Lead

Sources of Occupational Exposure, Clinical Toxicology, and Control

Lead in the Environment

• Lead (207Pb) is a natural element, heavy metal, end product of radionuclide decay

• Radioactive lead (210Pb, t1/2 = 22 y) is a convenient way to trace lead

• Lead was insignificant environmentally until about 1800

• Human activity has mobilized lead in the environment

Useful Properties of Lead

• Ductility

• Low melting point

• Density, absorption of radiation, sound and vibration

• Chemical properties (e.g. combines with nitrogen)

• Resists acid and corrosion

Historical Sources of Lead Exposure

Ancient/Premodern History

• Lead oxide as a sweetening agent

• Lead pipes (“plumbing”)

• Ceramics• Smelting and foundries

Modern History• Gasoline• Ceramics• Crystal glass• Soldering

– pipes– “tin” cans– car radiators

• House paint

Contemporary Sources of Lead Exposure

• Residue of leaded gasoline• Lead smelting and recycling• Solder (Pb + Sn), welding (minor)• Metalworking• Ammunition and explosives• Exterior paints and remediation• Avocational exposure in crafts• Kohl and certain herbal remedies

Future Sources of Exposure to Lead

• Gasoline, in some developing countries• Plastics containing Pb additives (e.g. one type

of “thin” Venetian blinds)• Compounding “litharge”, used in making

ferrite ceramic magnets• Pb compounds with piezoelectric and

thermoelectric properties• Unregulated cosmetics, remedies

Settings for Lead Exposure

• Smelting and metalworking

• Lead sulfate battery operations

• Activities related to firearms and ammunition

• Crafts involving glass, ceramics

• Hazardous waste disposal

• Imported or customized products

Biologically Important Properties of Lead

• Readily combines with sulfide, sulfhydryls

• Affinity for bone and other calcified tissue

• Readily absorbed and mobilized in the body

• Cumulative body burden

• Narrow margin between population reference levels and toxicity levels

• OrganoPb compounds more bioavailable

Lead Exposure in Children

• Pica and passive exposure: oral

• Pb removed from gasoline

• Blood Pb, FEP• CNS more likely to be

affected• Needleman

controversy

Lead Exposure in Adults

• Mostly occupational: inhalation

• Maintenance at workplace

• Peripheral neuropathy more common

• Blood Pb, ZPP• Renal effects more

likely

Cardinal Symptoms of Lead Intoxication

Acute• GI effects

– colic, severe pain– severe constipation

• Acute encephalopathy• Acute nephropathy

Children• Growth retardation• Behavioural

Chronic• Peripheral, central

neuropathy• Cardiac toxicity • Chronic nephropathy• Saturnine gout• Reproductive effects• Hypertension?• Anemia

Signs of Extreme Lead Toxicity

• Acute lead encephalopathy– fatal in 25%– poor prognosis for full neurological recovery– severe clinical impairment in 40%

• Severe lead colic

• “Burtonian” lines (gingival deposition of Pb sulfide)

Mechanisms of Damage to the Nervous System by Lead

Central• Cerebral edema• Necrosis of brain tissue• Glial proliferation around blood vessels

Peripheral• Demyelination• Reversible NCV• Irreversible axonal degeneration

Neurological Manifestations of Lead Toxicity

Central/Pediatric• Lethargy, wakeful• Irritability• Clumsiness, ataxia• Projectile vomiting• Visual s• Delerium, convulsions,

coma IQ performance

Peripheral/Adult• Lead palsy

– median n.c. slowing

– wrist/foot drop

– demyleinating disease

• Lead colic• Muscle weakness• Behavioural, memory

Anemia and Lead Toxicity

• Normochromichypochromic, normocyticmicrocytic

• Reduced rbc survival time• Compensatory rbc production

– reticulocytosis

• Basophilic stippling– variable– represents damaged cell organelles, RNA

Haeme Synthesis and Lead Toxicity

• Pb inhibits -aminolevulinic acid dehydratase -ALA in urine

• Pb inhibits co-proporphyrinogen decarboxylase Co-proporphyrinogen in urine

• Pb inhibits ferrochelatase Protoporphyrine IX accumulates in rbcs

• FEP, ZPP tests are based on this

Diagnostic Criteria for Lead Toxicity (CDC)

