Lead and Arsenic

Toxicity
Lead Poisoning
Physical Properties
4 Lead (Pb) has been used by humans for at least 7000 years,
because it is widespread, easy to extract, and easy to work with.
It is highly malleable and ductile as well as easy
to smelt.
4 Leads elemental symbol Pb, is an abbreviation
of its Latin name plumbum .
4 Metallic lead (Pb0) is resistant to corrosion
and can combine other metals to form
various alloys(Lead alloys are used in batteries,
shields from radiation, water pipes, and ammunition)
4 Inorganic Lead
Organic Lead
Lead has no known biological function.



Uses and Sources of Lead:

4 Lead paint:
Food containers(painted with
lead-based paint or lead-containing glaze ,
canned foods)
4 Petrol (tetraethyl lead)
4 Toys and Jewelry
4 Herbal remedies
from India, China, and other
parts of Asia may be potential
sources of lead exposure.


Uses and Sources of Lead:
4 Soil:
Exposure to soil that contains particulate lead has been shown to
be significantly hazardous for children, who are more commonly
exposed by ingestion of house dust or soil than by paint chips.
4 Water:
Drinking water is also a major source of lead
Exposure.
4 Occupational sources:
Remodeling construction
Smelters
Battery factories
Ammunition



.




4 Soil:
Exposure to soil that contains particulate lead has been shown to
be significantly hazardous for children, who are more commonly
exposed by ingestion of house dust or soil than by paint chips.
4 Water:
Drinking water is also a major source of lead
Exposure.
4 Occupational sources:
Remodeling construction
Smelters
Battery factories
Ammunition factories
Ceramic glazes



.




Contribution of Sources


Contribution of Sources


Toxicokinetics
4 Absorption of Lead:
4 GI:
Children absorb lead well orally
(~50%) adults poorly (~10%).
Lead absorption is enhanced if diet
is poor in iron or calcium.
High fat intake and inadequate
calories have also been associated
with enhanced lead absorption.
4 Respiratory:
Inorganic lead
4 Skin:
Organic lead

Toxicokinetics
Distribution:
4 95% in bone
(%70 in children)
4 4% in soft tissue
(brain, liver, kidneys, bone marrow)
4 1% blood
4 Lead readily crosses the placenta


Toxicokinetics

4Half-life Of Lead

25 DAYS -- BLOOD
40 DAYS -- SOFT TISSUE
20 YEARS -- BONE

Toxicokinetics
4 Hepatic Metabolism/Excretion
4 Inorganic lead is not metabolized but is excreted unchanged.
4 Organic or alkyl-lead,(leaded gasoline, also identified as
tetraethyl- and tetramethyl-lead) undergoes oxidative
dealkylation to the highly neurotoxin metabolites, triethyl- and
trimethyl-lead.
4 The major route of excretion of absorbed lead is the kidney.
Urine: %65
Bile: %35
Children excrete less of their daily uptake than adults,
with an average retention in adults of %1-4 versus
%33 in children.
Toxic Effects of Lead
4 Nervous System
Neurological, Neurobehavioral, and Developmental
Effects in Children
4 Clinically overt lead encephalopathy may occur in children with
high exposure to lead, probably at BLL of 70 g/dL or higher.
4 Symptoms of lead encephalopathy:
Lethargy
Vomiting
Irritability
Loss of appetite
Dizziness
Progressing to obvious ataxia, and a reduced level of
consciousness, which may progress to coma and death
Toxic Effects of Lead
Neurological, Neurobehavioral, and Developmental
Effects in Children

4 The pathological findings at autopsy are severe edema of the
brain due to extravasations of fluid from capillaries in the brain.
This is accompanied by the loss of neuronal cells and an
increase in glial cells.
4 Recovery is often accompanied by sequelae including epilepsy,
mental retardation, and, in some cases, optic neuropathy and
blindness.
4 Most studies report a 2- to 4-point IQ deficit for each
g/dL increase in BLL within the range of 535 g/dL.
Toxic Effects of Lead
Neurological, Neurobehavioral, and Developmental
Effects in Children

