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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION





    SAFETY EVALUATION OF CERTAIN FOOD
    ADDITIVES AND CONTAMINANTS



    WHO FOOD ADDITIVES SERIES: 44





    Prepared by the Fifty-third meeting of the Joint FAO/WHO
    Expert Committee on Food Additives (JECFA)





    World Health Organization, Geneva, 2000
    IPCS - International Programme on Chemical Safety

    CONTAMINANTS


    LEAD

    First draft prepared by Dr C. Carrington1, Dr M. Bolger1, Dr J.C.
    Larsen2 and Dr B. Peterson3

    1US Food and Drug Administration, Washington DC, USA; Department of
    Biochemical and Molecular Toxicology, Institute of Toxicology, Danish
    Veterinary and Food Administration, Soborg, Denmark; and 5 Novigen
    Sciences Inc., Washington DC, USA 

    Explanation
    Biological data
       Biochemical aspects
            Absorption, distribution and excretion
            Biotransformation
            Effects on enzymes and other biochemical parameters
            Pharmacokinetic models
            Biomarkers
       Toxicological studies
            Acute toxicity
            Carcinogenicity
            Other effects in laboratory animals
       Observations in humans
            Death
            Haematological effects
            Neurological effects
            Renal effects
            Cardiovascular effects
            Developmental effects
            Reproductive effects
            Carcinogenesis
    Exposure to lead
       Residue data submitted by national governments
       National exposure estimates
            Total intake of lead from food
            Contribution of foods/food categories to total lead intake
       Intake assessments based on the GEMS/Food regional diets and
       selected lead concentrations for those foods
            Intake estimates based on the proposed CCFAC limits for lead
            in selected foodstuffs
                 Methods
                 Results
            Intake estimates based on estimates of the 'typical'
            concentrations of lead in selected foods
                 Methods
                 Results
            Intake estimates based on estimates of a realistic 'maximum'
            concentration of lead in selected foods
                 Methods
                 Results

            Discussion and conclusions
            Exposure from non-dietary sources
                 Migration from food containers
                 Soil
                 Paint
            Surveys of blood lead concentrations
       Quantitative risk assessment
            Exposure assessments
                 Population estimates of dietary lead exposure
                      Frequently consumed foods
                      Infrequently consumed foods
                 Simulations of the effect on exposure of a commodity
                 with a high concentration of lead
                 Relation of dietary lead to blood lead
                      Drinking-water and blood lead in bottle-fed
                      infants
                      Drinking-water and blood lead in adults
            Dose-response assessment
                 Designing an analysis
                 Dose-response models for blood lead and IQ
                 A sample diet-response simulation 
    Comments
    Evaluation
    References

    1.  EXPLANATION

         The Committee first evaluated lead at its sixteenth meeting
    (Annex 1, reference  30), when a provisional tolerable weekly intake
    (PTWI) of 3 mg of lead per person, equivalent to 50 g/kg bw, was
    established. This PTWI was reconfirmed by the Committee at its
    twenty-second meeting (Annex 1, reference  47). At its thirtieth
    meeting (Annex 1, reference  73), the Committee assessed the risk posed
    by lead to the health of infants and children and established a PTWI
    of 25 g/kg bw for this population group. The Committee again
    evaluated lead at its forty-first meeting (Annex 1, reference  107),
    when the previous PTWI of 50 g/kg bw for adults was withdrawn, and
    the existing PTWI of 25 g/kg bw for infants and children was
    reconfirmed and extended to people in all age groups. The review of
    the health effects of lead at the forty-first meeting was based on a
    recent assessment of inorganic lead performed by an International
    Programme on Chemical Safety (IPCS) Task Group and published as an
    Environmental Health Criteria monograph (WHO, 1995).

         At its present meeting, the Committee was requested to assess the
    risk of dietary exposure of infants and children, with special
    emphasis on the most critical effect, which was considered to be
    impaired neurobehavioural development. The Committee considered
    several models that had been developed to define the relationship

    between the health effects of current levels of exposure to lead and
    the impact on health that might be anticipated from reducing exposure.
    The current PTWI was not reconsidered and was retained at its present
    value.

         The scientific literature on lead is extensive and numerous
    reviews have been published. This monograph relies mainly on the
    Environmental Health Criteria monograph on inorganic lead (WHO, 1995)
    and a document from the Agency for Toxic Substances and Disease
    Registry (1997); earlier and later studies of particular significance
    are also cited. Only brief summaries of toxicological effects are
    given, but studies of the effects critical for the risk assessment are
    evaluated in more detail. The main emphasis is laid on studies in
    humans.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

         The rate of absorption of lead after ingestion can range from 3%
    to 80%. It is heavily influenced by food intake, much higher rates of
    absorption occurring after fasting than when lead is ingested with a
    meal. This effect may be due mainly to competition from other ions,
    particularly iron and calcium, for intestinal transport pathways.
    Absorption is also affected by age, the typical absorption rates in
    adults and infants being 10% and 50%, respectively (O'Flaherty, 1995;
    Agency for Toxic Substances and Disease Registry, 1997).

         In blood, most lead is found in erythrocytes. The ability of
    erythrocytes to sequester lead is attributable to binding by
    haemoglobin and other proteins; however, higher plasma:erythrocyte
    ratios are seen with increasing blood lead concentrations as a result
    of saturation of binding sites (Agency for Toxic Substances and
    Disease Registry, 1997).

         After its absorption and distribution in blood, lead is initially
    distributed to soft tissues throughout the body. Subsequently, lead is
    deposited in bone, where it eventual accumulates. The half-life of
    lead in blood and other soft tissues is 28-36 days (WHO, 1995). Lead
    that is deposited in physiologically inactive cortical bone may
    persist for decades without substantially influencing the
    concentrations of lead in blood and other tissues (Rabinowitz et al.,
    1976), but lead that is accumulated early in life may be released
    later, when bone resorption is increased as result of, for example,
    calcium deficiency or osteoporosis. Lead that is deposited in
    physiologically active trabecular bone is in equilibrium with blood.
    The accumulation of high concentrations in blood when exposure is
    reduced may be due to the ability of bone to store and release lead.

         Dietary lead that is not absorbed in the gastrointestinal tract
    is excreted in the faeces. Lead that is not distributed to other
    tissues is excreted through the kidney and to a lesser extent by
    biliary clearance (Agency for Toxic Substances and Disease Registry,
    1997).

    2.1.2  Biotransformation

         Inorganic lead is not metabolized, although it may be conjugated
    with molecules such as glutathione. Organic lead may be metabolized to
    inorganic lead.