• Blood– Blood lead > 80 g/dL– FEP > 190 g/dL– ZPP

• Urinary Pb Excretion (24 hour)– Pb > 0.15 mg/L -ALA > 19 mg/L– Coproporphyrin III > 150 g/L

Other Considerations in the Diagnosis of Lead Toxicity

• Blood lead is most generally useful• FEP not useful below about 20 g/dL• Evidence clearly suggests that children

should be considered at risk if BPb > 10 g/dL

• Early evidence that there may be risk at 5 g/dL

• Congenital anomalies have been reported

Toxicokinetics of Lead, I

• Ingestion (children), inhalation (adults)

• Readily absorbed by inhalation route

• Slow absorption by ingestion, with Fe deficiency

• OrganoPb compounds (e.g. Et4Pb) much more rapidly absorbed

• Cumulative exposure

Toxicokinetics of Lead, II

• Carried by red cell, mostly bound to haemaglobin A2

• Rapidly distributed perfusion

• Affinity for bone, which acts as sink (94%)

• Bone constitutes reservoir in equilibrium with blood; turnover slow

• t = 28 - 36 days in adult

Toxicokinetics of Lead, III

• Inorganic Pb is not metabolised

• Organic (alkyl) Pb compounds are dealkylated in the liver

• Dealkylation involves cytochrome P450

• Some alkyl Pb is dealkylated, stays behind as inorganic Pb, and remobilizes

• Children have much less capacity to metabolize than adults

Toxicokinetics of Lead, IV

• Excretion of Pb generally reflects body burden, not route of exposure

• Ingested Pb not absorbed passes in feces

• Enterohepatic circulation, biliary secretion

• Excretion by two pathways:– biliary excretion (major with high exposures)– urinary excretion (major)

Susceptibility Factors

Genetic Predispositions• Inborn errors of haeme

metabolism (porphyrias)

• Hereditary anemias (e.g. the thalassemias)

Acquired Characteristics• Children < 6 y• Pregnant, lactating

women• Nutritional deficiency,

esp. Fe, Ca++, vit D• Neurological or renal

disease• ?Alcohol abuse

Occupational Exposure Levels

OSHA PEL 0.05 mg/m3, 8-h TWA

NIOSH REL 0.10 mg/m3, 10-h TWA; BEI, Pb compounds covered differ

ACGIH TLV 0.05 mg/m3, 8-h TWA

OSHA Pb Standard Actions

BPb >60 on asingle sample

Medicalremoval

Repeat BPb qmonth

BPb > 50 avelast 3 samples

Medicalremoval

Repeat BPb qmonth

BPb 40 - 60 Actionlevel is 50

Repeat BPb q 2months

BPb < 40 RTW:Confirm 2wks

Repeat BPb q 6months

Management of Lead ExposureAdults

• Prohibit eating, drinking, smoking at work

• Housekeeping

• Ventilation

• Personal protection

• Medical removal

• Control exposure to OSHA Pb standard

• Review other possible sources of contamination

Management of Lead ExposureChildren

• Optimize nutrition, avoid fasting• Report through public health dept. • Home Pb abatement

– Dust control– water– food containers– home and yard

• Rule out passive exposure

Chelation

• Not a decision to be taken lightly

• Requires close monitoring

• Inefficient process, typically reducing body burden only 1 - 2 %

• Chelating agents may not significantly reduce tissue levels, esp. in CNS

Chelation with Agents Other than Succimer

• Chelation can be dangerous!– May result in Ca++ depletion, hypercalcemia– May result in nephrotoxicity if serum Pb

• Agents– CaNa2EDTA 1000-1500 mg/m2/d, iv– BAL 300 - 450 mg/m2/d, 50 - 75 mg/m2 q4h

3 - 5 d, im– D - penicillamine (second-line drug)

Chelation with Succimer

• Dimercaptosuccinic acid• Oral administration• 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

Paediatric Chelation Therapy - Encephalopathy - 1

• A medical emergency!

