Environmental Toxicity
1. Toxicity of Heavy Metals
Periodic table has 105 elements, 80 are considered metals that
they are charecterized by:
- luster, malleability, electric and thermal conductivity;
- Chemically form bases which can react with acids and
tendency to lose electrons and become positive ions (cations),
Examples of heavy metals and metalloid
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There are ~35 metals that concern us because of occupational
or residential exposure.
Depending on their physicochemical characteristics (e.g. sp.
gravity, atomic wt. , ….), some of them are classified as
heavy metals ( metal having an atomic weight greater than
sodium, sp. gravity >5 g/cm3)
Aluminum, antimony, arsenic, bismuth, cadmium,
chromium, cobalt, copper, gallium, gold, iron, lead,
manganese, mercury, nickel, platinum, selenium, silver,
thallium, tin, uranium, vanadium, and zinc
Small amounts of some of these elements are common in our
environment and diet and are actually necessary for good
health.
Large amounts of any of them may cause acute or chronic
toxicity (poisoning).
Indoor concentration of heavy metals is generally less than
their outdoor concentration
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Heavy metal environmental pollution is mainly produced
from industrial activities, and deposit slowly in the
surrounding water, air and soil
Heavy metals are found in everyday existence and are
frequently hard to avoid entirely. Most people can excrete
toxic heavy metals from the body successfully. However,
some people—especially those who suffer from chronic
conditions—cannot excrete them efficiently enough and
toxicity occurs
Heavy metal toxicity is an excessive build-up of metals in the
body. The most hazardous heavy metals that humans are
exposed to are arsenic (As), lead (Pb), mercury (Hg),
cadmium (Cd), aluminum (Al)and iron (Fe)
Examples of specific gravities of heavy metals: arsenic, 5.7;
cadmium, 8.65; iron, 7.9; lead, 11.34; and mercury, 13.546
Treatment of heavy metal toxicities
• Medicinal treatment for heavy metal poisoning is done by
chelation therapy by administering compounds known as
chelators or chelating agents. For example
1- Dimercaprol (British Anti-Lewisite ;BAL), It is a bidentate
chelator (i.e. it forms two bonds with the metal ion,
preventing it from binding to tissue proteins and permitting
its rapid excretion. It is a universal chelating agentthat is
used to treat toxicities with many heavy metals like Hg, AS,
and Pb. It is oily liquid given by parentral administration. Its
administration is associated with many side effects like
hypertension, tachycardia, headache, nausea, vomiting,
paresthesia, swelling, hematoma at the site of injection and
fever especially in children. Long-term use may associated
with thrombocytopenia andincrease prothrombin time.
2- Dimercaptosuccinic acid (DMSA, Succimer), another
bidentate chelating agent. It occurs in two diastereomers,
meso and the chiral dl forms. The meso isomer is used as a
chelating agent. It acts as conger of BAL with oral
bioavailability. It mainly used to treat arsenic and mercury
poisoning. It is also effective to treat lead toxicity in both
children and adults. It is less toxic than BAL but some GI
distress, skin rhashes,paresthesia and slight elevation in liver
enzymes may occur.
3-
2,3,-dimercaptopropane-1-sulfonate (Dimaval, Unithiol
; DMPS): It is a bidentate chelating agents that form
complexes with various heavy metals. It mainly used as
antidote for treatment of mercury poisoning. There are
indications that DMPS is also suitable for the increase of
heavy metal elimination in poisoning with arsenic (except
for poisoning with arsine), copper, lead, antimony,
chromium, cobalt.
4- D-Penicillamine (DPCN); It is a bidentate chelating agent.
It is a derivative of penicillin. It is used in treating of copper
poisoning and Wilson’s disease (presence of copper overload
causing hepatic and CNS symptoms).It also used as adjuvant
therapy in treatment of gold, arsenic, and lead intoxication. It
is given orally ,absorbed well from GIT and excreted
unchanged. Adverse effects could be severe like proteinurea,
pancytoprnia and hemolytic anemia.
5- Disodium calcium EDTA (ethylene diaminetetraacetic
acid); It is a polydentate chelating agent that is efficiently
used for polyvalent heavy metal detoxification like Lead
toxicity, Zinc toxicity, and acute cadmium poisoning. It is
administered parentrally. Side effects include nephrotoxicity
and ECG changes
6- Desferrioxamine (DFO); it has natural origin (a derivative
of the iron-bearing metabolite, ferrioxamine B, from
Streptomyces pilosus) . It is polydentate chelating agent used
mainly for Iron poisoning, and also in aluminum poisoning. It
is poorly compete with heme iron in hemoglobin and
cytochromes. Deferoxamine is also used in treatment of
Aceruloplasminemia (an autosomal recessive disorder of
iron
metabolism
characterized
by
progressive
neurodegeneration of the retina and basal ganglia and
development of diabetes mellitus). Side effects include skin
hypersenstivity, renal and hepatic toxicity and neurotoxicity.
