lead and arsenic toxicity

8/2/2019 Lead and Arsenic Toxicity

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Lead and Arsenic

Toxicity



Uses and Sources of Lead:

Lead paint:Food containers(painted with

lead-based paint or lead-containing glaze ,

canned foods) Petrol (tetraethyl lead)

Toys and Jewelry

Herbal remediesfrom India, China, and other

parts of Asia may be potential

sources of lead exposure.



Uses and Sources of Lead:

Soil:Exposure to soil that contains particulate lead has been shown to

be significantly hazardous for children, who are more commonlyexposed by ingestion of house dust or soil than by paint chips.

Water:Drinking water is also a major source of lead

Exposure.

Occupational sources:Remodeling construction

Smelters

Battery factories

Ammunition

Soil:Exposure to soil that contains particulate lead has been shown to

be significantly hazardous for children, who are more commonlyexposed by ingestion of house dust or soil than by paint chips.

Water:Drinking water is also a major source of lead

Exposure.

Occupational sources:Remodeling construction

Smelters

Battery factories

Ammunition factories

Ceramic glazes



Contribution of Sources



Toxicokinetics Absorption of Lead:

GI:Children absorb lead well orally(~50%) adults poorly (~10%).

Lead absorption is enhanced if dietis poor in iron or calcium.

High fat intake and inadequatecalories have also been associatedwith enhanced lead absorption.

Respiratory:Inorganic lead

Skin:Organic lead



Toxicokinetics

Distribution:

95% in bone

(%70 in children)

4% in soft tissue

(brain, liver, kidneys, bone marrow)

1% blood

Lead readily crosses the placenta



Toxicokinetics

Half-life Of Lead

• 25 DAYS -- BLOOD

• 40 DAYS -- SOFT TISSUE

• 20 YEARS -- BONE



Toxicokinetics

Hepatic Metabolism/Excretion Inorganic lead is not metabolized but is excreted unchanged.

Organic or alkyl-lead,(leaded gasoline, also identified astetraethyl- and tetramethyl-lead) undergoes oxidativedealkylation to the highly neurotoxin metabolites, triethyl- and

trimethyl-lead. 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

Nervous SystemNeurological, Neurobehavioral, and Developmental

Effects in Children

Clinically overt lead encephalopathy may occur in children withhigh exposure to lead, probably at BLL of 70 μg /dL or higher.

Symptoms of lead encephalopathy:

Lethargy

Vomiting

Irritability

Loss of appetiteDizziness

Progressing to obvious ataxia, and a reduced level ofconsciousness, which may progress to coma and death




Neurological, Neurobehavioral, and Developmental Effects in Children

The pathological findings at autopsy are severe edema of thebrain due to extravasations of fluid from capillaries in the brain .This is accompanied by the loss of neuronal cells and anincrease in glial cells .

Recovery is often accompanied by sequelae including epilepsy,mental retardation, and, in some cases, optic neuropathy andblindness.

Most studies report a 2- to 4-point IQ deficit for eachμg /dL increase in BLL within the range of 5 –35 μg /dL.




Neurological, Neurobehavioral, and Developmental Effects in Children

Lead can affect the brain by multiplemechanisms:

Lead may act as a surrogate for calcium and/ordisrupt calcium homeostasis.

Lead affects virtually every neurotransmitter systemin the brain, including glutamatergic, dopaminergic,

and cholinergic systems.(All these systems play a critical role in synapticplasticity and cellular mechanisms for cognitivefunction, learning, and memory.)



Toxic Effects of Lead Neurotoxic Effects in Adults

CNS :

Fatigue, irritability, lethargy, insomnia, headache,difficulty concentrating, memory loss and tremor.

Sever lead intoxication can result in an encephalopathycharacterized by depressed consciousness, seizure,and coma, in association with cerebral edema.

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 Hematologic Effects

Lead has multiple hematologic effects,ranging from increased urinaryporphyrins, coproporphyrins, δ - aminolevulinic acid (ALA), and zinc-protoporphyrin to anemia.




Renal ToxicityAcute lead nephrotoxicity consists of proximal tubular dysfunction and can be reversed by

treatment with chelating agents.

Chronic lead nephrotoxicity consists ofinterstitial fibrosis and progressive nephron loss,

azotaemia and renal failure.

Fanconlike syndrome A characteristic microscopic

change is the presence of

intranuclear inclusion bodies.




Effects on Cardiovascular System

The most important manifestation of lead toxicity on thecardiovascular system is hypertension.

The pathogenesis of lead-induced hypertension ismultifactorial including:

(1) Inactivation of endogenous nitric oxide and cGMP,

possibly through lead-induced reactive oxygen species.

(2) Changes in the rennin – angiotensin – aldosterone

system, and increases in sympathetic activity, importanthumoral components of hypertension.

(3) Alterations in calcium-activated functions of vascularsmooth muscle cells including contractility by decreasingNa+/K+-ATPase activity and stimulation of the

Na+/Ca++ exchange pump.

(4) Possible rise in endothelin and thromboxane.