    2.1.3  Effects on enzymes and other biochemical parameters

         Lead is known to affect a number of enzymes and physiological
    systems, resulting in a wide variety of changes in humans (WHO, 1995).
    The best-documented biochemical mechanism is inhibition of
    delta-aminolaevulinic acid dehydratase, resulting in binding of lead 
    to sulfhydryl groups. The concentrations of coproporphyrin in urine 
    and of 5-aminolaevulinate in blood and urine are increased in 
    individuals exposed to high concentrations of lead as a result of 
    inhibition of this enzyme.

         Other enzymes have also been reported to be inhibited by lead.
    Changes in circulating vitamin D concentrations after exposure to lead
    have been attributed to inhibition of 25-hydroxyvitamin D-1
    alpha-hydroxylase. The activity of dihydrobiopterin reductase, an
    enzyme involved in the synthesis of catechola-mines, is reduced by
    lead in rat brain. The activity of nicotinamide adenine dinucleotide
    synthetase in erythrocytes may also be inhibited by lead.

    2.1.4  Pharmacokinetic models

         Several pharmacokinetic models have been developed in an attempt
    to relate exposure to lead to concentrations in blood and other
    tissues. A model developed by the United States Environmental
    Protection Agency (1994) of lead in air, diet, dust, paint, soil, and
    drinking-water allows modelling of distribution in a 10-compartment
    model that includes plasma, erythrocytes, trabecular bone, and
    cortical bone. The parameters in the model were chosen to represent
    children, and the model presumes that exposure and pharmaco-kinetics
    are in a steady state. Population distributions are derived by using
    the model output to estimate the population geometric mean and a fixed
    geometric standard deviation.

         O'Flaherty (1991, 1993, 1995) developed another pharmacokinetic
    model which represents the temporal relationships in the transfer of
    lead between blood, bone, and other tissues. It is thus more useful
    for predicting physiological lead concentrations when exposure is
    inconstant. It also accounts for changes that occur as a function of
    age. In particular, the model accounts for differences in

    pharmacokinetics attributable to changes in body size and in
    age-related changes in absorption, bone growth, or metabolism that
    occur during childhood, pregnancy, menopause, and old age. The model
    does not attempt to account for population variation, but when it is
    used in a simulation designed to represent population variation, the
    exposure inputs and some of the biological parameters (such as
    absorption rates) can be varied to reflect population differences.

    2.1.5  Biomarkers

         The concentration of lead in blood is the most widely used
    biomarker of exposure, largely because it is the measure that is the
    easiest to obtain. Blood lead concentration is typically reported in
    micrograms per deciliter. Because blood concentrations are strongly
    influenced by recent exposure, they may not reflect long-term
    exposure, particularly to intermittent or infrequent, high levels.

         A marker that was widely used before techniques for measuring
    blood lead became widely available is plasma delta-aminolaevulinic
    acid dehydratase activity, which correlates strongly with blood lead
    concentration (Agency for Toxic Substances and Disease Registry,
    1997). Related markers that have sometimes been used are the urinary
    and blood concentrations of delta-amino-laevulinic acid and plasma
    d-aminolaevulinic acid synthetase. Both of these markers correlate
    positively with exposure to lead.

         Other markers that have been employed on occasion include bone
    lead concentration, urinary concentration, and dentine lead (Agency
    for Toxic Substances and Disease Registry, 1997). Urinary lead is
    limited as a marker because the concentrations fluctuate more with
    current exposure than in blood, and they tend to be lower and more
    difficult to measure. Tooth lead has the advantage of reflecting
    chronic exposure to lead and can be collected from children. Bone lead
    is also a marker of chronic exposure and can be measured  in vivo by
    X-ray fluorescence; however, variation in intra-individual
    measurements make this technique unreliable for measuring
    concentrations of lead in populations that are not heavily exposed.

    2.2  Toxicological studies

    2.2.1  Acute toxicity

         Lead is a classical chronic or cumulative poison. Health effects
    are generally not observed after a single exposure, and no LD50
    values have been reported in the literature. The lowest observed
    lethal doses in animals after short-term oral exposure to lead
    acetate, lead chlorate, lead nitrate, lead oleate, lead oxide, and
    lead sulfate range from 300 to 4000 mg/kg bw, the doses having been
    given in multiple administrations (Lewis, 1992; Agency for Toxic
    Substances and Disease Registry, 1997). The wide range is attributable
    to differences in absorption of the various lead salts and differences
    in exposure.

    2.2.2  Carcinogenicity

         Studies of carcinogenicity in rodents have been conducted with
    lead arsenate and lead phosphate. In several studies, increased
    frequencies of renal tumours were seen in both male and female rats,
    with a greater increase in males. The doses used in these studies were
    quite high, and production of detectable increases in renal tumour
    frequency apparently required doses in excess of 10 mg/kg bw per day.
    Such concentrations also cause renal toxicity in rodents.

    2.2.3  Other effects in laboratory animals

         Many of the effects that have been observed in laboratory animals
    have also been observed in humans (WHO, 1995). These include effects
    on haem synthesis, neurological and behavioural effects, renal
    effects, cardiovascular effects, and effects on the reproductive
    system. In addition, lead has been shown to have effects on bone and
    on the immune system in laboratory animals. Impaired learning ability
    has been reported in rats exposed to lead at concentrations of 15-20
    g/dL and in nonhuman primates exposed to < 15 g/dL. Visual and
    auditory impairments have been reported in experimental animals. Renal
    toxicity in rats appeared to occur at concentrations exceeding 60
    g/dL, while cardiovascular effects have been noted at 40 g/dL.

    2.3  Observations in humans

    2.3.1  Death

         Increased death rates have been reported after occupational
    exposure to lead resulting in blood lead concentrations in excess of
    50 g/dL. The causes of death most often associated with such exposure
    are cardiovascular disease, renal disease, and cancer (Cooper, 1988;
    Agency for Toxic Substances and Disease Registry, 1997).

    2.3.2  Haematological effects

         A primary symptom of chronic lead poisoning, long associated with
    exposure to lead, is anaemia. This results from reductions in
    erythrocyte life-span and inhibition of haem synthesis by
    delta-aminolaevulinic acid dehydratase and ferrochelatase. Inhibition 
    of delta-aminolaevulinic acid dehydratase can be detected at low blood 
    lead concentrations and has been considered for use as a biomarker of
    exposure, but haemoglobin concentrations are generally not inhibited
    sufficiently to result in clinically observable anaemia until a
    concentration of at least 80-100 g/dL is reached (Goyer, 1996).