Long-term use may cause blood coagulopathies.
1- Toxicity of Iron
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In nature, iron is usually found in its oxidized form, ferric oxide,
which is insoluble. Ferrous iron is soluble and its toxicity varies,
largely with the integrity of the gastrointestinal lining.
Most of iron toxicity usually refers to an acute overload rather than a
gradual one. It has been primarily associated with ingestion of items
contaminated with iron compounds or consumption of large quantities
of iron supplement pills, such that happen with young children
mistaking iron colored pills that they usually resemble candies.
Other sources of iron are drinking water, iron pipes, and cookware.
Target organs are the brain, liver, cardiovascular system, and kidneys.
The amount of iron ingested may give a clue to potential toxicity.
The therapeutic dose for iron deficiency anemia is 3-6 mg/kg/day.
Toxic effects begin to occur at doses above 10-20 mg/kg of elemental
iron.
Ingestions of more than 50 mg/kg of elemental iron are associated
with severe toxicity.
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A 325-mg tablet of ferrous sulfate has 65 mg (20%) of elemental iron
A 325-mg tablet of ferrous gluconate has 39 mg (12%) of elemental
iron
A 325-mg tablet of ferrous fumarate has 107.25 mg (33%) of
elemental iron
Symptoms of iron toxicity:
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Ingestion accounts for most of the toxic effects of iron because iron is
absorbed rapidly in the gastrointestinal tract. The corrosive nature of iron
seems to further increase the absorption.
Symptoms begin with a pain in the stomach, as the stomach lining
becomes ulcerated. This is accompanied by nausea and vomiting. The
pain then subsides for 24 hours as the iron passes deeper into the body
and damages internal organs, particularly the brain and the liver, and
metabolic acidosis develops. The body goes into shock and death from
liver failure.
Treatment:
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Later stage treatment consists of cleaning the iron from the blood, using a
chelating agent such as deferoxamine. If this fails then dialysis is the next
step.
2-Toxicity of Aluminum
 Although aluminum is not a real heavy metal (specific gravity of 2.552.80), it makes up about 8% of the surface of the earth.
 It is readily available for human ingestion through the use of food
additives, antacids, buffered aspirin, astringents, nasal sprays, and
antiperspirants; from drinking water; from automobile exhaust and
tobacco smoke; and from using aluminum foil, aluminum cookware,
cans, and ceramics.
 DFO is the recommended chelating agent in treatment of acute
toxicity of aluminum.
 Aluminium has no known function in living cells and presents some
toxicity if it is consumed in excessive amounts.
 Its toxicity can be traced to deposition in bone and the central
nervous system, which is particularly increased in patients with
reduced renal function. Many studies suggested multiple role of
aluminium in development of different pathological disorders affect
those targets.
 Because aluminium competes with calcium for absorption, increased
amounts of dietary aluminium may contribute to the reduced skeletal
mineralization and muscleoskeletal weakness manifested as
osteomalacia (softening of the bones) and fractures, even in the
relatively young (40-50 age group).
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A small percentage of people are allergic to aluminium and experience
contact dermatitis, digestive disorders, vomiting or other symptoms
upon contact or ingestion of products containing aluminium, such as
deodorants or antacids.
Aluminium is a potent neurotoxin. It may contribute to poor memory
and concentration and mood disorders such as depression and anxiety
by interfering with communication between brain cells.
In very high doses, aluminium is linked with increased production of
beta-amyloid proteins and altered function of the blood-brain
barrier that relate aluminium with developing Alzheimer's disease.
Aluminium is known to be genotoxic - it damages genetic material. It
has been strongly linked to breast cancer (especially from
antiperspirants) due both to the damage it exerts on DNA and because
it interferes with the function of oestrogen.
Aluminium also interferes with key energy producing reactions
within every cell and thus can be a significant contributor to
symptoms of chronic fatigue and general malaise.
3-Toxicity of Mercury
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Mercury is ranked
3rd on “the Top 20 Hazardous
Substances” that made by of US Agency for Toxic
Substances and Disease Registry (ATSDR).
