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    MONOGRAPH FOR UKPID




    LEAD




    Grainne Cullen
    Alison Dines
    Stoyko Kolev

    National Poisons Information Service (London Centre)
    Medical Toxicology Unit
    Guy's & St Thomas' Hospital Trust
    Avonley Road
    London
    SE14 5ER
    UK


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    1  SUBSTANCE/PRODUCT NAME

    1.1  Origin of substance

    Lead rarely occurs in the elemental state. It is present in the
    earth's crust at 15 g/ton or 0.002% (depth of crust: 16 km). It occurs
    as several ores galena (sulphide ore which is most common), cerussite
    (carbonate), mimetite and pyromorphite and anglesite (sulphate). It is
    recovered from the ore and purified. Lead also occurs in various
    uranium and thorium minerals arising directly from radioactive decay
    (Budavari, 1989, Beliles 1994).

    1.2  Name

    1.2.1  Brand/trade name

    1.2.2  Generic name

    1.2.3  Synonyms

     Metallic lead: lead flake, lead inorganic, lead metal, plumbum.
     Lead acetate: dibasic lead acetate, lead (II) acetate, plumbous
    acetate, salt of saturn, sugar of lead, lead acetate trihydrate.
     Lead chloride: lead dichloride, lead (II) chloride, plumbous
    chloride.
     Lead chromate: chrome yellow, Cologne yellow, King's yellow, Leipzig
    yellow, Paris yellow
     Lead dioxide: brown lead, lead peroxide, lead superoxide, lead (IV)
    oxide
     Lead fluoride: lead difluoride, plumbous fluoride
     Lead hydroxide: lead oxide hydrate, basic lead hydroxide
     Lead monoxide: lead oxide yellow, plumbous oxide, litharge,
    massicot, lead protoxide
     Lead tetraoxide: lead oxide, mineral orange, mineral lead, Paris
    red, orange lead, red lead, red lead oxide, trilead tetraoxide

     Tetraethyl lead: tetraethylplumbane, lead tetraethide
     Tetramethyl lead: tetramethylplumbane

    1.2.4  Common names/street names

    Not applicable.

    1.3  Chemical group/family

    Lead is a metal atomic weight 207.2, atomic number 82. It has four
    naturally occurring isotopes 204 (1.4%), 206 (25.2%), 207 (21.7%) and
    208 (51.7%). Valence 2 and 4.

    Lead acetate C4H6O4Pb molecular weight 325.28
    Lead azide Pb(N3)2 molecular weight 291.26
    Lead Borate Pb(BO2)2.H2O
    Lead Bromate Br2O6Pb

    Lead Bromide Pb Br2 molecular weight 367.04
    Lead Butyrate Pb(C4H7O2)2 molecular weight 381.40
    Lead chlorate Pb(ClO3)2
    Lead chloride PbCl2 molecular weight 278.12. Occurs naturally as the
    mineral cotunnite.
    Lead chromate (VI) PbCrO4 molecular weight 323.22
    Lead dioxide PbO2 molecular weight 239.21
    Lead fluoride PbF2 molecular weight 245.21
    Lead hydroxide 3PbO.H2O molecular weight 687.59
    Lead iodide PbI2 molecular weight 461.05
    Lead monoxide PbO molecular weight 223.21
    Lead nitrate Pb(NO3)2 molecular weight 331.23
    Lead phosphate Pb3(PO4)2 molecular weight 811.54
    Lead sulphate PbSO4 molecular weight 303.28. Occurs as the minerals
    anglesite and lanarkite.
    Lead sulphide PbS molecular weight 239.28. Occurs as the mineral
    galena.
    Lead tetraoxide Pb3O4 molecular weight 685.63

    Tetraethyl lead Pb(C2H5)4 molecular weight 323.45
    Tetramethyl lead PbC4H12 molecular weight 267.33

    1.4  Substance identifier and/or classification by use

    1.5  Reference numbers

    Lead           CAS       07439/92/1
                   RTECS     OF7525000
                   EINECS    2311004

    Lead acetate   CAS       301-04-2
                   RTECS     AI5250000
                   UN        1616

    Lead azide     CAS       13424-46-9
                   RTECS     OF8650000
                   EINECS    2365421
                   UN        0129

    Lead Bromide   CAS       10031-22-8
                   EINECS    2330844

    Lead chloride  CAS       7758-95-4
                   RTECS     OF9450006
                   EINECS    2318455

    Lead chromate  CAS       7758-97-6
                   RTECS     GB2975000

    Lead dioxide   CAS       1309-60-0
                   RTECS     OG0700000
                   EINECS    2151745
                   UN        1872

    Lead fluoride  CAS       778-34-62
                   RTECS     OG1225000
                   EINECS    2319988

    Lead hydroxide CAS       19783-14-3
                   EINECS    2433103

    Lead iodide    CAS       10101-63-0
                   EINECS    2332569

    Lead monoxide  CAS       1317-36-8
                   RTECS     OG1750000
                   EINECS    2152670

    Lead nitrate   CAS       10099-74-8
                   RTECS     OG2100000
                   UN        1469

    Lead phosphate CAS       7446-27-7
                   RTECS     OG3675000

    Lead sulphate  CAS       7446-14-2
                   RTECS     OG4375000

    Lead sulphide  CAS       1314-87-0
                   RTECS     OG4550000
                   EINECS    2152466

    Lead tetraoxide  CAS     1314-41-6
                   RTECS     OG5425000

    Tetraethyl lead  CAS     78-00-2
                   RTECS     TP4550000

    Tetramenthyl lead CAS    75-74-1
                   RTECS     TP4725000
                   UN        1649

    1.6  Manufacturer

         Name
         Address
         Telephone
         Fax

    1.7  Supplier/importer/agent/ licence holder

         Name
         Address
         Telephone
         Fax

    1.8  Presentation

    1.8.1  Form

    1.8.2  Formulation details

    1.8.3  Pack sizes available

    1.8.4  Packaging

    1.9  Physico-chemical properties

    Physical state

    Metallic lead: metal - highly lustrous when freshly cut, tarnishes
    upon exposure to air. Very soft and malleable, easily melted, cast,
    rolled and extruded
    Lead acetate: colourless crystals or white granules or white powder
    Lead azide: needles or white powder
    Lead borate: white powder
    Lead bromate: colourless crystals
    Lead butyrate: colourless scales or viscid mass
    Lead chlorate: coulourless deliquescent crystals
    Lead chloride: white powder
    Lead chromate: yellow or orange-yellow powder
    Lead dioxide: dark brown powder
    Lead fluoride: white to colourless crystals
    Lead hydroxide: white powder
    Lead iodide: bright yellow powder
    Lead monoxide: reddish to reddish-yellow tetragonal crystals or yellow
    orthorhombic crystals
    Lead nitrate: white or colourless translucent crystals
    Lead phosphate: white powder
    Lead sulphate: white crystalline powder
    Lead sulphide: black powder
    Lead tetraoxide: bright red powder

    Tetraethyl lead: colourless liquid
    Tetramethyl lead: colourless liquid

    Colour

    Metallic lead: Bluish - white, silvery, grey
    Lead acetate: colourless or white
    Lead azide: white
    Lead borate: white
    Lead bromate: colourless
    Lead butyrate: colourless
    Lead chlorate: colourless
    Lead chloride: white
    Lead chromate: yellow or orange-yellow
    Lead dioxide: dark brown

    Lead fluoride: white to colourless
    Lead hydroxide: white
    Lead iodide: bright yellow
    Lead monoxide: reddish to reddish-yellow or yellow
    Lead nitrate: white or colourless
    Lead phosphate: white
    Lead sulphate: white
    Lead sulphide: black
    Lead tetraoxide: bright red

    Tetraethyl lead: colourless
    Tetramethyl lead: colourless

    Odour

    Tetraethyl lead: characteristic fruity odour
    Tetramethyl lead: characteristic fruity odour

    Viscosity

    Metallic lead: of molten lead 3.2 centipoises (cp) at 327C, 2.32 cp
    at 400C, 1.54 cp at 600C, 1.23 cp at 800C.

    Solubility in water and organic solvents

    Metallic lead: insoluble in hot or cold resistant to tap water,
    attacked by pure water, resistant to hydrofluoric acid, brine, organic
    solvents. Soluble in nitric acid and hot concentrated sulphuric acid.
    Lead acetate: 1 g dissolves in 1.6 ml water, 0.5 ml boiling water, 30
    ml alcohol; freely soluble in glycerol
    Lead azide: solubility in water 0.023% at 18: 0.09 at 70 freely
    soluble in acetic acid, insoluble in ammonium hydroxide
    Lead borate: insoluble in water, soluble in dilute nitric acid
    Lead bromate: slightly soluble in cold water, moderately in hot water
    Lead butyrate: insoluble in water, soluble in dilute nitric acid
    Lead chlorate: soluble in 0.7 part water, freely in alcohol
    Lead chloride: soluble in 93 parts cold water, 30 parts boiling water,
    readily soluble in solution of ammonium chloride, ammonium nitrate,
    alkali hydroxides, slowly in glycerol
    Lead chromate: one of the most insoluble salts (0.2 mg/L H2O),
    soluble in solutions of fixed alkali hydroxides, soluble in dilute
    nitric acid
    Lead dioxide: insoluble in water, soluble in hydrochloric acid with
    the evolution of chlorine, soluble in dilute nitric acid (in the
    presence of hydrogen peroxide, oxalic acid or other reducers), soluble
    in alkali iodide solutions with liberation of iodine, soluble in hot
    caustic alkali solutions
    Lead fluoride: solubility in water 0.057 g/100 ml water at 0: 0.065
    g/100 ml water at 20 - the solubility increases in the presence of
    nitric acid or nitrates
    Lead hydroxide: insoluble in water, soluble in dilute acids and fixed
    alkali hydroxides

    Lead iodide: 1 g dissolves in 1350 ml cold water or 230 ml boiling
    water, soluble in concentrated solutions of alkali iodides, freely
    soluble in solution of sodium thiosulphate, soluble in 200 parts cold
    or 90 parts hot aniline, insoluble in alcohol or cold hydrochloric
    acid
    Lead monoxide: insoluble in water and alcohol, soluble in acetic acid,
    soluble in dilute nitric acid, soluble in warm solutions of fixed
    alkali hydroxides
    Lead nitrate: 1 g dissolves in 200 ml cold or 0.75 ml boiling water,
    2500 ml absolute alcohol, 75 ml absolute methanol, insoluble in
    concentrated nitric acid
    Lead phosphate: insoluble in water and alcohol, soluble in nitric acid
    and fixed alkali hydroxides
    Lead sulphate: soluble in about 2225 parts water, more soluble in
    dilute hydrochloric acid or nitric acid, less in dilute sulphuric
    acid, soluble in sodium hydroxide, ammonium acetate or tartrate
    solution, soluble in concentrated hydriodic acid, insoluble in alcohol
    Lead sulphide: insoluble in water, soluble in nitric acid and hot
    dilute hydrochloric acid
    Lead tetraoxide: insoluble in water or alcohol, soluble in excess
    glacial acetic acid, in hot hydrochloric acid with evolution of
    chlorine, soluble in dilute nitric acid in the presence of hydrogen
    peroxide

    Tetraethyl lead: practically insoluble in water, soluble in benzene,
    petroleum ether and gasoline, slightly soluble in alcohol

    Important chemical interactions

    Metallic lead: reacts with hot concentrated nitric acid, with boiling
    concentrated hydrochloric or sulphuric acid. Can react vigorously with
    oxidising materials. Forms a violent reaction on ignition with
    chloride trifluoride, concentrated hydrogen peroxide and ammonium
    nitrate. Ground mixtures of sodium carbide and lead can react
    vigorously.
    Lead chloride: incompatible with strong oxidisers, hydrogen peroxide,
    acids.
    lead monoxide: incompatible with chlorinated rubber, chlorine,
    ethylene, hydrogen trisulphide, metals, peroxy formic acid, glycerol.
    Tetramethyl lead: dangerous when exposed to oxidisers

    Major products of combustion/pyrolysis

    Many inorganic lead compounds give off toxic lead fumes on combustion
    (lead chloride, lead chromate, lead sulphate, lead sulphide).

    Explosion limits

    Metallic lead is moderately explosive in the form of dust when exposed
    to heat or flame.
    Tetraethyl lead and tetramethyl lead are dangerous when exposed to
    heat or flame.

    Flammability

    Tetraethyl lead and tetramethyl lead are flammable.

    Boiling point

    Metallic lead:      1740C
    Lead chloride:      950C
    Lead fluoride:      1293C
    Tetraethyl lead:    198-202C
    Tetramethyl lead:   110C

    Melting point

    Metallic lead:      327.4C
    Lead bromide:       373C
    Lead butyrate:      90C
    Lead chloride       501C
    Lead chromate:      844C
    Lead fluoride:      824C
    Lead monoxide:      888C
    Lead phosphate:     1014C
    Lead sulphate:      1170C
    Tetraethyl lead:    125-150C
    Tetramethyl lead:   18C

    Density

    Metallic lead:      11.34
    Lead chromate (VI): 6.3
    Lead dioxide:       9.38
    Lead formate:       4.63
    Lead hydroxide:     7.41
    Lead iodide:        6.16
    Lead monoxide:      9.53
    Lead nitrate:       4.53
    Lead oxalate:       5.28
    Lead sulphate:      6.2

    Tetraethyl lead:    1.653

    Flash point

    Tetraethyl lead:    200F
    Tetramethyl lead:   100F

    1.10  Hazard/risk classification

    1.11  Uses

    Used as construction material for tank linings, piping and other
    equipment handling corrosive gases and liquids, used in the
    manufacture of sulphuric acid, petroleum refining, halogenation,

    sulphonation, extraction, condensation; for X-ray and atomic radiation
    protection; manufacture of tetraethyl lead, pigments for paints and
    other organic and inorganic lead compounds; bearing metal and alloys;
    storage batteries; in ceramics, plastics and other lead alloys; in the
    metallurgy of steel and other metals (Budavari, 1989).