    2.3.3  Neurological effects

         The clearest clinical effect that is attributable to very high
    levels of exposure to lead is encephalopathy. This effect usually
    occurs at blood lead concentra-tions exceeding 300 g/dL, although
    more subtle and infrequent effects on the central nervous system have

    been noted at 100 g/dL (Goyer, 1996; Agency for Toxic Substances and
    Disease Registry, 1997). This syndrome has been observed most often in
    children, the source of lead usually being paint chips.

         Lead-induced encephalopathy may develop within weeks of exposure
    and is characterized by irritability, poor attention span, headache,
    muscular tremor, loss of memory, and hallucinations. Severe cases are
    often fatal. More subtle neurological effects occur after exposure to
    lower concentrations. The neurological effects that have been
    associated with concentrations in the range of 50-300 g/dL include
    disturbances of motor function, cognitive function, and intelligence
    scores and altered emotional states. Effects on the peripheral nervous
    system have also been noted. In particular, reductions in nerve
    conduction velocity have been associated with blood lead
    concentrations in excess of 30 g/dL.

    2.3.4  Renal effects

         There are two forms of lead-induced nephropathy. Acute renal
    nephropathy, which occurs after short exposure to lead, involves
    dysfunction of the proximal tubules and is largely reversible. This
    form of renal toxicity is often reported in children after oral
    exposure. It is attributable to impairment of energy-dependent
    transport functions resulting from inhibition of mitochondrial
    respiration and phosphorylation. Detectable effects on renal function
    may occur with blood lead concentrations as low as 40 g/dL (Goyer,
    1989; WHO, 1995). Chronic lead-induced nephropathy involves reductions
    in glomerular filtration rate and irreversible atrophy of the proximal
    and distal tubules. This disease is most often associated with higher
    and longer exposure than that required for the acute effect. This
    disease is most often associated with occupational exposure to lead.

    2.3.5  Cardiovascular effects

         Exposure to lead has been associated with increased incidences of
    hyper-tension and cardiovascular disease (Pirkle et al., 1985; Agency
    for Toxic Substances and Disease Registry, 1997). The relationship
    between blood lead and blood pressure appears to be greatest at
    concentrations below 50 g/dL, and increases in blood lead
    concentration beyond this level do not appear to correlate with
    greater hypertension. The causal relationship between lead and
    hypertension is not clear, however: the elevation may be secondary to
    effects on other organ systems such as the kidney or the haematopoetic
    system.

    2.3.6  Developmental effects

         The potential developmental effects of maternal exposure to lead
    have been studied in several populations. Needleman et al. (1984)
    reported a higher incidence of minor congenital anomalies, including
    angiomas and papillae, in the offspring of women in Boston (USA) who
    had been exposed to lead during pregnancy, but the effects were not

    strongly correlated with blood lead concentration. Reduced birth
    weight and gestational age have also been associated with exposure to
    lead  in utero (Baghurst et al., 1987; Dietrich et al., 1987), but
    conflicting results were obtained (Graziano et al., 1990; Agency for
    Toxic Substances and Disease Registry, 1997).

         The most important and best-documented effect of lead at the
    concentrations most commonly encountered outside occupational settings
    is on the neurobehavioural development of children of mothers exposed
    to lead. Early indications of a possible effect were difficult to
    disentangle from other factors known to influence development. In a
    cross-sectional study, however, Needleman et al. (1979) reported an
    association between blood lead concentration and reduced intelligence
    quotients (IQs) in a population of middle-class children who were
    similar with respect to known confounders. Since that study, a number
    of large prospective studies have been conducted, in all of which
    cohorts of several hundred children were followed-up from birth to
    childhood.

         In a study of a cohort of 249 middle-class children in Boston
    (USA), blood lead was measured at birth (in cord blood) and at 6
    months, 12 months, 18 months, 24 months, 57 months, and 10 years of
    age. The mean concentrations in cord blood ranged from < 3 to 25
    g/dL. Mean concentrations of 6-8 g/dL were found at ages < 57
    months, which had decreased to 2.9 g/dL at 10 years of age.
    Behavioural performance tests were administered at the same time as
    the blood lead was measured. Prenatal and postnatal blood lead
    concentrations were related to performance on the Bayley mental
    development index (MDI) and the Bayley psychomotor development index
    (PDI) at the age of 6-24 months, to the McCarthy scales of childrens
    abilities (MSCA) at 57 months, and to the Weschler intelligence scale
    for children (WISC) and the Kaufman test of educational achievement at
    10 years of age. The authors reported an inverse correlation between
    cord blood lead concentration and MDI scores at 6, 12, 18, and 24
    months of age, and inverse relationships were noted between blood lead
    concentration at 24 months and MSCA scores at 57 months and WISC and
    Kaufman scores at 10 years. There appeared to be a greater effect of
    lead on MDI performance at 57 months in infants with a higher
    socioeconomic status. No correlation was seen between cord blood lead
    concentration and performance on the PDI scale or between postnatal
    blood lead concentration and performance on the MDI or PDI scale.
    Furthermore, no relationship was noted between cord blood lead
    concentration and scores at 57 months or 10 years (Bellinger et al.,
    1991; National Research Council, 1993).

         In a prospective study conducted in Port Pirie, Australia, 723
    children were followed from birth to the age of 7 years. Blood lead
    was measured at birth (cord blood) and at 6 months, 15 months, 24
    months, 36 months, and 4 years of age. The mean cord blood
    concentration was 8.3 g/dL, whereas the mean concentration in blood
    from children up to 48 months was 15-21 g/dL. Behavioural performance
    was evaluated on the Bayley scales at 24 months, as MSCA at 48 months,

    and on the WISC at 7 years of age. The authors reported a weak inverse
    correlation between cord blood lead concentration and MDI scores at 6
    months and an inverse correlation between the integrated average of
    postnatal blood lead concentrations and MSCA scores at 48 months and
    WISC scores at 7 years of age (Baghurst et al., 1987, 1992; National
    Research Council, 1993).

         A prospective study conducted in Cincinnati (USA) involved
    following 305 children from birth to 78 months of age. Blood lead was
    measured at birth (cord blood) and at various times up to 5 years of
    age. The mean blood lead concentration was about 6 g/dL at birth and
    up to 3 months, rose to 21 g/dL at the age of 24 months, and then
    fell to a population mean of 12 g/dL at 5 years of age. Behavioural
    performance was evaluated on the Bayley scales at 3, 6, 12, and 24
    months, with the Fluarty speech and language screening test at 39
    months, with the Kaufman assessment battery for children at 48 and 60
    months, with the Bruininks-Osetretsky test of motor proficiency at 72
    months, and on the WISC at 78 months. The authors reported an inverse
    correlation between cord blood lead concentration and MDI score at 3,
    6, and 12 months but a positive association at 24 months. The MDI
    scores did not appear to be associated with postnatal measures of
    exposure to lead. Inverse associations were found between the Fluarty
    test score at 39 months and cord blood lead concentration, the Kaufman
    score at the age of 5 and mean blood lead concentration in the
    previous year, and the WISC and Bruininks-Osetretsky scores and
    integrated measures of postnatal exposure (Dietrich et al., 1987,
    1992, 1993; National Research Council, 1993).