Mercury is generated naturally in the environment from the
degassing of the earth's crust, from volcanic eruption.
Occurs in three forms (elemental, inorganic salts, and organic
mecurrial compounds).
Contamination results from mining, smelting, and industrial
(e.g. chlioralkali, paper, …) discharges.
Atmospheric mercury is dispersed across the globe by winds
and returns to the earth in rainfall, accumulating in soil and
aquatic food chains and fish in lakes .
Mercury compounds were added to paint as a fungicide
(these compounds are now banned) however, old paint
supplies and surfaces painted with these old supplies still
exist).
Mercury continues to be used in manufacturing of
thermometers,
thermostats,
sphygmomanometers,
stalagmometers, fluorescent light bulbs, disc batteries,
electrical switches, and manometers.
Medical substances, such as antiseptics (mercurochrome ,
merbromin, and merthiolate), and presarvative in some
vaccines (thimerosal) are still available, Calomel (Hg2Cl2) is
still used in some regions of the world as a laxative and
dental filling (silver amalgam that contain about 50 %
mercury, there is increasing evidence that Hg is leached from
dental amalgam and that Hg can vaporize from fillings,
fillings which crack can also be a source of mercury toxicity).
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In addition,some skin beauty preparations ( creams, lotions,
and antiseptic soaps) might contain mercury that are
marketed as skin lighteners and anti-aging treatments that
remove age spots, freckles, blemishes and wrinkles.
Fungicides(ethylmercury chloride and phenylmercury
acetate), and seeds treated With mercurial Fungicides are
potential source
Hg industrial wastes usually bioaccumulates in the aquatic
food-chain, which may lead to high concentrations in fish
(especially Large fishes like tuna and swordfish) , shellfish,
and marine mammals. Mercury cannot be eliminated by
cooking.
Mood of Exposure
Elemental
Liquid at room temperature that volatizes readily
Inhalation is the main source of intoxication, rapid
distribution in body by vapor, poor in GI tract. Can affect
CNS. Skin contact may also considered.
Inorganic
Poorly absorbed in GI tract, but can be caustic
Dermal exposure has resulted in toxicity
Organic
Lipid soluble and well absorbed via GI, lungs and skin. Cross
BBB and affects CNS
Can cross placenta and into breast milk
The organic form is readily absorbed in the GIT (90-100%); lesser
but still significant amounts of inorganic mercury are absorbed in
the GIT (7-15%). Target organs are mostly the nervous system,
kidneys, respiratory system, dermal tissues, GIT, and immune
system
Toxicokinetics
Mechanisms of toxicity:
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Altering the tertiary and quaternary structure of proteins and by
binding with sulfhydryl and irreversibly inhibit activities of
selenoenzymes, such as thioredoxin reductase . Thioredoxin
reductase is antioxidant enzyme that playing multiple roles such as
restores vitamins C and E, as well as a number of other important
antioxidant molecules.selenohydryl groups. High mercury exposures
deplete the amount of cellular selenium available for the biosynthesis
of thioredoxin reductase and other selenoenzymes.
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interfere with DNA transcription.
Symptoms of toxicity
(a)
Elemental Mercury
At high concentrations, vapor inhalation produces acute
necrotizing bronchitis, pneumonitis, and death may occur at very
high dose. Skin, and nose irritation or even burns may occur
Long term exposure affects CNS.
Early: insomnia, impaired memory, anorexia, mild tremor
Late: progressive tremor and erethism (red palms, emotional
lability (characterized by irritability, excessive shyness,
confidence loss, and nervousness),
Salivation, excessive sweating, renal toxicity (proteinuria, or
nephrotic syndrome)
(b) Inorganic Mercury
Gastrointestinal ulceration or perforation and hemorrhage are
rapidly produced, followed by circulatory collapse.
Breakdown of mucosal barriers leads to increased absorption and
distribution to kidneys (proximal tubular necrosis and anurea).
Acrodynia (Pink disease, erythroedema, or Feer’s disease)
usually from dermal exposure
The fingertips, toes and nose turn pink, maculopapular rash
with pus-filled skin eruptions , swollen and painful
extremities with hands and feet turn deep pink with bluish
patches , peripheral neuropathy, hypertension, and renal
tubular dysfunction.
(c) Organic Mercury
Toxicity occurs with long term exposure (especially
methylmercury, dimethylmercury and ethylmercury) and effects
the CNS ( Minamata disease)
Signs progress from paresthesias to ataxia, in hand and feets
followed by generalized muscle weakness, narrowing of the
field of vision and talking and hearing impairment, tremor
and muscle spasticity In extreme cases, paralysis, coma and
death follow within weeks of the onset of symptoms.