Reproductive systemImpairment of both male and female reproductive function is

associated with over plumbism.

GastrointestinalLead 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.




Bone EffectsLead 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 anddelays in fracture repair.

In children exposed to lead, a higher bone mineral density

(BMD) was observed.



Carcinogenicity

2B. Agent is possibly carcinogenicto humans

•Human epidemiology data weak

•Animal data positive



Children Vulnerability

CHILDREN are more vulnerable

exposure than ADULTS

SizeConsume More Food

Inhale More Air

Developing Nervous System

Increased need for Calcium



Recommended Lead level<0.48 (10µg/dl)

< 0.48µmol/l (10µg/dl)= NHMRC Goal.

>0.48µmol/l (10µg/dl)= elevated.

>0.72µmol/l (15µg/dl)=substantially elevated.

Notifiable level.

>1.20µmol/l (25µg/dl)= dangerously elevated.

>2.20µmol/l (45µg/dl)=Symptomatic



Clinical Presentation Blood lead concentration (µg/L)

Children: <400 Adults: <400

400-500 400-600

500-700 600-1000

>700 >1000

GITract

Nil ±Abdominal pain±Constipation

Abdominal pain,constipation,weight loss,

loss of appetite

Abdominal colic,vomiting

Blood Subclinicalinhibition of

RBC enzymes

Subclinicalinhibition of RBC

enzymes

Mild anaemia Severe anaemia

CNS Effects on IQ inchildren?

Mild fatigue,irritability,

slowed motorneurone

conduction

Fatigue,poor

concentration[Peripheralneuropathy]

Encephalopathy- delirium

- ataxia- fits- coma

Other Nil Muscle pain Hypertension,nephrotoxicity,lowered Vit Dmetabolism

Hypertension,nephrotoxicity,lowered Vit Dmetabolism



IDENTIFY & REMOVE from SOURCE

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



Consider the use of chelation therapy

- Chelaton terapy is wildely recomended forasymptomatic children with BLL >450µg/l

Increase lead excretion,reduce bloodcocentration,and reverse hemotologicmarkers of toxcity.



EDTA - Sodium Calcium Edetate

1000-1500 mg/m2/d, IV,IM

- IV for severe toxicity, particularly encephalopathy

- Well tolerated, <1% nephrotoxicity

BAL-Dimercaprol

450 mg/m2/dIM for severe toxicity only, particularly encephalopathy.

DMSA - 2,3dimercaptosuccinic acidOral 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 (آµg/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 70-100Succimer 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

EncephalopathyBAL 450 mg/m2/d 75 mg/m2 IM every 4 h for 5 d

CaNa2EDTA 1500 mg/m2/dContinuous 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/d350 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)

20-44Routine chelation not

indicated

If succimer used, same regimen as

per above group

Attempt exposure reduction

<20 Chelation not indicated

Attempt exposure reduction



ARSENIC

A i



ArsenicIntroduction

Arsenic has been known and used since ancient times as the

Poison of Kings and the King of Poisons

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

A i



Arsenic

Organic Arsenic:

Less toxic that inorganic As

Produced by Biomethylation• Organisms in soil and water

• Humans (detoxify inorganic

As)• High in shrimp

Introduction

A i



ArsenicIntroduction

Arsenic is common in the environment

SourcesGroundwater

Arsenic containing mineral ores Industrial processesSemiconductor manufacturing (gallium arsenide)

Fossil fuels

Wood treated with arsenic preservatives

Smelting (copper, zinc, lead) and refining of metalsand ores

Glass manufacturing



Commercial productsWood preservatives

Pesticides

Herbicides

Fungicides

Food Seafood and fish

Soil pica behavior: when children ingest largeamounts of soil at a time (e.g. up to 1teaspoon or 5,000mg)

ArsenicIntroduction

A i



ArsenicToxicokinetics (absorbtion)

Inorganic arsenic is well absorbed (80 –90%) fromthe gastrointestinal tract.

Often metabolized by methylation, and thenexcreted primarily in urine.

Arsenic compounds of low solubility (e.g.,arsenictrioxide,arsenicselenide,leadarsenide,andgallium arsenide) are absorbed less efficientlyafter oral exposure.

Skin is a potential route of exposure to arsenic, andsystemic toxicity has been reported in personshaving dermal contact with solutions of inorganicarsenic.

Airborne arsenic is largely trivalent arsenic oxide.

