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Lead, organic

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    1. NAME
     1.1 Substance
       Tetraethyl lead and Tetramethyl lead
     1.2 Group
       Lead alkyl compounds
     1.3 Synonyms
       lead tetraethyl
       lead tetramethyl
       TEL
       Tetraethylplumbane
       Tetramethylplumbane
       TML
     1.4 Identification numbers
       1.4.1 CAS number
             Tetraethyl lead : 78-00-2
       1.4.2 Other numbers
             Tetraethyl lead : NIOSH TP4550000
             Tetramethyl lead: NIOSH TP4725000
     1.5 Brand names, Trade names
       No data available
     1.6 Manufacturers, Importers
       No data available
    2. SUMMARY
     2.1 Main risks and target organs
       The central nervous system is particularly sensitive to 
       organic  compounds of lead.
       
       Poisoning due to organic compounds is a consequence of 
       industrial exposure.  Indirect exposure arises from 
       environmental contamination. Humans can be  exposed to lead 
       from breathing air, drinking water, and eating foods that  
       contain lead. A large number of occupations may be associated 
       with risk of  exposure to organic lead compounds, particularly 
       the cleaning of gasoline  tanks.
       
       Some reports have associated the risks of repeated inhalation 
       of leaded  gasoline as a drug of abuse (Edmindster, 1985). 
       Other possible source of  exposure is skin absorption from 
       gasoline burns.
       
       Subclinical effects have been identified with sensitive 
       methods used to detect cognitive and behavioral changes, 
       especially in children. There are subtle neuropsychiatric, 
       reproductive and renal effects of chronic low-dose lead 
       exposure, children being particularly susceptible. The effects 
       of low-dose of lead in adults remains to be cleared. 
       Hypertension, gout, nephropathies, and neurotoxic 
       manifestations may be related to lead exposure. 
       
       Organic compounds of lead have toxic properties which require 
       precautions against both their percutaneous and respiratory 
       absorption.
     2.2 Summary of clinical effects
       Poisoning by organic lead compounds presents mainly acute 
       effects on  the central nervous system. The chronic form of 

       this intoxication has been  observed following prolonged and 
       deliberate inhalation of leaded gasoline  vapours ("gasoline 
       sniffing") (Hansen et al, 1978). Poisoning may result  from 
       the absorption of a sufficient quantity of lead, whether 
       briefly at a  high rate or for prolonged periods at a lower 
       rate. Ingestion is not a  significant occupational hazard. 
       Respiratory and percutaneous absorption are  the main routes 
       of exposure. 
       
       Mild manifestations are: insomnia and nervous excitation, 
       nausea, vomiting,  associated with tremor, hyperreflexia, 
       muscular contractions, bradycardia,  arterial hypertension, 
       and hypothermia. 
       
       Most severe cases present episodes of complete disorientation, 
       mania, ataxia, hallucinations, exaggerated muscular activity, 
       and violent  convulsive seizures, which may terminate in coma 
       and death. 
       
       In severe cases, muscle, hepatic and renal damage may occur. 
       The clinical picture may persist for days and weeks. A rapid 
       onset of symptoms after exposure indicates a poor prognosis. 
       When the onset of symptoms is delayed  for many days recovery 
       is usually complete, but some neurological sequelae have been 
       reported.  Prolonged compulsive sniffing of gasoline has 
       resulted in encephalopathy and death.
     2.3 Diagnosis
       Is based on history of exposure to lead alkyl compounds 
       (occupational in most cases) and occurrence of nausea, 
       vomiting and CNS  symptoms: irritability, anxiety, 
       restlessness and more severe disorders  (tremor, confusion and 
       seizures).
            
       The laboratory studies to confirm the diagnosis are:
       
       In blood: complete blood-count, whole blood-count lead level 
       free  erythrocyte protoporphyrin red cell delta aminolevulinic 
       acid dehydratase  activity.
       
       In urine: 24-hour urine lead levels delta aminolevulinic acid 
       and  coproporphyrin
       
       Sample collection: a 24-hour specimen of urine is preferable 
       to a single specimen; the blood sample should be taken and 
       stored in specially cleaned   glassware.
     2.4 First aid measures and management principles
       -    Remove the patient from further exposure, send for 
       medical  assistance.
       -    Remove and discard contaminated clothing.
       -    Exposed eyes should be irrigated with copious amounts of 
       water.
       -    Wash skin with soap and copious amount of water.
       -    Control convulsions with appropriate drug regimen.
       -    In case of ingestion, unless vomiting is extensive, 
       perform  gastric lavage and administer a cathartic.  If the 

