bisc 313 - heavy metals

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
http://upload.wikimedia.org/wikipedia/commons/a/ae/Medta.png


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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

bisc 313 - heavy metals

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