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Lead Sources of Occupational Exposure, Clinical Toxicology, and Control.

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Presentation on theme: "Lead Sources of Occupational Exposure, Clinical Toxicology, and Control."— Presentation transcript:

1 Lead Sources of Occupational Exposure, Clinical Toxicology, and Control

2 Lead in the Environment Lead ( 207 Pb) is a natural element, heavy metal, end product of radionuclide decay Radioactive lead ( 210 Pb, t 1/2 = 22 y) is a convenient way to trace lead Lead was insignificant environmentally until about 1800 Human activity has mobilized lead in the environment

3 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

4 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

5 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

6 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

7 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

8 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

9 Lead Exposure in Children Pica and passive exposure: oral Pb removed from gasoline Blood Pb, FEP CNS more likely to be affected Needleman controversy

10 Lead Exposure in Adults Mostly occupational: inhalation Maintenance at workplace Peripheral neuropathy more common Blood Pb, ZPP Renal effects more likely

11 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

12 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)

13 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

14 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 

15 Anemia and Lead Toxicity Normochromic  hypochromic, normocytic  microcytic Reduced rbc survival time Compensatory  rbc production –reticulocytosis Basophilic stippling –variable –represents damaged cell organelles, RNA

16 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

17 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

18 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

19 Toxicokinetics of Lead, I Ingestion (children), inhalation (adults) Readily absorbed by inhalation route Slow absorption by ingestion,  with Fe deficiency OrganoPb compounds (e.g. Et 4 Pb) much more rapidly absorbed Cumulative exposure

20 Toxicokinetics of Lead, II Carried by red cell, mostly bound to haemaglobin A 2 Rapidly distributed  perfusion Affinity for bone, which acts as sink (94%) Bone constitutes reservoir in equilibrium with blood; turnover slow t  = days in adult

21 Toxicokinetics of Lead, III Inorganic Pb is not metabolised Organic (alkyl) Pb compounds are dealkylated in the liver Dealkylation involves cytochrome P 450 Some alkyl Pb is dealkylated, stays behind as inorganic Pb, and remobilizes Children have much less capacity to metabolize than adults

22 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)

23 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

24 Occupational Exposure Levels OSHA PEL 0.05 mg/m 3, 8-h TWA NIOSH REL 0.10 mg/m 3, 10-h TWA; BEI, Pb compounds covered differ ACGIH TLV 0.05 mg/m 3, 8-h TWA

25 OSHA Pb Standard Actions

26 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

27 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

28 Chelation Not a decision to be taken lightly Requires close monitoring Inefficient process, typically reducing body burden only % Chelating agents may not significantly reduce tissue levels, esp. in CNS

29 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 mg/m 2 /d, iv –BAL mg/m 2 /d, mg/m 2 q4h  d, im –D - penicillamine (second-line drug)

30 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

31 Paediatric Chelation Therapy - Encephalopathy - 1 A medical emergency! BAL and CaNa 2 EDTA at 1500 mg/m 2 /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

32 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 ml/m 2 /d

33 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

34 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 d, to equilibrate

35 Paediatric Chelation Therapy BPb  g/dl If asymptomatic, treatment with succimer is preferred Succimer initiated with 30 mg/kg/d or 1050 mg/m 2 /d in three divided doses  5 d Succimer maintained at 20 mg/kg/d or 70 mg/m 2 /d in two divided doses  14 d Consider hospitalization if home abatement is not possible

36 Paediatric Chelation Therapy BPb  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

37 Paediatric Chelation Therapy BPb  g/dl Excessive exposure to Pb Currently not considered as indication for chelation Home Pb abatement and control of exposure is recommended

38 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

39 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

40 Adult Chelation Therapy - 2

41 Adult Chelation Therapy - 3 Encephalopathy: –BAL 450 mg/m 2 /d, 75 mg im q4h  5 d –EDTA 1500 mg/m 2 /d, iv  5 d –Start EDTA 4 hours after stat BAL Symptomatic, BPb > 70 –BAL mg/m 2 /d, mg im q4h  d –EDTA , otherwise as above

42 Adult Chelation Therapy - 4 Mild Symptoms treated with Succimer –Succimer mg/m 2 /d –Give 350 mg/m 2 (or 10 mg/kg)  5 d, then bid  14 d The availability of a safe chelating agent does not mean that prophylaxis is acceptable.

43 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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