       patient is obtunded, convulsing, comatose, insert an oro- or a 
       naso-gastric tube and lavage after endotracheal intubation.
       -    Open and maintain at least one intravenous route.
       -    Administer intravenous fluids.
       -    Chelation is indicated only if blood levels are high. 
       Penicillamine and calcium disodium edetate have been used 
       and the increased urinary excretion of lead does not 
       correspond with clinical improvement.
       -    In case of encephalopathy, BAL and edetate calcium 
       disodium are indicated.
       -    In cases of inhalation of vapours and fumes, symptomatic 
       and supportive treatment are indicated. Ensure patient's 
       airway and ventilation. Supportive measures include 
       oxygen and artificial respiration.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Organic lead compounds include a number of common high-
       pressure  lubricants (lead soaps) and the gasoline anti-knock 
       agents tetraethyl lead  (TEL) and tetramethyl lead (TML). TEL 
       and TML are lipid-soluble liquids of  high volatility and are 
       prepared by chemical synthesis.
     3.2 Chemical structure
       Chemical name: Tetraethyl lead and Tetramethyl lead
       Molecular weight: TEL: 323.45 TML: 267.3
       Structural formula: Pb(C2H5)4     Pb (CH3)4
     3.3 Physical properties
       Boiling point: TEL =  200 C (decomposes)  TML = 
       110 C
       Melting point: TEL = -136.8 C            TML = -
       27.5 C
       Flash point:   TEL =   93.3 C           TML =  
       37.7 C
       
       Autoignition temperature:
       Relevant density (20 C) : TEL = 1.653    TML =   
       1.99
       Relative vapour density:                 TML =   
       9.2
       Vapour pressure:    TEL = 1 mmHg at 38.4 C    
                           TML = 22 mmHG (25 C)
       
       Solubility:    TEL =     soluble in benzene, 
       ethyl alcohol petrol  ether, gasoline and ethyl 
       ether; insoluble in water.
       
                      TML =     slightly soluble in 
       benzene, ethyl alcohol and ethyl ether; 
       insoluble in water.
       
       Explosive limits: no data available.
       Viscosity: no data available.
       Relative molecular mass: no data available.
       pH: no data available.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance

       3.4.2 Shelf-life of the locally available formulation
       3.4.3 Storage conditions
       3.4.4 Bioavailability
       3.4.5 Specific properties and composition
    4. USES
     4.1 Indications
       Organic compounds of lead can be used as solvents for 
       fatty materials and rubber. TEL and TML are liquid 
       compounds of lead, which are  miscible in all 
       proportions with gasoline (and other organic solvents) 
       and  are available as "anti-knock" ingredients in 
       gasoline fuel for the internal  combustion engine (WHO, 
       1977; Budavari, 1989; Sax, 1989).
       
       Alkyl lead compounds, the organic forms of lead, have 
       been in use as  anti-knock additives in gasoline for 
       almost 60 years. Use of these compounds  (almost 
       exclusively tetraethyl lead and tetramethyl lead) 
       increased steadily up to 1973. A decline in consumption 
       was started as more cars fitted with catalysts requiring 
       lead-free gasoline have come into use (WHO, 1977).
     4.2 Therapeutic dosage
       4.2.1 Adults
       4.2.2 Children
     4.3 Contraindications
       Workers may be exposed to organic lead compounds in a wide 
       variety of occupations, including alkyl lead manufacture, 
       gasoline processing, transportation, tank cleaning, filling 
       station operators and garage workers. Both TEL and TML are 
       absorbed through the skin and the respiratory tract. Ingestion 
       is not a significant occupational hazard (WHO, 1977; ILO, 
       1983; Gosselin, 1984; Sax, 1989).
    5. ROUTES OF ENTRY
     5.1 Oral
       Accidental or deliberate ingestion of alkyl lead compounds may 
       occur, but is not frequent.
     5.2 Inhalation
       Inhalation of vapours of alkyl lead compounds should be 
       considered as a major route of entry (ILO, 1983).  It may 
       occur in the  occupational setting or as a result of "sniffing 
       gasoline".
     5.3 Dermal
       Dermal absorption is an efficient route of entry for organic 
       compounds of lead (ILO, 1983; Sax, 1989).
     5.4 Eye
       Not relevant.
     5.5 Parenteral
       Not relevant.
     5.6 Other
       Not relevant.
    6. KINETICS
     6.1 Absorption by route of exposure
       Accidental or deliberate ingestion of alkyl lead compounds is 
       not  frequent. Inhalation of mists and vapours of alkyl lead 
       compounds should be  considered as the major route of entry. 