4 Lead can affect the brain by multiple
mechanisms:
Lead may act as a surrogate for calcium and/or
disrupt calcium homeostasis.
Lead affects virtually every neurotransmitter system
in the brain, including glutamatergic, dopaminergic,
and cholinergic systems.
(All these systems play a critical role in synaptic
plasticity and cellular mechanisms for cognitive
function, learning, and memory.)
Toxic Effects of Lead
4 Neurotoxic Effects in Adults
4 CNS :
Fatigue, irritability, lethargy, insomnia, headache,
difficulty concentrating, memory loss and tremor.
Sever lead intoxication can result in an encephalopathy
characterized by depressed consciousness, seizure,
and coma, in association with cerebral edema.
4 PNS:
More than a half-century ago, foot drop and wrist drop
characterized the house painter and other workers with
excessive occupational exposure to lead.
Axonopathy motor disturbance
Upper extremities, extensor

Toxic Effects of Lead
4 Hematologic Effects
Lead has multiple hematologic effects,ranging from increased urinary
porphyrins, coproporphyrins, -aminolevulinic acid (ALA), and zinc-
protoporphyrin to anemia.
Toxic Effects of Lead
4 Renal Toxicity
Acute lead nephrotoxicity consists of proximal
tubular dysfunction and can be reversed by
treatment with chelating agents.
Chronic lead nephrotoxicity consists of
interstitial fibrosis and progressive nephron loss,
azotaemia and renal failure.

4 Fanconlike syndrome
4 A characteristic microscopic
change is the presence of
intranuclear inclusion bodies.
Toxic Effects of Lead
4 Effects on Cardiovascular System
The most important manifestation of lead toxicity on the
cardiovascular system is hypertension.
4 The pathogenesis of lead-induced hypertension is
multifactorial including:
(1) Inactivation of endogenous nitric oxide and cGMP,
possibly through lead-induced reactive oxygen species.
(2) Changes in the renninangiotensinaldosterone
system, and increases in sympathetic activity, important
humoral components of hypertension.
(3) Alterations in calcium-activated functions of vascular
smooth muscle cells including contractility by decreasing
Na+/K+-ATPase activity and stimulation of the
Na+/Ca++ exchange pump.
(4) Possible rise in endothelin and thromboxane.


Toxic Effects of Lead
4 Reproductive system
Impairment of both male and female reproductive function is
associated with over plumbism.
4 Gastrointestinal
Lead colic is a major gastrointestinal symptom of severe lead
poisoning, and is characterized by abdominal pain, nausea,
vomiting, constipation, and cramps.
It is rarely seen today.

Toxic Effects of Lead
4 Bone Effects
Lead has an extremely long half-life in bone,
accounting for over 90% of the body lead in adults.
Lead can affect bone by interfering with metabolic and
homeostatic mechanisms including parathyroid hormone,
calcitonin, vitamin D, and other hormones that influence
calcium metabolism.
Lead substitutes for calcium in bone.
Lead is known to affect osteoblasts,osteoclasts, and
chrondrocytes and has been associated with osteoporosis and
delays in fracture repair.
In children exposed to lead, a higher bone mineral density
(BMD) was observed.
Carcinogenicity

2B. Agent is possibly carcinogenic
to humans
Human epidemiology data weak
Animal data positive

4CHILDREN are more vulnerable
exposure than ADULTS
Size
Consume More Food
Inhale More Air
Developing Nervous System
Increased need for Calcium

Recommended Lead level
<0.48 (10g/dl)
4 < 0.48mol/l (10g/dl)
= NHMRC Goal.

4 >0.48mol/l (10g/dl)
= elevated.

4 >0.72mol/l (15g/dl)
=substantially elevated.
Notifiable level.

4 >1.20mol/l (25g/dl)
= dangerously elevated.

