Guid-Pb
Document Sample
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
• 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 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
– 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 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