       Dermal absorption is an efficient  process: organic compounds 
       of lead are capable of penetrating the intact  skin rapidly 
       (Gosselin, 1984; Sax, 1989).
     6.2 Distribution by route of exposure
       Lead is distributed in man according to a three-compartment 
       pharmacokinetic model. Blood and soft tissues represent the 
       active pool and bones the storage pool. Lead is distributed to 
       kidney tubular epithelium and to liver. There is 
       redistribution by  deposition in bone, teeth and hair. The 
       long bones contain more lead and about 95% of the body load is 
       stored in the skeleton. The largest part of circulating lead 
       is bound to haemoglobin in erythrocytes, in which the 
       concentration of lead is about 16 times greater than in plasma 
       (WHO, 1977).
     6.3 Biological half-life by route of exposure
       The biological half-life of lead is extremely difficult to 
       estimate (WHO, 1977). The half-life of lead in erythrocytes is 
       35 days; in soft tissues (kidney, liver and nervous tissue) 
       the half-life is 40 days; the half-life in bone is 20 to 30 
       years (Ellenhorn, 1988; Garettson, 1990).
     6.4 Metabolism
       Alkyl lead compounds are transformed in trialkyl derivatives 
       by  dealkylation in the liver. TEL and TML are not the primary 
       toxins but they  are converted to triethyl lead and inorganic 
       lead (WHO, 1977; Garettson,  1990).
     6.5 Elimination by route of exposure
       The rate of excretion of lead is low. Renal clearance of 
       unchanged lead occurs essentially by glomerular filtration but 
       at high  levels some active tubular transport occurs. Urinary 
       excretion accounts for 76% of daily losses, while
       gastrointestinal secretions for 16% and hair, nails, sweat and 
       other routes for 8% (WHO, 1977; Ellenhorn, 1988).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
       7.1.2 Pharmacodynamics
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     7.2.1.1   Adults (volunteer and clinical case  
                     data) The precise doses of the alkyl lead 
                     compounds  responsibe for the effects are rarely,
                      if ever, known.  Patients with organic lead 
                     poisoning due to gasoline  sniffing have been 
                     shown to have blood lead levels higher  than 100 
                     g/dl (Keenlyside, 1984). A lead urine 
                     concentration of about 350 g/dl is seen in 
                     severe TEL poisoning (ILO, 1983). The lowest 
                     reported  lethal dose in man (LDL0) is 1470 
                     g/kg (Sax, 1989).
             7.2.1.2 Children
                     No data available.

       7.2.2 Relevant animal data
             Tetraethyl lead: 
             
             Lowest toxic dose oral mouse: 11 mg/kg
             LD50 oral rat: 1200 g/kg
             LC50 inhalation rat: 850 mg/m3
             LD50 intraperitoneal rat: 850 mg/kg
             LD50 intravenous rat: 14400 g/kg
             Lowest lethal dose skin dog: 547 mg/kg
             
             Tetramethyl lead: 
             
             Lowest toxic dose oral rat: 112 mg/kg
             LD50 oral rat: 105 mg/kg
             LD50 intraperitoneal rat: 90 mg/kg
             LD50 intravenous rat: 88 mg/kg
             LC50 inhalation rat: 8870 mg/m3
             Lowest lethal dose oral rabbit: 24 mg/kg
             Lowest lethal dose skin rabbit: 3391 mg/kg
             Lowest lethal dose intravenous rabbit: 90 mg/kg
             
             There is no qualitative difference between the toxic 
             effects of TEL and TML. However, the inhalation LC50 for 
              tetramethyl lead is about 10 times greater than that 
             for tetraethyl  lead (WHO, 1977; Sax, 1989).
       7.2.3 Relevant in vitro data
             Biochemical studies of the respiration of brain slices 
             incubated with inorganic lead compared with triethyl 
             lead (the  active metabolite of TEL) have demonstrated a 
             fundamental  difference in the action of alkyl lead 
             compounds on the brain (WHO, 1977).
     7.3 Carcinogenicity
       A study of workers manufacturing TEL revealed an excess of 
       respiratory cancers (15 observed, 11.2 expected) and brain 
       cancer (3  observed, 1.6 expected) but the evidence for 
       carcinogenicity in humans is  inadequate (IARC, 1987). Alkyl 
       lead compounds have not been tested  adequately: the evidence 
       for carcinogenicity of organolead compounds in  animals is 
       inadequate (IARC, 1987).
     7.4 Teratogenicity
       No adequate animal studies exist of the possible teratogenic 
       effects of lead (WHO, 1977).
     7.5 Mutagenicity
       TEL and TML did not induce mutation in bacteria (IARC, 1987).
     7.6 Interactions
       Interactions between lead and other environmental pollutants 
       occur. Lead forms lead sulfate in both water and air in the 
       presence of the sulfate ion (ATSDR, 1990).
     7.7 Main adverse effects
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
                     Not available

             8.1.1.2 Biomedical analyses
                     Blood may be collected at any time. It is  
                     essential to avoid contamination: use only lead 
                     free  needles, containers and stoppers; 
                     anticoagulant must be  lead free. Urine can be 
                     collected at any time. A 24-hour  specimen of 
                     urine is preferable to a single specimen.
                     Avoid lead contamination from containers (ACGIH, 
                     1986).
             8.1.1.3 Arterial blood gas analysis
                     Not relevant.
             8.1.1.4 Haematological analyses
                     Avoid lead contamination of samples
             8.1.1.5 Other (unspecified) analyses
                     No data available
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
                     Blood and urine samples should be stored in  
                     specially cleaned glassware, and refrigerated as 
                     indicated  for the specific method.     
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
                     Transport of samples should be done in  
                     refrigerated containers.
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
                     Analysis of lead in blood is done by the wet  
                     chemical dithizone method.
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
                     Blood concentrations of lead are determined by  
                     atomic absorption spectroscopy. Lead in urine is 
                     analyzed  after chelation and extraction by 
                     means of atomic  absorption.
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
             The concentration of lead in blood varies, in general, 
             it is  slightly elevated but in some cases of poisoning 
             it is nearly  normal. In cases of repeated gasoline 
             sniffing the content of lead  in blood is high. No close 

