Toxicology

Lead Poisoning

Heavy Metal poisoning

• Lead, Mercury, Arsenic occupy 1^st, 2^nd, & 3^rd,rank among most toxic wastes
• Based on prevalence & severity of toxicity
• Bone, Liver & kidneys sequester metals in high concentration for years.
• Metals are excreted mostly through urine, & stool, but some portion also excreted in saliva, sweat, milk, hair, nails & epidermis
• Copper & selenium are essential for normal metabolic function of body as trace element but are toxic in high doses

Introduction

• Lead obtained prior to 2000 B.C. as a by-product of smelting silver.
• Hippocrates in 370 B.C. described an attack of colic in a man who extracted the metal.
• In 2^nd century B.C. Nicander drew a relationship of constipation, abdominal pain & pallor to the effect of this element
• By 1^st century A.D. lead poisoning was a well recognised clinical entity and Dioscorides fully described the syndrome.
• By 17^th century subtle forms of intoxication were recognised and the first record of experimental investigations on lead is found in an 1814 treatise on toxicology by Orfila
• In 20^th century it was rated as the most hazardous substance.

Properties

• It is a heavy, soft, steel grey metal.
• Its compound was used as an astringent but has no therapeutic use now
• Salts of Lead
• Lead acetate (sugar of lead)(salt of Saturn)
• Lead sub acetate- chief constituent of Gouldards extract (Liquor plumbi subacetatis)
• Lead carbonate white crystalline powder called Safeda used in pigment was used in ointment
• Other salts are nitrate, sulphate, chromate,chloride, iodide, sulphide,& monoxide(Mudrasang-syphilis), tetraoxide (Red lead, Minium, Sindur, Metia sindur)
• Used in pigment/dyes for applications in painting calicoprinting, hair dye, Surma, medicine etc.

Sources of Poisoning

• Home
• White lead paint used in water pipes and other purposes of painting
• Pica- Flakes of paint that contain lead
• Whisky distilled through motor car radiator “ Moonshine” whisky in USA
• Eating of games shot with pellets of firearms
• Lead shot/ projectile embedded in body, dust from firing range
• Automobile exhaust using leaded fuel
• Contaminated herbal remedies, food /water from improperly glazed ceramics, candies.

Sources of Poisoning

• Industrial consumption of lead is millions of tons
• Mining, smelting, petroleum, storage battery manufacture, printing, paint & pigment manufacture, ceramic and glass industry, Dust from demolition or sanding of lead painted houses, construction (mainly plumbing and insulation ), ammunition manufacture, wrecking and salvage(acetylene torch & electric arc volatilising lead paint and alloys), purification of silver, men cleaning large empty petrol tanks

Metabolism

• Absorption
• Ingestion- Majority of household cases. Even when soluble salt is ingested only 8-12% is absorbed and mostly from small intestine. Absorption more with constipation and less with diarrhoea
• Inhalation- Most of cases of industrial poisoning from fumes & dust.Absorbed from all parts including nasal passage. More rapid & complete than orally
• Dermal absorption.- Not of inorganic compounds from intact skin but organic lead (tetra-ethyl-lead) rapidly penetrates
• Subcutaneous or Intramuscular sites- Embedded projectiles

Metabolism

• Distribution
• Blood- 95 – 99 % sequestered in RBC (Lead estimation not done from serum)
• Distributed widely in soft tissues- kidneys(Highest), liver. Half life in soft tissue ~ 30 days
• 15 % of ingested lead sequestered in bone, teeth & hair with half life >20 yrs. This lead is inert & not harmful unless again mobilised in blood
• Factors favouring deposition in bone
• High phosphate intake. Lead behaves like Calcium and deposited as insoluble tertiary lead phosphate.
• Vit D- Intake promotes deposition provided phosphate available
• Factors favouring mobilisation from bones
• Low phosphate,high calcium, parathyroid hormone, dihydrotachysterol, acidosis, iodides, bicarbonates

Metabolism

• Excretion
• Mostly in urine but also in other body fluids including sweat & milk,
• Faeces (excreted through bile)
• Factors promoting excretion
• Procedures and conditions that favour mobilization from bones and soft tissue loads
• Chelating agents-BAL, EDTA, Penicillamine enhance excretion of inorganic lead
• Mechanism of Action
• Interferes with mitochondrial oxidative phosphorylation , ATPases, calcium dependent messengers. Enhances oxidation & cell apoptosis