    Lead acetate is used in dyeing and printing cottons, in the
    manufacture of lead salts, in varnishes, chrome pigments, manufacture
    of insecticides, as a colour additive in hair dyes, in small amounts
    in some explosives and as an astringent in some lotions. It was
    previously used in medicine in poultices and washes for the treatment
    of poison ivy inflammation and in lotions for treatment of bruises.

    Lead azide is used as a primer in explosives.

    Lead carbonate is used as a white pigment in oil paints and water
    colours, as a component of cement, putty and ceramics and in the
    manufacture of lead carbonate paper.

    Lead chloride is used in the preparation of lead salts and lead
    chromate pigments, in solder and fluxes and in some flame retardants.

    Lead chromate is used as a pigment in oil and water colours, printing
    fabrics, decorating china and porcelain, in chemical analysis or
    organic substances and in traffic paints.

    Lead dioxide is used as an electrode in batteries, oxidising agent in
    manufacture of dyes, manufacture of rubber substances, manufacture of
    pigments.

    Lead fluoride is used in electronic and optical applications and in
    the manufacture of lead compounds, glass and underwater paints.

    Lead monoxide is used in ointments and plasters, glazing pottery and
    in lead glass. It is also used in oil refining, in the manufacture of
    paints and inks.

    Lead nitrate is used in the manufacture of matches and special
    explosives, in dyeing and printing textiles, in the manufacture of
    lead compounds, nylon, polyesters and rodenticides.

    Lead phosphate is used as a stabilizer for plastics.

    Lead sulphate is used as a pigment, in galvanising batteries, in
    lithography, weighting fabrics.

    Lead sulphide is used for glazing earthenware.

    Inorganic lead compounds - tetraethyl lead and tetramethyl lead are
    used as antiknocking additives in petrol.

    1.12  Toxicokinetics

    1.12.1  Absorption

    In adults approximately 5% to 10% of an ingested lead dose is absorbed
    in the gut, the remainder appears in the faeces. In children
    gastrointestinal absorption of lead is higher and may be as much as
    40%. Gastric acid solubilizes lead salts and lead absorption occurs in
    the small bowel by both active and passive transport (Ellenhorn and
    Barceloux 1988, Tsuchiya 1986). Absorption may be augmented in
    individuals with iron, zinc or calcium deficiency (Poisindex 1994).
    Heard and Chamberlain (1982) demonstrated that lead absorption
    decreases if equivalent doses of calcium and phosphate are added in
    human volunteer studies.

    Lead may also be absorbed via lungs. Absorption of inorganic lead may
    depend on particulate size and physical state of the compound
    (Tsuchiya 1986). It is estimated that between 50% and 70% of an
    inhaled dose is absorbed if the particle size (less than 1 m) allows
    the material to reach the alveoli (Ellenhorn and Barceloux 1988). This
    is the primary route of absorption of organic lead.

    There is some evidence to suggest that inorganic lead may be absorbed
    via skin (Florence et al 1988). However in this study increases in
    lead levels in sweat and saliva were reported but there was no
    corresponding increase in blood lead levels or urine lead levels. It
    was postulated that inorganic lead absorbed through skin was
    transported in plasma and rapidly concentrated into the extracellular
    fluid pool of sweat and saliva without significant uptake by the
    erythrocytes and with a very low transient concentration in the
    plasma. Organic lead however is absorbed via skin in sufficient
    quantities to produce toxicity (Ellenhorn and Barceloux 1988).

    1.12.2  Distribution

    To summarise, absorbed lead is transported by blood and initially
    distributed in various organs and tissues. It is then gradually
    redistributed to form an exchangeable compartment (blood and soft
    tissues) and a storage compartment, essentially bone (Tsyuchi 1986).
    With continuing exposure the lead which is at first only loosely
    deposited in bone, gradually becomes fixed to bone probably as inert
    and insoluble lead phosphate. Lead deposits in the area of the
    skeleton which are growing most rapidly. These areas include the
    radius, tibia and femur which are the most metabolically active. The
    hypermineralisation is reflected in the densities that are seen as
    characteristic lead lines observed on X-ray. The width of the lead
    lines is related to the duration of the exposure. These lines reflect
    "bone growth arrest" not deposition.

    In healthy humans the kinetics of lead metabolism fit a
    three-compartment model. The first compartment includes the blood.
    About 95% of the lead in the circulation exists in the erythrocytes
    where it has a half life of 35 days and distributes into the soft 

    tissues or bone stores. Hence blood lead levels may not reflect the
    total body lead burden (Ellenhorn and Barceloux 1988). This first
    compartment receives lead absorbed from the gut, delivers some of it
    to the urine and communicates with the other two pools.

    The second compartment is the soft tissues, i.e. kidney, liver,
    nervous tissue, about 10% of the total body lead burden equilibrates
    here where the half life is 40 days with distribution of some of it to
    hair, nails, sweat, saliva, bile and other digestive secretions.

    The third compartment, the skeleton, contains the vast bulk of the
    total body burden, here lead has a very long half life although bones
    may differ in their rates of lead turnover (Rabinowitz et al 1976).
    Bones are the major depository for lead in the body with about 90% of
    the total lead body burden existing in the skeleton. The half life of
    lead in bone is approximately 20 to 30 years. Some equilibration
    between bone and blood lead does occur. Up to 70% of blood lead may
    derive from the bone.

    The lead content of dense human bone increases steadily with age
    whereas in spongy bone lead reaches a plateau or even decreases.

    1.12.3  Metabolism

    Inorganic lead is not metabolized. Alkyl lead compounds, however, are
    oxidized by the hepatic P450 system. Experimental studies have shown
    that tetraethyl lead is converted to triethyl lead and inorganic lead.
    Triethyl lead is relatively stable and becomes rapidly distributed
    between brain, liver, kidney and blood (Reynolds et al 1993).

    1.12.4  Elimination

    About 90% of ingested lead is eliminated unabsorbed through faeces
    (Tepper and Levin, 1972). Absorbed lead is excreted mainly in the
    urine (about 76%); other routes are gastrointestinal secretions (about
    16%) and hair, nails and sweat (< 8%). The rate of biliary excretion
    in man is not known. The mechanism of urinary excretion appears to be
    essentially glomerular filtration with some renal tubular resorption.
    With elevated blood levels, excretion may be augmented by trans
    tubular transport (Reynolds et al 1993).

    Lead is also excreted in human milk in concentrations of up to 12 mg/L
    (Klaassen, 1980).

    1.12.5  Half-life

    The total body burden of lead may be divided into at least two kinetic
    pools, which have different rates of turnover. The larger and
    kinetically slower pool is the skeleton with a half life of more than
    20 years, and a much more labile soft tissue and a rapidly
    exchangeable bone fraction pool with a half life 19-21 days. Other
    studies indicate that mean retention of lead in the blood and soft
    tissues is about 3 weeks to one month and in the bone about five years
    (Klaassen, 1980).

    1.12.6  Special populations

    Children appear to be more susceptible than adults to the toxic
    effects of lead because of incomplete development of the blood brain
    barrier, greater intestinal absorption of lead and a tendency to put
    objects or their hands into their mouths thereby increasing ingestion
    of contaminated substances. In addition, they have a smaller
    proportion of dense bone tissue than adults and this prevents the
    transfer of the absorbed lead into bone, it remains in the soft
    tissues where it produces toxic effects (Knodel, 1995).

    Disproportionate numbers of children from lower socioeconomic
    backgrounds have high lead levels. This may be because they live in
    older poorly maintained housing where old lead paint and lead water
    pipes may remain (Bellinger et al 1989).

    It is thought that millions of workers may be exposed to lead in the
    United States and Europe (Cullen et al 1983). The highest and most
    prolonged lead exposures have been seen among workers in the lead
    smelting, refining and manufacturing industries. Potentially high lead
    levels may also occur in steel welding or cutting operations,
    construction, rubber products and plastics industries, printing
    industries and other industries requiring flame soldering of lead
    solder (Clement International Corporation 1993).

    There have been reported cases of lead toxicity in occupations
    including stained glass workers (Baxter et al 1985), mechanics
    (Goldman et al 1987), painters (Ennever et al 1995), in the
    manufacture of batteries and lead smelting (Williamson and Teo 1986),
    manufacture of lead pigments (Davies 1984) and workers on firing
    ranges (Chau et al 1995).

    There is some evidence to suggest that people with iron-deficiency
    anaemia are more prone to lead toxicity and that lead exposure impairs
    iron utilization for haem biosysnthesis and therefore exacerbates iron
    deficiency. Also calcium deficiency greatly enhances lead absorption
    and during periods of low calcium, lead may be mobilised from tissue
    stores particularly bone. Lead poisoning may also recur in the
    presence of osteoporosis indicating that bone can be a significant
    source of lead level elevation in conditions associated with
    accelerated resorption (Shannon et al 1988).

    Some ethnic groups may be more at risk of lead poisoning because of
    the use of traditional remedies (Middleton 1989) or cosmetics.

    In some groups the inhalational abuse of leaded petrol can be
    relatively common (Burns and Currie 1995).

    2  SUMMARY

    3  EPIDEMIOLOGY OF POISONING

    Lead has been used both industrially and domestically since
    pre-historic times. Since lead and lead compounds are utilized in a
    wide variety of industrial and domestic situations, many people and
    all age groups may potentially be exposed and could be at risk of lead
    toxicity.

    The general population is exposed to lead in ambient air, many foods,
    drinking water and dust. Human exposure to lead above baseline levels
    is common. Exposure may occur from living in an urban environment,
    particularly in areas with high traffic flow, or near a lead industry
    (e.g. lead smelters), consumption of produce from lead contaminated
    soil, renovation of homes containing lead paint, pica, contact with
    interior lead paint dust, smoking and wine consumption.

    Occupational exposure

    Since the industrial revolution environmental concentrations of lead
    have risen steadily (Landrigan 1983). It is thought that millions of
    workers may be exposed to lead in the United States and Europe (Cullen
    et al 1983).

    The highest and most prolonged lead exposures have been seen among
    workers in the lead smelting, refining and manufacturing industries.
    Potentially high lead levels may also occur in steel welding or
    cutting operations, construction, rubber products and plastics
    industries, printing industries and other industries requiring flame
    soldering of lead solder (Clement International Corporation 1993).

    There have been reported cases of occupational lead toxicity in
    stained glass workers (Baxter et al 1985), mechanics (Goldman et al
    1987), painters (Ennever et al 1995), and in those involved in the
    manufacture of batteries and lead smelting (Williamson and Teo 1986),
    manufacture of lead pigments (Davies 1984) and operating firing ranges
    (Chan et al 1995).

    In work the major routes of lead exposure are inhalation and ingestion
    involving both lead dusts and fumes. Airborne dusts settle onto food,
    water, clothing and other objects and may therefore be transferred to
    the mouth. Workers involved in the production of petrol additives,
    tetraethyl lead and tetramethyl lead are exposed to both inorganic and
    organic lead. The major potential hazard to these workers appears to
    be from dermal exposure since organic lead may be absorbed through the
    skin (Clement International Corporation 1993).

    There have been many epidemiological studies on blood lead
    concentrations in exposed workers and people living in urban and rural
    areas. In a large health screening programme within the USA during
    1976-80 over 27,000 residents aged 6 months to 74 years were examined.
    Blood lead concentrations were examined in a subsample of 9933 

    individuals and yielded a mean value of 130 g/L (0.67 mol/L). In
    another study residents in the centre of large urban areas were found
    to have blood lead levels of 149 g/L (0.72 mol/L), while in rural
    areas it was 130 g/L (0.62 mol/L). Male workers in occupations with
    a high potential for lead exposure had mean blood lead levels of 162
    g/L (0.78 mol/L) for non-drinkers and non-smokers and 197 g/L (0.95
    mol/L) for drinkers or smokers. During this study a true decrease of
    37% in blood lead levels was seen (WHO 1995).

    Non-occupational exposure

    Exposure of the general population to lead is most likely to occur
    through the ingestion of contaminated food or drinking water and by
    the inhalation of lead particulates in ambient air. Direct inhalation
    of lead accounts for only a small part of the total human exposure,
    mainly from lead that is adsorbed to soil and inhaled as dust. Fruits,
    vegetables and grains may contain levels of lead in excess of
    background levels as a result of direct deposition of lead onto plant
    surfaces or plant uptake of lead from soils (Clement International
    Corporation 1993, Carrington at al 1993). Foods may also become
    contaminated during processing (Kocak et al 1989) and food in lead
    soldered cans (which are uncommon) may contain high lead levels.

    A new European safety limit was introduced in 1995 which recommended
    that lead levels in tapwater should not exceed 10 g/L. It is
    estimated that as many as 20% households in Great Britain exceed this
    safety limit, where a survey in 1994 found that 3.2% of households
    failed the old safety margin which was 50 g/L (Pearce 1995).

    Adults and children may be at risk of lead poisoning from the use of
    lead utensils (Roberge and Martin 1992), lead glazed ceramics, lead
    crystal (Graziano and Blum 1991, Zuckerman 1991), lead foil on wine
    bottles (Marks and Taylor 1987) the use of contaminated health foods
    (Crosby 1977), traditional remedies (Middleton 1989), aphrodisiacs
    (Brearley and Forsythe 1978) or cosmetics (Anon 1985) and crayons
    (Wilks et al 1994).

    There have also been cases of lead contamination of heroin and lead
    toxicity has resulted from the intravenous use of heroin (Montefort et
    al 1987, Parras et al 1989) and lead contaminated methamphetamine
    (Norton et al 1989).

    The abuse of petrol by inhalation is relatively common in some groups
    and sniffing leaded petrol can result in lead toxicity (Burns and
    Currie 1995).

