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    LEAD (EVALUATION OF HEALTH RISK TO INFANTS AND CHILDREN)

    EXPLANATION

         Lead was previously evaluated at the sixteenth meeting of the
    Joint FAO/WHO Expert Committee on Food Additives (Annex 1, reference
    30). The Committee established a provisional tolerable weekly intake
    of 3 mg of lead/person, equivalent to 0.05 mg/kg b.w. for adults. This
    level does not apply to infants and children. The provisional weekly
    tolerable intake established by JECFA at that time related to all
    sources of exposure to lead. The Committee indicated that any increase
    in the amount of lead derived from drinking water or inhaled from the
    atmosphere will reduce the amount that can be tolerated in food. A
    toxicological monograph was published (Annex 1, reference 31).

         Two other publications of WHO have dealt with effects of lead on
    human health (WHO, 1973; WHO, 1977). These publications did not deal
    specifically with the health risks for infants and children. However,
    JECFA and the other WHO committees recognize that children should be
    considered a high-risk group in relation to lead exposure.

         JECFA at its twenty-first meeting (Annex 1, reference 44)
    discussed the problem of exposure of infants and children to
    contaminants in foods. The IPCS (International Program on Chemical
    Safety) and CEC (Commission of the European Communities), recognizing
    the need for a special approach to evaluating the health risks from
    chemicals during infancy and early childhood, have recommended
    principles for evaluating these risks (WHO, 1986).

         The basis of the special concern for infants and children relates
    to certain structural, functional, and behavioural differences between
    infants and young children and adults, in particular, the higher
    metabolic rate and therefore higher oxygen consumption and air intake
    per unit body weight in the young, the large surface area to weight
    ratio, the rapid body growth, different body composition, immaturity
    of the kidney, liver, nervous system, and immune system, and the rapid
    growth and development of organs and tissues such as bone and brain.
    The higher energy requirements of infants and children and the higher
    fluid, air, and food intake per unit body weight place them in a
    special position with regard to intake of chemicals from air, water
    and food. The absorption and retention of a number of metals appear to
    be greater in the young than in adults, and there are differences in
    the distribution, biotransformation, and excretion of chemicals in
    infants, children, and adults. Additionally, the dependence of young
    infants on milk or infant formula as their sole source of nutrition

    may raise special problems. Particular behavioural characteristics of
    children, such as heightened hand to mouth activity, may place them at
    particular risk from environmental contaminants. The nutritional and
    health status of the young may also modify their response to chemical
    contaminants and the social and cultural attitudes to child rearing
    may influence the degree of exposure to chemicals.

    EXPOSURE AND INTAKE

    Sources of exposure

         It is important to identify sources of exposure, particularly
    those that may be of significance to infants and children. This will
    provide information for developing strategies for control of exposure,
    if needed.

         Although lead is ubiquitous in the environment of industrialized
    nations, the contribution of natural sources of lead to concentrations
    in the environment is low compared to the contribution from human
    activities (Patterson, 1965). Through human activities such as mining,
    smelting, refining, manufacturing, and recycling, lead finds its way
    into the air, water, and surface soil. Lead-containing manufactured
    products (gasoline, paint, printing inks, lead water pipes,
    lead-glazed pottery, lead-soldered cans, battery casings, etc.) also
    contribute to the lead burden. Lead in contaminated soil and dust can
    find its way into the food and water supply.

    Food, drinking water, and air

         Lead in foods may be derived from the environment in which the
    food is grown or from food processing. Agricultural crops grown near
    heavily travelled roads or industrial sources of lead can have
    significant concentrations because of airborn lead deposited on them
    or in the soil. Canned foods are a source of lead which is leached
    from the solder in the seams of the cans. However, exposure from this
    source can be reduced by the use of seamless cans. Among cases of lead
    poisoning cited in the literature, lead from ceramic glazed storage
    vessels, leached out by acid foods, is the most frequently-reported
    source of high lead concentrations in foods (Mahaffey, 1983). The
    major source of lead contamination of drinking water is the
    distribution system itself. Where lead water pipes or lead-lined
    cisterns are used, lead may contaminate the water supply and
    contribute to increased blood levels in children who consume the water
    (Elias, 1985). Water used to prepare infant formula is always a
    significant source of lead for infants if it contains high lead levels
    (Sherlock & Quinn, 1986).

         The atmospheric levels of lead depend on geographical location,
    with major differences in lead in the atmosphere in urban and remote
    areas of the world. The highest concentrations are observed near
    sources of lead such as smelters. Levels range from 0.000076 g/m3
    in remote areas to up to 10 g/m3 in areas near smelters
    (Elias, 1985).

    The domestic environment

         The domestic environment, in which infants and children spend the
    greater part of their time, is of particular importance as a source of
    lead intake. In addition to exposure from general environmental
    sources, some infants and young children, as a result of normal,
    typical behaviour, can receive high doses of lead through mouthing or
    swallowing of non-food items. Pica, the habitual ingestion of non-food
    substances, which occurs among many young children, has frequently
    been implicated in the etiology of lead toxicity.