Metabolism

• Lead concentration in respired air should be
• below 0.15 mg/ cuM-inorganic lead
• 0.1 mg /cuM for tetraethyl lead
• Normal daily oral intake of lead is 0.3 mg or less
• Positive lead balance begins at 0.6 mg daily intake but toxic level not reached during life time
• Daily intake of 2.5 mg- toxic level in 4 years
• Daily intake of 3.5 mg- toxic level in a few months
• Concentration of lead in blood
• > 70 µg/dL of blood - Recent exposure
• >100 µg/dL of blood - Heavy exposure
• >500 µg/dL of blood - Unusual but may be very heavy exposure
• >1 mg /dL of blood - Sample contaminated

Clinical Features of Lead Poisoning

• Inorganic Lead poisoning
• Acute Poisoning- mostly by Lead acetate- poisoning uncommon
• Chronic Poisoning- Takes three forms
• Abdominal form (Alimentary form)
• Neuromuscular form
• Encephalopathic form
• Organic Lead Poisoning -tetraethyl and tetramethyl lead poisoning
• Acute- When exposure massive
• Chronic- Slow exposure- encephalopathic form

Acute Poisoning

• Symptoms-
• Astringent effect, thirst, metallic taste, nausea, pain abdomen, vomiting
• BPb level
• BPb of > 60-80 µg/dL causes
• Haematopoiesis-acute haemolytic crisis,severe anaemia, haemoglobinuria.
• Renal tubular function- renal damage, oliguria or anuria
• neuro transmission, and neuronal cell death
• Central & peripheral nervous system effect- paresthesia, pain, and muscle weakness

Acute Poisoning by Lead

• BPb level
• BPb of > 80-120 µg/dL – Acute encephalopathy, convulsion, coma & death
• Fatal Dose - uncertain ,about 20 gm of lead acetate
• Fatal Period– 1-2 days
• Picture of chronic poisoning appears in those who survive

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Chronic Lead Poisoning (Plumbism)

• Picture common to all forms
• Pallor, insomnia, headache, dizziness and irritability
• High lead level is associated with increased risk of hypertension in both sexes.
• People from urban background are specially prone to this intoxication
• High lead level in bones during pregnancy is also associated with lower birth wt. Head circumference, birth length, & neurodevelopmental performance in child up to 2 yrs.of age

Picture common to all forms

• Blue black‘Lead line’(Burtonian line) at‘gingival-tooth’ margin of some or all teeth due to lead sulphide deposit
• ‘Stippling of retina’ found adjacent to optic disk. It is an early sign
• Chronic renal failure interstitial nephritis
• Saturnine gout
• In lead poisoning due to moon shine whisky, gout is precipitated as a result of reduced clearance of urates

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Chronic Lead Poisoning

• Other features with BPb of > 40 µg/dL
• Anorexia, constipation, abdominal pain, lethargy, arthralgia, myalgia depression, impaired short term memory, loss of libido
• Increased risk of, demyelinating peripheral neuropathy (mainly motor), cardiac conduction delays, diminished sperm count, spontaneous abortions

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Clinical Picture (Cont.)

• Chronic exposure in children(Subclinical)
• Risk of impairment in IQ even with minimal detectable level that is BPb of 1 µg/dL and higher
• BPb of > 25-60 µg/dL causes mental retardation, impaired motor function, balance, hearing, school performance( behaviour and language specially affected)
• BPb of > 80 µg/dL- Anorexia,constipation, abdominal pain irritability, lethargy, Fanconi’s syndrome, pyuria, azotemia
• ‘Lead line’ seen on epiphyseal plates of long bones- Rings of increased density in the ossification centre of the epiphyseal cartilage and a series of transverse lines in the diaphysis.
• Anaemia is a constant feature

Forms of Chronic poisoning

• Forms may occur separately or combined
• Alimentary form (abdominal syndrome) tends to result from very slowly developing intoxication
• Colicky pain called painter’s or lead colic due to spasm of bowel is the cardinal feature- Intermittent often severe and sense of pressure between attacks.
• Abdomen not tender, there may be relief on pressure
• Anorexia and marked Constipation.
• Persistent metallic taste & wt. Loss is common

Forms of Chronic poisoning

• Neuro muscular form (Lead Palsy)
• This is also described as subacute toxicity
• Easy fatigue & Weakness of muscle groups precede actual paralysis.
• Weakness/ palsy involves most active muscle group like extensors of forearm, wrist, fingers and extraocular muscles more commonly than flexors or lower extremities.
• Paralysis may be localised to predominant side used
• Wrist drop and foot drop in absence of sensory loss may be considered pathognomonic.
• Degenerative changes in motor neurones, their axons and impairment of high energy phosphate metabolism in muscles is described.