Teratogen with large chronic exposure
Asymptomatic mothers with severely affected infants
Infants appeared normal at birth, but psychomotor
retardation, blindness, deafness, and seizures developed over
time (congenital Manimata disease).
Treatment of Hg toxicity:
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Diagnosis is made by history of exposure, physical findings,
and an elevated body burden of mercury. Lab analysis of
elemental and inorganic mercury can be measured in 24 hour
urine collection (plasma conc. is not useful that mercury's
short half-life in the blood); while for organic mercury
whole-blood (blood mercury concentrations limit is <
6 μg/L) or hair analysis is more reliable than urinary mercury
levels.
The most important and effective treatment is to identify the
source and end the exposure
Chelating therapy for acute inorganic mercury poisoning can
be done with DMSA, DMPS, DPCN, or BAL. Only DMSA
is approved for treating mercury poisoning in children,
organic mercury poisoning, and poisoning due to mercury
vapor
4- Toxicity of Lead
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Lead is ranked 2nd on “the Top 20 Hazardous Substances”
that made by of US Agency for Toxic Substances and Disease
Registry (ATSDR).
Lead is a ubiquitous toxicant in the environment. It is one of
the oldest chemical toxins and it is responsible for most of
chemical-related chronic toxicities especially in children.
Lead is a soft, malleable metal existed in nature. It is chiefly
obtained by the primary smelting and refining of natural ores,
or by the widespread practice of recycling and secondary
smelting of scrap lead products.
Commonly used in the building industry for roofing and
flashing and for soundproofing. Lead-containing pigments
still are used for outdoor paint products because of their
bright colors and weather resistant properties leading to
chronic exposure from weathering, flaking, chalking, and
dust (banned)
Used in pipes and drains. Lead even used in manufacturing of
some types of PVC plastics
When combined with tin, it forms solder, used in electronics
and in other applications to make connections between solid
metals, in cable covering
Lead is also used in ammunition and for batteries and
ray sheilding
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Tetraethyl and tetramethyl lead are still used as additives in
gasoline in severaliga
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Lead existed also in ciggaret smoke.
Lead used in crystal glass production
As paint pigments in many manufacturing like ceramic,
potteries and surface paints on the toys.
Lead existed in many cosmetics like lip sticks, blush, kohl,
eye liners…..
Mood of Exposure:
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Lead exists in the environment in various forms, organic and
inorganic compounds.
Inorganic lead compounds are less toxic and poisoning
could happen mainly by direct ingestion of lead compounds
or items contaminated with them.
Significant quantities of lead can be ingested from stagnant
water in pipes or water coolers with lead solder.
Cases of paint ingestion have increased markedly. Children
are apparently attracted to the paint because of the bright
colour and sweet taste of lead acetate found in these paints.
Poisoning by inorganic lead could also occur over long
period of exposure by ingestion of traces that either trapped
in the upper respiratory tract from dust, or tobacco smoke or
introduced into the mouth on fingers, food, or other objects.
Toxicity symptoms usually developed gradually over time to
build up high body burden that is necessary to cause toxic
effects by this way.
Lead interferes with a variety of body processes and is toxic
to many organs and tissues. The heart, bones, teeth intestines,
kidneys, thyroid gland reproductive and nervous systems
represent its main targets. Lead can cross placental barrier
and exists in breast milk to affect fetus and nursing babies
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Poisoning from the more toxic organic lead (e.g. tetraethyl
lead) is now minimal, because lot of countries across the
world have phased out the use of organic lead compounds as
gasoline additives, but such compounds are still used in
industrial settings.
Organic lead poisoning could occurs by Inhalation of fumes,
mists, vapours, and car exhaust or even dust. In industry
(e.g., smelting, battery production etc.), inhalation is more
common than ingestion. Organic lead compounds are
readily absorbed from the skin and respiratory tract, affect
mainly the CNS.