    Pica

    Pica (from the Latin for magpie) is the compulsive eating of
    non-nutritional substances. It may occur either through deliberate
    ingestion or through the mouthing of objects or hands. Pica is common
    in young children and it is thought that pica may explain the higher
    blood lead levels that occur in young children compared to adults

    (Norman and Bordley 1995). House dust is probably the most important
    source relevant to pica (Gallacher et al 1984). There may be a variety
    of sources for high concentrations of lead in house dust, older houses
    may contain a lot of leaded paint (Shannon 1989) and indeed children
    may eat flakes or chips of peeling lead paint (Goldfrank et al 1990),
    children may live near a lead industry or in an area of heavy traffic
    (Gallacher et al 1984) and parents who work in lead industries may
    bring home lead dust on their clothing, skin, cars etc (Landrigan
    1983). Children may also swallow small lead weights, lead bullets,
    toys etc.

    Disproportionate numbers of children from lower socioeconomic
    backgrounds have high lead levels (Bellinger et al 1989, Guinee 1972).
    This may be because they live in older poorly maintained housing where
    old lead paint may remain and lead pipes may be used in plumbing or
    because of poor nutrition. It has been found that independent of
    socioeconomic status, children who live in older housing may be more
    at risk of lead toxicity (Paulozzi et al 1995, Rosen 1995).

    It is estimated that in the UK 26.9% of children have blood lead
    concentrations >100 g/L (0.48 mol/L) and 0.5% children have blood
    lead concentrations of >250 g/L (1.22 mol/L). In London 55.5% of
    children are estimated to have blood lead concentrations >100 g/L
    (0.48 mol/L) and 3.9% with blood lead concentrations >250 g/L (1.22
    mol/L) (Millstone and Russell 1995).

    There were 139 deaths related to lead poisoning in the United States
    between 1979 and 1988. The death rate was higher in older age groups,
    higher amongst males than females and greatest among blacks and
    persons living in the southeastern states. Eleven deaths were reported
    in children, 9 of these were younger than 3 years old. Three ingested
    leaded paint, one ingested a lead object and one ingested a home
    remedy. Of the 25 people in the older age groups in which a lead
    source was identified 20 ingested illegally produced alcohol
    (moonshine), two inhaled leaded petrol and three had occupational
    exposures (Staes et al 1995).

    4  MECHANISM OF ACTION/TOXICITY

    4.1  Mechanism

    Bone marrow

    The anaemia caused by lead results from two basic red cell defects,
    shortened life-span and impaired haem synthesis. The mechanism by
    which synthesis of the red cell pigment haem is inhibited by lead
    involves at least two enzymes, a cytoplasmic one (delta-aminoleuvinic
    acid dehydrogenase - ALAD) at the beginning of haem synthesis and a
    mitochondrial one, ferrochelatase, at the end of synthesis. The
    inhibition of ALAD is observed at lead blood concentrations as low as
    100 g/L (0.49 mol/L). The conversion of ALA to porphobilinogen is
    blocked, resulting in plasma concentrations of 0.2 to 1.4 g/ml
    (normally 0.1 g/ml) and ALA urinary concentrations of 50 g/L or

    more. The inhibition of ferrochelatase which plays a role in the
    insertion of Fe 3+ into protoporphyrin during the formation of haem in
    bone marrow occurs at a slightly higher lead blood concentration (140-
    200 g /L). This inhibition results in an increase in the free
    erythrocyte protoporphyrin (FEP). The increases in ALA and FEP are
    earlier indicators of anaemia which is generally not observed until
    the blood concentration reaches 40 g/L. The red blood cell zinc
    protoporphyrin blood test measures the effects of lead on bone marrow
    occurring in the preceding 120 days and begins to occur in children at
    150 g/L (0.72 mol/L) in women at 200 g/L (0.97 mol/L) and in men
    at 300 g/L (1.45mol/L).

    Indicators of lead exposure relate to the inhibition by lead of the
    synthesis of haem. The inhibition of delta-aminoleuvinic acid
    dehydrase (ALAD) an enzyme involved in the biosynthesis of cytochromes
    and haemoproteins and porphyrins leads to an increase in levels of
    delta-aminoleuvinic acid (ALA) in blood and urine. The discovery that
    lead forms a specific complex with the substrate ALA indicates this
    may be the inhibitory action. The blood and urine levels of
    coproporphyrin III and free erythrocyte protoporphyrins (FEP) are also
    usually elevated. The FEP combine with zinc in the blood to form zinc
    protoporphyrin (ZPP) which is the moiety assayed (Hathaway et al 1991,
    Gosselin 1984).

    ALAD remains active in the circulating red cell, but the activity of
    ferrochelatase disappears as soon as the red cells reach circulation,
    along with the disappearance of the mitochondria. From the usual
    measurements of ALAD in peripheral blood and the substrate
    erythroporphyrin (EP) from changes in ferrochelatase activity, the
    direct action of lead on circulating blood is evaluated very early.
    However the inhibition of medullary erythroblastic ferrochelatase from
    the action of lead in the bone marrow is evidenced only indirectly by
    a late and gradual increase in EP corresponding to the gradual
    maturation and slow release of mature red cells carrying
    protoporphyrin from the marrow to the circulating blood. This is why
    EP concentrations may continue to rise after all other biologic
    measurements of lead effects have improved or returned to normal and
    long after environmental lead exposures have ceased (Beliles 1994).

    One study has found a metallothionen-like lead containing protein
    within human erythrocytes which may act to sequester lead into a
    non-bioavailable form hence protecting the body from lead toxicity. In
    this study two lead poisoned patients were examined. One patient who
    had a blood lead concentration of 1800 g/L (8.69 mol/L) had 70% of
    their erythrocyte lead bound to this protein and remained
    asymptomatic. The other patient had a blood lead concentration of 1610
    g/L (7.77 mol/L) with only 20% of erythrocyte lead bound to this
    protein and showed signs of lead toxicity. It is not clear if the
    second patient had less metallothionen-like protein or a much higher
    total lead body burden than the first patient (Church et al 1993).

    CNS

    The exact nature of the effect on the central nervous system is
    unknown but it may involve neurotransmitters. In one study rats of
    various ages were fed lead acetate. Lead values in the brains of all
    rats were similar. There were decreases in brain levels of
    noradrenaline, GABA, and glutamate decarboxylase and increases in
    levels of glutamate, glutamine and asparagine, tyrosine and monoamine
    oxidase in the brains of rats prenatally or 5 days postnatally exposed
    to lead. Brain ammonia, alanine, aspartic acid and dopamine levels
    were not affected by the prenatal or 5 day postnatal treatment.
    Exposure of 5 week old rats to lead did not affect the brain
    catecholamine and amino acid levels. These results suggest that the
    brains of young rats are more sensitive to lead exposure than those of
    adult rats.

    Another study showed alterations in the concentrations of the
    transmitters noradrenaline and dopamine in addition to changes in the
    activities of the enzyme tyrosine hydroxylase and
    phenylethanolamine- N-methyl transferase. The activity of choline
    acetyltransferase was also altered.

    Segmental demyelination of peripheral nerves causes decreased nerve
    conduction velocities in adults. Lead crosses the blood-brain barrier
    disrupting mitochondrial function. Other studies have suggested that
    the permanent neuropsychological deficits seen after exposure to high
    lead concentrations may be due to impairment of astrocyte function
    especially in their capacity to regulate the ionic and amino acid
    concentrations in the extracelluler milieu, brain energy metabolism
    and cell volume. These functions are under monoaminergic control
    (Beliles 1994).

    Other

    In children exposed to lead, elevations in urinary catecholamine
    metabolites have been shown (Beliles 1994). Significant increases in
    plasma noradrenaline and adrenaline have also been found in children
    with chronic lead poisoning which suggests that this may play a part
    in the mechanism of hypertension and hyperactivity (de Castro 1990).

    Lead may be associated with increased serum lipid levels. High doses
    in animal and human studies may have a direct toxic action on the
    heart. There may also be evidence to suggest that lead at low doses
    may cause altered myocardial contractility. Schwartz (1995) carried
    out meta-analysis of epidemiological studies and found a relationship
    between blood lead and systolic BP in males in that a decrease of
    blood lead from 10 mg/L to 5 mg/L is associated with a decrease in BP
    of 1.25 mmHg. Animal data suggests a mechanism i.e. disturbance of
    calcium messenger system regulation of blood pressure (there may be
    modulation of BP through control of vascular tone).

    4.2  Toxic dose/Levels

    In children, blood lead concentrations (prior to any treatment or
    other action to abate exposure) of:-
    a) greater than 250g/L (1.2mol/L) may require chelation therapy
    although there is no consensus.
    b) greater than 400g/L (1.9mol/L) require treatment with either
    succimer or sodium calciumedetate.
    c) greater than 600g/L (2.9mol/L) are a medical emergency and
    require immediate chelating agent, sodium calciumedetate being the
    treatment of choice.

    Pharmacological intervention is not needed for blood lead
    concentrations of less than 250g/L (1.2mol/L).

    In adults, blood lead concentrations (prior to any treatment or other
    action to abate exposure) of:-
    a) greater than 400g/L (1.92mol/L) may require treatment with
    chelating agents if the patient is symptomatic, although this is
    unlikely.
    b) greater than 800g/L (3.86mol/L) will require treatment with
    chelating agents if the patient is symptomatic which is quite likely.
    c) greater than 1200g/L (5.79mol/L) require treatment with chelating
    agents as patients are very likely to have symptoms.

    Lead levels in preindustrial humans has been estimated at around 0.16
    g/L (0.8 nmol/L). This estimate is 50-200 fold lower than the lowest
    reported lead levels of contemporary humans in remote regions of the
    Northern and Southern hemispheres and approximately 600 times lower
    than the upper blood lead concentration of 100 /L (0.48 mol/L) that
    is currently considered acceptable in children (Flegal and Smith
    1992).

    5  FEATURES OF POISONING

    5.1  Acute

    5.1.1  Ingestion

     Adults: The most common acute effect is gastrointestinal colic. This
    is characterised by nausea, vomiting, anorexia, and diffuse paroxysmal
    abdominal pain. Acute exposures have also resulted in malaise,
    convulsions, coma, encephalopathy, hepatic and renal damage, anaemia,
    hypertension and bradycardia (Carlton et al 1987, Khan et al 1983,
    Parras et al 1989).

     Children: Ingestion of lead or lead salts may result in a metallic
    taste in the mouth, severe abdominal pain or cramping, vomiting and
    diarrhoea often with discoloured stools. There may also be anorexia,
    irritability, malaise, fatigue, muscle weakness and shock.
    Neurological effects include headache, insomnia, drowsiness and more
    rarely convulsions.

    5.1.2  Inhalation

    Lead does not cause any local irritation but may cause the same
    effects as for ingestion if enough is inhaled.

     Organic lead

    Organic lead compounds can cause severe toxicity by inhalation, the
    latent period between acute exposure and the onset of symptoms varies
    from a few hours in the more severe cases to as much as ten days. The
    initial effects are anorexia, vomiting, insomnia, tremor, weakness,
    fatigue, nausea, headache, aggression, depression, irritability,
    restlessness, hyperactivity, confusion and memory impairment. From the
    onset of the initial effects there may be a delay of hours or even
    days before acute mania, convulsions, delirium, fever and coma.
    Apparent complete recovery can take two to six months to occur and
    some effects may persist for some time (Grandjean and Nielsen 1979).

    5.1.3  Dermal

     Inorganic lead

    Inorganic lead salts may cause mild local irritation but systemic
    toxicity from this route has not been described.

     Organic lead

    Acute poisoning may occur from dermal exposure to organic lead
    compounds. There is often a latent period between exposure and onset
    of symptoms. Effects within 24 hours indicate a severe exposure while
    in mild cases it may take up to 14 days before effects are apparent.

    Mild effects include anxiety, irritability, insomnia, anorexia,
    nausea, vomiting, metallic taste, pallor, mild diarrhoea, dizziness
    and lack of coordination.

    Moderate effects include disorientation, hyperexcitability, tremor,
    twitching, chorea, hyperreflexia, bradycardia, hypotension,
    hypothermia and nystagmus.

    Severe effects include delusions, hallucinations, mania, decreased
    nerve conduction velocity, convulsions, cerebral oedema, coma and
    death.

    5.1.4  Ocular

     Inorganic lead

    Lead metal foreign bodies in the eye are unlikely to cause any toxic
    effects but may cause mechanical injury.

    Lead chloride and lead sulphate placed in the anterior chamber of
    rabbits have caused a moderate purulent reaction and general
    inflammation of the eye. Lead acetate was formerly applied in aqueous
    solutions to the eye for astringent effect but induced opacities and
    lead encrustation of the cornea and conjunctiva. Lead sulphide (from
    the eye cosmetic surma) has caused minute conjunctival abrasions but
    no toxic injury to the eye (Grant and Schuman 1993).

     Organic lead

    Gasoline containing tetraethyl lead applied to rabbit eyes caused
    immediate pain and blepharospasm. When the application is repeated ten
    times in the course of 5 minutes under local anaesthesia it produced
    conjunctival hyperaemia and moderate flocculent discharge but no
    damage to the cornea. Scanning electron microscopy has revealed
    changes in the corneal epithelium from exposure to leaded gasoline
    (Grant and Schuman, 1993).

    5.1.5  Other routes

     Inorganic lead

    Lead toxicity has occurred by the intravenous route by the use of
    contaminated heroin (Montefort et al 1987, Parras et al 1989).

    Systemic lead toxicity has also occurred from gunshot wounds and the
    presence of lead shot in the synovial fluid. Lead toxicity from this
    route may take many years to manifest (Manton 1994). An insoluble lead
    phosphate coat is formed around retained pellets and lead poisoning is
    a risk if the pellets are in a position where the coating may be
    eroded (e.g. a joint).