         A prospective study was conducted in Cleveland (USA) in which a
    cohort of 359 children was followed from birth through 10 years of
    age. Blood lead was measured at birth (cord blood) and at 6 months, 2
    years, and 3 years of age. The mean blood lead concentration was about
    6 g/dL at birth and rose to about 17 g/dL at 2 and 3 years of age.
    Neonatal behavioural performance was evaluated on a neonatal behaviour
    assessment scale and in the Gram-Rosenblith behavioural examination.
    The Bayley tests were administered at 6, 12, and 24 months and a
    sequenced inventory of communication development at 12, 24, and 36
    months. Behaviour at the ages of 4-10 was evaluated on the Eschler
    preschool and primary scales of intelligence. The authors reported an
    inverse correlation between cord blood lead concentration and the
    Gram-Rosenblith score at birth and the MDI and PDI scores at 6 months.
    No other associations were noted (National Research Council, 1993).

         In a prospective study conducted in Sydney, Australia, 318
    children were followed from birth through 4 years of age. Blood lead
    was measured at birth (cord blood) and every six months until the end
    of the study. The mean blood lead concentration was about 8 g/dL at
    birth, rose to about 15 g/dL at 2 years of age, and then fell to 10
    g/dL at 4 years of age. Behavioural performance was assessed on the

    Bayley scales at 6, 12, and 24 months and on the MSCA at 3 and 4 years
    of age. No association was noted between any index of exposure to lead
    and performance on the tests (Cooney et al., 1989; National Research
    Council, 1993).

         A prospective study was conducted in two towns in Kosovo,
    Yugoslavia, to follow 332 children from birth through 4 years of age.
    Behavioural performance was compared for children living in a town in
    which a lead smelter was located (Titova Mitrovica) with that of
    children living in the other (Pristina). Blood lead was measured every
    six months. The geometric mean blood lead concentrations in children
    in the two towns were 22 and 5.4 g/dL at birth and 40 and 9.6 g/dL
    at 4 years of age. Behavioural performance, evaluated on the MSCA at
    the age of 4, was associated with all measurements of blood lead,
    those taken after 24 months providing stronger associations than
    earlier measurements (Graziano et al., 1990; Factor-Litvak et al.,
    1991; Wasserman et al., 1992; Agency for Toxic Substances and Disease
    Registry, 1997).

         A number of cross-sectional and longitudinal studies have been
    conducted to study the relationship between lead concentration in
    blood or teeth to the outcomes on various tests of behavioural
    performance (National Research Council, 1993).

    2.3.7  Reproductive effects

         Exposure of women to lead before or during pregnancy is
    associated with miscarriage and stillbirth (Agency for Toxic
    Substances and Disease Registry, 1997), but statistically significant
    associations have been observed only in studies in which direct
    occupational exposure resulted in blood lead concentrations > 20
    g/dL. Impairment of male reproductive function, in the form of
    decreased sperm counts and increased numbers of abnormal sperm, has
    been reported in men with heavy occupational exposure to lead (WHO,
    1995; Agency for Toxic Substances and Disease Registry, 1997).

    2.3.8  Carcinogenesis

         Evidence of the carcinogenicity of lead comes from both
    epidemiological and experimental studies. The standardized mortality
    ratios for cancers of the lung, digestive tract, and kidney were found
    to be increased from 1 to 2.5 in studies of workers in lead production
    and battery plants who had blood concentrations of 40-100 g/dL
    (Cooper, 1976; Agency for Toxic Substances and Disease Registry,
    1997).

    3.  EXPOSURE TO LEAD

         Exposure to lead can occur from many sources but usually arises
    from industrial use. Lead and its compounds can enter the environment
    at any time during mining, smelting, processing, use, recycling, or
    disposal. The main uses of lead are in batteries, cables, pigments,

    plumbing, gasoline, solder and steel products, food packaging,
    glassware, ceramic products, and pesticides. The main exposure of the
    general non-smoking adult population is from food and water. Airborne
    lead may contribute significantly to exposure, depending on such
    factors as use of tobacco, occupation, and proximity to sources such
    as motorways and lead smelters. Food, air, water, and dust or soil are
    the main potential sources of exposure of infants and young children,
    and milk, formula, and water are significant sources of exposure of
    infants up to 4 or 5 months of age (WHO, 1995).

         Exposures to lead as a result of its ingestion in food, water, or
    air all make important contributions in national assessments. Although
    this assessment was limited to food and water, rational
    decision-making requires estimates of the major sources of exposure
    and the probable impact of proposed controls on exposure.

         Estimates of the intake of a contaminant in food are complicated
    by the skewed distributions of residues, since food is not
    contaminated in a controlled or predictable agricultural or
    manufacturing process. This is particularly true for lead, as will be
    seen. Nonetheless, it is often possible to control contamination, and
    such controls should have the maximum effect on lead intake. For this
    assessment, the data that were submitted to the Committee were
    reviewed to identify the range and 'typical' concentrations of lead in
    the food categories for which limits have been proposed by the Codex
    Alimentarius Commission. The objective of the assessment was to
    provide information on exposure for use in evaluating the effect of
    the proposed limits.

         Several countries submitted estimates of the intake of lead by
    their populations, and those estimates were reviewed and, when
    possible, compared with corresponding data derived from monitoring.
    Both bottled and tap water are also potential sources of lead.
    Regional diets were developed by WHO within the Global Environment
    Monitoring System-Food Contamination Monitoring and Assessment
    Programme (GEMS/Food) and have been used by WHO and others since 1987
    to estimate the intake of pesticides and contaminants. The diets were
    derived from food balance sheets compiled by FAO and thus provide data
    that are comparable across different countries and regions of the
    world. The data are based on the countries' annual food production,
    imports, and exports. They do not take into account waste at the
    household or individual level and are thus expected to be
    overestimates of consumption; comparisons with data from detailed
    national food consumption surveys indicate that actual food intakes
    are overestimated by about 15%. The data do not permit analysis of the
    intakes of subgroups such as children and infants consuming the
    regional diets.

         Data on lead intake in more than 25 countries available from
    GEMS/Food (1992) are summarized below. Intake of lead was also
    estimated in the GEMS/Food regional diets in combination with the
    values for residues that had been submitted, i.e. maximum, 'typical',

    or the maximum limits proposed to the Codex Committee on Food
    Additives and Contaminants (CCFAC). In view of the toxicity of lead,
    the Committee considered the available data and also estimated
    children's intakes of lead.