             correlation exists between blood lead  levels and the 
             severity of intoxication. The urinary excretion of  lead 
             is increased markedly (Hansen, 1978; ILO, 1983; Gilman, 
             1990;  Garrettson, 1990).
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
                     Determination of whole-blood lead level.
                     Determination of red cell delta-aminolevulinic 
                     acid  dehydratase activity. Determination of 
                     free erythrocyte  protoporphyrin.
             8.3.1.2 Urine
                     24-hour urine lead level. Urinary delta-
                     aminolevulinic acid. Urinary coprophyrin.
             8.3.1.3 Other fluids
                     Lead in urine after calcium disodium EDTA
                     mobilization test.
       8.3.2 Arterial blood gas analyses
             Not relevant.
       8.3.3 Haematological analyses
             Full blood count (red cells, white cell and platelet
             count). Determination of haemoglobin content and
             reticulocyte count.
       8.3.4 Interpretation of biomedical investigations
             In case of recent exposure or poisoning: whole-blood 
             levels  rarely exceeds 500 g/L. Red cell delta-
             aminolevulinic dehydratase  activity is inhibited 
             (normal 30-60 IU). The concentration of  protoporphyrin 
             in erythrocytes may be increased (normal: 600 g/L),  
             but the results are inconsistent. In severe organic lead 
             poisoning  the concentration of lead in urine is rarely 
             less than 3500 g/L.  The urinary delta-aminolevulinic 
             acid (ALA-U) (normal: 4.5 mg/L)  and the urinary 
             coproporphyrin (CP-U) (normal: 150 g/L) may be  
             increased. The urinary lead excretion is increased by 
             calcium  disodium EDTA or D-penicillamine). Anaemia and 
             basophilic stippling are uncommon. These findings occur 
             in chronic exposure, as in gasoline sniffing cases, but 
             the chemical and morphological abnormalities in  blood 
             are absent in acute exposure (Beattie, 1972; ILO, 1983;  
             Gilman, 1990; Garrettson, 1990).
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
       Serum creatinine, urinalysis, 24-hour creatinine and protein 
       (evaluation of renal function). Serum creatine phosphokinase 
       (CPK), lactic dehydrogenase (LDH) and serum glutamic 
       oxaloacetic  transaminase (SGOT): muscle and hepatic damage. 
       Peripheral motor nerve  conduction velocity (damage to 
       peripheral nerves) only in cases of chronic  exposure. 
       Intelligence and personality tests: evaluation of 
       psychological  and neurological impairment.  
       Electroencephalogram: in cases of lead encephalopathy (ILO, 
       1983;  Garrettson, 1990).

     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
       Determination of lead in urine is the most commonly used 
       indicator of lead organic exposure (ILO, 1983; Garrettson, 
       1990).
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Acute poisoning from ingestion is rare. In one case of 
             massive ingestion of pure tetraethyl lead the initial 
             signs and  symptoms were related to increased 
             intracranial pressure. The  patient died 36 hours later 
             with pulmonary oedema (Gosselin, 1984).
       9.1.2 Inhalation
             Inhalation is the most important route of absorption in 
             the  working environment. Inhalation induces sneezing, 
             irritation of the  upper respiratory tract and mild to 
             severe systemic responses:  insomnia, lassitude, nervous 
             excitation, anxiety states, associated  with tremors, 
             hyperreflexia, spasmodic muscular contractions,  
             bradycardia, vascular hypotension, and hypothermia. The 
             most severe  responses include complete disorientation 
             with hallucinations, and facial contortions. Such 
             episodes may progress  to maniacal and violent 
             convulsive seizures which may terminate in  coma and 
             death (ILO, 1983; Gosselin, 1984; Garrettson, 1990).
       9.1.3 Skin exposure
             Skin is a very important route of exposure, as alkyl 
             lead  compounds are easily absorbed through the intact 
             structures.  In contact with the skin they induce 
             itching, burning  and transient redness (ILO, 1983).  In 
             one case of massive skin  exposure, a patient remained 
             asymptomatic even though the urinary  lead excretion was 
             very high (Gosselin, 1984).
       9.1.4 Eye contact
             In contact with the ocular membranes organolead 
             compounds induce itching, burning, and transient redness 
             (ILO, 1983).
       9.1.5 Parenteral exposure
             No available data.
       9.1.6 Other
             Not relevant.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Chronic poisoning by ingestion is not described.
       9.2.2 Inhalation
             No chronic form has been observed in a population 
             exposed  occupationally (ILO, 1983). Chronic 
             recreational sniffing of leaded  gasoline as a drug of 
             abuse has led to neurological damage: tremors,  
             exaggerated tendon reflexes, severe encephalopathy, and 
             death  (Hansen et al, 1978; Gosselin, 1984; Garrettson, 
             1990).

       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             Not relevant.
       9.2.6 Other
             Not relevant.
     9.3 Course, prognosis, cause of death
       Illness resulting from acute episodes may persist for days or 
       weeks, with intervals of quietude readily triggered into over-
       activity by any type of disturbance. Arterial hypotension and 
       loss of body weight are common. 
       