Toxicocokinetics:
Absorption:
Lungs: depends on size particle
GI:
Adults: 20-30%
Children: as much as 50% of dietary lead
Inadequate intake of protein, Ca, Zn, Se, Fe, or Vit
E cause increase Pb absorption. Fluoride increases
Pb absorption
Skin:
Inorganic lead is not absorbed
Organic lead is well absorbed
Lead is carried bound to the RBC
Distribution:
• Distributed extensively throughout tissues: bone (> 70% of body
burden), teeth, liver, lung, kidney, brain, reproductive tissues
and spleen. Body lead storage: bones- can constitute a source of
remobilization and continued toxicity after the exposure has
ceased
• Lead crosses the BBB and concentrates in the gray matter
• Lead crosses the placenta
Excretion:
By kidneys, the excretion increases with increasing body
stores (30g-200 μg/day)
Also in Feces (about 10-20%)
Mechanism of toxicity:
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Lead perturbs multiple protein, and enzyme systems
especially those with sulfhydryl groups (SH). They are
vulnerable to lead toxicity rendering them nonfunctional and
deplete glutatione that contributing in increased levels of
free radicals in tissue and impairment in oxidative balance.
Pb2+ disturbs the intracellular Ca2+ homeostasis Lead's
toxicity is largely due to its capacity to mimic calcium and
substitute it in many of the fundamental cellular processes
that depend on calcium leading to inhibition of cellular
function requiring calcium e.g. muscular contractility,
immune function, neurotransmitter and hormonal release.
Furthermore, it alters the functioning of many Ca2+ dependentthe enzymatic machineries like protein kinase C.
Also, Lead interferes with synthesis of metalloproteins like
heme. diminished heme production leading to decrease the
rate of production of many substances related to heme like
hemoglobin, cytochromes C, CYP450 enzymes.
Lead also interfere with steroid metabolism and membrane
integrity.
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Interference in vitamin D synthesis in renal tubular cells
(conversion of 1-hydroxyvitamin D to 1,25-hydroxyvitamin
D)
Oxidative stress triggers many harmful changes in gene
expression pattern that associated with many harmful
changes like autoimmunity, oncogenesis, neuropathy,
nephropathy, cardiomyopathy, and many others.
Symptoms of Toxicity:
Acute toxicity (from intense exposure of short duration)
CNS symptoms (headach, irritability, confusion, acute
encephalopathy, tremors, renal failure and in most sever
cases seizures, coma and death)
GI symptoms (Severe abdominal cramping, vomiting and
loss of appetite)
Other organs ( liver and kidney dysfunction)
In most sever cases, seizures, coma and death may occur.
Chronic toxicity (from repeat low-level exposure over a
prolonged period)
• Lead poisoning (also known as plumbism), is a medical
condition caused by increased levels of the lead in the body.
• Early symptoms manifested as:
- Diffuse muscle weakness, and paresthesias
- General fatigue/lethargy
- Attention deficiency and confusion/ irritability
- Joint and muscle pain
- Unusual metallic taste in mouth
• Then complicated with
- Intermittent abdominal cramping, vomiting, and conistipation
- Loss of appetite and diminished libido
- Weight loss and anemia and increase systolic blood pressure.
- Tremors and peripheral neuropathy in extensor surfaces that
manifested as wrist drop and/or foot drop (most common
neurological symptom in adults)
- Short-term memory loss
- Depression and Insomnia
- Cerebral edema (headach, incoordination,
and sometimes seizures)
Renal insufficiency
- A "lead hue" of the skin with pallor and blue line along the
gum, with bluish black edging to the teeth are another features of
chronic lead poisoning.
- Lead affects both the male and female reproductive systems.
In men, oligospermia occure in addition to changes occur in
volume of sperm, their motility, and their morphology.
- A pregnant woman's elevated blood lead level can lead to
miscarriage, prematurity, low birth weight, and problems
with development during childhood.
- Children are particularly vulnerable to lead toxicity that they
tend to absorb lead more easily than adults do because their
metabolism is faster.
- Also they are more exposed to higher intake( especially those
under 5 yrs old) that they often play on the floor, and tend to
put their hands , toys and other stuffs in their mouths.
- Children plumbism is charecterized by loss of appetite,
abdominal pain, vomiting, weight loss, constipation, anemia,
diminished renal function, irritability, lethargy, and
confusion. Also, Lead interfere with It interferes with the
growth rate and development of the nervous system causing
potentially permanent learning disability and behavior
disorders.
- Children may also experience hearing loss, aggression and
delayed growth (Epiphyseal lead lines in growing children
long bones especially around the knees)
Treatment of Pb toxicity:
• The signs of lead poisoning are difficult to distinguish , they may look
so general, and confusing with other conditions. Good treatment
depends on good diagnosis.
• Diagnosis includes determining the clinical signs and the medical
history, with inquiry into possible routes of exposure. The main tool
in diagnosing and assessing the severity of lead poisoning is
laboratory analysis of the blood lead level (BLL), CBC, and
sometimes concentration of lead in bones (X-ray fluorescence,
XRF)- to asses the whole body burden.