    Soil and dust in and about the home

         The extent of the contribution of inhaled airborne lead to the
    lead burden of children is probably small. However, lead-containing
    particles that deposit from the air can be responsible for high
    concentrations of lead in dust that children ingest (Charney, 1982). A
    study of urban and suburban infants (USA) followed from birth to 2
    years of age found that the average blood lead levels highly
    correlated with amounts of lead in indoor dust, top soil, and paint in
    their immediate environment (Rabinowitz et al., 1984). Children
    living near high-level sources of lead such as smelters are at high
    risk from lead poisoning (Landrigen et al., 1976). Exhaust from
    vehicles using leaded gasoline is a common source of atmospheric lead
    which contributes to the lead content of dust. Data from the United
    States Second National Health and Nutrition Examination Survey
    (NHANES II) indicate that leaded gasoline is a more significant source
    of lead than previously thought. Annest et al. (1983), using data
    from this study, correlated major reductions in the amounts of lead
    added to gasoline sold in the United States with significant
    reductions in children's blood lead levels. A similar relationship
    between leaded gasoline sales and umbilical cord blood lead levels was
    shown by Rabinowitz and Needleman (1983). However, other studies have
    indicated that the influence of lead from gasoline on blood lead
    levels may be relatively low (Quinn, 1985). In general, lead in soil
    and dust appears to be responsible for blood lead levels in children
    increasing above background levels when the concentration in the soil
    or dust exceeds 500-1,000 ppm (Milar & Mushak, 1982).

    Lead-based paint in the home

         Lead-based paint in the home has been and continues to be the
    major source of high-dose lead exposure and symptomatic lead poisoning
    for children, in spite of the fact that the use of lead in interior
    paints has been restricted in some countries for many years (Lin-Fu,
    1982). In the past, some interior paints contained 20-30% lead and
    these paints remain in many older homes. Overt lead poisoning, when it
    occurs, is usually seen in children under 6 years of age who live in
    deteriorated older housing.

    Indirect occupational exposure in the home

         Lead dust that clings to the skin, hair, and clothing of workers
    can be carried from the workplace to the home. In one study
    (Baker et al., 1977) it was shown that when a parent worked with
    lead, the amount of lead in the blood of children correlated with the
    concentration of lead in dust in their homes. Children have been
    poisoned by lead-bearing dust brought home on parents' work clothing
    (Chisolm, 1982).

    Intake

         Children are more vulnerable to exposure to lead than adults
    because of metabolic and behavioural differences. The degree to which
    individual sources of lead contribute to the intake of lead by infants
    and children varies according to its availability in particular
    environmental circumstances. While lead in air, food, and water
    generally is at lower levels than lead in paint, soil, and dust, the
    former contribute to the background or baseline level which determines
    how much extra lead is needed from other sources before toxicity
    ensues. It has been estimated that in the United States, an average
    two-year old child may receive 44% of his daily lead intake from dust,
    40% from food, 14.6% from water and beverages, and 1% from inhaled air
    (Elias, 1985). Detailed reviews of intake of lead are available
    (WHO, 1977; Elias, 1985; FAO, 1986a).

    Food

         Among children the higher food intake relative to size and the
    higher metabolic levels and greater motor activity compared to adults
    leads to higher dietary lead consumption (Mahaffey, 1985). Reported
    intakes of lead from food are quite variable (WHO, 1977). However,
    developing a reasonable estimate of lead in the diet is a continuing
    problem because of (1) methodological weaknesses in the accurate
    analysis for lead in foods and (2) the need for good dietary survey
    data. Beloian (1985) has proposed a mathematical model for estimating
    daily intake. A detailed report of dietary intake of lead by infants
    and children has been compiled by FAO (1986a). There has been a
    considerable reduction in dietary intake of lead in infants in the 0-5
    month age group since the 1970s, probably due to improvements in
    packaging and handling of foods during processing and to reduction in
    lead solder in cans used for milk and infant food.

    Air

         Inhaled lead contributes little to the background body burden
    compared to intake from food, water, beverages, and dust. Airborne
    lead, however, represents an important source of lead exposure in
    children when deposited in dust and dirt. However, different studies
    reach widely different assessments of the contribution of air lead to
    food lead and hence body burden (Royal Commission on Environmental
    Pollution, 1983).

    Dust

         Dust contributes a greater proportion of lead to the background
    body burden of young children than to adults and older children
    because of their greater proclivity for ingesting dust due to their
    greater hand-to-mouth activity. It has been calculated that dust
    contributes only 7 to 11% of the baseline lead in adults, but 44% in
    2-year old children (Elias, 1985).

    Indices of exposure

         For practical reasons, lead exposure in infants and children is
    based primarily upon measurements of lead in the blood, sometimes
    supplemented by measurement of lead in urine, particularly after
    treatment with chelating agents.  These measurements correlate
    imperfectly with lead levels in the tissue or organ where the toxic
    effect may be observed. Furthermore, blood lead levels reflect only
    recent exposure to lead, not long-term exposure. Other methods to
    determine total body burden involve measurement of lead in hair, bone,
    or teeth (Goyer, 1982).

         The use of the lead content of teeth as an index of lead exposure
    in the general population has been considered an important advance,
    particularly in the investigations of the neuropsychological effects
    of ordinary levels of lead in the environment, since this reflects
    lead exposure over the child's lifetime, not merely recent exposure.
    However, considerable variations may occur in tooth lead
    concentrations in different teeth from the same child, especially when
    teeth are different types or from upper and lower jaws. Also, there is
    a marked variation of lead concentration throughout the tooth
    (Delves et al., 1982; Smith et al., 1983). Because of these
    variations, there is always a need to make suitable adjustments when
    using teeth for assessing lead body burden.