         The ideal estimates of the intake of lead from food would be
    derived from the entire distribution of residue concentrations in
    foodstuffs. This would be particularly desirable, given the skewed
    distributions of lead. The data were not, however, submitted in a form
    that would permit such an analysis or the numbers of samples were too
    limited. The analysis was further complicated by the extremely wide
    variety of foods for which data were submitted and the manner in which
    the data were reported: for instance, one country would report 'oil,
    vegetable' while another would specifiy items such as 'soya bean oil,
    pizza, dried tomatoes, and vacuum-packed tofu'.

         The data do provide an indication of the range of lead
    concentrations in different types of food from different countries and
    an indication of national intake levels. These data and the proposed
    maximum limits on lead (CCFAC, 1999) were used in combination with
    GEMS/Food regional diets to derive estimates of potential lead intakes
    around the world. This method provides a measure of the concentrations
    of lead in foodstuffs moving in international trade, the likely role
    of those concentrations in dietary intake estimates, and the likely
    impact of limiting lead concentrations by establishing maximum limits.
    These estimates should be combined with expert judgement to establish
    appropriate controls on food. Additional data should be collected to
    refine the predictions of concentrations in foods before and after
    establishing limits.

    3.1  Residue data submitted by national governments

         Data were submitted to the Committee from more than 30 countries
    representing all seven continents. Most of the data were summarized
    and the original data were not submitted. The submission from the
    United States Total Diet Study was the only one in which values in
    individual samples were reported, each of which represented a
    composite of samples taken from three supermarkets. Detailed data on
    lead residues were also provided for Australia, Slovakia, and France.
    Values for lead residues in some beverages in Finland were obtained
    from the literature.

         The United States Food and Drug Administration collects samples
    of more than 200 foods from supermarkets four times each year and
    analyses them for contaminants and nutrients. Lead is one of the
    contaminants (Food & Drug Administration, 1993-96).

         The Australia-New Zealand Food Authority (1998) has monitored
    foods for lead as a part of a market basket survey to estimate
    potential intake. In this survey, foods are sampled by categories of
    core, national, and regional foods. Each sample represents a composite
    of three to four samples, and the number of samples analysed varies

    depending upon the food, ranging from as few as six up to 28 samples.
    The study is repeated each year. All foods are analysed in the form in
    which they would be consumed. Samples are taken from 14 major foods
    groups: cereal and cereal products, meat and poultry, seafood, eggs,
    fats and oils, dairy products, vegetables, fruit, nuts and seeds,
    beverages, snack foods, sugar/confectionery, condiments, and foods for
    infants.

         Lead concentrations in Slovakia were determined in a 'study in 
    which duplicate samples of meals were consumed and statistically
    representative samples were collected four times a year (Ursnyov & 
    Hladkov,1998). France provided data from its nationwide survey.

         A total diet study was conducted in China, and the results from
    the 1990 survey (Chen & Gao, 1993) and from a model diet study (Gao,
    1998) were available.

    3.2  National exposure estimates

    3.2.1  Total intake of lead from food

         The GEMS/Food (1992) report provides estimates for adults and
    children in more than 25 countries. The mean weekly intakes of lead
    based on monitoring in the 1980s ranged from less than 1 g/kg bw to
    more than 60 g/kg bw. When data were available for both children and
    adults, the children's intake of lead was found to be two to three
    times the adult intake when expressed on the basis of body weight.

         The data in GEMS/Food for 1993 represent residue levels in the
    1980s. More recent estimates of the intake of lead are available for
    populations in Australia, China, Finland, France, New Zealand,
    Slovakia, Sweden, and the United States. In some of these countries,
    more than one study was conducted to determine lead intake. For
    example, Australia provided estimates of lead intake from their market
    basket study (Australia-New Zealand Food Authority, 1998) and from
    their 'Diamond' model (Baines, 1999), which permits assessment of
    individuals such as high consumers because it includes data from the
    1995 National Nutrition Survey and also water consumption. The intakes
    ranged from 1.6 to 7 g/kg bw per week, depending on the method used,
    the subgroup evaluated, and the residue data used. The inclusion of
    estimates of lead concentrations in water further increased the
    estimated exposure in Australia to 5.6-12 g/kg bw per week.

         Australia, New Zealand, France, China, Canada, Slovakia and the
    United States provided estimates of lead intake for a variety of age
    groups including young children (Table 1).

         The Ministry of Agriculture, Fisheries and Food in the United
    Kingdom conducts a total diet study each year by collecting foods from
    retail outlets in 20 towns and preparing them for consumption before
    analysis for contaminants. The results for 1982-91 were available for

    this evaluation and show that lead intake declined over that period,
    from 0.036-0.69 mg/person per day to 0.015-0.028 mg/person per day.

    3.2.2  Contribution of foods and food categories to total lead intake

         In a recent study in a non-industrialized area of the United
    Kingdom, the concentrations of lead ranged from 0.008 to 0.340 g/g in
    plant materials, the value being greater for grasses > herbs >
    vegetables > cereals > fruits (Ward & Savage, 1994). Root vegetables
    tended to have higher concentrations than other plant stuffs, at
    0.02-0.125 g/g, carrots, leeks, and onions having the largest
    amounts.

        Table 1. Weekly intake of lead in population groups in various countries
                                                                                           

    Country or        Group                  Weekly lead intake       Assumptions
    region                                                            (g/kg bw)
                                                                                           

    Australia         Adults                                          High consumer intakes
                      Males                  2.6-3.4                  95th percentile
                      Females                2.4-3.3
                      12-year-olds
                      Boys                   1.6-2.5
                      Girls                  1.7-2.7
                      2-year-olds            3.1-5.0
                      Infants (9 months)     2.0-5.1
                      Total                  4.9 without water
                                             6.3 including water
                      Adults                 4.2 without water
                                             5.6 including water
                      Infants                2.5
                      2-year-olds            7.0 without water
                                             11.9 including water

    Canada            Children 1-4 years     5.25                     Assumed body weight
                      20 kg bw
                      Adults 20-33 years     3.3
                      70 kg bw
                      Total population       2.4
                      70 kg bw 

    China             Adults                 10.1                     From total diet study
                      60 kg bw                                        Assumed body weight
                      Children               24.4
                      16.5 kg bw
                      Standard man           9.8                      From model diet study
                      58 kg bw
                      Children 2-7 years     29.7
                      16.5 kg bw

    Table 1. (cont'd)
                                                                                           

    Country or        Group                  Weekly lead intake       Assumptions
    region                                                            (g/kg bw)
                                                                                           