• CBC examination may reveal
basophilic stippling of red
RBCs, as well as the changes
normally associated with irondeficiency anemia (microcytosis
and hypochromasia).
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The US CDC and WHO state that a blood lead level of 10 μg/dL or
above is a cause for concern; however, lead may impair development
and have harmful health effects even at lower levels, and there is no
known safe exposure level.
Relation between lead blood concentration and Lead-induced
Health Effects in Adults and Children
Blood lead
levels
Adults
10 g/dL
Hypertension may occur
20 g/dL
Inhibition of heme synthesis
Increased erythrocyte
protoporphyrin
Children
• Crosses placenta
• Impairment IQ, growth
• Partial inhibition of heme
synthesis
Beginning impairment of
nerve conduction velocity
30 g/dL
• Systolic hypertension
• Impaired hearing()
Impaired vitamin D
metabolism
40 g/dL
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Infertility in males
Renal effects
Neuropathy
Fatigue, headache, abd pain
Hemoglobin synthesis
inhibition
50 g/dL
Anemia, GI sx, headache,
tremor
Colicky abd pain,
neuropathy
100 g/dL
Lethargy, seizures,
encephalopathy
Encephalopathy, anemia,
nephropathy, seizures
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The basis of lead poisoning treatment are removal from the source of
lead and, for people who have significantly high blood lead levels or
who have symptoms of poisoning, chelation therapy.
The chelating agents used for treatment of lead poisoning are
CaNa2EDTA, and BAL, which are injected, and DMSA, and
DPCN, which are administered orally depending on the BLL and
developed symptoms.
Treatment of iron, calcium, and Zn deficiencies, which are
associated with increased lead absorption especially in children, is
another part of treatment for lead poisoning.
A good substantial diet is important; lead absorption is increased
when a diet rich in fats is consumed. Also, diets low proteins,
complex CHOs and vitamin C increase the likelihood of lead
absorption and resultant lead poisoning. Dietary fiber helps promote
good peristalsis and decreases the opportunity for lead absorption.
Management guidelines to treat lead poisoning
Blood lead
level (μg/dL)
Treatment
10–14
Education,
repeat screening
15–19
Repeat screening, case
management to abate sources
20–44
Medical evaluation,
case management
45–69
Medical evaluation,
oral chelation, case management
>69
Hospitalization, immediate
parentral chelation, case management
5-Toxicity of Arsenic
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 Arsenic and many of its compounds are especially potent poisons.
 Arsenic is the most common cause of acute heavy metal poisoning in
adults and is number 1 on the ATSDR's "Top 20 List”.
 Arsenic is released into the air by volcanoes, through weathering of
arsenic-containing minerals and ores, and by commercial or industrial
processes.
 Arsenic occurs naturally in the earth’s crust, and much of its dispersion in
the environment stems from mining and commercial uses.
 In industry, arsenic is a byproduct of the smelting process for many
metal ores such as cobalt, gold, lead, nickel, and zinc.
 Also, arsenic is released into the environment by the manufacturing of
some chemicals like used in paints and dyes for clothes, paper, and
wallpaper, galvanization and glass manufacturing. Some arsenicals are
used as chemical warfare like Chlorovinyl dichloroarsine (also known as
lewisite) it causes severe skin burns on contact at very low
concentrations.
 Arsenic is existed in cigarette smoke , and from burning of fossil fuels
that contain arsenic.
 Arsine gas is a common byproduct produced by the manufacturing of
pesticides like insecticides, algaecides, funjicides, rodenticdes ,and
herbicides (such as weed killers and wood preservatives e.g. copper
chromated arsenic, and Scheele's Green) that contain arsenic. Also,during
glass manufacture.
 Also, arsenicalas are and have been used medicinally. Arsenic is currently
used for induction and consolidation chemotherapy for acute
promyelocytic leukemia and other cancers . Arsenic may be found in
some traditional remedies from a number of Asian countries like
“Fowlers solution,” which is 1% arsenic trioxide, was used to treat skin
conditions such as psoriasis and eczema. Arsphenamin (is another
arsenical compound that was the first effective cure for syphilis until
replaced by antibiotics after World War II
 Arsenic is widely used in the industry of electronics (like discrete
microwave devices, lasers and light-emitting diodes, and photoelectric
chemical cells) and semiconductor devices in the form of gallium
arsenide.