A i



ArsenicToxicokinetics (excretion)

Excretion of absorbed arsenic is mainly via theurine

Arsenic has a predilection for skin and isexcreted by desquamation of skin and in sweat,particularly during periods of profuse sweating

It also concentrates in forming fingernails andhair

T1/2 of inorganic arsenic in the blood is 10 hrsand of organic arsenic is around 30 hours

2-4 weeks after the exposure ceases, most ofthe remaining arsenic in the body is found in

keratin-rich tissues (nails, hair, skin)

A i



ArsenicToxicokinetics (metabolism)

The intermediate metabolites, methylarsonous acid (MMA3+) anddimethylarsinous acid(DMA3+), are generated during this process, and thesetrivalent methylated arsenicals are now thought to be more toxic than even the

inorganic arsenic species

A i



ArsenicToxicokinetics

As5+ (Arsenate)

As3+ (Arsenite)

Methylarsenite (in liver)

Dimethylarsenite

(readily eliminated – urine)

A i



ArsenicAcute Poisoning

Ingestion of large doses (70 –180 mg) ofinorganic arsenic can be fatal

Symptoms of acute intoxication include:

Fever Anorexia

Hepatomegaly

Melanosis

cardiac arrhythmia

in fatal cases, eventual cardiac failure

A i




Acute arsenic ingestion can damage:

mucous membranes of the gastrointestinal tract(irritation,vesicleformation,andevensloughing)

Sensory loss in the peripheral nervous system is themost common neurologic effect, appearing at 1 –2weeks after large doses (a condition that is reversible if exposure is stopped )

Anemia and leucopenia(granulocytopenia ), (few daysfollowing high-dose arsenic )(reversible)

Acute exposure to a single high dose can produceencephalopathy, with signs and symptoms ofheadache , lethargy,mentalconfusion,hallucination,seizures,andeven

coma

Arsenic



M a

n i f e s t a t i o n

s o f a c u t e a

r s e n i c

p o

i s o n i n g

Bodily system affected Symptoms or signs Time of onset

Systemic ThirstHypovolemia, Hypotension

MinutesMinutes to hours

Gastrointestinal Garlic or metallic tasteBurning mucosaNausea and vomitingDiarrhea

Abdominal painHematemesisHematochezia, melenaRice-water stools

ImmediateImmediateMinutesMinutes to hoursMinutes to hoursMinutes to hoursHoursHours

Hematopoietic system HemolysisHematuriaLymphopeniaPancytopenia

Minutes to hoursMinutes to hoursSeveral weeksSeveral weeks

Pulmonary

(primarily in inhalationalexposures)

Cough

DyspneaChest PainPulmonary edema

Immediate

Minutes to hoursMinutes to hoursMinutes to hours

Liver JaundiceFatty degenerationCentral necrosis

DaysDaysDays

Kidneys ProteinuriaHematuria

Acute renal failure

Hours to daysHours to days

Hours to days


Arsenic




Arsine gas(ASH3), generated byelectrolytic or metallic reduction ofarsenic in nonferrous metal production.

It is a potent hemolytic agent, producingacute symptoms of nausea, vomiting,shortness of breath, and headacheaccompanying the hemolytic reaction.

Exposure to arsine is fatal in up to 25% ofthe reported human cases.

Arsenic



ArsenicChronic Toxicity

Skin major target organ in chronic inorganic arsenic

exposure

Diffuse or spotted hyperpigmentation and,

alternatively, hypopigmentation can first appearbetween 6 months to 3 years with chronic exposure toinorganic arsenic

Skin cancer is common with

Palmar-plantar hyperkeratosisusually follows the initial

appearance of arsenic-inducedpigmentation changes within aperiod of years

Arsenic




Liver Characteristic of long-term or chronic arsenic

exposure, manifests :

jaundice

abdominal pain

Hepatomegaly

progress to cirrhosis and ascites

even to hepatocellular carcinom

Arsenic




Peripheral neurophathy Repeated exposure to low levels of inorganic arsenic

can produce

This neuropathy usually begins with :

sensory changes

numbness in the hands and feetpainful “pinsand needles” sensation

motor nerves be affected

muscle tenderness weaknes progressing from proximal to distal

muscle groupss

Effects are dose-related

Arsenic




cardiovascular disease Peripheral vascular disease has been

observed in persons with chronic exposure to

inorganic

It is manifested :

acrocyanosis

Raynaud’s phenomenon

progress to endarteritis and

gangrene of the lower extremities

(Blackfoot disease).

Arsenic



ArsenicCarcinogenicity

The carcinogenic potential of arsenic wasrecognized over 110 years ago

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

It has been difficult to confirm thecarcinogenicity of inorganic arsenic inexperimental animals



Pathophysiology

Trivalent forms: bind to sulfhydryl groups leading to inhibition of enzymatic

systems

inhibit the Krebs cycle and oxidative phosporylation. These leadto inhibition of ATP production.

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.

Endothelial damage, loss of capillary integrity, capillary

leakage, volume loss, shock Arsine gas

formed by the reaction of hydrogen with arsenic, and is a potenthemolytic agent



Treatment of acute poisoning

Gastric lavage

Activated charcoal does not bind wellinorganic arsenic

Whole bowel irrigation with polyethylene glycol

Skin decontamination in dermal exposure



Treatment of acute poisoning

Supportive care

Chelation therapy should be institutedpromptly (minutes to hours)

BAL (British anti-Lewisite)- IM Succimer (DMSA)- PO

DMPS – PO, IV

D-Penicillamine- less effective

For chronic poisoning,chelator therapyhas not proven effective in relievingsymptoms

lead and arsenic toxicity

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