LEAD TOXICITY

INTRODUCTION

Lead is a naturally occurring, most important toxic heavy

element in the environment which is found in the Earth’s
crust. Its widespread use has resulted in extensive
environmental contamination, human exposure and significant
public health problems in many parts of the world.

Due to its important physico-chemical properties, its use can

be retraced to historical times. Globally it is an abundantly
distributed, important yet dangerous environmental chemical.
Its important properties like softness, malleability, ductility,
poor conductibility and resistance to corrosion seem to make
difficult to give up its use. Due to its non-biodegradable
nature and continuous use, its concentration accumulates in
the environment with increasing hazards.

SOURCES OF LEAD IN THE ENVIRONMENT

Important sources of environmental contamination include-

• Mining
• Smelting
• leaded paint
• leaded gasoline
• leaded aviation fuel.
• lead-acid batteries for motor vehicles.
• Lead is also used in many other products, for
example
✓ pigments,
✓ paints,
✓ solder,
✓ stained glass
✓ lead crystal glassware,
✓ ammunition,
✓ ceramic glazes,
✓ jewellery,
✓ toys
✓ some cosmetics
✓ traditional medicines.
✓ Drinking water delivered through lead pipes or
pipes joined with lead solder may contain lead.
✓ Much of the lead in global commerce is now
obtained from recycling.
PREVALCE OF LEAD TOXICITIES

1. YOUNG CHILDREN
Young children are particularly vulnerable to the toxic
effects of lead and can suffer profound and permanent
adverse health effects, particularly affecting the
development of the brain and nervous system.
2. ADULT
Lead also causes long-term harm in adults, including
increased risk of high blood pressure and kidney damage.
3. PREGNANT WOMEN
Exposure of pregnant women to high levels of lead can
cause miscarriage, stillbirth, premature birth and low
birth weight.

SOURCES AND ROUTE OF EXPOSURE

People can become exposed to lead through occupational

and environmental sources.

This mainly results from:

• inhalation of lead particles generated by burning

materials containing lead, for example, during smelting,
 recycling, stripping leaded paint, and using leaded
gasoline or leaded aviation fuel

• ingestion of lead-contaminated dust, water (from leaded

pipes), and food (from lead-glazed or lead-soldered
containers).

• Young children are particularly vulnerable to lead

poisoning because they absorb 4–5 times as much
ingested lead as adults from a given source. Moreover,
children’s tendency to put hand-to-mouth which result in
their mouthing and swallowing lead-containing or lead-
coated objects, such as contaminated soil or dust and
flakes from decaying lead-containing paint.

• This route of exposure is magnified in children with a

psychological disorder called pica (persistent and
compulsive cravings to eat non-food items), who may,
for example pick away at, and eat, leaded paint from
walls, door frames and furniture.
• Exposure to lead-contaminated soil and dust resulting
from battery recycling and mining has caused mass lead
poisoning and multiple deaths in young children

• Inorganic lead may be absorbed through the

gastrointestinal (GI) tract, the respiratory system, and the
skin. Ingested inorganic lead is absorbed more efficiently
from the GI tract of children than that of adults, readily
crosses the placenta, and in children penetrates the
blood – brain barrier.

• Initially, lead is distributed in the blood, liver, and

kidney; after prolonged exposure, as much as 95% of the
body burden of lead is found in bone tissue.

• Once lead enters the body, it is distributed to organs such

as the-
a) brain,
b) Hemopoietic system
 c) kidneys,
d) liver
e) bones.
• Several of the enzymes involved in the synthesis of heme
are sensitive to inhibition by lead, the two most
susceptible enzymes being ALAD and heme synthetase
(HS). Although clinical anemia occurs only after
moderate exposure to lead, biochemical effects can be
observed at lower levels.

• For this reason, inhibition of ALAD or appearance in the

urine of aminolevulinic acid (ALA ) can be used as an
indication of lead exposure.
• The nervous system is another important target tissue for
lead toxicity, especially in infants and young children in
whom the nervous system is still developing

HEALTH EFFECT OF LEAD POISONING ON

CHILDREN

1) Lead exposure can have serious consequences for the

health of children. At high levels of exposure, lead
attacks the brain and central nervous system to cause –
 a. Delirium
b. Seizures
c. Stupor
d. Coma
e. Convulsions
f. even death.

• Children who survive severe lead poisoning may be left

with mental retardation and behavioural disorders.

• At lower levels of exposure that cause no obvious

symptoms lead is now known to produce a spectrum of
injury across multiple body systems.

• In particular lead can affect children’s brain

development resulting in
a) reduced intelligence quotient (IQ)
b) behavioural changes such as reduced attention
span
c) increased antisocial behavior
d) reduced educational attainment.
• Lead exposure also causes-
a) Anaemia
b) Hypertension
c) Renal impairment
d) Immunotoxicity
e) Toxicity to the reproductive organs.
f) peripheral neuropathy
g) Ataxia
h) Tremor
i) Headache
j) loss of appetite
k) weight loss
l) fatigue
m) muscle pain
n) joint aches,
o) changes in behavior and concentration
p) gout
q) nephropathy
r) lead colic ( intestinal colic associated with obstinate constipation due to

chronic lead poisoning. — called also painter's colic. )

Adverse Health Effects of Prenatal Exposure

• Lead readily crosses the placenta by passive diffusion

and has been detected in the foetal brain as early as the
end of the first trimester.