 Escaped arsenicals contaminate soil and water supplies worldwide with
agricultural runoff and improperly industrial disposed arsenical
chemicals, or mining. This was leading to exposure grains and produces
that cultivated in contaminated soils or irrigated with contaminated water
and all manufactures out of them like juices, cerials,……etc. Arsenic
may be found in meat, poultry, and seafood s like fishes, shellfishes,
crabs, lobsters, and certain seaweed.
 Drinking water could be a source of arsenic toxicity especially those
come from
groundwater
like wells supplied by geologically
contaminated aquifers, and some lakes and
 Red blood cells, kidneys, and central nervous, digestive, and keratinized
tissues (skin, hair and nails) are the main targets of arsenicals.
Mood of Exposure:
 Arsenic exists in the environment in major three forms, organic and
inorganic arsenic compounds in addition to arsine gas.
 Organic arsenicals (e.g. arsenobetaine and arsenocholine), are 500 times
less harmful than inorganic arsenic. Organic arsenic exposure can occur
by food ingestion especially meat, seafood, and poultry account for 80%
of dietary arsenic intake . sometimes referred to as "fish arsenic." which
has low toxicity to humans and is rapidly excreted in urine within 48 hrs.
 other organic arsenicals (e.g. methyl and phenyl arsenates) can produce
health effects similar to those produced by inorganic arsenic
 Two forms of inorganic arsenic, reduced (trivalent As (III)) which is more
toxic than oxidized form (pentavalent As(V)) are existed. Unlike the
organic form, inorganic arsenic is quite harmful even in minute
quantities.
 Inorganic arsenic poisoning can be related to human activities such as
mining and ore smelting but is more often associated with dissolved
solids naturally ground water and soil. Deep wells contain predominantly
arsenite (arsenic III) and surface water will contain predominantly
arsenate (arsenic V).
 Arsine gas forms when acid or other reducing substances are added to
arsenic-containing compounds. Arsine gas is the most toxic arsenical
causes acute exposures by inhalation. Other airborne arsenic in the
workplace is generally in the form of arsenic trioxide.
 Dermal contact when handling preserved wood products containing
arsenic could result in arsenic toxicity
Toxicocokinetics:
 Many arsenic compounds (especially inorganic arsenic) are readily
absorbed through the GI tract when delivered orally in humans
 Absorption within the lungs is dependent upon the size of the arsenic
compound, and it is believed that much of the inhaled arsenic is later
absorbed through the stomach after (respiratory) mucocillary
clearance.
 After the absorption of arsenic compounds, it accumulate in tissues
and body fluids the primary areas of distribution are the liver, kidneys,
lung, spleen, aorta, and skin. Arsenic compounds are also readily
deposited in the hair and nails
 In the liver, RBCS, and WBCs the metabolism of organic arsenic
involves enzymatic and non-enzymatic methylation, the most
frequently excreted metabolite (≥ 90%) in the urine of mammals is
dimethylarsinic acid (DMA(V).
 Inorganic arsenic is reduced nonenzymatically from pentoxide to
trioxide, using glutathione (GSH). Reduction of arsenic pentoxide to
arsenic trioxide increases its toxicity and bioavailability . Reduction is
followed by sereis of methylation occurs through methyltransferase
enzymes. Resulting metabolites are monomethylarsonous acid
(MMA(III)) and dimethylarsinous acid (DMA(III)).
 Methylation had been regarded as a detoxification process. While in
fact reduction from As+5 to may be considered as a bioactivation and
increase toxicity instead.
 Methylation accelerates renal execretion (> 70%).
Mechanism of Toxicity:
Two mechanisms of arsenic toxicity that impair tissue respiration are
described below.
 As (III) binds with sulfhydryl groups and disrupts sulfhydryl containing
enzymes; As a result of critical enzyme inhibition of the pyruvate
oxidation pathway and the krebs cycle, impaired gluconeogenesis, and
reduced oxidative phosphorylation.
 Another mechanism involves substitution of As (V) for phosphorus in
many biochemical reactions.Replacing the stable phosphorus anion in
phosphate with the less stable As (V) anion leads to rapid hydrolysis of
high energy bonds in compounds such as ATP, a process that leads to loss
of high energy phosphate bonds and effectively “uncouples"
mitochondrial respiration
 Also, As (III) binds to SH- containing proteins thus reacts with a variety
of structural and enzymatic proteins leading to inhibition of their activity
(like glutathione reductase and thioredoxin reductase) that increase the
oxidative stress condition.
