuricemia)
Theproximal renal tubular dysfunction
also creates low phosphate levels in theblood (hypophosphatemia), causing
muscle weakness and sometimes coma
Decreased phophate reabsorption
Low phosphate levels also linked to poor
bone mineralization
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Theproximal renal tubular dysfunction also will affect conversion
of 25(OH) vitamin D to 1,25-(OH)2 vitamin D this will in turn
decrease calcium reabsorption at small intestine and decrease
bone mineralization due to low serum calcium levels
C It i it i di i T
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Located in the Hokuriku region on
Honshu island of Japan
Mining was prevalent in the Toyama
Prefecture of Japan starting around
the year 710
After World War I, new mining
technology arriving from Europe
made the Kamioka Mines in Toyama
among the most productive in the
world
Starting all the way back in 1910
cadmium was being released in
significant quantities into the Jinzu
River in Toyama
Case: Itai-itai disease in Toyama
Prefecture
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This was a major problem because cadmium in the
water killed all fish, not to mention it was the major
source for irrigation for the surrounding paddy fields, as
well as drinking water
In 1912, first documented case of disease emerged
Itai-Itai resulted primarily from consumption of
cadmium contaminated rice
From 1939 to 1954, ~200 peopleaffected
Itai-itai disease literally translates to
ouch-ouch disease, named for the
painful screams of its victims
Major symptoms of this disease:
Osteomalacia (softening of the bones)
Osteoporosis (loss of bone mass and
weakness)
Kidney failure
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Arsenic is a naturally occurring
element widely distributed in theearth's crust
Occurs naturally in soil andminerals and may enter the air,water, and land from wind-blown
dust and may get into water fromrunoff and leaching
Man-made sources: Smelting of gold, silver, copper, lead
and zinc ores
Combustion of fossil fuels
Agricultural uses as herbicides andfungicides
Cigarette smoke
Occupational: largest source ismanufacture of pesticides andherbicides
Arsenic
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Elemental/metallic: As0 Element is a steel gray, very brittle, crystalline, semi-metallic solid
Readily absorbed due to its lack of charge and is lipid soluble It easily crosses cell membranes and barriers
Inorganic salts: primarily in two oxidation states (+3
to +5) Arsenic acid: AsO(OH)3
Arsenous acid: As(OH)3
Arsine, AsH3, an extremely poisonous gas
Rapidly absorbed through the lungs
Organic: Arsenic can be methylated by bacteria, algae, fungi, vascular plants,
and animals
Methylated arsenic (V) compounds include: Monomethylarsonic acid,
CH3AsO(OH)2; Dimethylarsinic acid, (CH3)2AsOOH; Trimethylarsine
oxide, (CH3)3AsO
Methylated arsenic (III) compounds include: Monomethylarsine,
CH3AsH
2; Dimethylarsine, (CH
3)
2AsH; Trimethylarsine, (CH
3)3As
Absorption due to being highly lipid soluble
Chemical forms of arsenic
Arsenous acid
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Ranking of toxicity: organic
arsenics > inorganic arsenics >elemental
Trivalent forms more toxic thanpentavalent forms
Acute exposure: severe
abdominal pain, fever, cardiacarrhythmia
Chronic exposure: muscleweakness and pain, gross edema,gastrointestinal disturbances,liver and kidney damage, swellingof peripheral nerves (neuritis),paralysis Liver injury jaundice
Peripheral vascular diseaseblackfoot disease
Cancer (skin, lung, kidney, bladder)
Arsenic toxicity
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Sporadic cases of BFD occurred as early as in the early 20th
century, and peak incidence was noted between 1956 and 1960
Human exposure primarily from arsenic contaminated drinkingwater (seen in southwest coast of Taiwan and Bangladesh)
Severe form of peripheral vascular disease in which blood vessels
in lower limbs are severely damaged, resulting eventually in
progressive gangrene Skin disease:
keratosis of hands and feet, and hyperpigmentation
Blackfoot disease
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Minimize/eliminate exposure tosources containing heavy metals
Metallotioneins
Phase III efflux transporters
Chelating agents
Decreasing heavy metal toxicity
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The word chelation comes from Greek work chele
meaning claw Chelators bind directly with metal ions to form stable
complexes that remove the metal from competition
with the body's cells
Because a chelated metal is water soluble, it can be
excreted readily by the kidney
For reduction of body burdens associated with toxic metals
Examples of chelating agents:
1. DMPS 2,3-dimercapto-1-propanesulfonic acid
2. DMSA dimercaptosuccinic acid
3. D-Penicillamine
4. EDTA ethylenediaminetetraacetic acid
Chelating agents
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Chelating agents have variable denticity
Denticity refers to the number of atoms in a single ligand (chelator) that bind to a
central atom (metal) in a coordination complex
Monodentates (1 atom binds to metal) and polydentates (2 or more atoms binds to
metal) Most are polydentates (ranging from 2 to 6 atoms)
For example, EDTA is a hexadentate ligand while DMPS is a bidentate ligand
DMPS
Desirable attributes for chelating
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Gain access to the metals
Tightly bind and control the metals
Not injure recipient Accelerate mobilization and/or removal
of the metals
Cheap
Easy to administer
Desirable attributes for chelating
agents