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					             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    Modern History
  History            • Gasoline
• Lead oxide as a    • Ceramics
  sweetening agent   • Crystal glass
• Lead pipes         • Soldering
  (“plumbing”)
                        – pipes
• Ceramics              – “tin” cans
• Smelting and          – car radiators
  foundries          • 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                      Chronic
• GI effects               • Peripheral, central
   – colic, severe pain      neuropathy
   – severe constipation   • Cardiac toxicity
• Acute encephalopathy     • Chronic nephropathy
• Acute nephropathy        • Saturnine gout
Children                   • Reproductive effects
• Growth retardation       • Hypertension?
• Behavioural             • 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       Peripheral/Adult
• Lethargy, wakeful     • Lead palsy
• Irritability             – median n.c. slowing
• Clumsiness, ataxia       – wrist/foot drop
                           – demyleinating disease
• Projectile vomiting
                        • Lead colic
• Visual s
                        • Muscle weakness
• Delerium,
  convulsions, coma     • Behavioural, memory
                          
• IQ performance
    Anemia and Lead Toxicity
• Normochromichypochromic,
  normocyticmicrocytic
• 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     Acquired Characteristics
• Inborn errors of haeme    • Children < 6 y
  metabolism                • Pregnant, lactating
  (porphyrias)                women
• Hereditary anemias        • Nutritional deficiency,
  (e.g. the thalassemias)     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 a     Medical       Repeat BPb q
single sample    removal       month
BPb > 50 ave     Medical       Repeat BPb q
last 3 samples   removal       month
BPb 40 - 60      Action        Repeat BPb q 2
                 level is 50   months
BPb < 40         RTW:          Repeat BPb q 6
                 Confirm 2     months
                 wks
    Management of Lead Exposure
             Adults
•   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 Exposure
         Children
• 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
  – CaNa2EDTA 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 Therapy
         BPb > 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 Therapy
        BPb 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 Therapy
        BPb 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 Therapy
        BPb 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

Encephalo   Any BPb   BAL +     High
pathy                 EDTA      dosages
Symptoma    BPb > 100 BAL +     Lower
tic                   EDTA      dosages
Mild        BPb 70 - Succimer
symptoms    100       po
Asymp-      BPb < 70 Medical
tomatic               removal
   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
    -5d
  – 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

				
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posted:5/18/2012
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