    5.2  Chronic toxicity

    5.2.1  Ingestion

     Inorganic lead

     Adult: effects from chronic exposure include gastrointestinal signs
    such as nausea, vomiting, abdominal pain, metallic taste, anorexia and
    general feeling of malaise or fatigue. With longer exposures the
    patient may also have joint pain, progressive fatigue and anaemia.
    There is a strong association between elevated blood lead
    concentrations and anaemia which is characterised as hypochromic
    monocytic with a decrease in mean corpuscular haemoglobin and
    stippling of erythrocytes and reticulocytes. There may also be altered
    renal and hepatic function. Motor weakness may progress to paralysis
    of the extensor muscles of the wrist (wrist drop) and less often the
    ankles (foot drop). Adults may have a bluish gingival "lead-line".
    Encephalopathy rarely occurs in adults except from exposure to organic
    lead.

     Child: clinical effects from chronic exposures include severe
    gastrointestinal disturbances with constipation, abdominal pain and
    tenderness. Other effects include anaemia, weakness, pallor, anorexia,
    insomnia, renal hypertension and mental fatigue. There may be a bluish
    "lead line" on the gums although this is not often present. Lead may
    also be drawn to areas of the skeleton that grow most rapidly and in
    some cases hypermineralisation of the radius, tibia and femur can be
    seen on X-ray with the development of metaphyseal lines (Goldfrank et
    al 1990).

    Children with increased lead body burden may be asymptomatic but it is
    likely that they have metabolic effects involving haem synthesis, red
    cell nucleotide metabolism, vitamin D and cortisol metabolism and
    renal function (Piomelli et al 1984).

    Neuromuscular dysfunction may result in signs of motor weakness and
    paralysis of the extensor muscles of the wrist and ankles.
    Encephalopathy can occur in patients with previously mild symptoms.
    Effects include vomiting, confusion, ataxia, apathy, bizarre behaviour
    and coma and convulsions due to cerebral oedema.

    Nephropathy may occur and is characterised by albuminuria, glycosuria
    and renal tubular acidosis.

    Chronic low level exposures in children are linked with decreased
    intelligence and behavioural and learning disorders. There is evidence
    to suggest that growth may be inhibited. Thyroid and adrenal functions
    may also be inhibited.

    Children with chronically elevated blood lead levels of 600-1000 g/L
    (2.90-4.83 mol/L) showed squint, foot drop, albuminuria and delayed
    growth. An inverse correlation was found between height, weight and
    chest circumference with blood lead concentration (Angle et al 1989).
    In another study there was evidence of decreased insulin-like growth
    factor and diminished 24 hour secretion of growth hormone in children
    with lead levels >400 g/L (1.93 mol/L). These children also showed
    signs of growth retardation. With chelation therapy normal growth
    velocity was resumed when the lead levels came down to <250 g/L
    (1.21 mol/L). Levels of insulin-like growth factor also returned to
    normal (Huseman et al 1992).

    Pica, pallor and irritability is commonly seen at blood lead
    concentrations of 400-600 g/L (1.93-2.90 mol/L). Children with these
    levels typically have iron-deficient anaemia with basophilic
    stippling. "Lead-lines" in the gums and long bones may be seen and
    there may be abdominal radiopacities of ingested lead. Glycosuria,
    aminoaciduria, abnormal liver function tests and peripheral neuropathy
    is common.

    Early childhood exposure to environmental lead may result in subtle
    deficits in neuropsychological development. One study has found an
    inverse relationship between blood lead concentration and visual-motor
    performance (Baghurst et al 1995). Other studies have found that
    increased blood lead concentrations decrease IQ (Pocock et al 1994).

    At chronic low level exposure it may not be apparent that children are
    being exposed to lead without determination of blood lead
    concentrations (Dowsett and Shannon 1994). It has been suggested that
    there may be no threshold for adverse effects of lead in children
    (Needleman 1993).

    5.2.2  Inhalation

     Organic lead

    This is the main route for absorption of tetraethyl lead and
    tetramethyl lead. The initial symptoms of poisoning are nonspecific
    and include asthenia, weakness, fatigue, pallor, headache, nausea,
    vomiting, diarrhoea, anorexia and weight loss. Insomnia is usually
    present. Ataxia, tremor, hypotonia, bradycardia and hypothermia may
    also develop. In more severe poisoning disorientation, hallucinations,
    facial contortions and episodes of intense hyperactivity may occur. In
    severe cases maniacal behaviour and convulsions may develop which may
    lead to coma and death. Recovery may take weeks or months and may be
    incomplete (Hathaway et al 1991).

    5.2.3  Dermal

     Inorganic lead

    Inorganic lead and lead compounds may cause mild local irritation and
    may be absorbed through the skin, but it is not clear whether this
    type of exposure would increase the lead body burden and toxicity from
    this route is thought to be unlikely.

     Organic lead

    Organic lead compounds are mildly irritant and may be absorbed through
    the skin. The initial symptoms of poisoning are nonspecific and
    include asthenia, weakness, fatigue, pallor, headache, nausea,
    vomiting, diarrhoea, anorexia and weight loss. Insomnia is usually
    present. Ataxia, tremor, hypotonia, bradycardia and hypothermia may
    also develop. In more severe poisoning disorientation, hallucinations,
    facial contortions and episodes of intense hyperactivity may occur. In
    severe cases maniacal behaviour and convulsions may develop which may
    lead to coma and death. Recovery may take weeks or months and may be
    incomplete (Hathaway et al 1991).

    5.2.4  Ocular

    There are no reports of chronic toxicity in the eye and systemic
    effects from ocular exposure would not be expected.

    5.2.5  Other routes

     Inorganic lead

    Systemic lead toxicity has also occurred from gunshot wounds and the
    presence of lead shot in the synovial fluid. Lead toxicity from this
    route may take many years to manifest (Manton 1994). An insoluble lead
    phosphate coat is formed around retained pellets and lead poisoning is
    a risk if the pellets are in a position where the coating may be
    eroded (e.g. a joint).

    5.3  Systematic description of clinical effects

    5.3.1  Cardiovascular

     Inorganic lead

     Acute: Hypertension may be seen.

     Chronic: Low level exposure to lead can result in hypertension
    (Sharp 1990). In a study of 23 severely poisoned adult patients 40%
    were mildly hypertensive (Whitfield et al 1972). Increases in blood
    pressure have been associated with and increase in the risk of
    cardiovascular and cerebrovascular disease in prospective
    epidemiological studies.

     Organic lead

    Bradycardia and hypotension may be observed with organic lead
    poisoning.

    5.3.2  Respiration

     Inorganic lead

    Although inorganic lead compounds can be absorbed by inhalation, they
    do not cause respiratory effects.

     Organic lead

    Organic lead compounds can be absorbed by inhalation and may also
    cause mild respiratory irritation.

    5.3.3  Neurological

     Inorganic lead:

    Acute exposures have resulted in fatigue, malaise, convulsions and
    encephalopathy. Encephalopathy is rare in adults.

     Adults:

    Chronic exposures in adults may result in fatigue and malaise. There
    may also be insomnia, aggressive behaviour.

    Seppalainen et al (1983) have shown in a study of workers exposed to
    lead in their occupations that nerve conduction velocities especially
    in the arm nerves decreased. They also noted that the motor and
    sensory conduction velocities decreased. These changes were noted only
    in workers whose blood lead levels were between 300 and 500 g/L
    (1.45-2.41 mol/L). No change in conduction velocity was seen in
    workers with blood lead levels of below 300 g/L (1.45 mol/L).

    A study was carried out on 23 adults (13 men, 10 women) who attended
    one hospital (over a ten year period) with lead encephalopthy. All had
    been consuming illicit alcohol which had been contaminated with lead.
    Only one patient who worked with lead products as a plumber was known
    to have additional exposure to lead. 82% (18/23) patients had
    recurrent seizures either generalised or focal, 40% (10/23) were
    either comatose or semicomatose on admission. The remainder had a
    variety of neurological effects including confusion, dizziness,
    lethargy, headache, disorientation with bilateral blindness and
    fainting (Whitfield et al 1972).

     Children:

    Developmental defects including learning disabilities, lowered IQ and
    behavioural abnormalities can occur in the absence of any other signs
    of lead toxicity and at low blood lead levels. It is possible that
    neurological injury can occur at levels above 100 g/L (0.48mo/L).
    High lead levels are associated with encephalopathy with imminent risk
    of death or permanent mental retardation and motor deficits.

    A study of 160 children who lived near a lead smelting works were
    assessed on a battery of psychometric tests. Blood lead concentrations
    in this group ranged from 70 to 330 g/L (0.34-1.59 mo/L) and the
    group performed within the average range on all tests of attainment
    and intelligence. There was, however, a significant association
    between blood lead concentrations and attainment scores on reading,
    spelling and intelligence tests but not on mathematics tests. Analyses
    suggested that while only a small proportion of the variance in
    intelligence is explained by blood lead concentrations, the
    relationship is independent of social class (Yule et al 1981).

    The Port Pirie cohort study in Australia found that visual-motor
    functions were lead sensitive. Children's VMI scores
    (visual-motor-integration) were inversely associated with both
    prenatal (i.e. maternal) and postnatal blood lead concentrations
    (Baghurst et al 1995). Another study has demonstrated that increased
    postnatal blood lead levels have adverse effects on intelligence
    (Angle et al 1993).

    It is now thought that decreases in the cognitive abilities of
    children occurs at blood lead levels >100 g/L (0.048 mol/L). Also
    there seems to be a consistent link between low-level lead exposure
    during early development and later deficits in intellectual and
    academic performance (Rosen 1995). In one study 249 children were
    studied form birth to 2 years. They were initially divided into three
    groups according to blood lead concentrations in the umbilical cord at
    birth - high (umbilical cord blood level >100 g/L (0.48 mol/L)),
    medium (umbilical cord blood level 60-70 g/L (0.29-0.34 mol/L)) and
    low (umbilical cord blood level 30 g/L (0.14 mol/L)). Development
    was assessed every six months. It was found that at all ages infants
    in the high prenatal exposure group had lower development scores than
    infants in the low and medium groups (Bellinger et al 1987). Pocock et
    al (1994) found an inverse relationship between body lead burden and
    blood lead concentration as low as 100 g/L (0.48 mol/L). Another
    study measured lead levels in teeth and concluded that children with
    high levels were more likely to need special services such as speech
    therapy, remedial teaching for reading and behavioural counselling. It
    was also thought that even slight elevations of blood lead
    concentrations at age 2 years are associated with significant
    decrements in intellectual and academic performance at age 10 years
    (Needleman, 1993).

     Organic lead

    These can cause severe toxicity by inhalation, the latent period
    between acute exposure and the onset of symptoms varies from a few
    hours in the more severe cases to as much as ten days. The initial
    effects are anorexia, vomiting, insomnia, tremor, weakness, fatigue,
    nausea, headache, aggression, depression, irritability, restlessness,
    hyperactivity, confusion and memory impairment. From the onset of the
    initial effects there may be a delay of hours or even days before
    acute mania, convulsions, delirium, fever and coma. Apparent complete
    recovery can take two to six months to occur and some effects may
    persist for some time (Grandjean and Nielsen 1979).

    5.3.4  Gastrointestinal

     Inorganic lead

    Nausea, vomiting, abdominal pain or cramping and diarrhoea or
    constipation are common features of lead toxicity.

     Organic lead

    Nausea, vomiting, diarrhoea, anorexia and weight loss may be seen.

    5.3.5  Hepatic

     Inorganic lead

    Abnormal liver function tests and hepatitis are seen in adults and
    children.

     Organic lead

    Elevated LFTs may be observed.

    5.3.6  Urinary

     Inorganic lead

    Renal tubular damage can be characterised by aminoaciduria,
    hypophosphataemia and glycosuria sometimes followed by
    hyperphosphataemia.

    Nephropathy has been associated with chronic lead poisoning in workers
    exposed to lead. (Hathaway et al 1991). Most of the excess deaths
    occurred before 1970 among men who began work before 1946 suggesting
    that current lower levels of exposure may reduce the risk.

    Most studies of kidney function involving lead have used levels of
    blood urea nitrogen (BUN), serum creatinine or urinary protein as
    measurements of renal function. However because the kidney has a great
    reserve capacity these measures of excretory function can be normal or
    in the normal range despite major unrecognised impairment of kidney
    function. BUN and creatinine will be increased only when approximately
    two thirds of kidney function is lost. These tests are unlikely
    therefore to detect mild or moderate renal impairment due to lead
    toxicity and are unlikely to discover a lead nephropathy.

    There are thought to be two main stages of lead nephropathy.
    1) Stage I involves acute reversible stages with intranuclear
    inclusion bodies and alteration of mitochondrial morphology. These
    intranuclear inclusion bodies have been extensively studied in
    experimental animals and from renal biopsy from exposed workers and
    children with acute lead poisoning. The intranuclear inclusion bodies
    are reported to be the most characteristic feature of stage one
    nephropathy. These occur in the lining cells of the proximal tubules
    and are composed of sulphydryl-rich lead protein complex. They are
    thought to serve as protective temporary storage mechanisms by which
    soft tissue lead is complexed in a non-diffusable form thereby
    reducing the concentration of lead available to disrupt essential cell
    function.

    The renal proximal tubules are rich in mitochondria and in
    experimental animals swelling of mitochondria can be observed at
    relatively low lead concentrations. In exposed workers distortion of
    the proximal tubules have been noted after a couple of months of
    exposure.

    2) Stage II is defined as a chronic condition characterised by
    interstitial fibrosis, tubular atrophy and dilatation and
    arteriosclerotic changes. These have been found in lead workers with
    excessive lead exposure for more than two years but these workers did
    not have to exhibit renal failure until many years later. It has also
    been found in workers exposed over ten years.

    A relationship between gout and lead nephropathy has been recognised
    for centuries and gout (sometimes termed saturnine gout) occurs more
    frequently in the presence of chronic lead nephropathy than in any
    other type of chronic renal disease. There is some evidence to suggest
    that chronic low level environmental lead exposure may affect kidney
    function (Bernard and Becker 1988).