                      Children 8-12 years    24.5
                      29.4 kg
                      Males 20-50 years      22.0
                      63 kg bw
                      Females 20-50 years    19.9
                      53 kg bw

    Finland                                  1.4

    France            Adults                 8.3                      Assumed body weight
                      60 kg bw
                      Children 2-8 years     19.4
                      20 kg bw

    New Zealand       Males 19-24 years      3.3
                      Males > 25 years       3.3
                      Females > 25 years     2.5
                      Children 4-6 years     5.3
                      Children 1-3 years     6.3

    Slovakia          Children
                      Vegetarian             9.9-48.6                 Median-maximum
                      Non-vegetarian         6.7-57

    Sweden                                                            2-6

    Taiwan                                                            2.6

    United            Total population       3.3
    Kingdom

    United States     Infant 6-11 months     0.6                      Assumed body weight
                      10 kg bw
                      Children 2 years       1.1
                      15 kg bw
                      Children 6 years       1.4
                      18 kg bw
                      Children 10 years      1.2
                      22 kg bw
                      Females 14-16 years    0.4
                      60 kg bw
                      Females 25-30 years    0.4
                      70 kg bw
                      Females 40-45 years    0.3
                      70 kg bw

    Table 1. (cont'd)
                                                                                           

    Country or        Group                  Weekly lead intake       Assumptions
    region                                                            (g/kg bw)
                                                                                           

                      Females 70 years       0.4
                      70 kg bw
                      Males 14-16 years      0.4
                      70 kg bw
                      Males 25-45 years      0.4
                      70 kg bw
                      Males 70 years         0.5
                      70 kg bw
                                                                                           
    
         The commodities with the highest reported concentrations in the
    Australian market basket study were samples of lettuce, dried
    tomatoes, and psyllium husks. The lead concentrations in most foods in
    the United States Total Diet Study were very low, and no categories
    had typically high levels. Residue data for Australia were combined
    with food consumption data to estimate the contribution of individual
    foods or food categories to total intakes across the population. Most
    foods contributed less than 1% to total exposure. With one exception,
    only heavily consumed foods such as wheat flour and meat contributed
    more than 5% to the total intake. The exception was broccoli which
    contributed 22% to the total. The foods that contributed to the
    exposure of children and infants were milk (16%), pineapple juice
    (9%), apple juice (8%), sugar (8%), bread (8%), and tea (3%) for
    schoolchildren and milk (24%), juice (21%), and bread (5%) for
    toddlers. In Finland, beverages were reported to account for about
    one-fifth of the total lead intake from foods (Tahvonen, 1997).
    Cereals and vegetables contributed most of the lead intake in the
    Chinese total diet study (Chen & Gao, 1998).

         Milk and formula are the major components of the diets of most
    infants. For infants in Slovakia, the weekly median and range of lead
    intake (g/kg bw per week) was 4.7 (< 0.5-27) from breast milk, 6
    (1-8.5) from infants' formula, and 5.6 (2.7-24) from cow's milk
    (Ursnyov & Hladikova, 1997). No lead was detected in breast milk in
    Australia (Australia/New Zealand Food Authority, 1998) but a range of
    concentrations similar to that found in Slovakia was reported in
    infant formula (mean, 9 g/kg; maximum, 18 g/kg). Cows' milk was not
    tested in Australia. The Food and Drug Administration (1993-96)
    reported a maximum of 3 g/kg in cows' milk and did not detect
    residues in infant formula. Breast milk was not analysed. As it is not
    known whether the data from the three countries are for similar
    products or whether the products were analysed in the same form,

    comparisons should be considered to be qualitative. In particular, it
    is not known whether any of the products had been preserved in
    lead-soldered cans. The GEMS/Food (1992) summary reported mean intakes
    of 38 g/kg bw from a diet that included infant formula in
    lead-soldered cans and 8 g/kg bw when unsoldered cans were used.

    3.3  Intake assessments based on the GEMS/Food regional diets and
         selected lead concentrations in those foods

         In order to obtain a global perspective and to permit regional
    comparisons of the potential intake of lead, a series of analyses were
    conducted of the current GEMS/Food regional diets with various
    assumptions about the concentrations of lead in those foods. Three
    scenarios were considered: (1) the maximum limits currently proposed
    to CCFAC, (2) 'typical' concentrations based on average concentrations
    in monitored foodstuffs (the average residue in foods in the United
    States between 1993 and 1996 was chosen as the 'typical'
    concentration), and (3) 'high' concentrations based on those measured
    during monitoring. The Committee noted that these values are not true
    mean or maximum international values but considered them to be
    measures of the range of residues encountered in a wide variety of
    countries.

    3.3.1  Intake estimates based on the proposed CCFAC limits for lead in
           selected foodstuffs

    3.3.1.1  Methods

         Estimates of consumption in the GEMS/Food diets were used, and
    the intake of each food group with a proposed Codex limit was derived
    as the product of the Codex limit and the consumption level. In some
    instances, it was necessary to compute total consumption of a specific
    food group. For instance, the regional diets do not provide an
    estimate of total fruit juice intake. Therefore the estimate was
    derived as the sum of all fruit juices identified with the same code.
    The total intake was estimated as the sum of all food-specific
    intakes. In all these calculation, an average body weight of 60 kg was
    used.

    3.3.1.2  Results

         The estimated weekly intake of lead in each of the regional diets
    derived from the proposed Codex limits is 17 g/kg bw in the Middle
    Eastern diet, 15 g/kg bw in the Far Eastern diet, 13 g/kg bw in the
    African diet, 13 g/kg bw in the Latin American diet, and 20 g/kg bw
    in the European diet. The contribution of each food category to the
    total intake is presented in Table 2.

    3.3.2  Intake estimates based on estimates of the 'typical'
           concentrations of lead in selected foods

    3.3.2.1  Methods

         The procedure described above was repeated but substituting a
    'typical' observed lead concentration for the proposed limit. The
    'typical' value assumed for each food category was derived from United
    States Total Diet Study (Food & Drug Administration, 1993-96), and the
    estimated 'typical' intakes were derived from the average detectable
    concentrations reported in 12 market basket sample collections of 234
    foods. The foods were grouped and values selected to represent the
    lead concentrations in the WHO regional diets. Samples that contained
    no detectable lead residues were assumed to contain residues at the
    concentration of the limit of detection. Body weight was assumed to be
    60 kg for adults; some data are expressed as milligrams per day.