         The haematopoietic system is considered by many to be the most
    reliable and sensitive indicator of lead toxicity. The clinical
    endpoint is anaemia, which apparently occurs at lower blood lead
    levels in children that in adults (Goyer, 1982). The elevation of
    erythrocyte protoporphyrin (EP) has been well studied and can be
    reliably measured (U.S. CDC, 1985). Among the biologic markers of lead

    toxicity, this method has been the most useful in screening programs
    because its measurement is not susceptible to error from lead
    contamination and the test can be performed on capillary blood.
    However, correlation with blood lead at levels below 30 g/dl is poor,
    and there is a rather high proportion of false negative results
    (Meredith et al., 1979; Bush et al., 1982). High EP values in the
    absence of elevated blood lead levels may indicate iron deficiency
    (Piomelli, 1977).

    Blood lead levels in children

         In general, blood lead levels of children up to 6-7 years of age
    are higher than those of non-occupationally exposed adults. Blood lead
    levels are highest in children aged 2-3 years, but they decrease again
    in children aged 6-7 years. There are no significant differences in
    blood lead levels between males and females less than 7 years of age.
    However, males in the 7+ age group generally have higher blood lead
    levels than females. In the United States NHANES II found that the
    mean blood lead concentration among children under 6 years of age was
    about 16 g/dl, with mean values in about 5% of the population equal
    to or greater than 30 g/dl. After the age of 5, mean blood levels
    declined until age 17. Mean blood levels of adult females remained
    lower, but blood levels in adult males were similar to those of
    younger children (Mahaffey, 1985).

         A similar pattern of distribution of blood lead levels with age
    in children and infants was reported in the U.K. and European Economic
    Community (EEC) Blood Lead Survey, 1979-1981 (Quinn, 1985), with
    average blood lead concentrations in the range 9-11.5 g/dl. In
    addition, these studies reported the effect of geographical,
    environmental and personal factors on the average blood lead
    concentrations (Pollution Report No. 18, 1983).

    Blood lead levels of concern in screening programmes

         The U.S. Centers for Disease Control (U.S. CDC) has lowered its
    definition of an elevated blood lead level from 30 to 25 g/dl. Lead
    toxicity is defined as an elevated blood level with an EP level in
    whole blood of 35 g/dl or greater (U.S. CDC, 1985). The U.S. CDC has
    also described a system for grading the severity of lead toxicity
    using two distinct scales, one for use in screening and the other for
    use in clinical management. For example, at a blood level of 25 g/dl
    or less and an EP of 35 g/dl or more, the U.S. CDC recommends that
    children be retested, with additional assessment of iron studies.
    Also, in terms of clinical management, the U.S. CDC points out that
    the first priority is for environmental investigation and intervention
    and the single most important factor is to reduce exposure to lead.

         The EEC directive on the biological screening of the population
    and specific groups in the population indicated certain reference
    levels for each survey. The reference levels are as follows: no more
    than 50% should be above 20 g/100 ml, no more than 10% above
    30 g/100 ml, and no more than 2% above 35 g/100 ml. It was also
    recommended that if these levels were exceeded, action should be taken
    to trace and reduce the source of exposure. Follow-up investigations
    should be carried out in individuals over 30 g/100 ml (EEC, 1977).

         In the U.K. it has been recommended that when a blood level over
    25 g/100 ml has been confirmed in a person (particularly a child),
    action should be taken to investigate the individual's environment and
    steps should be taken to reduce lead exposure (Department of the
    Environment and the Welsh Office, 1982).

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption and retention

         The main route of lead absorption in infants and children is the
    gastrointestinal tract. Children absorb lead with greater efficiency
    than do adults. It has been estimated that 40-50% of dietary lead is
    absorbed in children, whereas in adults normally 5-10% of dietary lead
    is absorbed from the gastrointestinal tract. However, absorption in
    adults shows considerable variation depending on whether the lead is
    present in food or water or if the lead is ingested between meals.
    Decreased intake of essential metals such as iron, zinc, and calcium
    as well as poor nutritional status increase lead absorption
    (Rosen, 1985). In experimental animals there is some evidence that
    milk may promote lead absorption (Stephens & Waldron, 1975). The
    estimated gastrointestinal absorption rate of lead from soil and dust
    has been reported to be somewhat lower than from food, approximately
    30% (Lepow et al., 1975).

         In a study by Zeigler et al. (1978) faecal excretion of lead in
    infants generally exceeded intake when the dietary intake of lead was
    less than 4 g/kg/day. When intake of dietary lead exceeded
    5 g/kg/day, net absorption averaged 42% of intake, and retention
    averaged 32% of intake. Absorption and retention of lead expressed as
    a percentage of intake increased significantly with increasing lead
    intake. Absorption may be higher when nutrition is not optimal.

    Correlation between blood lead levels and exposure

         In a study with infants Ryu et al. (1983) demonstrated that
    with low non-dietary exposure to lead, a mean intake of 3-4 g
    lead/kg b.w. was not associated with an increase in blood lead
    concentration. However, increased blood lead levels did occur when the
    dietary intakes of lead were 8-9 g/kg b.w./day.