     Organic lead

    Urinary retention has been reported.

    5.3.7  Endocrine and reproductive system

    In a study of workers exposed to lead there was a high prevalence of
    low serum thyroxine concentrations, none had clinical features of
    hypothyroidism (Cullen et al 1983).

    There may also be reduced vitamin D and cortisol metabolism and
    adrenal function. Inhibition of insulin-like growth factor has been
    seen in children.

    The reproductive effects of lead in the male are limited to sperm
    morphology and count.

    Most recent information relates to reports of occupational cohorts and
    of populations living in polluted areas near industrial plants. There
    is a qualitative evidence that lead is toxic to the reproduction
    system in both men and women. However, there are insufficient data to
    provide the basis for estimation of dose effect relationship in women
    (WHO, 1995).

    A study of pregnancies in the centre and surroundings areas of lead
    smelter town showed that the incidence of miscarriages (22 or 23) and
    stillbirths (10 or 11) was higher in women living close to the
    smelter. Some studies have also found decreased length of gestation in
    women whose lead level were greater than 230 mg/L. Other studies have
    not shown a significant association between birth weight and lead
    exposure.

    5.3.8  Dermatological

     Inorganic lead

    Inorganic lead and lead compounds are not irritant and may be absorbed
    through the skin, but it is not clear whether this type of exposure
    would increase the lead body burden and toxicity from this route is
    thought to be unlikely.

     Organic lead

    Organic lead compounds are not irritant but may be absorbed through
    the skin.

    5.3.9  Eye, ears, nose and throat

     Inorganic lead

    Hearing impairment has been described in children with elevated lead
    levels (Clement International corporation 1993).

     Organic lead

    Nystagmus may be a feature of organic lead exposure. Limited upward
    gaze has also been reported (Poisindex, 1994). Tinnitus has been
    reported following the inhalation of tetraethyl lead fumes (Poisindex
    1994).

    5.3.10  Haematological

     Inorganic lead

    Lead may cause haemolysis and hypoproliferative anaemia (Cullen et al
    1983). This is generally hypochromic monocytic anaemia with a decrease
    in mean corpuscular haemoglobin and stippling of erythrocytes and
    reticulocytes.

    Red blood cell zinc protoporphyrin (known as erythrocyte
    protoporphyrin or EP) will be raised.

     Organic lead

    Anaemia, basophilic stipling and neutrophilia may occur.

    5.3.11  Immunological

     Inorganic lead

    There is some evidence to suggest that lead may cause adverse effects
    on the cellular component of the immune system in lead workers with
    blood lead levels exceeding 500 g/L (2.41 mol/L) but there few human
    studies have been carried out (Clement International Corporation 1993,
    WHO 1995).

    5.3.12  Metabolic

    5.3.12.1  Acid-base disturbances

    No data.

    5.3.12.2  Fluid and electrolyte disturbances

    No data.

    5.3.12.3  Other

     Inorganic lead

    ALAD is depressed which leads to an increase in urinary and blood
    delta-aminolevulinic acid (ALA) concentrations. Urinary coproporphyrin
    is also usually raised.

    Blood concentrations of 1,25 dihydroxy vitamin D may be reduced.

     Organic lead

    Both hypothermia and pyrexia have been reported. ALAD concentrations
    may be reduced.

    5.3.13  Allergic reactions

    No data

    5.3.14  Other clinical effects

    No data.

    5.4  At risk groups

    5.4.1  Elderly

    No data.

    5.4.2  Pregnancy

    5.4.3  Children

    Children appear to be more susceptible than adults to the toxic
    effects of lead because of incomplete development of the blood brain
    barrier, greater intestinal absorption of lead, and a tendency to put
    objects or their hands into their mouths thereby increasing ingestion
    of contaminated substances. In addition, they have a smaller
    proportion of dense bone tissue than in adults which reduces the total
    transfer of the absorbed lead into bone, so that it remains in the
    soft tissues where it produces toxic effects (Knodel, 1995).

    Disproportionate numbers of children from lower socioeconomic
    backgrounds have high lead levels. This may be because they live in
    older poorly maintained housing where old lead paint and lead water
    pipes may remain (Bellinger et al 1989).

    5.4.4  Enzyme deficiencies

    No data.

    5.4.5  Enzyme induced

    No data.

    5.4.6  Occupations

    It is thought that millions of workers may be exposed to lead in the
    United States and Europe (Cullen et al 1983).

    The highest and most prolonged lead exposures have been seen among
    workers in the lead smelting, refining and manufacturing industries.
    Potentially high lead levels may also occur in steel welding or
    cutting operations, construction, rubber and plastics industries,
    printing industries and other industries requiring flame soldering of
    lead solder (Clement International Corporation 1993).

    There have been reported cases of lead toxicity in occupations
    including stained glass workers (Baxter et al 1985), mechanics
    (Goldman et al 1987), painters (Ennever et al 1995), in the
    manufacture of batteries and lead smelting (Williamson and Teo 1986),
    manufacture of lead pigments (Davies 1984) and workers on firing
    ranges (Chan et al 1995).

    5.4.7  Others

    There is some evidence to suggest that people with iron-deficiency
    anaemia are more prone to lead toxicity, as lead impairs iron
    utilization for haem biosysnthesis and thus exacerbates iron
    deficiency. Calcium deficiency greatly enhances lead absorption and
    during periods of low calcium lead may be mobilised from tissue stores
    particularly bone. Lead poisoning may also recur in the presence of
    osteoporosis indicating that bone can be a significant source of lead
    level elevation in conditions associated with accelerated resorption
    (Shannon et al 1988).

    Some ethnic groups may be more at risk of lead poisoning because of
    the use of traditional remedies (Middleton 1989) or cosmetics.

    In some groups the inhalational abuse of leaded petrol can be
    relatively common (Burns and Currie 1995).

    6.  MANAGEMENT

    6.1  Decontamination

     Inorganic lead:

    An X-ray should be performed to confirm the acute ingestion of a lead
    weight or similar foreign body. Gastric decontamination is not
    indicated, although a mild laxative may be given. A further X-ray
    should be done if the foreign body has not been passed in the stools
    after 48 hours and surgical removal may be indicated if it has become
    lodged in the gastrointestinal tract or the patient develops marked
    symptoms.

    Gastric lavage is recommended within 2 hours of an acute ingestion of
    lead salts and an X-ray will confirm effective removal. Activated
    charcoal does not adsorb lead.

    In cases of chronic toxicity an abdominal X-ray should be performed to
    determine whether lead is present in the gut. Specks or flecks of
    highly radio-opaque material will be seen, almost as if the film has
    faults. Chelation therapy should not begin until the X-ray is clear so
    a mild laxative should be given or whole bowel irrigation performed,
    depending on the clinical condition of the patient and the urgency to
    start chelation therapy.

    In cases of patients who have retained gun shot pellets they do not
    have to be removed unless they are in a position where the insoluble
    lead phosphate coating will be eroded (e.g. in a joint).

     Organic lead

    In cases of dermal exposure contaminated clothing should be removed
    and the area thoroughly irrigated.

    6.2  Supportive care

     Inorganic lead:

    Management entails identifying and removing the source of the lead,
    symptomatic care and using chelating agents if indicated.

    GI disturbances and renal impairment should be treated supportively.
    Anaemia should be treated with iron supplements.

    Convulsions as a result of acute encephalopathy may be treated with
    diazepam. Mannitol and corticosteroids should be used for cerebral
    oedema.

     Organic lead:

    Chelating agents are not useful for organic lead poisoning. Treatment
    is symptomatic and supportive.

    6.3  Monitoring

     Inorganic lead:

    Blood lead concentration should be determined to confirm the diagnosis
    of lead toxicity, the urgency of this analysis will depend on the
    clinical condition of the patient. In children ensure blood samples
    are obtained by venipuncture only, as finger-puncture or capillary
    blood samples may show elevated lead concentrations as a result of
    skin contamination.

    In children, blood lead concentrations (prior to any treatment or
    other action to abate exposure) of:-
    a) greater than 250g/L (1.2mol/L) may require chelation therapy
    although there is no consensus.
    b) greater than 400g/L (1.9mol/L) require treatment with either DMSA
    (succimer) or sodium calciumedetate.
    c) greater than 600g/L (2.9mol/L) are a medical emergency and
    require immediate chelating agent, sodium calciumedetate is the
    treatment of choice.

    Pharmacological intervention is not needed for blood lead
    concentrations of less than 250g/L (1.2mol/L), however in all cases
    the source of the lead must be identified and removed. The blood lead
    concentration should be monitored at least every three months and
    ideally every 4-6 weeks.

    In adults, blood lead concentrations (prior to any treatment or other
    action to abate exposure) of:-
    a) greater than 400g/L (1.92mol/L) may require treatment with
    chelating agents if the patient is symptomatic, although this is
    unlikely.
    b) greater than 800g/L (3.86mol/L) will require treatment with
    chelating agents if the patient is symptomatic which is quite likely.
    c) greater than 1200g/L (5.79mol/L) require treatment with chelating
    agents as patients are very likely to have symptoms.

    Most standard tests of renal function do not appear to detect early
    effects of lead exposure (Winship, 1989). However renal function
    should be assessed as renal tubular damage, characterised by
    aminoaciduria, hypophosphataemia and glycosuria, sometimes followed by
    hyperphosphataemia, has been reported. Increased urinary uric acid and
    hyperuricaemia are seen as a consequence of chronic renal damage.

    Since several nutritional and dietary deficiencies will increase the
    absorption of lead they must be excluded. Assess plasma concentrations
    of calcium, phosphorous, iron and zinc as well as total intake of
    calories, fat, ascorbic acid, vitamin D and protein.

    Chelating agents can be nephrotoxic (sodium calcium edetate),
    hepatotoxic (succimer) and deplete systemic copper and zinc. If the
    drugs are being used regular monitoring must taken place.

    Full blood count and iron studies should be performed as microcytic
    hypochromic anaemia is common. Reticulocytosis and punctate basophilia
    can occur.

    The following tests may be considered but are not considered
    essential: red blood cell zinc protoporphyrin (known as erythrocyte
    protoporphyrin or EP) is raised, urinary delta-aminolevulinic acid and
    coproporphyrin are also raised and the blood concentration of 1,25
    dihydroxy vitamin D is reduced.

    6.4  Antidotes

    There are a number of chelating agents available to treat inorganic
    lead toxicity. The aim of chelation therapy is to reduce the lead
    concentration to less than 150 g/L (0.72 mol/L) and ideally to less
    than 100 g/L (0.48 mol/L). After therapy there is a period of
    re-equilibriation of 10-14 days after which the lead concentration
    should be measured in order to determined the need for further courses
    of chelation. 

    Antidotes are of no benefit in organic lead poisoning.

    a) SODIUM CALCIUMEDETATE (Ledclair)
    This drug forms chelates with metal ions that have a higher affinity
    for sodium calciumedetate than calcium. It has to be given
    parenterally because of its low bioavailability following ingestion.
    It has a high incidence of side effects and should be given with
    antihistamine cover, however it is the treatment of choice in serious
    lead toxicity. When sodium calciumedetate is given in combination with
    dimercaprol there is a more rapid decline in lead concentrations
    (Chisholm, 1992) but the rationale for the use of these two agents
    together has recently been questioned (O'Connor, 1992).

     Dosage: up to 80mg/kg body weight/day in 2 equal divided doses (8-12
    hours apart) by slow IV infusion for 5 days. Contents of 5ml ampoule
    should be diluted with 250-500ml of normal saline or 5% dextrose and
    the dilute solution given over at least an hour. The concentration
    should not exceed 3% of the infusate.

    The above daily regime can be given by IM. injection divided into 2 or
    4 injections with procaine as an anaesthetic.

    Therapy is continued for up to 5 days, followed at least 48 hours
    later, by a further course for a maximum of 5 days. If further courses
    are necessitated there must be an interval of at least 7 days before
    recommencing therapy.

     Adverse effects: Nausea and cramp, particularly during IV
    administration. Can be nephrotoxic so i.v. hydration is required and
    U&Es should be checked daily

    b) SUCCIMER (MESO-2,3-DIMERCAPTOSUCCINIC ACID, DMSA)
    (Chemet - 100mg only)
    This is a water-soluble analogue of dimercaprol which is active
    orally. It appears to be relatively specific for heavy metals and to
    only minimally enhance the excretion of iron, zinc and calcium. It is
    not licensed for use in the UK and is available on a named-patient
    basis from NPIS (London) as 100mg or 300mg capsules (the 100mg
    capsules are also available from McNeil, USA). There are several
    reviews on the use of succimer (Mann and Travers 1991, Glotzer 1993).

     Dosage: orally 30 mg/kg body weight daily, in three divided doses,
    for 5 days, then 20 mg/kg, in two divided doses, for 14 days.

     Adverse effects: Gastrointestinal symptoms and rashes may occur.
    Mild to moderate neutropenia has been reported and a complete blood
    count should be obtained prior to and weekly during treatment with
    succimer. Transient mild elevations of serum transaminases have been
    reported so serum transaminases should be monitored prior to and
    weekly during treatment with succimer.

    c) DIMERCAPROL (BAL)
    Chelation complexes are formed between the sulphydryl groups of this
    drug and metals. It cannot be administered orally and is given as a
    deep IM injection in peanut oil. It is contraindicated in patients
    sensitive to peanuts. It is available in 2ml ampoules of 50mg/ml.

     Dosage: By IM injection 2.5-3 mg/kg every 4 hours for 2 days, 2-4
    times on the third day, then 1-2 times daily for 10 days or until
    recovery.