    3.3.2.2  Results

         The estimated weekly intake of lead in five regions of the world,
    assuming that foods contain a typical concentration of lead as
    determined from monitoring in the United States, is 1 g/kg bw in the
    Middle Eastern, Far Eastern, African, and Latin American diets and 2
    g/kg bw in the European diet. The 'typical' values and estimated
    intakes of each category of food are shown in Table 3, which shows
    that no category contributes the preponderance of the total intake.

    3.3.3  Intake estimates based on estimates of a realistic 'maximum'
           concentration of lead in selected foods

    3.3.3.1  Methods

         The procedure described above was repeated but substituting a
    likely maximum observed lead concentration for the proposed limit. The
    likely maximum concentration was also derived from Total Diet Study of
    the United States Food and Drug Administration. The estimated intakes
    were derived from average maximum detectable lead concentrations.
    Expert judgement was applied in selecting those values, and they
    should not be presumed to represent actual concentrations of lead. The
    foods were grouped and values selected to represent the lead
    concentrations in the WHO regional diets.

    3.3.3.2  Results

         The resulting intake estimates for individual foods are presented
    in Table 4, which shows that no category contributes the preponderance
    of the total intake.


        Table 2. Estimated intake of lead based on WHO regional diets and proposed CCFAC maximum limits
                                                                                                  

    Food                     Maximum    Intake (mg/person per day)
                             limit                                                                
                             (mg/kg)    Middle     Far       African     Latin       European
                                        Eastern    Eastern               American
                                                                                                  

    Citrus fruits            0.100      0.005      0.001     0.001       0.005       0.0049
    Pome fruits              0.100      0.001      0.001     0.000       0.001       0.0051
    Stone fruits             0.100      0.001      0.000     0.000       0.000       0.0023
    Bulb vegetables          0.100      0.003      0.001     0.001       0.001       0.0031
    Fruiting vegetables,     0.100      0.009      0.001     0.002       0.003       0.0078
    non-cucurbits
    Fruiting vegetables,     0.100      0.008      0.002     0.000       0.003       0.0038
    cucurbits                
    Total roots and tubers   0.100      0.006      0.011     0.032       0.016       0.024
    Brassica vegetables      0.300      0.002      0.003     0.000       0.003       0.012
    Leafy vegetables         0.300      0.002      0.003     0.000       0.005       0.015
    Total cereals            0.200      0.086      0.090     0.064       0.051       0.045
    Total pulses             0.200      0.005      0.004     0.004       0.005       0.0024
    Legume vegetables        0.200      0.002      0.000     0.000       0.001       0.0052
    Meat of cattle,          0.050      0.002      0.002     0.001       0.002       0.0075
    pigs, and sheep
    Poultry meat             0.050      0.002      0.001     0.000       0.001       0.0026
    Fat, mammalian           0.050      0.000      0.000     0.000       0.000       0.00038
    Poultry, fats            0.050      0.000      0.000     0.000       0.000       0.00026
    Total vegetable          0.050      0.002      0.001     0.001       0.001       0.0019
    oils and fats
    Edible offal of          0.500      0.002      0.001     0.001       0.003       0.0062
    cattle, pigs, and
    sheep
    Milk of cattle,          0.020      0.002      0.001     0.001       0.003       0.0059
    goats, and sheep
    Secondary milk           0.020      0.000      0.000     0.000       0.000       0.00094
    products
    Fish                     0.200      0.002      0.005     0.006       0.008       0.0067

    Table 2. (continued)
                                                                                                  

    Food                     Maximum    Intake (mg/person per day)
                             limit                                                                
                             (mg/kg)    Middle     Far       African     Latin       European
                                        Eastern    Eastern               American
                                                                                                  

    Crustaceans, fresh       0.050      0.000      0.000     0.000       0.000       0.00015
    and frozen
    Molluscs,                1.000      0.000      0.004     0.001       0.001       0.0083
    excluding
    cephalopod frsh
    Fruit juices             0.050      0.001      0.000     0.000       0.000       0.0005

    Total (mg/person                    0.144      0.131     0.114       0.114       0.173
      per day)

    Weekly potential                    17         15        13          13          20
    intake (g/kg bw, 
    if all foods contain 
    proposed maximum
    CCFAC limit levels)
                                                                                                  

    Table 3. Estimated intake of lead based on WHO regional diets and average residues from
    the United States Total Diet Study
                                                                                             

    Food category             Mean     Intake (mg/person per day)
    (no. of samples)                                                                         
                                       Middle     Far        African    Latin       European
                                       Eastern    Eastern               American
                                                                                             

    Total cereals (32)        0.011    0.005      0.005      0.004      0.003       0.003
    Citrus fruits (2)         0.007    0.000      0.000      0.000      0.000       0.000
    Pome fruits (4)           0.012    0.000      0.000      0.000      0.000       0.001
    Stone fruits (3)          0.016    0.000      0.000      0.000      0.000       0.000
    Fruit juices              0.006    0.000      0.000      0.000      0.000       0.000
    Milk of cattle, goats,    0.008    0.001      0.000      0.000      0.001
    and sheep (6)             0.002
    Secondary milk            0.013    0.000      0.000      0.000      0.000
    products (11)             0.001
    Meat of cattle, pigs,     0.013    0.000      0.000      0.000      0.001
    and sheep (14)            0.002
    Edible offal of cattle,   0.031    0.000      0.000      0.000      0.000
    pigs, and sheep (1)       0.000
    Total vegetable oils      0.034    0.001      0.000      0.001      0.001
    and fats (1)              0.001
    Poultry meat (5)          0.010    0.000      0.000      0.000      0.000       0.001
    Bulb vegetables (1)       0.008    0.000      0.000      0.000      0.000       0.000
    Brassica vegetables (3)   0.009    0.000      0.000      0.000      0.000       0.000
    Fruiting vegetables,      0.013    0.001      0.000      0.000      0.000
    cucurbits (7)             0.001
    Total pulses (5)          0.008    0.000      0.000      0.000      0.000       0.000
    Leafy vegetables (6)      0.011    0.000      0.000      0.000      0.000       0.001
    Fruiting vegetables,      0.009    0.001      0.000      0.000      0.000
    non-cucurbits (9)         0.001
    Legume vegetables (2)     0.008    0.000      0.000      0.000      0.000       0.000
    Total roots and           0.010    0.001      0.001      0.003      0.002       0.002
    tubers (12)
    Crustaceans, fresh and    0.039    0.000      0.000      0.000      0.000
    frozen (1)                0.000
    Fish (3)                  0.011    0.000      0.000      0.000      0.000       0.000

    Table 3. (continued)

                                                                                             

    Food category             Mean     Intake (mg/person per day)
    (no. of samples)                                                                         
                                       Middle     Far        African    Latin       European
                                       Eastern    Eastern               American
                                                                                             
    Total (mg/person                   0.012      0.009      0.009      0.010       0.017
    per day)

    Total(mg/kg bw                     0.001      0.001      0.001      0.001       0.002
    per week)
                                                                                             

    Assuming 60 kg bw
    Samples that contained no detectable lead residues were assumed to contain
    residues at the concentration of the limit of detection.