Encephalopathic Syndrome

• Occurs primarily in children but some times also in adults
• There may be history of behavioural changes
• Restlessness, loss of memory, confusion, insomnia, hallucination, ataxia, vertigo, & projectile vomiting
• Presenting manifestations are
• Convulsions, mania, delirium, & coma
• Signs of raised intracranial tension
• Mortality rate is about 25%
• 40 % of those who survive have residual neurological abnormality like
• Mental retardation, EEG abnormality, epilepsy, cerebral palsy, optic atrophy, deafness
• Hypertension, chronic nephritis, & cerebral haemorrhage in later life also reported.

Organic Lead Poisoning

• Tetraethyl and tetramethyl lead are lipid soluble antiknock additives to petrol. These are highly volatile and also absorbed through intact skin.
• Exposure from automobile exhaust
• Exposure while cleaning petrol tanks
• Poisoning- At slow rate typical encephalopathic form of toxicity is presented as ethyl lead is converted in to inorganic lead in body
• With massive exposure an acute illness results
• Headache, insomnia, restlessness, forgetfulness, delusion, delirium, signs of violent mania, hypothermia, bradycardia, hypotension, convulsion, coma and death between few hrs to several weeks.

Laboratory findings

• BPb level near or > 80µg/dL
• Punctate basophilia (basophilic stippling of RBC) (the aggregation of RNA) occurs due to inhibitory effect of lead on pyrimidine-5-nucleotidase
• It is non-specific, not pathognomonic of lead poisoning
• Not seen in tetraethyl lead poisoning
• Seen only in 60 % cases of children
• But stippled cell count of 35000 cells per million cells is significant
• Hypochromic microcytic anaemia
• More common in children
• Similar to iron deficiency anaemia
• Decreased life span of RBC
• An inhibition of heme synthesis

Laboratory findings

• Red fluorescence-
• When wet fresh film of blood is examined under UV light 75-100 % of RBC are found to have intense fluorescence because of increased erythrocytes protoporphyrin to which Zinc is incorporated in place of iron
• Decreased life span of RBC
• Decreased osmotic fragility
• Haemoglobinemia, haemoglobinuria, aminoaciduria, renal glycosuria, fructosuria, hyperphosphaturia, and citraturia
• Increased excretion of lead in urine
• Normal range- 0.00 to 0.06 Mean 0.03 µg
• Safe range 0.01 to 0.15 Mean 0.08 µg
• Dangerous 0.08 to 0.4 Mean 0.2 µg
• K-x-ray fluorescence(KXRF) can safely make in vivo measurements of lead level in bones

Treatment

• Removal from source of exposure
• Gastric Lavage, purgative (Mag-sulph),
• Calcium gluconate I.V. to control colic (more effective than morphine)
• Diazepam for convulsions
• Treatment of shock,
• Fluid & electrolyte balance high fluid intake unless intracranial tension raised.
• Mannitol & dexamethasone for raised intracranial tension
• Chelation not effective in organic lead poisoning except removing the portion converted in to inorganic lead. So treatment is symptomatic.

Treatment

• Chelating agents are used if for BPb level >50-60µg/dL-
• There are four chelators
• Cal.disodium EDTA 30-50 mg/kg daily in two divided doses Given deep I.M. or I.V. in 6-12 hrs.(In lead encephalopathy combined with dimercaprol)
• Dimercaprol- 4 mg/kg I.M. every 4 hrs for 48 hrs then 6 hrs/48 hrs,then 6-12 hrs for 7 days
• Penicillamine 30 mg/ kg- 250 mg /6 hrsly orally – 5 days
• Succimer orally active better safety and efficacy than penicillamine for children – 10 mg/kg 8 hrsly for 5 days then every 12 hrs for additional 2 weeks
• Relief with chelation is dramatic and symptoms disappear with 7-10 days
• After 2 weeks from completion of course BPb to be measured to find out rebound increase.

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Autopsy findings

• Blue line on gum
• Paralysed muscles flaccid and show fatty degeneration
• Intestine thickened and contracted
• Liver & kidneys hard and small
• Tubules show inclusion bodies
• Heart hypertrophied- atheroma may be present in aorta & aortic valves
• Cerebral oedema punctate haemorrhages and proliferative meningitis may be present

Medico- Legal Aspects

• Industrial disease since antiquity
• Mostly accidental chronic poisoning
• Suicidal rare
• Homicidal rare
• Criminally used to procure abortion as paste in abortion stick
• Occasionally used as cattle poison