     Adverse effects: These are relatively frequent but are almost always
    reversible. The following have all been reported: hypertension;
    tachycardia; nausea and vomiting; a burning sensation of the lips,
    mouth, throat and eyes; salivation and lacrimation; conjunctivitis;
    rhinorrhoea; muscle pain and spasm; headache; tingling of the hands
    and other extremities; a feeling of constriction in the chest and
    throat; sweating of the forehead and hands. Local pain and abscess may
    occur at the site of the injection and children can develop a fever
    after the second or third injection which persists until treatment is
    terminated.

    d) PENICILLAMINE (Distamine, Pendramine)
    Penicillamine is well absorbed from the gastrointestinal tract so is
    used orally and is available as 50mg, 125mg and 250mg tablets. There
    is a risk that patients allergic to penicillin may have an anaphylatic
    reaction to penicillamine but preparations no longer contain traces of
    penicillin (Klaassen, 1990). With the introduction of succimer the use
    of penicillamine in lead poisoning is declining.

     Dosage: Orally, adults 1-2g daily and children 20 mg/kg body weight
    per day in divided doses until blood lead level falls below toxic
    level.

     Adverse effects: Nausea, anorexia, fever and rash. Thrombocytopenia
    and less commonly neutropenia can occur, so full blood counts should
    be carried out weekly or fortnightly during therapy. Proteinuria and
    rarely haematuria and other complications such as Stevenson-Johnson
    syndrome have been described.

    6.5  Elimination techniques

    Elimination is dependent chiefly on the urinary excretion of the
    lead-chelate complex and there is no indication for extracorporeal
    elimination.

    6.6  Investigations

    a) Sodium calciumedetate mobilization (challenge) test
    This is used to assess the size of the chelatable lead stores. A
    single IV dose of 1g (adults) and 500mg/m2 (children, maximum dose of
    1g) sodium calciumedetate, diluted in 250-500ml of 5% dextrose or
    normal saline is given over 1 hour. Alternatively it can be given IM
    undiluted with procaine. The patient's urine is then collected for the
    next 24 hours (adults) or 6-8 hours (children). The lead excretion
    ratio calculated is the total urinary lead (in g) excreted per
    milligram of sodium calciumedetate administered i.e.

                   total urinary lead excreted (g)
              total dose of sodium calciumedetate given (mg)

    The test is considered positive if the ratio exceeds 1 by some authors
    (Markowitz and Rosen 1984) or 0.6 in children (Piomelli et al 1984).

    b) Succimer provocation test
    Succimer (DMSA) has been used instead of sodium calciumedetate as a
    diagnosis of lead poisoning (Bentur et al 1987). 270mg of succimer was
    administered orally and the ratio above used, substituting the dose of
    sodium calciumedetate with that of succimer.

    Other workers (Lee et al 1995) have compared provocation chelation
    with succimer and sodium calciumedetate, using an oral dose of
    succimer of 10mg/kg in adults. They conclude that using succimer may
    provide an estimate of lead in storage sites that is more directly
    relevant to the health effects of lead.

    c) Radiographic studies
    Bone X-rays are used in the diagnosis of lead poisoning as increased
    density is an indication of exposure to lead of several months
    duration.

    X-ray fluorescence can be used to non-invasively quantify bone lead
    stores. A superficial bone, such as the tibia, is exposed to a low
    energy X-ray beam and the fluorescence photons are counted. This count
    can be converted into a bone lead concentration. The technique has
    been used evaluate sodium calciumedetate chelation therapy on the bone
    lead levels (Rosen and Markowitz 1993).

    d) Identifying the source of the lead
    The most important aspect in the successful treatment of lead
    poisoning is the identification and elimination of the source of the
    lead.

    In adults this is usually occupational, although it may result from
    contaminated food or water or through the use of traditional
    medicines. In children it is often as a result of behavourial
    disturbances such as pica.

    A comparison of the isotopes of lead in samples of suspected sources
    (e.g. water, air, soil, food, cooking utensils, paint or jewellery) to
    the lead isotopes found in the blood can be used to confirm the source
    of lead. The blood lead concentrations of patient's immediate family
    should also be determined.

    6.7  Management controversies

    Children, and especially young children, are much more susceptible
    than adults to the effects of lead poisoning. However, despite the
    fact that gross effects on health were well recognised, a survey of
    paediatric departments in the United States found no common approach
    for the treatment of lead toxicity (Glotzer and Bauchner 1992).
    Factors contributing to this are the concerns about neurotoxicity with
    blood lead concentrations of 100 g/L and the availability of a safer
    orally acting antidote, succimer. The decision as to when to begin
    chelation therapy is not clear-cut, especially at blood lead
    concentrations of between 250g/L and 400g/L. The controversies and
    suggested protocols are well reviewed in two recent papers (Commitee
    on Drugs 1995, Mortensen and Walson 1993).

    Although chelation therapy has been used for many years in the
    treatment of lead poisoning, there is a lack of data regarding its
    efficacy in terms of clinical outcome (Kosnett, 1992). Chelation
    increases the urinary excretion of lead, but does excretion equal
    efficacy? The Food and Drug Administration in the United States has
    approved succimer for use in childhood lead poisoning with little
    published data on its pharmacokinetics in children. Pharmacokinetics,
    proper dosing and efficacy are particularly important because of the
    potential that the drug will be widely used in children with low-level
    asymptomatic lead poisoning (Mortensen, 1994).

    There is no evidence that available chelation agents have significant
    access to lead stored in the brain. A study in rats found that brain
    lead content increased following a single dose of sodium
    calciumedetate (Cory-Slechta et al 1987) which raises concerns that
    chelating agents redistribute lead from less to more vulnerable body
    tissues (e.g. bone to brain).

    7  CASE DATA

    Cases 1, 2 and 3: Chronic ingestion in children

    A 2 year 6 month old boy presented to the casualty department
    convulsing. Phenobarbital failed to control the fitting which
    eventually abated after diazepam was administered. The child's mother
    stated that the boy had a 2 week history of irritable behaviour and
    difficulty sleeping. He appeared thin, pale and malnourished with 

    blood pressure 100/80 mm Hg, pulse 120 beats/min, temperature 38.5C
    and respiration 32 breaths/min. Hard faeces were found on rectal
    examination. Neurological examination revealed diffuse hypotonia with
    symmetrically depressed deep-tendon reflexes and bilateral plantar
    extension. The neck was supple and there was no papilloedema. A lumbar
    puncture was performed but because the opening pressure was
    unexpectedly high (230 mm Hg) only a small amount of fluid was
    collected. A mannitol infusion was started immediately. Blood analysis
    showed normal values for glucose, BUN, electrolytes and LFTs. The CBC
    showed Hb 9.8 g/100ml, Hct 33% and WBC count 14,000/mm3. The
    differential was normal except for the presence of RBCs with
    basophilic stippling. The reticulocyte count was 3.9%. The CSF protein
    was 70 mg/100ml, glucose 55 mg/dL, with 12 WBCs (all lymphocytes).
    Gram stain India ink prep for cryptococcus, and AFB stains of the CSF
    sediment failed to reveal any organisms. The ECG showed sinus
    tachycardia with normal axis for the patient's age, and T wave
    inversions in V5 and V6. A urine sample obtained after treatment
    had 2+ glucose and 1+ protein but no ketones or cells.

    The mother noted that her other two sons (aged 4 and 6 years) had also
    been irritable, listless and apathetic and on occasion had refused to
    eat over a period of several weeks, but both had recently had a
    flu-like illness. When questioned further she stated that the symptoms
    were vomiting, headache, and diffuse aches and pains. The 6 year old
    was physically examined and no abnormalities were found. The 4 year
    old was found to be ataxic, with bilateral wrist-drop and a blue line
    at the base of the gums.

    Abdominal X-ray of the 2 and 4 year old showed characteristic
    opacities suggesting recent ingestion of lead containing particles.
    Lead poisoning was confirmed by the presence of 3+ qualitative urinary
    coproporphyrins and elevated erythrocyte protoporphyrin. Both children
    were admitted and given a magnesium sulphate cathartic, a cleansing
    enema and chelation therapy. X-rays of the wrists and knees revealed
    lead lines in all three children (Goldfrank et al 1990)

    Case 4: Chronic ingestion - confusion in diagnosis

    Symptoms such as abdominal pain, anorexia, joint pain and anaemia can
    be confused with other disorders. In this case lead poisoning was
    mistaken for sickle cell crisis in a 12 year old boy known to have
    sickle cell anaemia.

    The patient presented to hospital complaining of severe abdominal and
    bilateral knee pain with intermittent vomiting. His last sickle cell
    crisis had occurred five months earlier and gave rise to abdominal
    pain. Physical examination revealed enlarged tonsils and erythematous
    oropharynx. Blood pressure was 100/70 mmHg; pulse 100, respirations 16
    and temperature 37.1C rectally. Laboratory analysis revealed normal
    urinanalysis, haemocrit 16.3%, WBC 13,000 cells/mm2 (with 39 bands,
    33 neutrophils, 16 lymphocytes, 12 monocytes and reticulocytes 14.1%).
    A diagnosis of vasooclusive crisis was made and the patient discharged
    home on codeine 15 to 30 mg by mouth every three to four hours as
    needed.

    The patient returned three days later complaining of continued
    abdominal pain as well as a convulsion that lasted two to three
    minutes and resolved spontaneously. The patient's mother described it
    as a generalized tonic-clonic convulsion. The patient had no history
    of convulsions and denied any drug ingestion. Blood pressure was 95/70
    mmHg, pulse 110, respirations 18 and temperature 37.2C rectally.
    Physical examination revealed dried blood in the right nostril,
    diffuse abdominal tenderness and a normal neurological examination.
    Laboratory data included haemocrit 18.3%, WBC 19,600 cells/mm2 (with
    a normal differential and reticulocytes 23.8%). The impression was of
    vasooclusive crisis and the patient was again discharged home with
    codeine.

    The patient returned again 24 hours later complaining of anorexia,
    constipation, persistent vomiting as well as abdominal and knee pain.
    He became increasingly lethargic and obtunded. Vital signs were as
    follows: blood pressure 90/60 mmHg, pulse 125, respirations 22 and
    temperature 38.5C rectally. The abdomen was soft with diffuse
    tenderness and decreased bowel sounds. On neurological examination the
    patient occasionally responded to vocal commands. Cranial nerves were
    intact although a right gaze preference was noted. The patient was
    hyperreflexic and hypertonic. He moved all limbs appropriately in
    response to pain. Initial laboratory results were as follows:
    haemocrit 19.6%, WBC 24,500 cells/mm2 (with two myolocytes, 23 bands,
    48 neutrophils, 10 lymphocytes, 14 monocytes and 3 atypical
    lymphocytes), normal electrolytes and ammonia. A blood urine and urine
    toxicology screen which did not include heavy metals was negative. The
    patient was admitted to the paediatric intensive care unit for further
    investigation. Lumbar puncture, computed tomography scan with contrast
    and EEG were normal. A chest X-ray showed mild cardiomegaly. Knee
    X-rays showed bilateral bands of increased density at the metaphyseal
    plate. During the next few days the patient became increasingly
    obtunded with occasional periods of agitation. His lead level was 1001
    mg/L. Treatment with dimercaprol 500 mg/m2/day and calcium edetate
    1,500 mg/m2/day was started immediately. After three days of
    chelation therapy his lead level had fallen to 500 mg/L and one week
    after chelation therapy started he had begun to respond to verbal
    commands. The patient was eventually discharged from a chronic care
    facility after two months. During a routine follow up investigation
    one year later the patient was found to have a less severe case of
    clinical lead poisoning but further chelation therapy was not
    necessary. The source of the lead was thought to be house paint
    (Nelson and Chisholm 1986).

    Case 5: Child - ingestion of traditional remedy

    A 2 year old boy was admitted to hospital with a temperature of
    37.8C. The diagnosis was dehydration and severe electrolyte imbalance
    following prolonged diarrhoea syndrome which lasted for seven days and
    hypochromic anaemia. The patient died within a few hours of
    hospitilization. The child had been given a teaspoonful of a yellow
    powder three times a day for 3 days prior to admission. One sister of
    the patient had died in similar circumstances. A postmortem was not 

    performed but the yellow powder was identified as lead oxide by
    analysis (Cueto et al 1989).

    Case 6: Chronic in a child - reversible acute renal
    failure

    A 26 month old girl was admitted to hospital with a one week history
    of anorexia, vomiting, lethargy and pallor. She had been routinely
    screened at another healthcare facility three weeks earlier and had an
    elevated blood lead level of 970 g/L. She had been hospitalised and
    given calcium disodium edetate 150 mg and dimercaprol (BAL) 48 mg
    intramuscularly every four hours for seven days. Blood urea nitrogen
    level was 22 mg/100ml before and after therapy. Serum creatinine
    concentrations had not been measured. Follow up had revealed a blood
    lead level of 320 g/L.

    Physical examination of the patient showed a pale, mildly dehydrated
    child with normal pulse, respiration and temperature. Her blood
    pressure was 92/64 mmHg. She was admitted to hospital and blood
    analysis revealed a haemocrit of 22.1%, reticulocytes 0.3%, platelets
    340,000/mm3 and leucocytes 20,400/mm3 with a normal differential.
    The red blood cell indices indicated iron deficiency anaemia. There
    was no basophilic stippling. Bleeding and coagulation profiles were
    normal except for glucose-6-phosphate dehydrogenase deficiency.
    Urinanalysis revealed proteinuria, BUN 113 mg/100ml and serum
    creatinine 13.4 mg/100ml. The urine was not examined for amino acids.
    Her serum cholesterol was elevated. In view of this severe renal
    failure further management included complete restriction of protein
    and appropriate intravenous fluid administration. Her blood lead level
    on admission was 210 g/L. The patient was discharged after 17 days
    and two weeks later urinanalysis was normal. Twenty months after
    admission the patient was in excellent health. This severe acute renal
    failure could have been associated with either chelation therapy or
    preexisting lead nephropathy or both and was further complicated by
    glucose-6-phosphate dehydrogenase deficiency (Khan et al 1983).