• Elevated lead levels in pregnancy have been associated

with several adverse outcomes, including-
a. gestational hypertension
b. spontaneous abortion
c. low birth weight
d. impaired neurodevelopment

There is no known 'safe' blood lead concentration; even blood

lead concentrations as low as 5 µg/dL, may be associated with
decreased intelligence in children, behavioral difficulties and
learning problems. As lead exposure increases, the range and
severity of symptoms and effects also increases.

Burden of disease from lead exposure

The Institute for Health Metrics and Evaluation (IHME) &

WHO estimated that in 2017, lead exposure accounted for
1.06 million deaths and 24.4 million years of healthy life lost
(disability-adjusted life years (DALYs)) worldwide due to
long-term effects on health.

MECHANISM OF LEAD TOXCITY/ MECHANISM OF

HUMAN EXPOSURE

❖ Lead is a ubiquitous environmental toxin that is capable

of causing numerous acute and chronic circulatory,
neurological, hematological, gastrointestinal,
reproductive and immunological pathologies.

❖ The prime targets to lead toxicity are the heme synthesis

enzymes, thiol-containing antioxidants and enzymes
(superoxide dismutase, catalase, glutathione peroxidase,
glucose 6-phosphate dehydrogenase and antioxidant
molecules like GSH).

❖ The low blood lead levels are sufficient to inhibit the

activity of these enzymes and induce generation of
reactive oxygen species and intensification oxidative
stress.
❖ OXIDATIVE STRESS

✓ Oxidative stress plays important role in pathogenesis of

lead-induced toxicity and pathogenesis of coupled
disease.

✓ The primary target of lead toxicity is the central nervous

system. Oxidative stress represents an imbalance
between the production of free radicals and the biological
system's ability to readily detoxify the reactive
intermediates or to repair the resulting damage.
✓ It has been reported as a major mechanism of lead
induced toxicity. Under the influence of lead, onset of
oxidative stress occurs on account of two different
pathways operative simultaneously; first comes
the generation of ROS, like hydroperoxides (HO2 •),
singlet oxygen and hydrogen peroxide (H2O2), and
second, the antioxidant reserves become depleted
 GLUTATHIONE

✓ The antioxidant defenses of the body come into play to

nullify the generated ROS. The most important
antioxidant found in cells is glutathione (GSH). It is a
tripeptide having sulfhydryl groups .

✓ It is an important antioxidant for quenching free radicals.

Glutathione exists in two form

e. Reduced (GSH)
f. Oxidized form (GSSG).
✓ The reduced state of glutathione donates reducing
equivalents (H+ + e–) from its thiol groups present in
cysteine residues to ROS and makes them stable.

✓ After donating the electron, it readily combines with

another molecule of glutathione and forms glutathione
disulfide (GSSG) in the presence of the
enzyme glutathione peroxidase (GP X).

✓ GSH can be regenerated from GSSG by the enzyme

glutathione reductase (GR).
✓ Under normal conditions, 90% of the total glutathione
content exists in reduced form (GSH) and around 10% is
in the oxidized form (GSSG). Under conditions of
oxidative stress, the concentration of GSSG is much
higher than that of GSH.

✓ Lead inactivates glutathione by binding to sulfhydryl

groups present in it. This results in synthesis of GSH
from cysteine via the γ-glutamyl cycle, which is usually
not effective in replenishing the supply of GSH .

✓ Similarly, lead inactivates enzymes like δ-amino

levulinic acid dehydratase (ALAD), glutathione
reductase (GR), glutathione peroxidase (GPX) and
glutathione-S-transferase, which further depresses the
glutathione levels

❖ LIPID PEROXIDATION
✓ Lipid peroxidation is another biomarker of oxidative
stress and is one of the most investigated consequences
of ROS on lipid membranes.

✓ The generated free radical captures electrons from the

lipids present inside the cell membranes and damages the
cell.

✓ Apart from lipid peroxidation, lead also causes

hemoglobin oxidation, which directly causes RBC
hemolysis.

✓ This occurs due to inhibition of ALAD, which results in

an increased concentration of substrate ALA in both
blood and urine.

✓ These elevated ALA levels generate hydrogen peroxide

and superoxide radical and also interact with
oxyhemoglobin, resulting in the generation of hydroxyl
radicals.
 Progression of all the above mentioned mechanisms
makes the cell extremely vulnerable to oxidative
stress and may lead to cell death.

OTHER CELLULAR MECHANISMS

❖ There are different cellular, intracellular and molecular

mechanisms of lead neurotoxicity: such as-

a) induction of oxidative stress

b) intensification of apoptosis of neurocites
c) interfering with Ca(2+) dependent enzyme
like nitric oxide synthase.
❖ Population studies have demonstrated a link between
lead exposure and subsequent development of
hypertension and cardiovascular disease.

❖ The vascular endothelium is regarded as the main target

organ for the toxic effect of lead. Lead affects the
vasoactive function of endothelium through
a) the increased production of reactive oxygen
species, inactivation of endogenous nitric
oxide

b) downregulation of soluble guanylate cyclase

by reactive oxygen species, leading to a
limiting nitric oxide availability, impairing
nitric oxide signaling.