       When the symptoms occur within in a few hours the exposure, an 
       early fatal outcome is possible. When the interval is longer, 
       the prognosis  is better. Partial or recurrent disorientation 
       and depressed circulatory  function may persist for weeks. 
       Residual damage to the nervous system has not been described. 
       
       Cause of death is direct damage to the brain (encephalopathy) 
       involving capillary dysfunction, cerebral oedema, and 
       interference with cerebral metabolism. In one case pulmonary 
       oedema was described as terminal event. 
       
       Reported long term effects of chronic gasoline inhalation are 
       body weight loss, muscular weakness, cramps, and neurasthenia. 
        Recovery is complete and no evidence of neurological sequelae 
       have been reported (Hansen et al, 1978; ILO, 1983; Keenlyside, 
       1984; Gosselin, 1984).
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute  : Arterial hypotension. Bradycardia.
             Chronic: Arterial hypotension.
       9.4.2 Respiratory
             Acute  : pulmonary oedema.
             Chronic: not relevant.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Acute: Insomnia, lassitude, muscle weakness,  
                     nervous excitation, anxiety, tremors, 
                     hyperreflexia.   Disorientation, hallucinations, 
                     facial contortions,  episodes of mania, 
                     convulsions. Encephalopathy with severe headache,
                      convulsions, delirium and coma may occur.
                     
                     Chronic: Disturbed sleep, headache, anxiety, 
                     irritability, intermittent stupor, generalized 
                     myoclonus, ataxia. Suicidal tendencies, 
                     psychosis,  mania.  Lead encephalopathy includes 
                     vertigo, ataxia, headache, insomnia, 
                     restlessness and irritability; delirium, tonic-
                     clonic convulsions, coma; increased
                     intracranial pressure.

             9.4.3.2 Peripheral nervous system
                     Acute and chronic: paraesthesiae, pain, muscle
                     weakness.
             9.4.3.3 Autonomic nervous system
                     Acute and chronic: not relevant.
             9.4.3.4 Skeletal and smooth muscle
                     Acute and chronic: weakness and tremor;  muscle  
                     damage is confirmed by elevated serum creatine  
                     phosphokinase (CPK).
       9.4.4 Gastrointestinal
             Nausea, vomiting, anorexia.
       9.4.5 Hepatic
             Transient elevation of transaminases.
       9.4.6 Urinary
             9.4.6.1 Renal
                     Proteinuria.
             9.4.6.2 Other
                     Not relevant.
       9.4.7 Endocrine and reproductive systems
             Not relevant.
       9.4.8 Dermatological
             Itching, burning and transient redness of skin.
       9.4.9 Eye, ear, nose, throat: local effects
             Acute: conjunctivitis. Paroxysmal sneezing.
             Chronic: not relevant.
       9.4.10 Haematological
              Acute: not relevant.
              Chronic: erythrocytes with basophilic stippling are
              described in some cases.  Anemia is uncommon and 
              substrates of the  haem synthesis, such as erythrocyte 
              protoporphyrin may be normal.
       9.4.11 Immunological
              Not described.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       Not relevant.
              9.4.12.2 Fluid and electrolyte disturbances
                       Not relevant.
              9.4.12.3 Others
                       Not relevant.
       9.4.13 Allergic reactions
              Not relevant.
       9.4.14 Other clinical effects
              Pallor of the face, loss of body weight in chronic
              exposure.
       9.4.15 Special risks
              There are no reliable data on the risk of spontaneous 
              abortions and still births. Lead crosses the placenta 
              and the fetal  blood concentration at birth 
              approximates that of the mother. Lead  is also excreted 
              in human milk in concentrations as high as 12  g/L. 
              Animal studies demonstrate that low-level exposure to 
              lead  during prenatal or postnatal life results in 
              retarded growth.
              
              (WHO, 1977; Hansen et al, 1978; ILO, 1983; Gosselin, 
              1984;  Keenlyside, 1984; Ellenhorn, 1988; Garrettson, 
              1990).
     9.5 Other
       Not available
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Treatment is symptomatic in the acute stages of poisoning 
         and chelation therapy is indicated only if inorganic lead 
         levels are high. In case of ingestion of organic lead 
         compounds or exposure to vapours, it is mandatory to 
         decontaminate the patient and remove him from further 
         exposure.
         
         In case of chronic poisoning, prevent further exposure and 
         treat  symptomatically. Individuals with blood lead levels 
          > 600 g/L must be  removed from the work place.
         
         General supportive treatment is based on: maintenance of 
         clear airway and respiration, control of convulsions, 
         reduction of cerebral oedema, and eventually chelation 
         therapy, if indicated.
                   
         The treatment of organic lead poisoning is mainly 
         symptomatic: in acute  phase, the drugs of choice are 
         diazepam to control convulsive seizures, and mannitol and 
         steroids to reduce cerebral oedema. In  cases of chronic 
         poisoning, chelation therapy with calcium disodium edetate  
         (EDTA), penicillamine, dimercaprol (BAL) or succimer will 
         promote the  excretion of the inorganic lead produced from 
         the metabolism of organic  lead. Chelation therapy is 
         indicated in all symptomatic patients and  patients whose 
         blood lead levels exceed 700 g/L. 
         