    Case 7: Child - ingestion of metallic lead

    A nine year old girl complaining of abdominal cramping presented to an
    emergency department two days after ingesting a lead muzzle ball. An
    abdominal X-ray confirmed the presence of the ball in the right upper
    quadrant of the small intestine. A baseline blood lead level was 150
    g/L. She was given magnesium citrate cathartic and discharged home.
    She returned to hospital six days later having had normal bowel
    movements but had not passed the ball. She had experienced
    intermittent abdominal cramping and the day before returning to
    hospital she had felt lethargic, with a decreased appetite, headache
    and dysuria. At the time of presentation her temperature was 39.5C,
    pulse 128 beats per minute, respiration 28 per minute and blood
    pressure 128/72 mmHg. Her abdomen was soft with normal bowel sounds.
    She had diffuse abdominal tenderness with no rebound or guarding.
    Laboratory analysis revealed a white blood cell count of 3.3x103/mm3 

    with 62% segmented neutrophils, 6% band neutrophils and 31%
    lymphocytes. The remainder of the complete blood count, serum
    electrolytes, urinanalysis and erythrocyte sedimentation rate were all
    normal. Serial abdominal X-rays during her stay in hospital showed
    gradual movement of the ball through the bowel. A 24 hour urine
    collection for lead excretion revealed a lead concentration of <100
    g/L. On the second and third days in hospital her blood lead levels
    were 80 g/L and 70 g/L respectively. The rest of her stay in
    hospital was uneventful apart from mild diffuse abdominal cramps. On
    the fourth day in hospital (11 days post ingestion) the lead ball was
    passed in the stools completely intact with no evidence of corrosion.
    The blood lead level after the ball had been passed was found to be 50
    g/L. Analysis of the muzzle ball revealed that it was 95% lead and 5%
    antimony with traces of titanium, manganese, iron, nickel and copper
    also detected (Durback et al 1989).

    Case 8: Fatal in a child - ingestion of metallic lead

    A 23 month old female presented with a two week history of flu-like
    symptoms and an episode of vomiting on the day of admission. The child
    had shown normal growth and development following a premature birth
    and surgical repair for gastroschisis. Physical examination showed the
    child to be rather pale. She was crying but was easily consolable and
    was alert and cooperative. Her temperature was 37.2C (oral), blood
    pressure 112/70, pulse 110 beats per minute and a respiratory rate of
    16 per minute. Her abdomen was soft with no guarding, rebounding or
    tenderness. Neurological examination was normal. Blood tests showed
    haemoglobin of 8.0 g/100ml with a mild hypochromic microcytic smear.
    White blood cell count was 16,700 per mm3 with 25% bands. A
    diagnosis was made of probable gastroenteritis and anaemia of unknown
    etiology. The patient's mother was told to continue giving clear oral
    fluids and to return if symptoms worsened. Later that day the
    patient's mother contacted the surgeon who had performed the
    gastroschisis repair and the patient was admitted to the surgical unit
    for evaluation of possible intermittent intestinal obstruction. At the
    time of admission the physical examination was unchanged. Repeat
    laboratory analysis showed haemoglobin 8.2 g/100ml and haemocrit 24%.
    White blood cell count was 15,700 per mm3 with 29% bands. Platelet
    count was 338,000. SGOT was 43 units per ml. Total bilirubin was 1.2
    mg/100ml. Serum ammonia was 22 g/100ml. Serum osmolality was 279
    milliosmoles. Sodium was 140 mEq/L, potassium 4.6 mEq/L, chloride 106
    mEq/L total CO2 was 16.1 mEq/L, creatinine 1.6 mg/100ml. Repeat
    urinanalysis was normal. An abdominal X-ray was taken to rule out the
    possibility of obstruction. This revealed a small radiopaque object in
    the left upper quadrant but no evidence of obstruction. The
    significance of the presence of a foreign body was not appreciated and
    the initial impression was that of a probable viral syndrome; and the
    patient was rehydrated intravenously. Approximately ten hours after
    admission the patient had a grand mal tonic clonic convulsion and was
    found unresponsive in respiratory arrest. Her pupils were fixed and
    dilated with the eyes deviating to the right. Phenobarbitone was
    administered. She was transferred to the intensive care unit where

    over the next couple of hours she became comatose with response to
    painful stimuli only. Convulsions continued which were treated with
    phenobarbitone and the patient was ventilated. Despite aggressive
    supportive therapy the patients condition continued to worsen becoming
    decerebrate, completely unresponsive with fixed dilated pupils and 18
    hours after admission the patient was pronounced dead. Shortly after
    her death the abdominal X-ray films were reexamined and because of her
    overall clinical course and the presence of the radiopaque body in her
    stomach the possibility of lead poisoning was considered. Her
    premortem blood lead level was 2830 g/L. Postmortem findings included
    diffuse cerebral oedema and hyperaemia of the lungs, liver and spleen.
    A 2 cm x 3 cm metallic body was found in the stomach which was later
    identified as a lead curtain weight. The object was bile stained with
    some local mucosal irritation which suggested that it had been in the
    stomach for some time. The patient's mother estimated that the child
    must have ingested it approximately one month prior to admission
    (Hugelmeyer et al 1988).

    Case 9: Chronic ingestion in an adult - illegally distilled
    alcohol (moonshine)

    A 28 year old chronic alcoholic male presented to the casualty
    department with a history of twelve convulsions over the previous four
    days. He appeared lethargic and disorientated. His vital signs were
    normal apart from a raised temperature. Physical examination revealed
    purulent conjunctivitis. A preliminary diagnosis of diffuse metabolic
    encephalopathy of unknown etiology and possible lead poisoning was
    made.

    Blood tests showed white blood cell count of 13,000/mm3 with 91%
    neutrophils. There was marked basophilic stippling of the red cells in
    the peripheral blood. His convulsions continued. On the fifth day of
    admission lead encephalopathy was suspected and intravenous Ca EDTA
    therapy was started. Over the next two days the convulsions abated and
    the patient was able to give appropriate responses to simple
    questions. The lead levels determined in 24 hour urine collection on
    the first two days of therapy were 6.6 and 5.2 mg/L respectively.
    Three separate five day courses of CaEDTA therapy were given over the
    next three weeks. The patient was left with a chronic brain syndrome
    thought to be due to lead encephalopathy (Whitfield et al 1972).

    Case 10 Acute ingestion in an adult - traditional
    remedy

    A 50 year old man complaining of impotence for several months
    consulted his general practitioner after developing progressive
    general malaise, anorexia, vague abdominal discomfort and impaired
    taste. A blood count was arranged as part of his investigations. This
    showed mild anaemia with a haemoglobin concentration of 11.9 g/100ml
    and a normal white cell and platelet count. His peripheral blood film
    showed coarse basophilic stippling and occasional circulating
    nucleated red cells. His physical examination was normal. His blood
    lead level was 960 g/L and erythrocyte (zinc) levels were high at 89

    g/100ml. Analysis of urinary porphyrins showed total porphyrins 1446
    g/100ml (normal <150), urinary delta aminolaevulinic acid levels
    raised at 319 g/100ml (normal <34) and normal urinary
    porphobilinogen of 5.8 mol/L. His bone marrow showed erythoid
    hyperplasia with prominent siderotic granules and ringed sideroblasts
    consistent with lead toxicity. He had no history of occupational
    exposure to lead and his wife's lead level was 20 g/L. He admitted
    taking three preparations given to him by an traditional Asian
    practitioner for the treatment of impotence. These consisted of a
    brown paste, some brown pellets and a yellow-white powder. He had been
    taking these orally for five weeks before presentation. Samples of
    these preparations were analysed for lead and the yellow-white powder
    was shown to have a very high lead content. It contained lead oxide,
    lead nitrate, and lead sulphate with a total of 84% elemental lead by
    weight. Since he had no major clinical problems after consultation,
    chelation therapy was deemed unnecessary and after four weeks his
    blood lead levels had decreased to 550 g/L (Dolan et al 1991).

    Case 11: Lead poisoning from retained bullet

    A 73-year old man complained of suffering from increasing weakness,
    progressive difficulty in carrying out routine tasks and shortness of
    breath over a period of 2 weeks. He also complained of accentuation of
    longstanding bilateral leg pain that resulted from a gunshot wound to
    his right hip 52 years earlier. For several months he had suffered
    from decreased appetite and chronic epigastric pain. He had a previous
    history of hypertension, cholecystectomy and left hernia repair.

    Physical and neurological examinations were normal. He had a
    haemoglobin of 6.9 g/100ml and a haemocrit of 21.7%. His white blood
    cell count was 6000 cells/100ml, platelet count 234000/100ml and his
    reticulocyte count was elevated at 5.7%. A peripheral blood smear
    showed marked polychromasia with occasional target cells, histocytes
    and ovalocytes. The patient was investigated for haemolytic anaemia
    and an autoimmine process was excluded. A bone marrow biopsy showed
    features of refractory anaemia with ring sideroblasts. The patient's
    serum lead level was found to be elevated at 4600 g/L (normal <250
    g/L). X-rays showed a bullet partially imbedded in the medial portion
    of the right acetabulum and partially protruding into the joint space.
    There were several tiny metallic fragments within the joint cavity.
    The right hip joints had changes of severe osteoarthritis with
    osteophytes, joint space narrowing, subchondral cysts and sclerosis.
    The left hip joint was normal. The patient was given three units of
    packed red blood cells and underwent removal of the intra-articular
    bullet fragments together with a total hip replacement. He made a
    satisfactory recovery with symptomatic improvement (Peh et al 1995).

    Case 12: Lead poisoning from sniffing petrol

    A 14 year old boy was admitted with a six day history of chorea and
    increasing mental confusion. He was known to have sniffed petrol for
    several hours a day for four or five years and was in the habit of
    falling asleep beside an open petrol can. He appeared mute and unable

    to follow simple commands. He had upward gaze limitation and rotary
    nystagmus on lateral gaze. Deep tendon reflexes were absent and both
    plantar responses were extensor. His haemoglobin was 14.2 g/100ml with
    moderate basophilic stippling, BUN 44 mg/100ml, serum creatinine
    phosphokinase (CPK) 38,193 iu/L (normal 5-98 iu/L), SGOT 163 iu/L
    (normal 4-20 iu/L), blood ammonia 143 g/L (normal 20-120 g/L) and
    blood lead 1690 g/L. X-rays of his distal radius showed no lead
    lines. His EEG showed generalised 1 to 6/s, 10 V waves but no
    cortical activity. His conduction velocities were slowed to 60% of
    normal. He passed a small amount of blood stained urine and his BUN
    and plasma potassium rose rapidly. Peritoneal dialysis was started as
    was disodium calcium edetate therapy. During the following week his
    signs of hepatocellular and muscle damage regressed and he passed
    increasing amounts of isothenuric urine. Despite chelation therapy his
    blood lead level remained elevated at 1490 g/L and there was no
    change in his level of consciousness or his movement disorder. He
    suffered a cardiorespiratory arrest associated with the introduction
    of 500 ml of diasylate into the peritoneal cavity. Despite rapid
    restoration of cerebral perfusion his chorea was replaced by
    decerebrate posturing and he died two weeks later. By the 22nd day he
    had received eight 500 mg doses of disodium calcium edetate and his
    blood lead level had fallen to 390 g/L.

    At postmortem the brain was found to be oedematous and there was
    hypoxic changes with necrosis of hippocampal nerve cells and a focus
    of demyelination in the ventral aspect of the pons. The cut surface of
    the liver showed small foci of yellowish discolouration due to
    centrilobular necrosis compatible with hypoxic damage. The left kidney
    contained several abscesses and the right kidney had an oedematous
    stroma and diffuse changes of acute and chronic inflammation but
    preservation of glomerular and tubular architecture (Robinson 1978).

    Case 13: Probable intentional lead poisoning

    A 27 year old female painter presented to a hospital in Germany
    complaining of general malaise, nausea and vomiting, colicky abdominal
    pain and constipation. The appendix was removed at laparotomy and was
    found to be normal. Her abdominal pain persisted. She was noticed to
    have a blue line on her upper gingival margin and lead poisoning was
    suspected. Her haemoglobin was 7.4 g/100ml with no basophilic
    stippling, blood lead level 3.7 mol/L, delta-aminolaevulinic acid
    excretion was 83.9 mol/24 h and her bone marrow was sideroblastic.
    Oral penicillamine improved her symptoms but no source of lead could
    be found in her home.

    One year later she presented to a UK hospital again complaining of
    general malaise and intermittent colicky abdominal pain. Subacute
    bowel obstruction was diagnosed. Her haemoglobin was 12.0 g/100ml, her
    blood lead level 1.9 mol/L with basophilic stippling and her 24 hour
    urinary delta-aminolaevulinic acid excretion was normal. Her symptoms
    resolved but one month later she returned with similar symptoms as
    well as bilateral wrist drop and muscle pains. On this occasion her

    blood lead level was 4.3 mol/L, urinary 15,300 nmol/24h (normal
    <300) and her faecal excretion was 313,066 g/24 h (normal 200-500)
    which indicated further exposure.

    The patient used an Indian eye-liner which was found to contain 69%
    lead. She stopped using this and was treated with intravenous calcium
    edetate and oral penicillamine. However her symptoms continued and her
    blood lead level remained at 4-5 mol/L. She was admitted to hospital
    several times with exacerbations of her symptoms and found to have
    raised urinary lead levels. She persistently denied deliberate
    ingestion of lead. Her home and art studio were searched for the lead
    source. The patient had bought a large sack of what she believed to be
    "titaniun white" powder in Germany several years before. This was
    found to contain 47% lead by weight and was probably "lead white" i.e.
    basic lead carbonate. The patient denied the common practice of
    painters licking their paintbrushes to achieve a fine point but
    admitted that she often mixed the powder to form a paste and applied
    it to the canvas with her hands. Also when she scooped powder out of
    the sack some would be blown up as dust and inhaled. This source of
    exposure was removed and her blood lead levels fell rapidly to normal
    (Graham et al 1981).