• BAL and CaNa2•EDTA at 1500 mg/m2/d, iv

• Stat BAL + continuous EDTA infusion

• EDTA alone may cause deterioration

• Generally continued 5 days

• D/C BAL at 3 days, continuing EDTA if prompt response and BPb <50 g/dl

Paediatric Chelation Therapy - Encephalopathy - 2

• Fluid management critical– risk of cerebral edema, SIADH– monitor I/O, spec grav, electrolytes

• NPO for first several days• Adequate fluid replacements

– 1 ml/kcal/d energy requirements (100/kg first 10 kg, then 50 for next 10, thereafter 20)

– Urine output: 0.5 ml/kcal/d or 350 - 500 ml/m2/d

Paediatric Chelation Therapy - Encephalopathy - 3

• Seizure control by benzodiazepines

• Suspect cerebral edema– avoid LP– mannitol, glycerol hyperosmotic therapy– modest hyperventilation– steroids– more aggressive management not evaluated

Paediatric Chelation TherapyBPb > 70 g/dl

• If milder symptoms and/or blood Pb > 70 g/dl, chelation on regimen similar to encephalopathy

• 3 days of BAL + 5 days EDTA

• PICU for first few days

• Repeated courses only if required:– Second course should follow >2 d– Third course by 10 - 14 d, to equilibrate

Paediatric Chelation TherapyBPb 45 - 69 g/dl

• If asymptomatic, treatment with succimer is preferred

• Succimer initiated with 30 mg/kg/d or 1050 mg/m2/d in three divided doses 5 d

• Succimer maintained at 20 mg/kg/d or 70 mg/m2/d in two divided doses 14 d

• Consider hospitalization if home abatement is not possible

Paediatric Chelation TherapyBPb 20 - 44 g/dl

• CDC and AAP recommend environmental interventions but not chelation

• These guidelines considered conservative• Reasonable to consider chelation if:

– Pb levels do not decline – symptoms, even if subtle– elevated FEP after Fe supplementation– Age < 2 y

Paediatric Chelation TherapyBPb 10 - 19 g/dl

• Excessive exposure to Pb

• Currently not considered as indication for chelation

• Home Pb abatement and control of exposure is recommended

Indications for Paediatric Therapy May Change

• Safety of succimer may change recommendations

• NIEHS is sponsoring a clinical trial: Treatment of Lead-Exposed Children (TLC)– multicentre– randomized, double-blind– succimer v. placebo– outcomes include developmental indices

Adult Chelation Therapy - 1

• Indicated for symptomatic Pb toxicity

• Generally less effective

• Never a substitute for control of exposure

• Unethical to give chelation for prophylaxis

• Indications for chelation depend on symptoms and BPb (g/dl), not BPb alone

Adult Chelation Therapy - 2

Encephalopathy

Any BPb BAL +EDTA

Highdosages

Symptomatic

BPb > 100 BAL +EDTA

Lowerdosages

Mildsymptoms

BPb 70 -100

Succimerpo

Asymp-tomatic

BPb < 70 Medicalremoval

Adult Chelation Therapy - 3

• Encephalopathy:– BAL 450 mg/m2/d, 75 mg im q4h 5 d– EDTA 1500 mg/m2/d, iv 5 d – Start EDTA 4 hours after stat BAL

• Symptomatic, BPb > 70– BAL 300 - 450 mg/m2/d, 50 - 75 mg im q4h

3 - 5 d– EDTA 1000 - 1500, otherwise as above

Adult Chelation Therapy - 4

• Mild Symptoms treated with Succimer– Succimer 700 - 1050 mg/m2/d– Give 350 mg/m2 (or 10 mg/kg) 5 d, then bid

14 d

• The availability of a safe chelating agent does not mean that prophylaxis is acceptable.

Every Case of Lead Toxicity is a Failure of Society

• Lead toxicity is entirely preventable

• This problem should not exist in 2000

• A worker exposed to lead represents an insult in the present

• A child exposed to lead represents an assault on the future