 Arsenic has very high carcinogenic potential. Various
possible
mechanisms were suggested to elucidate modes of arsenic carcinogenesis
These include modes that are predominately genotoxic (i.e.,
chromosomal abnormalities, oxidative stress, and gene amplification) vs.
more nongenotoxic (i.e., altered growth factors, enhanced cell
proliferation and promotion of carcinogenesis, and altered DNA repair).
 Arsine gas poisoning results in a considerably different syndrome from
that caused by other forms of arsenic. After inhalation, arsine rapidly
binds to red blood cells, producing irreversible cell membrane damage.
At low levels, arsine is a potent hemolysin, causing dose-dependent
intravascular hemolysis. At high levels, arsine produces direct
multisystem cytotoxicity. Arsine has local irritant effect and has the
ability to induce endothelial damage, loss of capillary integrity, and
capillary leakage.
Symptoms of toxicity:
Acute toxicity:
 Acute exposure to arsenic compounds can cause nausea, anorexia,
vomiting (hematemesis), abdominal pain, muscle cramps, diarrhea
(rice-water stool), Garlic-like breath, malaise,thirst and metalic taste,
fatigue and burning of the mouth and throat. In sever cases,
tachycardia, hypotension acute encephalopathy, acute renal failure,
congestive heart failure, stupor, convulsions, paralysis, coma and even
death can occur.
 In addition contact dermatitis, skin lesions and skin irritation are seen
in individuals whom come into direct tactile contact with arsenic
compounds.
Chronic toxicity:
 Repeat exposure to arsenic compounds have been shown to lead to the
development of multiple organ dysfunctions problems like
- Neuronal :peripheral neuropathy (increased sweating in the
distal lower extremities, muscle cramps, muscle tenderness,
numbness, paresthesia, and spontaneous pain in a symmetrical,
stocking glove distribution).In addition to, encephalopathy,
dementia, cognitive impairment, seizures and hearing loss
- CVS: peripheral vascular disease, EEG abnormalities,
hypertension, myocardial infarction, anemia and leukopenia
- Respiratory: pharyngitits, laryngitis, pulmonary insufficiency
- GIT: severe abrominal crampin and hematoemesis.
- kidney and liver damage
- Skin abnormalities: darkening of the skin and the appearance
of small "corns" or "warts" on the palms, soles, and torso(
palmar keratosis).
- Reproductive system: a s higher percentage of spontaneous
abortions , lower birth weights and congenital malformations.
- Carcinogenic: cancers of the skin, liver, respiratory tract,
kidney, bladder and gastrointestinal tract are well documented
in regards to arsenic exposure.
Treatment:
 Diagnosis includes determining the clinical signs and the medical
history.
 The main tool in diagnosing and assessing the severity of arsenic
poisoning is laboratory analysis of Urinary and whole blood arsenic
measurement. In addition to analysis of arsenic contents in hair and
fingernails
 Normal values
–
–
–
Spot urine= ~10 mcg/L
24 hours urine collection=<25 mcg/24 hours
Whole blood= <1mcg/L (usually is elevated in acute intoxication)
 For treatment of acute toxicity, follow the general measure to
decontaminate the poison (gastric lavage, activated charcoal ,whole





bowel irrigation with polyethylene glycol, hemodialysis, skin
decontamination in dermal exposure).
For acute and chronic intoxication, Chelation therapy should be
instituted promptly ASAP (BAL- IM, DMSA- PO, DMPS – PO, IV).
In addition to, supportive care and symptomatic treatment.
Studies suggest that the use of vitamin A analogs (retinoids) may be
useful in treating pre-cancerous rsenical keratoses.
Recovery from established chronic arsenic toxicity, particularly from
the resulting peripheral neuropathy, may take months and may not be
complete.
Nutritional status may play a role in preventing arsenic health effects.
Arsenic-induced disease has been shown to increase in individuals
who are mal- or under-nourished, possibly due to the decrease in
arsenic methylation. For example, arsenic and selenium may be
mutually antagonistic.Diet rich in selenium and other antioxidants
(such as vitamin E) helps promote methylation of arsenic which leads
to increased excretion.Also, Methyl donors such as folate may also be
of help in arsenic metabolism and excretion in humans.
Arsine
gas
poisoning
requires careful
monitoring of
hematocrit/hemoglobin and renal function. Therapy is supportive and
is primarily aimed at maintaining renal function. Red cell transfusion
may be necessary to replace the patient's hemolyzed red cells. Patients
with significant hemolysis may require folate or iron supplementation.