    It was later reported that the same patient was admitted about a year
    after these events to another hospital again with the symptoms of lead
    toxicity and a blood lead level of 3.7 mol/L. It was learnt that she
    had been admitted to at least two other hospitals in different parts
    of the country where lead poisoning was also diagnosed without the
    patient giving any history that this had been investigated for before.
    Again her home and studio were searched for a possible lead source and
    a canister of a white powder which contained 80% by weight of lead
    (probably basic lead carbonate) was discovered. Although there was no
    irrefutable evidence that this patient was deliberately ingesting lead
    her behaviour and length of intermittent exposure over five years
    suggest such a conclusion (Taylor et al 1985, Bass 1985).

    8  ANALYSIS

    8.1  Agent/toxin/metabolite

    8.2  Sample containers to be used

    Blood: 2ml plastic container with EDTA anticoagulant.
    Urine: 20ml in sterile universal container.

    8.3  Optimum storage conditions

    8.4  Transport of samples

    8.5  Interpretation of data

    8.6  Conversion factors

    To convert g/L to mol/L multiply by 0.004826
    To convert mol/L to g/L divide by 0.00486
    To convert g/100ml to mol/L multiply by 0.0486
    To convert mol/L to g/100ml divide by 0.0486

    8.7  Other recommendations

    9  OTHER TOXICOLOGICAL DATA

    9.1  Carcinogenicity

    Although there is no evidence that lead is carcinogenic in humans,
    there are several reports in which benign and malignant tumours were
    produced in experimental animals. In most of the studies malignant and
    benign neoplasms were induced in mice and rats by oral or parenteral
    administration of various types of lead compounds in high doses. A few
    clinical studies have found increased chromosomal defects in workers
    with blood lead concentration above 600 mg/L (WHO, 1995). A
    epidemiological study (Klaassen, 1980) of causes of mortality in 7000
    lead workers in the US, showed a slight increase of deaths from cancer
    but the statistical significance of these findings have been debated.

    Lead chromate is a suspected human carcinogen of the lung (Hathaway et
    al 1991) but a study of 1152 workers at a pigment factory did not find
    any relationship between exposure to lead chromate and lung cancer
    (Davies 1984).

    9.2  Genotoxicity

    No data.

    9.3  Mutagenicity

    Lead induced gene mutations in cultures of mammalian cells have only
    been observed at concentrations toxic to the cells. Studies for point
    mutations in bacterial systems have also yielded negative results.
    Insoluble lead sulphide and soluble lead nitrate were found to be
    mutagenic when added to Chinese hamster V79 cells. A 6 fold increase
    in mutation frequency was noted at a lead nitrate level of 500 mmol/L
    medium. However, the authors concluded that these effects may not have
    been the result of direct damage to DNA but may have occurred via
    indirect mechanisms including disturbances in enzyme functions
    important in DNA synthesis or repair. Studies on the production of
    chromosome aberrations, sister chromatin exchange and micronuclei by
    lead, whether in  in vitro or  in vivo, have given mixed results.

    9.4  Reprotoxicity

    The reproductive effects of lead in the male are limited to sperm
    morphology and count (Assennato et al 1986).
    It is not known if exposure to organic lead can cause similar problems
    (Barlow and Sullivan 1982).

    Lead is thought to represent a significant environmental hazard to
    pregnant women and their offspring (Angle and McIntire 1964, Palmisano
    et al 1969). Exposure to high environmental levels of lead has been
    associated with spontaneous abortion, premature rupture of foetal
    membranes and preterm delivery. There may also be obstetric
    complications at chronic low lead levels (Angell and Lavery 1982).

    Most recent information relates to reports of occupational cohorts and
    of populations living in polluted areas near industrial plants. There
    is a qualitative evidence that lead is toxic to the reproduction
    system in both men and women. However, there are insufficient data to
    provide the basis for estimation of dose effect relationship in women
    (WHO 1995).

    9.5  Teratogenicity

    A study of pregnancies in the centre and surroundings areas of lead
    smelter town showed that the incidence of miscarriages (22 or 23) and
    stillbirths (10 or 11) was higher in women living close to the
    smelter. Some studies have also found decreased length of gestation in
    women whose lead level were greater than 230 mg/L. Other studies have
    not shown a significant association between birth weight and lead
    exposure.

    9.6  ADI

     Provisional maximum tolerable weekly intake:

    Adults: 3 mg per person or 50 mg/kg body weight; children and infants:
    25 mg/kg body weight (Reynolds et al 1993).

     Amount of lead in food:

    In the UK is restricted to a maximum of 1 ppm with the exception of
    foods specially prepared for infants and children, where the limit is
    0.2 ppm (Reynolds et al 1993).

     Maximum exposure limit:

    In the UK the maximum exposure limit of lead and lead compounds
    (except tetraethyl lead) is 0.15 mg (as Pb) per m3 (long term) and
    for tetraethyl lead is 0.10 mg (as Pb) per m3

    In the US the permitted and recommended exposure limit of inorganic
    lead is 0.10 mg/m3 (long term) and for organic lead is less than
    0.10 mg/m3, so that blood concentrations are 0.6 mg/ml or less
    (Reynolds et al 1993).

    9.7  MRL

    9.8  AOEL

    9.9  TLV

    9.10  Relevant animal data

    In all species of experimental animals studied lead has been shown to
    cause adverse effects in several organ systems, including the
    haemopoetic, nervous, renal, cardiovascular, reproductive and immune
    systems. Lead also affects bone and has been shown to be carcinogenic
    in rats and mice.

    Despite kinetic differences between experimental species and humans,
    these studies provide strong biological support and plausibility for
    the findings in humans. Impaired learning and memory abilities have
    been reported in rats with lead concentrations of 150-200 mg/L and in
    non-human primates at lead levels not exceeding 150 mg/L. In addition,
    visual and auditory impairment has been reported in experimental
    studies.

    Renal toxicity in rats appears to occur at lead levels of 600 mg/L, a
    value similar to that reported to initiate renal effects in humans.
    Cardiovascular effects have been seen in rats after chronic low levels
    exposure resulting in lead concentrations of 50-400 mg /L. Tumours
    have been shown to occur at dose levels below the maximum tolerated
    dose of 200 mg lead (as lead acetate) per litre of drinking water.
    This is the maximum level not associated with other morphological or
    functional abnormalities (WHO 1995).

    9.11  Relevant  in vitro data

    10  ENVIRONMENTAL DATA

    10.1  Ecotoxicological data

     Solubility in water

    Metallic lead is insoluble in water.
    Tetraethyl and tetramethyl lead are poorly soluble.
    Trialkyl lead compounds are more soluble in water (WHO 1989).

    10.2  Behaviour

     Adsorption onto soil

    Lead is strongly adsorbed onto sediment and soil particles (WHO 1989).
    If released or deposited onto soil lead will be retained in the upper
    2 - 5 cm of soil especially in soils with at least 5% organic matter
    or pH 5 or above. Leaching is not important under normal conditions
    although there is some evidence to suggest that lead is taken up by
    some plants. Generally the uptake of lead by plants is not
    significant. It is expected to slowly undergo speciation to the more
    insoluble sulphate, sulphide, oxide and phosphate salts.

    10.3  Biodegradation

     Environmental fate

    Lead released into the atmosphere partitions to surface water, soil
    and sediment. Lead is transported in the atmosphere and in surface
    water.

     Photolysis

    Organic lead compounds are transformed in surface waters by
    photolysis.

     Hydrolysis

    Organic lead compounds are transformed in surface waters by
    hydrolysis.

    10.4  Environmentally important metabolites

    No data.

    10.5  Hazard warnings

    10.5.1  Aquatic life

    Aquatic plants: There is little evidence for toxicity of lead on
    aquatic plants at concentrations below 1 to 15 mg/L. Concentrations of
    more than 15 mg/L may be toxic.

    Aquatic invertebrates: The results of toxicity studies on aquatic
    invertebrates is difficult to interpret because of the variation in
    experimental conditions. Also organisms in some lead polluted waters
    may be more lead sensitive than others. Studies have shown that the
    larvae of the oyster  Crassostrea gigas had inhibited growth when
    incubated in water with a lead nitrate at a concentration of 0.01 or
    0.02 mg/L.

    Fish: The toxicity of lead-contaminated water in fish varies according
    to a number of conditions including pH and organic matter
    concentration. Uptake is also affected by the presence of other
    cations and the oxygen concentration. Organic lead is taken up more
    readily than inorganic lead and may be 10 to 100 times more toxic than
    inorganic lead. Long-term exposure of adult fish to inorganic lead
    induces sub-lethal effects on morphology as well as enzyme activities
    (e.g. delta-aminolevulinic acid dehydratase) and avoidance behaviour
    at available lead concentrations of 10-100 mg/L. Juvenile stages are
    generally more sensitive than adults. However eggs are thought to be
    less at risk of lead toxicity because lead is adsorbed onto the
    surface of the egg and excluded from the developing embryo. Generally
    lead does not appear to bioconcentrate significantly in fish (WHO
    1989).

    Amphibia: There is evidence that frog and toad eggs are sensitive to
    lead concentrations of <1 mg/L in standing water and 0.04 mg/L in
    flow-through systems. Lead at these concentrations may cause arrested
    development and delayed hatching. There are no significant effects in
    adult frogs at levels <5 mg/L in aqueous solutions but lead in the
    diet at a concentration of 10 mg/kg food may cause some biochemical
    abnormalities. (WHO 85 1993)

    10.5.2  Bees

    No data.

    10.5.3  Birds

    High dietary doses of lead salts (>100 mg/kg) are toxic to birds. A
    variety of effects have been reported at high doses but the most
    common effects are diarrhoea, lack of appetite and consequent anorexia
    and weight loss. Lethal and sublethal effects have not been reported
    at concentrations likely to occur in the wild.

    Metallic lead is toxic at high doses when fed as a powder. It is
    highly toxic however when given as lead shot. Ingestion of a single
    lead pellet can be fatal for some birds, however there is variable
    interspecies sensitvity and toxicity can be dependent on the diet.
    Birds have commonly been found in the wild with as many as 20 lead
    shot in the gizzard (WHO 1985). Clinical signs include ataxia, leg
    weakness, paralysis, emaciation and diarrhoea (Fahy 1987).

    There is limited information on the toxicity of organolead compounds
    in birds. When starlings were fed trialkyl lead compounds a dose of 2
    mg/day was fatal. There have been recurring incidents of bird deaths
    in estuaries near to industrial plants manufacturing leaded antiknock
    compounds. The total lead content of the livers was sufficiently high
    to cause mortalities: lead was mainly present in the alkyl form (WHO
    1993).

    10.5.4  Mammals

     Dogs: There is a high prevalence of lead toxicity in dogs. Usually
    gastrointestinal effects precede neurological signs by several days.
    The most common signs are vomiting, abdominal pain and anorexia. The
    abdominal pain or "lead colic" is manifest by whining, restlessness,
    tense abdomen and crying when the abdomen is palpated. Neurological
    signs include convulsions, hysteria (barking and crying continuously,
    running in all directions and biting at animate and inanimate
    objects), ataxia, blindness and chomping of the jaws.

     Cattle and sheep: in cattle the first signs are usually depression
    and anorexia. Gastrointestinal signs include constipation and
    diarrhoea. Abdominal pain may be evident and cattle may grind their
    teeth and appear to be chewing. Neurological signs include twitching
    of the ears, fine muscle tremor, eye blinking, head bobbing, circling
    and pushing against objects. There may be marked excitement and 

    convulsions prior to death. Terminal excitement and death may be the
    only signs observed. Death may occur a few hours to several days after
    the onset of clinical signs. Lead intoxication in sheep is similar and
    characterised by depressed rumen motility, lethargy and coarse body
    tremors immediately prior to death. Chronic lead exposure in lambs may
    result in osteoporosis and hydronephrosis.

     Horses: Acute lead poisoning is rare because of their selective
    eating habits but horses seem to be quite susceptible to chronic
    low-level poisoning. Generally affected horses live near lead
    industries and chronic poisoning occurs from lead contaminated
    pasture. Horses show more peripheral nerve involvement than other
    domestic animals. This is characterised by muscle weakness and
    "roaring" resulting from paralysis of the recurrent laryngeal nerve.
    Aspiration pneumonia may also result as a consequence of this
    paralysis. Sudden death may occur from anoxia precipitated by
    laryngeal paralysis. Other signs include progressive loss of weight,
    anorexia, muscle weakness, stiffness of joints and progressive arching
    of the back (Fahy 1987).

     Other species: Three fruit bats and 34 simian primates died in
    Washington Zoo after lead paint was used to paint their cages (WHO
    1989).

    10.5.5  Plants

    In terrestrial plants the availability of lead is limited since lead
    tends to form highly insoluble salts and complexes with various anions
    and lead compounds tend to be bound to soil. Translocation of the lead
    ion is limited and most bound lead stays at root or leaf surfaces.
    Most studies on lead toxicity to plants have shown that very high soil
    lead levels are needed (100-1000 mg/kg) to cause inhibition of
    photosynthetic rate and growth (WHO 1989).

    10.5.6  Protected species

    No data.

    10.6  Waste disposal data

    Authors

    Grainne Cullen
    Alison Dines
    Stoyko Kolev

    National Poisons Information Service (London Centre)
    Medical Toxicology Unit
    Guy's & St Thomas' Hospital Trust
    Avonley Road
    London
    SE14 5ER
    UK

    This monograph was produced by the staff of the London Centre of the
    National Poisons Information Service in the United Kingdom. The work
    was commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    March 1996

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    See Also:
       Toxicological Abbreviations
       Lead (EHC 3, 1977)
       Lead (ICSC)
       Lead (WHO Food Additives Series 4)
       Lead (WHO Food Additives Series 13)
       Lead (WHO Food Additives Series 21)
       Lead (WHO Food Additives Series 44)
       LEAD (JECFA Evaluation)