         In case of chronic poisoning, prevent further exposure and 
         treat  symptomatically.  In adults with blood levels up to 
         1000 g/L, combined  treatment with intramuscular BAL and 
         intravenous EDTA for 5 days is  indicated. Interrupt 
         treatment for 2 days and start EDTA if blood lead  levels 
         remain high (>1000 g/L). Then penicillamine should be 
         given for 3 -  6 months (20 mg/kg/day oral route).  Note 
         that some problems may arise in  the use of chelators (see 
         10.6)
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Blood and urine should be collected at any time. It 
                is essential to avoid contamination: needles, 
                containers and  anticoagulants must be lead-free. A 
                24-hour urine specimen is  preferable.
         10.2.2 Biomedical analysis
                Lead in blood and urine. Red cell delta-
                aminolevulinic acid  dehydratase activity. Free 
                erythrocyte protoporphyrin. Urinary  delta-
                aminolevulinic acid. Urinary coproporphyrin. Full 

                blood count  (red cells, white cells, platelets; 
                haemoglobin and reticulocyte  count). 
                Electroencephalogram (ILO, 1983; Gosselin, 1984; 
                Ellenhorn,  1988; Garrettson, 1990).
         10.2.3 Toxicological analysis
                Not available
         10.2.4 Other investigations
                Not available
      10.3 Life supportive procedures and symptomatic/specific
         treatment
         In case of severe poisoning, make a proper assessment of 
         breathing, circulation and neurological status. Maintain a 
         clear airway and  aspirate secretions from airway.  Start 
         artificial respiration at the first  sign of respiratory 
         failure. Administer oxygen if cyanosis is present.  Correct 
         dehydration.
         
         Analgesics may be necessary to control abdominal pain.
         
         If the patient is obtunded, convulsing or comatose, insert 
         an oro- or nasogastric tube and lavage after endotracheal 
         intubation. 
         
         If the patient is convulsing, administer diazepam 0.1 mg/kg 
         IV. Coma or convulsions may indicate increased intracranial 
         pressure; mannitol, steroids  and hypothermia, and referral 
         to a neurosurgical unit, may be necessary.
         
         Administer intravenous fluids. Monitor vital signs. A 
         successful outcome has  been achieved with sustained 
         supportive therapy in association with  persistent, vigorous 
         sedation (ILO, 1983; Garrettson, 1990).
      10.4 Decontamination
         In case of ingestion, provided convulsions are not imminent, 
         induce emesis or perform gastric lavage. In general, emesis 
         is not induced if the product solvent is a petroleum 
         distillate. 
         
         Gastric lavage may be performed if emesis fails, but bearing 
         in mind the  risk of imminent convulsions. 
         
         In cases of inhalation, the management is symptomatic and 
         supportive: remove from exposure and maintain the airway and 
         ventilation. Supportive measures include oxygen and 
         artificial respiration. 
         
         Skin - remove all contaminated clothing and wash the skin 
         and hair.
          
         Eyes - extensive irrigation with water or saline should be 
         performed.
      10.5 Elimination
         Chelation therapy will promote the excretion of inorganic 
         lead produced by the metabolism of organic lead through 

         urine. A good urinary  output is mandatory.  Haemodialysis 
         is indicated in case of impaired renal  function.
      10.6 Antidote treatment
         10.6.1 Adults
                There are no antidotes for tetraethyl lead, 
                tetramethyl lead or triethyl lead (Garrettson, 1990). 
                Lead chelators may be  used only to promote excretion 
                of inorganic lead produced by the metabolism of 
                organic lead compounds.
                
                Calcium disodium edetate (CaNa2EDTA): 1 to 2 g daily  
                (non-convulsing or comatose) patients 2 to 4 g daily 
                (convulsing or  comatose patients), in two divided 
                doses intramuscularly or IV in  saline infusion, 
                slowly, for 5 days.
                
                Dimercaprol (BAL): 2.5 to 4 mg/kg/dose 
                intramuscularly
                every 4 hours, for 48 hours; then, every 6 hours, for 
                48 hours; and  every 6 to 12 hours for more 7 days.
                
                Succimer could also be used.  
                
                D-penicillamine: 250 mg 4 times daily for 5 days. 
                Doses in  long-term treatment should not exceed 40 
                mg/kg/day.
                
                Problems with chelators:
                
                -    oral chelators may promote lead absorption from 
                the gastrointestinal tract.
                -    the chelator-lead complex is nephrotoxic; urine 
                output  must be monitored.
                -    chronic chelation therapy with EDTA or 
                penicillamine promotes loss of essential metals. 
                -     intra/muscular injection of EDTA is painful; 
                multiple sites should be used.
                -    BAL may cause local pain, nausea, vomiting; 
                hypertension has been reported after BAL therapy.  
                Antihistamines may be administered.
                -    D-penicillamine may cause alteration of taste, 
                neutropenia, allergic rashes, aplastic anaemia, 
                nephropathy  and hepatitis (Gosselin, 1984; Noji &  
                Kelen, 1989; Gilman, 1990; Garrettson, 1990).
         10.6.2 Children
                There are no antidotes for tetraethyl lead, 
                tetramethyl  lead or triethyl lead (Garrettson, 
                1990). Lead chelators may be  used only to promote 
                excretion of inorganic lead produced by the  
                metabolism of organic lead compounds.
                