         The Glasgow duplicate diet study (Sherlock & Quinn, 1986)
    reported a significant correlation between dietary lead intake and
    blood lead concentrations of 13-week old infants. The study involved a
    wide range of lead intakes (40 g to over 3000 g/week). The high
    levels of lead in the diet were derived from water used to prepare the
    diet. The blood lead concentrations appeared to have a "non-linear"
    (cube root) relationship between water lead concentrations and dietary
    intakes of lead, with the greatest increment in blood lead levels
    occurring at the lower range of exposure.

         Lead intake from air is relatively greater in children than in
    adults. In adults without prolonged previous exposure to lead, each
    1 g/m3 increase in ambient air lead increases the mean blood level
    by approximately 1 g/dl, while in children each 1 g/m3 increase in
    ambient air lead exposure causes a mean increase of 2 g/dl or more in
    the blood lead level (US EPA, 1977).

    Distribution and excretion

         A single dose of lead, orally ingested or inhaled, distributes to
    the various organs and systems in the body in relation to the rate of
    blood delivery and then redistributes in proportion to affinity of
    particular tissues for lead. The concentration of lead in blood
    reflects the overall balance between uptake and excretion and the
    equilibrium of exchange to and from soft and hard tissues. Lead is not
    uniformly distributed in the body but is apportioned among several
    physiologically-distinct compartments which differ in size and
    accessibility to lead (Rabinowitz et al., 1976; Rabinowitz et al.,
    1977). The blood and some components of soft tissue in rapid exchange
    with blood contain about 1% of the body lead, of which 90 to 99% is
    associated with the red blood cells. This accessible fraction
    correlates most closely with recent environmental exposure and to most
    toxic effects. Lead in this accessible portion has a mean half-life of
    about 36 days. Lead in other soft tissue has a mean half-life of about
    40 days; this compartment is slightly smaller than the blood
    compartment. The lead in bone and teeth has a long half-life, about
    10,000 days, and forms the largest and least accessible depot. There
    is variation in the amount of lead stored in various skeletal regions
    and in its accessibility (Rabinowitz et al., 1976).

         Animal experiments show that the tissue distribution of lead in
    the young and in adults differs. In the rat, a greater percent of the
    dose accumulates in the immature brain than in the adult brain. In
    fact, young animals retain a greater percentage of lead in all organs
    than do adults, even when the exposure of young and adults is the same
    on a g lead/kg b.w. basis. When the blood lead level concentration in
    rats is plotted against tissue lead levels, the slope of the
    regression line for the young is greater than that for adults,
    indicating that tissue lead levels rise faster than blood lead levels
    in the young animal (Mahaffey, 1983).

         Man excretes lead primarily by way of the kidneys (76%) and to a
    lesser extent via the gastrointestinal tract (16%) and through the
    sweat, bile, hair, and nails (8%) (WHO, 1977). Lead accumulates in
    bone due to an inherent affinity for osseus tissue and only slowly
    returns to the blood. The longer the period of exposure to lead, the

    slower the rate of removal from the body (Hammond, 1982). Although
    animal studies suggest that lead is excreted more slowly in the young
    than in the adult (Hammond, 1982), metabolic balance studies in normal
    infants suggest that infants and young children not only absorb lead
    more efficiently but also excrete it more rapidly than do adults
    (Rabinowitz et al., 1976).

    Transplacental transport of lead and lead in maternal milk

         Lead in fetal tissues has been detected by the twelfth week of
    gestation (Barltrop, 1972) with highest concentrations in bone,
    kidney, and liver, followed by blood, brain, and heart. Cord blood
    contains concentrations of lead that correlate with maternal levels.
    Lead appears in mothers' milk, but breast milk contains only about
    one-tenth of the maternal blood lead concentrations (Moore, 1983).

    Lead toxicity

    Lead impairment of normal metabolic pathways

         The biochemical basis for lead toxicity is its ability to bind
    the biologically-important molecules, thereby interfering with their
    function by a number of mechanisms. Lead may compete with essential
    metallic cations for binding sites, inhibiting enzyme activity, or
    altering the transport of essential cations such as calcium. At the
    subcellular level, the mitochondrion appears to be the main target
    organelle for toxic effects of lead in many tissues. Lead has been
    shown to selectively accumulate in the mitochondria and there is
    evidence that it causes structural injury to these organelles and
    impairs basic cellular energetics and other mitochondrial functions
    (Brierley, 1977; Holtzman et al., 1978).

         Lead has been reported to impair normal metabolic pathways in
    children at very low blood levels (Farfel, 1985). At least three
    enzymes of the haeme biosynthetic pathway are affected by lead and at
    high blood lead levels the decreased haeme synthesis which results
    leads to decreased synthesis of haemoglobin. (Haeme is also a
    prosthetic group of a number of tissue heme proteins such as
    myoglobin, the P450 component of the mixed function oxidases, and the
    cytochromes.) Blood lead levels as low as 10 g/dl have been shown to
    interfere with one of the enzymes of the haeme pathway, delta-
    amino-levulinic acid dehydrase (Hernberg & Nikkanen, 1970). No
    threshold for this effect has been established. Alterations in the
    activity of the enzymes of the heme synthetic pathway lead to
    accumulation of the intermediates of the pathway. There is some
    evidence that accumulation of one of the intermediates, delta-
    amino-levulinic acid, exerts toxic effects on neural tissues
    through interference with the activity of the neurotransmitter

    gamma-amino-butyric acid (GABA) (Silbergeld & Lamon, 1980). The
    reduction in heme production per se has also been reported to
    adversely affect nervous tissue by reducing the activity of tryptophan
    pyrollase, a heme-requiring enzyme. This results in greater metabolism
    of tryptophan via a second pathway which produces high blood and brain
    levels of the neurotransmitter serotonin (Litman & Correia, 1983).