>2.20mol/l (45g/dl)=
Symptomatic



Blood lead concentration (g/L)
Children: <400
Adults: <400
400-500
400-600
500-700
600-1000

>700
>1000

GI
Tract

Nil

Abdominal pain
Constipation

Abdominal pain,
constipation,
weight loss,
loss of appetite

Abdominal colic,
vomiting

Blood

Subclinical
inhibition of
RBC enzymes

Subclinical
inhibition of RBC
enzymes

Mild anaemia

Severe anaemia

CNS

Effects on IQ in
children?

Mild fatigue,
irritability,
slowed motor
neurone
conduction

Fatigue,
poor
concentration
[Peripheral
neuropathy]

Encephalopathy
- delirium
- ataxia
- fits
- coma

Other

Nil

Muscle pain


Hypertension,
nephrotoxicity,
lowered Vit D
metabolism

Hypertension,
nephrotoxicity,
lowered Vit D
metabolism


4 IDENTIFY & REMOVE from SOURCE
4 Nutrition Therapy:
Diets high in iron and calcium
Examples of foods high in iron are:
*Cheese, fish, meat, eggs, beans,
spinach, raisins

Examples of foods high in calcium are:
* Milk, cheese, ice cream, yogurt,
bread, fish, meat, broccoli, fruit,
nuts




4 Consider the use of chelation therapy
- Chelaton terapy is wildely recomended for
asymptomatic children with BLL >450g/l

4 Increase lead excretion,reduce blood
cocentration,and reverse hemotologic
markers of toxcity.

4 EDTA - Sodium Calcium Edetate
1000-1500 mg/m2/d, IV,IM

- IV for severe toxicity, particularly encephalopathy
- Well tolerated, <1% nephrotoxicity
4 BAL-Dimercaprol
450 mg/m2/d
IM for severe toxicity only, particularly encephalopathy.
4 DMSA - 2,3dimercaptosuccinic acid
Oral administration
Well tolerated .
The main problem is foul taste and smell !!
Minimal side effects in decade of experience.
Displaced D-penicillamine as oral agent since 1991.
If adverse reactions to succimer, EDTA, D-penicillamine is
the alternative.








Chelation Therapy Guidelinesa
Condition, BPb (g/dL) Dose Regimen/Comments
Adults
Encephalopathy BAL 450 mg/m2/d 75 mg/m2 IM every 4 h for 5 d

CaNa2EDTA 1500
mg/m2/d
Continuous infusion or 2-4
divided IV doses for 5 d (start 4 h
after BAL)
Symptoms suggestive of
encephalopathy or >100
BAL 300-450 mg/m2/d 50-75 mg/m2 every 4 h for 3-5 d
CaNa2EDTA 1000-1500
mg/m2/d
Continuous infusion or 2-4
divided IV doses for 5 d (start 4 h
after BAL)

Base dose, duration on BPb,
severity of symptoms
Mild symptoms or 70-100
Succimer 700-1050
mg/m2/d
350 mg/m2 tid for 5 d, then bid
for 14 d
Asymptomatic and <70 Usually not indicated Remove from exposure
Children
Encephalopathy
BAL 450 mg/m2/d 75 mg/m2 IM every 4 h for 5 d
CaNa2EDTA 1500 mg/m2/d
Continuous infusion or 2-4 divided
IV doses for 5 d (start 4 h after BAL)
Symptomatic or > 69
BAL 300-450 mg/m2/da 50-75 mg/m2 every 4 h for 3-5 d
CaNa2EDTA 1000-1500
mg/m2/da
Continuous infusion or 2-4 divided
IV doses for 5 d (start 4 h after BAL)

Base dose, duration on BPb,
severity of symptoms
Asymptomatic: 45-69
Succimer 700-1050 mg/m2/d
350 mg/m2 tid for 5 d, then bid for
14 d
or CaNa2EDTA, 1000
mg/m2/d
Continuous infusion or 2-4 divided
IV for 5 d
(or rarely, D-penicillamine)
20-44
Routine chelation not
indicated
If succimer used, same regimen as
per above group
Attempt exposure reduction
<20 Chelation not indicated
Attempt exposure reduction
ARSENIC
Arsenic
Introduction
E Arsenic has been known and used since ancient times as the
Poison of Kings and the King of Poisons
E Arsenicals have been used since ancient times as drugs and even
today are very effective against acute promyelocytic leukemia
Inorganic arsenic exists in the trivalent and pentavalent forms:
Inorganic trivalent arsenic: arsenic trioxide and sodium arsenite,
Inorgani cpentavalent arsenic: sodium arsenate, arsenic pentoxide,
and arsenic acid
Arsine (AsH3) is an important gaseous arsenical
Arsenic