                Calcium disodium edetate (CaNa2EDTA): 50 mg/kg/day in 
                two divided  doses (non-convulsing child) or 75 
                mg/kg/day in two divided doses  (convulsing child) 

                intramuscularly of IV in saline infusion, slowly,  
                for 5 days.
                
                Dimercaprol (BAL): 2.5 to 4 mg/kg/dose 
                intramuscularly every 4 hours, for 48 hours; then, 
                every 6 hours, for 48 hours; and  every 6 to 12 hours 
                for more than 7 days.
                
                Succimer could also be used.
                
                D-penicillamine: 20 to 40 mg/kg/day (maximum 1 g/day) 
                may be given  for 3 to 6 months.
      10.7 Management discussion
         Chelation therapy is effective in removing only inorganic 
         lead.  The  role of chelating agents in acute organic lead 
         poisoning is  controversial.The risks of chelation include 
         depletion of essential metals  due to rapid mobilization and,
          after oral administration, impaired  absorption from the 
         gastrointestinal tract.  Good therapeutic results with  
         chelators have been reported in cases of chronic exposure 
         (gasoline  sniffing). The efficacy of chelators in organic 
         lead encephalopathy has  recently been established (Hansen 
         et al, 1978; Gosselin, 1984; Gilman, 1990;  Garrettson, 
         1990).
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Four men cleaned a tank which had held leaded aviation 
         gasoline.   Exposure was followed shortly by illness in 
         which mental symptoms were  prominent. Blood lead levels 
         were raised to 645 to 925 g/L. Lead was found  
         predominantly in the lipid blood fraction. Urinary 
         coproporphyrin was  slightly raised in one case.  
         Erythrocyte protoporphyrin was slightly raised  in the three 
         more severe cases.  Blood delta aminolevulinic acid 
         dehydratase  activity was markedly reduced.  Urinary lead 
         excretion was increased by  D-penicillamine administration. 
         All men recovered in a few weeks (Beattie et  al, 1972).
         
         Several cases of organolead compound poisoning associated 
         with gasoline sniffing presented with lead blood levels 
         higher than 1000 g/L. Signs of organic lead poisoning, 
         mostly neurological symptoms,  have been detected in 
         children and adolescents who had been sniffing  gasoline for 
         periods ranging from 6 months to 5 years. Blood delta  
         aminolevulinic acid dehydratase activity was reduced. 
         Treatment with  chelating agents resulted in symptomatic 
         improvement (Keenlyside, 1984).
         
         Over 3 years, 62 persons burned by gasoline flame were 
         admitted to a burns  unit. Increased mortality associated 
         with gasoline burns led the authors to  question the 
         influence of lead in this problem. Urinary lead and  
         coproporphyrins were measured in 18 persons burned by 
         gasoline. The levels  were elevated above the normal or safe 
         limits in 14 (Wood et al, 1968).

      11.2 Internally extracted data on cases
         Not available
      11.3 Internal cases
    12. Additional information
      12.1 Availability of antidotes
         To be completed locally.
      12.2 Specific preventive measures
         Occupational exposure:
         
         -    use protective clothes (including shoes).
         -    the protective clothes and shoes must not leave the  
         plant.
         -    avoid skin contact with lead vapours.
         -    avoid contact of lead with oxidizers (such as 
         perchlorates, peroxides, permanganates, chlorates and 
         nitrates) and chemically active metals (such as potassium, 
         sodium, magnesium and  zinc) since violent reactions occur.
         -    insist on personal hygiene: do not smoke, do not eat, 
         do
              not drink in contaminated environment.
         -    eating facilities must be separated from working area.
         -    face and hand coverings should be made of impermeable
              material.
         -    medical surveillance programme for lead: pre-employment 
         and  pre-placement examination, periodical examination, 
         clinical tests, record-keeping and health education.
         -    immediate cleaning up of spills. Floors can be wet with 
         a
              fine spray to avoid stirring up dusts.
         -    storage receptacles should be kept covered to reduce 
         fumes and  dust.
         -    measurement of lead air levels (ILO, 1983; Glenn, 
         1987).
         
         Non-occupational exposure:
         
         -    avoid gasoline sniffing.
         -    control of lead emissions in air (ATSDR, 1990).
      12.3 Other
         In the 1980s it was considered that about 90 percent of 
         airborne lead  was derived from the exhaust gases of motor 
         vehicles. In many countries a  decrease in the use of lead 
         in petrol has been associated with reductions in  the air 
         lead concentrations of urban areas (UNEP, 1984).
         