         Red cell pyrimidine-5'-nucleotidase activity in children is
    inhibited at blood lead concentrations of 10-15 g/dl and no threshold
    was found even below these levels (Angle et al., 1982).

         Lead interferes with vitamin D metabolism, since it inhibits
    hydroxylation of 25-hydroxy-vitamin D to produce the active form of
    vitamin D. The effect has been reported in children at blood levels as
    low as 10-15 g/dl (Mahaffey et al., 1982).

         Rosen (1985) and Moore & Goldberg (1985) have published detailed
    reviews of the metabolic and cellular effects of lead.

    Target organs and systems

         Lead is a cumulative poison. It produces a continuum of effects,
    primarily on the haematopoietic system, the nervous system, and the
    kidneys.

    Haematopoietic system

         Excessive lead exposure in pediatric groups results in a
    microcytic, hypochromic, mildly haemolytic anemia. Increased blood
    concentrations and urinary excretion of the metabolic precursers of
    haeme, such as protoporphyrins and 6-amino-levulinic acid, occur
    before the development of overt anaemia. Blood lead concentrations in
    children in excess of 40 g/100 ml have been associated with an
    increased incidence of anaemia (WHO, 1977).

         Measurements of the inhibitory effects of lead on haeme synthesis
    have been widely used in screening tests to determine whether medical
    treatment for lead toxicity is needed for children in high-risk
    populations who have not yet developed overt symptoms of lead
    poisoning. Piomelli (1980) has reported that an increase of
    erythrocyte protoporphyrin could be measured at blood lead levels of
    14-17 g/dl in children and Cavelleri et al. (1981) found an
    increase at blood lead levels between 10 and 20 g/dl, suggesting that
    the erythrocyte protoporphyrin "no response" level is lower than
    10 g/dl in children. Specific changes relating to the haematopoietic
    system have been reported to occur at the following blood lead
    concentrations in children:

         5 - 10 g/100 ml    40% inhibition of erythrocyte
                             delta-amino-levulinic acid dehydratase

         10 - 25 g/100 ml   increased erythrocyte protoporphyrins

         20 - 25 g/100 ml   70% inhibition of delta-amino-levulinic acid
                             dehydratase

         30 - 40 g/100 ml   increased urinary excretion of
                             delta-amino-levulinic acid (above 5 mg/l)

         40 - 50 g/100 ml   decreased haemoglobin level

         The biological significance of the effects noted below
    40 g/100 ml are not known, since the degree of impairment is not
    sufficiently large to be reflected as a decrease in haemoglobin or
    haem synthesis. However there is general agreement that at levels
    greater than 40 g/100 ml, lead exerts a significant effect on the
    haematopoietic system.

         The haematological changes associated with lead are considered
    reversible.

    Effects on the nervous system

         Lead causes a continuum of nervous system effects in children
    ranging from slowed nerve conduction (Landrigan et al., 1976),
    behavioural changes (David et al., 1972; de la Burde et al., 1975;
    Landrigan et al., 1975; Winneke et al., 1982, 1983), and possible
    small decrements in cognitive ability at about 30-60 g lead/dl blood,
    to mental retardation (80 g/dl) and acute encephalopathy and death
    (80-100 g/dl) (Needleman et al., 1979; Needleman & Landrigan, 1981;
    Needleman, 1983). Encephalopathy and other effects on the nervous
    system develop in children at lower blood lead levels than in adults.

         Effects on the central nervous system are principally responsible
    for the morbidity and mortality due to lead poisoning
    (Mahaffey, 1977).

         Chelation therapy and earlier detection of lead toxicity have led
    to a marked decline in death from lead poisoning since the 1950s, but
    residual impairment of CNS function due to lead toxicity continues to
    occur, even in children treated with chelation therapy. Sequalae can
    include mental retardation, seizures, cerebral palsy, and optic
    atrophy. In studies with experimental animals, perinatal lead exposure
    delayed normal brain development in offspring and was associated with
    blood lead levels from 25-89 g/dl (Reiter, 1982). Indications of
    peripheral nerve dysfunction, as indicated by slowed nerve conduction
    velocities, have been shown in children at blood lead levels as low as
    30 g/dl (Landrigan et al., 1975).

         The neuropsychological effects of low-level lead exposure, below
    that causing overt toxic effects, represent a subject of increasing
    interest and of continuing controversy. The concern relates to the
    possibility that early asymptomatic environmental lead exposure
    results in adverse effects on I.Q., perception, and fine motor skills
    of children. In the past 12-15 years, both clinical studies of
    children and animal research have provided information which bears on
    the problem of CNS effects at low-level lead exposure. Data needed to
    define dose-response relationships in children come principally from
    retrospective epidemiological studies. These have the well-known
    methodological problems of controlling for confounding covariants, of
    selection bias, of obtaining sufficiently-large population samples to
    achieve statistical significance, and of appropriate statistical
    analysis. In the case of lead there is also the problem of the
    shortcomings of assessing the body lead burden by the most widely used
    and practical method, which is measurement of blood lead levels, and
    the difficulties with clinical measurements of neuropsychological
    function. The interpretation of statistical associations between
    raised lead levels and psychological impairment raises another
    question, that of the biological mechanism by which low-level lead
    exposure could cause the psychological damage.