E Organic Arsenic:
Less toxic that inorganic As
Produced by Biomethylation
Organisms in soil and water
Humans (detoxify inorganic
As)
High in shrimp



Introduction

Arsenic
Introduction
E Arsenic is common in the environment
E Sources
Groundwater
Arsenic containing mineral ores
Industrial processes
Semiconductor manufacturing (gallium arsenide)
Fossil fuels
Wood treated with arsenic preservatives
Smelting (copper, zinc, lead) and refining of metals
and ores
Glass manufacturing
E Commercial products
Wood preservatives
Pesticides
Herbicides
Fungicides
E Food
Seafood and fish
E Soil pica behavior: when children ingest large
amounts of soil at a time (e.g. up to 1
teaspoon or 5,000mg)



Arsenic
Introduction
Arsenic
Toxicokinetics (absorbtion)
E Inorganic arsenic is well absorbed (8090%) from
the gastrointestinal tract.
E Often metabolized by methylation, and then
excreted primarily in urine.
E Arsenic compounds of low solubility (e.g.,arsenic
trioxide,arsenicselenide,leadarsenide,and
gallium arsenide) are absorbed less efficiently
after oral exposure.
E Skin is a potential route of exposure to arsenic, and
systemic toxicity has been reported in persons
having dermal contact with solutions of inorganic
arsenic.
E Airborne arsenic is largely trivalent arsenic oxide.

Arsenic
Toxicokinetics (excretion)
E Excretion of absorbed arsenic is mainly via the
urine
E Arsenic has a predilection for skin and is
excreted by desquamation of skin and in sweat,
particularly during periods of profuse sweating
E It also concentrates in forming fingernails and
hair
E T
1/2
of inorganic arsenic in the blood is 10 hrs
and of organic arsenic is around 30 hours
E 2-4 weeks after the exposure ceases, most of
the remaining arsenic in the body is found in
keratin-rich tissues (nails, hair, skin)

Arsenic
Toxicokinetics (metabolism)
The intermediate metabolites, methylarsonous acid (MMA3+) and
dimethylarsinous acid(DMA3+), are generated during this process, and these
trivalent methylated arsenicals are now thought to be more toxic than even the
inorganic arsenic species
Arsenic
Toxicokinetics
As
5+
(Arsenate)

As
3+
(Arsenite)

Methylarsenite (in liver)

Dimethylarsenite
(readily eliminated
urine)
Arsenic
Acute Poisoning
E Ingestion of large doses (70180 mg) of
inorganic arsenic can be fatal
E Symptoms of acute intoxication include:
g Fever
g Anorexia
g Hepatomegaly
g Melanosis
g cardiac arrhythmia
g in fatal cases, eventual cardiac failure

Arsenic
Acute Poisoning
E Acute arsenic ingestion can damage:

^ mucous membranes of the gastrointestinal tract(
irritation,vesicleformation,andevensloughing
)
^ Sensory loss in the peripheral nervous system is the
most common neurologic effect, appearing at 12
weeks after large doses (a condition that is reversible if exposure is stopped )
^ Anemia and leucopenia(granulocytopenia ), (few days
following high-dose arsenic )(reversible)
^ Acute exposure to a single high dose can produce
encephalopathy, with signs and symptoms of
headache, lethargy,mentalconfusion,
hallucination,seizures,andeven
coma
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Bodily system affected Symptoms or signs Time of onset
Systemic
Thirst
Hypovolemia, Hypotension
Minutes
Minutes to hours
Gastrointestinal
Garlic or metallic taste
Burning mucosa
Nausea and vomiting
Diarrhea
Abdominal pain
Hematemesis
Hematochezia, melena
Rice-water stools
Immediate
Immediate
Minutes
Minutes to hours
Minutes to hours
Minutes to hours
Hours
Hours
Hematopoietic system
Hemolysis
Hematuria
Lymphopenia
Pancytopenia
Minutes to hours
Minutes to hours
Several weeks
Several weeks
Pulmonary
(primarily in inhalational
exposures)
Cough
Dyspnea
Chest Pain
Pulmonary edema
Immediate
Minutes to hours
Minutes to hours
Minutes to hours
Liver
Jaundice
Fatty degeneration
Central necrosis
Days
Days
Days
Kidneys
Proteinuria
Hematuria
Acute renal failure
Hours to days
Hours to days
Hours to days
Arsenic
Acute Poisoning
Arsenic
Acute Poisoning
Arsine gas(ASH3), generated by
electrolytic or metallic reduction of
arsenic in nonferrous metal production.
It is a potent hemolytic agent, producing
acute symptoms of nausea, vomiting,
shortness of breath, and headache
accompanying the hemolytic reaction.
Exposure to arsine is fatal in up to 25% of
the reported human cases.
Arsenic
Chronic Toxicity
Skin
E major target organ in chronic inorganic arsenic
exposure
E Diffuse or spotted hyperpigmentation and,
alternatively, hypopigmentation can first appear
between 6 months to 3 years with chronic exposure to
inorganic arsenic





^ Skin cancer is common with
protracted high-level arsenical exposure
Palmar-plantar hyperkeratosis
usually follows the initial
appearance of arsenic-induced
pigmentation changes within a
period of years
Arsenic
Chronic Toxicity
Liver
E Characteristic of long-term or chronic arsenic
exposure, manifests :
E jaundice
E abdominal pain
E Hepatomegaly
E progress to cirrhosis and ascites
even to hepatocellular carcinom
Arsenic
Chronic Toxicity
Peripheral neurophathy
E Repeated exposure to low levels of inorganic arsenic
can produce
E This neuropathy usually begins with :
sensory changes
numbness in the hands and feet painful pins
and needles sensation
motor nerves be affected
muscle tenderness
weaknes progressing from proximal to distal
muscle groupss

E Effects are dose-related
Arsenic
Chronic Toxicity
cardiovascular disease
E Peripheral vascular disease has been
observed in persons with chronic exposure to
inorganic
E It is manifested :
acrocyanosis
Raynauds phenomenon
progress to endarteritis and
gangrene of the lower extremities
(Blackfoot disease).


Arsenic
Carcinogenicity
E The carcinogenic potential of arsenic was
recognized over 110 years ago
E IARC has classified arsenic as a known human
carcinogen, associated with tumors of the skin,
lung, and urinary bladder, and possibly kidney,
liver, and prostate
E It has been difficult to confirm the
carcinogenicity of inorganic arsenic in
experimental animals




Pathophysiology
E Trivalent forms:
bind to sulfhydryl groups leading to inhibition of enzymatic
systems
inhibit the Krebs cycle and oxidative phosporylation. These lead
to inhibition of ATP production.
E Pentavalent forms
can replace the stable phosphate ester bond in ATP and produce
an arsenic ester stable bond which is not a high energy bond.
E Endothelial damage, loss of capillary integrity, capillary
leakage, volume loss, shock
E Arsine gas
E formed by the reaction of hydrogen with arsenic, and is a potent
hemolytic agent

Treatment of acute poisoning
E Gastric lavage
E Activated charcoal does not bind well
inorganic arsenic
E Whole bowel irrigation with polyethylene glycol
E Skin decontamination in dermal exposure
Treatment of acute poisoning
E Supportive care
E Chelation therapy should be instituted
promptly (minutes to hours)
BAL (British anti-Lewisite)- IM
Succimer (DMSA)- PO
DMPS PO, IV
D-Penicillamine- less effective
For chronic poisoning,chelator therapy
has not proven effective in relieving
symptoms