         Concern over improving the quality of the environmental by 
         lowering the lead content in gasoline and the control of the 
         occupational exposure decreased average blood levels of the 
         population in the USA by nearly 50% (Goyer, 1990).
    13. REFERENCES
    ACGIH - American Conference of Governmental Industrial Hygienists 
    (1986) Documentation of the threshold limit values and biological 
    exposures indices. 5th. ed. Cincinnati, p 343-345, BEI-19 to BEI-
    23.
    
    ACGIH - American Conference of Governmental Industrial Hygienists 
    1990) TLVs  Threshold Limit Values and Biological Exposures for 
    1990-1991, Cincinnati.
    
    ATSDR - Agency for Toxic Substances and Disease Registry (1990) 
    Toxicological profile for lead. US Public Health Service in 
    collaboration with US Environmental Protection Agency (EPA).
    
    Beattie AD, Moore MR & Goldberg A (1972) Tetraethyl lead 
    poisoning. Lancet 2 (7766): 12-15.
    
    Budavari S, ed. (1989) The Merck Index: an encyclopedia of 
    chemicals, drugs and biologicals, 11th ed. Rahway, New Jersey, 
    Merck and Co., Inc.
    
    Edminster SC, Bayer MJ (1985) Recreational gasoline sniffing. 
    Acute gasoline intoxication and latent organolead poisoning. Case 
    reports and literature  review. J. Emerg Med 3: 365.
    
    Ellenhorn MJ & Barceloux DG (1988) Medical Toxicology. Diagnosis 
    and Treatment of Human Poisoning. New York, Elsevier.
    
    FAO-WHO Expert Committee on Food Additives (1987) Tec Rep Ser WHO 
    No. 751.
    
    Garrettson LK (1990) Lead. IN. Haddad LM & Winchester JF ed. 
    Clinical management of poisoning and drug overdose. Philadelphia, 
    W. Saunders Co. p. 1017-1023.
    
    Gilman AG, Rall TW, Nies AS & Taylor P, eds. (1990) Goodman and 
    Gilman's The Pharmacological Basis of Therapeutics. 8th ed New 
    York, Pergamon Press.
    
    Glenn RA (1986) Workplace lead poisoning and Dr Alice Hamilton: a 
    struggle against indifference. OH&S Canada, 3(2): 20-21.
    
    Gosselin RE, Smith RP & Hodge HC (1984) Clinical Toxicology of 
    Commercial Products, 5th ed. Baltimore, Williams & Wilkins.
    
    Goyer RA (1990) Lead toxicity: from overt to subclinical to 
    subtle health effects. Environmental Health Perspectives, 86: 177-
    181.
    
    Hansen KS & Sharp FR (1978) Gasoline sniffing, lead poisoning, 
    and myoclonus. JAMA, 240 (13):1375-1376.
    
    IARC - International Agency for Research on Cancer (1987) IARC 
    Monographs on Carcinogenic Risks to Humans. Lyon, Suppl.7: 230-
    231.
    
    ILO - International Labour Office (1983) Encyclopedia of 
    Occupational Health and Safety. 3d ed. Geneva, vol 1, 1201-1205
    
    Keenlyside RA (1984) The gasoline-sniffing syndrome. In: 
    Grandjean P & Grandjean E, eds. Biological effects of organolead 
    compounds. Boca Raton, Florida, CRC Press, p. 219-225.
    
    Noji EK & Kelen GD (1989) Manual of Toxicologic Emergencies. 
    Chicago, Year Book Medical Publishers, Inc.
    
    NIOSH - National Institute for Occupational Safety and Health 
    (1978) Criteria for a recommended Standard Occupational Exposure 
    to Inorganic Lead - Revised Criteria. Cincinnati, DHEW (NIOSH) 
    Publication No. 78-158.
    
    Sax NI & Lewis RJ (1989) Dangerous Properties of Industrial 
    Materials, 7th ed. New York, Van Nostrand Reinhold.
    
    Spencer PS & Schaumburg HH (1980) Experimental and Clinical 
    Neurotoxicology. Baltimore, Williams & Wilkins, p. 885.
    
    UNEP - United Nations Environment Programme (1984) List of 
    Environmentally Dangerous Chemical Substances and Processes of 
    Global Significance. UNEP Report No 2, Geneva, IRPTC.
    
    Volans G, Henry J.A. (1984)  Br. Med. J., 289: 742-748.
    
    WHO - World Health Organization (1977) Lead. Environmental Health 
    Criteria No 3, Geneva, WHO.
    
    Wood MacD, Price WR, Childers D, Cook F (1968) Absorption and 
    excretion of lead in gasoline burns. Am J Surgey 116 (5): 622-
    626.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
    ADDRESS(ES)
    Author:        Alberto Furtado Rahde
                   Rua Riachuelo 677, app 201
                   90010 Porto Alegre
                   Brazil
    
                   Telephone:          55.512.275419   
                   Telefax:            55.512.246563
    
         Date:     December 1991
    
         Reviewer:
    
         Peer Review:   Newcastle-upon-Tyne, United Kingdom, February 1992
    
    
         Finalized by the IPCS: May 1994




    See Also:
       Toxicological Abbreviations