    Observations in animals

         Animal studies are available that provide information on the
    effects of neonatal low-level lead exposure on locomoter
    scheduled-controlled behaviour (Brown, 1975; Bushnell & Bowham,
    1979; Rice, 1984). Other studies provide suggestions as to the
    biological mechanisms that may underlie the neurophysiological or
    neuro-psychological effects of low-level lead exposure. In one recent
    study, cynomolgus monkeys were dosed from birth with 0, 50, or
    100 g/kg/day of lead, resulting in steady-state blood lead levels of
    3, 11, or 13 g/dl, respectively. At 3 years of age, the monkeys were
    tested on an intermittent schedule for the usual measures of
    differential reinforcement of low rate (DRL). The performance of
    treated monkeys did not improve as rapidly as controls, and the
    treated monkeys showed greater between-session variabilities during
    terminal sessions. These results suggest that blood lead levels
    comparable to those generally found in the human population may
    produce neurophysiological effects (Rice & Gilbert, 1985). Other
    studies with experimental animals have shown that lead (a) inhibits
    haeme biosynthesis at lead levels below 20-30 g/dl blood, with
    subsequent neurotoxic effects of 6-amino-levulinic acid or one of its
    metabolites, (b) interferes with the neuronal system that is
    responsive to acetylcholine, catecholamines, and GABA (Sibergeld &
    Lamon, 1980), and (c) affects intraneuronal haeme biosynthesis
    (Rice & Gilbert, 1985).

    Neuropsychological effects of lead in children

         Rutter (1980), Yule & Rutter (1983), DHSS (1980), Needleman
    (1980), and MRC (1986) have published reviews of studies on the
    neuropsychological effects of lead in on-overtly intoxicated children.
    Several categories of studies have been reviewed, including

    (1)  clinical studies of children thought to be at risk because of
         high blood levels,

    (2)  studies of children from general pediatric populations,

    (3)  studies of children living close to lead-emitting smelters,

    (4)  studies of mentally-retarded or behaviourally-deviant children,
         and

    (5)  chelation studies.

         Studies prior to 1980 suggested that lead could cause
    psychological impairment (lower IQ and behavioural deviance) at levels
    below those associated with overt clinical signs of toxicity. However,
    most of these studies were carried out with children with blood levels
    in the range 40-70 g/dl. There was little evidence that adverse
    neurophysiological effects could occur at much lower blood lead
    levels. For the studies to be applicable to the general population,
    studies should be carried out with children with blood lead levels
    below 35 g/dl, since the median blood level of the population in nine
    Member States of the CEC is 13 g/dl, with about 2% exceeding the
    critical level of 30 g/dl. Similar blood lead levels have been
    reported in the U.S. In addition, a number of major methodological
    issues have been identified. These include selection of children,
    neuropsychological measurements, estimates of body lead levels, and
    adequate statistical analysis to control the effects of possible
    confounding variables.

         Since 1979 a number of studies which have attempted to correct
    these design deficiencies have been reported. Studies by Needleman and
    his colleagues (Needleman et al., 1979; Needleman, 1983) using
    deciduous teeth of first and second grade school children (estimated
    age 5.5-7.5 years) indicated a small but possible effect of lead on
    several measurements of neuropsychological performance, as well as
    reducing the IQ by 1-5 points at tooth lead levels above 20 ppm
    (indicative of a level of exposure). The mean blood lead level of the
    children was about 30 g/dl. Similar findings were reported in other
    studies using tooth lead as an indicator of exposure in Germany
    (Winneke et al., 1982, 1983) and in the U.K. (Smith et al., 1983).

         In another series of studies, groups of children with blood lead
    levels ranging between less than 10 to 14 g/ml or greater than
    15 g/100 ml were studied. These studies also included groups from
    various socio-economic backgrounds. Although one study indicated an
    association between full-scale I.Q. and blood lead levels, a number of
    confounding factors, e.g. lack of information on socio-economic
    background and parental I.Q., made interpretation of the study
    difficult (Yule et al., 1981). However, in another study corrected
    for these factors, no significant association between blood lead
    levels and various neuropsychological tests was observed
    (Yule & Landsdown, 1983; Yule et al., 1984).

         The general conclusions relating to these and other studies have
    been summarized by Yule & Rutter (1983) and MRC (1986). Briefly, they
    indicate that because of the complexity of the situation, it is
    impossible from the available evidence to come to a definitive
    conclusion on the neurophysiological effect of "ordinary" levels of
    lead exposure. However, the possible neurophysiological effects of
    lead within the range in the ordinary environment without special
    risks (absence of excessive sources of environmental lead), are at
    most small.

         Electrophysiological studies on children with high and low lead
    levels, (teeth or blood) have also been carried out. However, the
    significance of the variations in EEGs is not understood.

    Effects of lead on the kidney

         The kidney is the major pathway for lead excretion and is
    directly subject to effects of lead toxicity that may lead to
    impairment of its multiple functions. The early or reversible effects
    of lead toxicity result in proximal renal tubular dysfunction,
    evidenced by increased urinary excretion of glucose, amino acids, and
    phosphate. These effects have been reported in children with
    relatively high blood levels of 150 g/dl (NAS, 1972). Chronic or
    irreversible lead nephropathy is characterized by intense interstitial
    fibrosis and tubular atrophy and dilation and results from prolonged
    exposure to high levels of lead.

    Effects on growth

         A recent analysis of 2695 children 7 years of age or younger,
    based on U.S. survey data (NHANES II), indicated that blood lead
    levels were a statistically-significant predictor of children's
    height, weight, and chest circumference. The strongest relationship
    was between blood lead and height, with no evident threshold found for
    the relationship down to the lowest observed blood lead level of
    4 g/dl (Schwarz et al., 1986). However, other factors need to be
    considered in the evaluation of these results, e.g. social factors.

    Available information on tolerable levels of lead intake for
    infants and young children

         Estimates of tolerable exposure to lead have been based on the
    maximum intake from all sources that would preclude accumulation of
    lead. The data used include (a) levels of lead in the blood of
    non-exposed and exposed individuals and of those with frank lead
    poisoning, (b) the results of experimental lead ingestion by adults,
    (c) measurements of faecal output of lead in exposed and non-exposed
    children, (d) the initial effects of increased lead ingestion, (e)
    rates of increase in levels of lead in the blood of exposed children,
    and (f) sequelae of lead poisoning. Based on the available data the
    U.S. Public Health Service established a daily permissible lead intake
    from all sources for children of 300 g/day, which has been considered
    a reference base in developing measures for prevention of lead
    poisoning in children (DHEW, 1970; King, 1971). At the time this
    standard was established, 40 g/dl of whole blood was considered
    evidence of undue absorption of lead; it was assumed that (1) 90% of
    the ingested lead was excreted and (2) total lead ingestion of
    600 g/day of lead for an adult or an estimated equivalent dose for a
    child 2 to 3 years old, i.e. 300 g/day, would not result in increased
    blood lead levels. In 1972, Barltrop estimated the permissible limits
    of intake for children of different ages from birth to 15 years by
    scaling down from the level which was not known to cause toxicity in
    adults. Since he considered the surface area of the body rather than
    body weight to be the major variable in determining metabolic
    activity, he calculated the acceptable daily intake, based on the WHO
    adult tolerable intake of 600 g/day (340 g/square meter), corrected
    for the caloric intake of children, and determined the permissible
    daily intake to be 72 g per square meter of body surface for a
    newborn and 298 g per square meter for a three-year old
    (Barltrop, 1972). When this value was adjusted for varying body size
    of infants between birth and three years of age, and when the newer
    information on the increased absorption of lead in infants compared to
    that of adults was taken into account, Mahaffey recommended that the
    maximum tolerable intake for lead from all sources for infants between
    birth and age 6 months should be as low as possible and less than
    100 g/day, and that intake should be no more than 150 g of lead/day
    for children between 6 months and 2 years (Mahaffey, 1977).

         In 1983, Ryu measured the relationship between dietary lead
    intake and blood lead concentration in infants from birth to 6.4
    months and showed that intakes of as little as 61 g/day resulted in
    increased blood levels of lead, an indication of lead accumulation.
    The metabolic balance studies reported by Ziegler et al. (1978)
    demonstrated that faecal excretion of lead generally exceeded intake
    when dietary intake of lead was less than 4 g/kg/day. The study by
    Ryu et al. (1983) showed that with low non-dietary exposure to lead,
    a mean dietary intake of 3-4 g/kg/day is not associated with an

    increase in blood lead concentration. Thus, the authors concluded that
    it seems reasonable to set the daily permissible intake for lead from
    all sources closer to 3 than to 8 g/kg/day, for infants. In addition,
    based on their observations in the Glasgow duplicate diet study,
    Sherlock & Quinn (1986) have developed an equation whereby they
    calculate that infants having a lead intake of 680 g/week (about
    100 g/day) will have an average blood lead level of 25 g/dl. This
    blood level is now considered to be one requiring intervention to
    determine and reduce sources of exposure. The calculations of DHEW, of
    Baltrop and of Mahaffey, were based on extrapolations from data
    obtained from adults while those of Ryu and Sherlock & Quinn were
    based on measured lead intake and blood lead levels in children and
    therefore should be more reliable. Furthermore, at the time the
    earlier calculations were made, the level of blood lead considered to
    be indicative of toxicity in children was considerably higher than the
    current level.

    Comments

         Because of special concern for them, the present Committee
    evaluated the health risks of lead to infants and children. The
    Committee noted that the previous principles governing the
    toxicological evaluation of metal contaminants (Annex 1, Reference 30,
    section 3.1), as well as the principles contained in the IPCS and CEC
    report (WHO, 1986) on the need for a special approach to evaluating
    health risks during infancy and early childhood, provide valuable
    guidelines for evaluating these risks. The basis of the special
    concern for infants and children relates to a number of factors,
    including higher metabolic rate, rapid body growth, different body
    composition, immaturity of the kidney, liver, nervous system, and
    immune system, and development of organs and tissues such as bone and
    brain. The higher energy requirements of infants and children and the
    higher fluid, air, and water intake per unit body weight results in a
    relatively greater intake of contaminants in food, compared to that of
    adults. In addition, particular behavioural characteristics of
    children such as heightened hand-to-mouth activity, as well as the
    ingestion of non-food items (pica), may result in significant exposure
    to lead from non-food sources. Social and cultural attitudes of child
    rearing may influence exposure to non-food sources. Because the
    evaluation of the health effects of lead relates to exposure from all
    sources, any increase in lead from non-food sources (e.g. water and
    air) will reduce the amount that can be tolerated from food. It is
    important to identify sources of exposure that may be of greater
    significance to infants and children than adults so that strategies
    for control may be developed.

         Detailed information on sources of exposure is available
    (FAO, 1986a; WHO, 1977). Sources include those from the general
    environment, the domestic environment, and food, air, and drinking
    water. Exposure in the domestic environment is a particularly
    important source of lead exposure for children and infants, and
    includes lead in indoor dust, top-soil, and paint in the immediate
    environment.

         Detailed information on levels of lead in food and total intake
    for infants and children is available (FAO, 1986a; WHO, 1977).

         There is a large amount of information on the toxic effects of
    lead. The information used in this evaluation has been largely derived
    from studies with infants and children. Children absorb lead from the
    diet with greater efficiency than do adults. Lead absorption for
    adults is normally in the range of 5-10% of dietary lead. Children
    with lead intakes of 5 g/kg b.w. per day are in positive balance for
    lead retention.

         The net absorption of dietary lead at this level averages 40% of
    the lead intake, and the net retention has been estimated to be about
    30% of intake. However, metabolic studies indicate a negative balance
    when lead intake is less than 4 g/kg b.w./day. The relationship
    between oral lead intake and blood lead levels is non-linear, with the
    greatest increases in blood lead levels occurring at the lower range
    of exposure.

    EVALUATION

         The Committee considered the available information, including
    correlations between blood lead levels and specific effects, blood
    lead levels in children in the general population, and controlled
    epidemiology studies. Based on the information that a mean daily
    intake of 3-4 g/kg b.w. of lead by infants and children was not
    associated with an increase in blood lead levels, a provisional
    tolerable weekly intake (PTWI) of 25 g/kg b.w. was established. This
    level refers to lead from all sources.

         The Committee recognizes that in some situations the PTWI may be
    exceeded, when blood lead levels may exceed 25 g/dl. In such
    circumstances investigations should be carried out to determine the
    major source(s) of exposure, and all possible steps should be taken to
    ensure that lead levels in food are as low as possible, and that
    contributions from other environmental sources are minimized. The
    following are possible strategies for achieving this:

         Reducing or eliminating the use of lead solder and other
    lead-containing materials in equipment and containers coming into
    contact with food during its processing and handling can reduce lead
    contamination of foodstuffs.

         Lead contamination of foods in tinplate cans with lead-soldered
    side-seams originates mainly from the solder used in can manufacture.
    Contamination of foodstuffs in soldered cans can be reduced by
    operating the can-making equipment in such a way as to minimize
    contamination of the inside of the can with solder (FAO, 1986b),
    replacing high-lead solder by low-lead or lead-free solder, and
    lacquering the cans after soldering. Other ways of reducing lead
    contamination of canned foods include using electro-welding or other
    techniques instead of soldering to manufacture the can body, using
    two-piece cans instead of three-piece cans, limiting the level of lead
    permitted in the tin used to manufacture tinplate for food cans, or
    replacing tinplate cans by other types of container.

         Some glazes used for ceramic foodware contain appreciable levels
    of lead. If such foodware is not fired correctly, it may release large
    amounts of lead to foods, especially acidic products, that come into
    contact with it. Contamination of foods with lead from this source can
    be reduced by using lead-free glazes. Foodware can be checked for
    levels of leachable lead using one of the standardized methods now
    available.

         Contamination of drinking water with lead from plumbing systems
    can be eliminated by replacing the lead in such systems with other
    materials. If this cannot be done, contamination of soft water
    (pH 4.5 - 5.5) with lead from plumbing systems can be reduced by
    increasing the pH of the water to about pH 8.5 by the addition of lime.

         In some circumstances, a major source of environmental lead
    pollution is tetraalkyl lead used as a petrol additive. Lead in motor
    vehicle exhausts increases lead exposure of infants and young children
    in several ways. Elevated lead levels in air result directly in
    increased lead exposure via inhalation. Atmospheric deposition of lead
    on growing crops or the use of sewage sludge contaminated with lead
    from highway runoff as fertiliser on agricultural land can result in
    increased lead levels in foodstuffs and animal fodder and thus
    indirectly in increased dietary exposure. This type of lead pollution
    can be reduced by reducing or eliminating the use of lead compounds as
    petrol additives.

         House paints used in the past sometimes contained high levels of
    lead and therefore it is prudent to warn the parents of young children
    of the serious health hazards associated with the ingestion of flakes
    of such paint. Similar considerations apply to the use of lead in
    cosmetics and toys.

         The discharge of lead into the environment by industry, e.g. lead
    ore mines and primary and secondary lead smelters, and from waste
    disposal may give rise to high levels of local pollution. If such
    pollution cannot be reduced, careful attention should be given to the
    problems inherent in the consumption of heavily lead-contaminated food
    produced in areas affected by such pollution.

         High lead levels from environmental sources in dust and soil can
    result in increased ingestion of lead by young children due to sucking
    of contaminated fingers and mouthing or swallowing of other non-food
    items contaminated with dust, Simple measures, such as teaching young
    children to wash their hands before eating, can help to reduce lead
    exposure from contaminated dust,

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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 44)
       LEAD (JECFA Evaluation)
       Lead (UKPID)