    Table 4. Estimated intake of lead based on WHO regional diets and the maximum residue for
    the food category from the United States Total Diet Study 
                                                                                             

    Food category                Maximum    Intake (mg/person per day)
    (no. of samples)             residue                                                     
                                 (mg/kg)    Middle    Far       African   Latin      European
                                            Eastern   Eastern             American
                                                                                             

    Total cereals (32)           0.022      0.009     0.010     0.007     0.006      0.005
    Citrus fruits (2)            0.013      0.001     0.000     0.000     0.001      0.001
    Pome fruits (4)              0.022      0.000     0.000     0.000     0.000      0.001
    Stone fruits (3)             0.034      0.000     0.000     0.000     0.000      0.001
    Fruit juices                 0.019      0.000     0.000     0.000     0.000      0.000
    Milk of cattle, goats,       0.015      0.002     0.000     0.001     0.002      0.004
    and sheep (6)
    Secondary milk               0.014      0.000     0.000     0.000     0.000      0.001
    products (11)
    Meat of cattle, pigs,        0.022      0.001     0.001     0.000     0.001      0.003
    and sheep (14)
    Edible offal of cattle,      0.080      0.000     0.000     0.000     0.000      0.001
    pigs, and sheep (1)
    Total vegetable oils         0.044      0.002     0.001     0.001     0.001      0.002
    and fats (1)
    Poultry meat (5)             0.018      0.001     0.000     0.000     0.000      0.001
    Bulb vegetables (1)          0.018      0.000     0.000     0.000     0.000      0.001
    Brassica vegetables (3)      0.032      0.000     0.000     0.000     0.000      0.001
    Fruiting vegetables,         0.037      0.003     0.001     0.000     0.001      0.001
    cucurbits (7)
    Total pulses (5)             0.019      0.000     0.000     0.000     0.000      0.000
    Leafy vegetables (6)         0.027      0.000     0.000     0.000     0.000      0.001
    Fruiting vegetables,         0.020      0.002     0.000     0.000     0.001      0.002
    non-cucurbits (9)
    Legume vegetables (2)        0.020      0.000     0.000     0.000     0.000      0.001

    Table 4. (continued)

                                                                                             

    Food category                Maximum    Intake (mg/person per day)
    (no. of samples)             residue                                                     
                                 (mg/kg)    Middle    Far       African   Latin      European
                                            Eastern   Eastern             American
                                                                                             

    Total roots and              0.017      0.001     0.002     0.006     0.003      0.004
    tubers (12)
    Crustaceans, fresh           0.210      0.000     0.000     0.000     0.000      0.001
    and frozen (1)
    Fish                         0.015      0.000     0.000     0.000     0.001      0.001

    Total (mg/person                        0.022     0.015     0.016     0.019      0.032
    per day)
    Total (mg/kg bw                         0.003     0.002     0.002     0.002      0.004
    per week)
                                                                                             
    
    3.4  Discussion and conclusions

         The WHO regional diets have been used in the GEMS/Food programme
    since 1987 to estimate exposure to pesticides and were used by the
    Committee at its forty-ninth meeting to estimate regional exposure to
    aflatoxins. The diets were used in this analysis to estimate potential
    exposure to lead under the assumption that all foods contain the
    maximum proposed Codex limits for lead. The analyses were repeated
    with information derived from national surveys of concentrations of
    lead in foods.

         The proposed Codex limits are higher than the vast majority of
    the concentrations observed during monitoring. If these concentrations
    occurred in all foods all of the time, the intake of lead by consumers
    would be higher than those found in national monitoring programmes.
    The concentrations have declined over the past decade, and high levels
    of contamination are not widespread; however, the available data from
    monitoring surveys may not capture the extreme values that occur due
    to localized pollution or due to the use of containers sealed with
    lead-solder.

         On the basis of the analyses conducted with the GEMS/Food
    regional diets and either 'typical' or maximum lead concentrations,
    consumers would not ingest more than the PTWI of 1500 g/week.

         The Committe also evaluated children's intakes. The GEMS/Food
    regional diets do not allow international estimates of children's
    intake, but national governments in a wide variety of locations have
    estimated the intake of lead by children. In the estimates provided by
    Australia, China, France, New Zealand, Slovakia, and the United States
    for infants and children, the highest estimated children's intakes
    were well below the PTWI in all but one country, those for Slovakia
    approaching the maximum limit under certain conditions. Five of the
    six countries provided estimates for both children and adults. In all
    five countries, the intake of children and infants tended to be
    somewhat higher than that of the total population when expressed on
    the basis of unit body weight. The Committee estimated that the
    intakes of children could be two to three times that of adults when
    expressed per unit body weight. The data from the national estimates
    provide assurance that children's intakes are also below the PTWI.

    3.5  Exposure from non-dietary sources

    3.5.1  Migration from food containers

         Lead may enter food from food containers or serving vessels
    containing lead (WHO, 1995). In particular, elevated concentrations of
    lead may result from storage in lead-soldered cans, in ceramic vessels
    with a lead glaze, or in leaded crystal. Although the use of lead
    solder has largely been discontinued, it was a major source of
    exposure in many parts of the world. Lead in ceramic-ware is a less

    widespread problem, but the most serious cases that have been
    documented have arisen from the consumption by children of fruit juice
    stored in ceramic pitchers.

    3.5.2  Soil

         The concentrations of lead in soil are typically in the range of
    5-100 mg/kg (WHO, 1995), whereas lead from anthropogenic sources may
    result in concentrations exceeding 10 000 mg/kg. In particular, soil
    in or adjacent to lead smelters, lead mines, houses painted with lead
    paint, orchards treated with lead arsenate, and urban areas where
    there has been heavy automobile traffic is likely to contain high
    concentrations of lead.

         Ingestion of soil may therefore result in exposure to lead. This
    may occur by direct ingestion, deposition of soil on the hands,
    contamination of food, or by inhalation. The relationship between soil
    lead and blood lead varies greatly by soil type (WHO, 1995), perhaps
    due to behavioural differences among individuals and differences in
    the rates of absorption of lead from different sources.

    3.5.3  Paint

         The paint used in older houses may have very high concentrations
    of lead, and very high exposure to lead, sufficient to cause severe
    clinical symptoms and death, may result from the direct ingestion of
    paint chips, particularly by children (WHO, 1995; Agency for Toxic
    Substances and Disease Registry, 1997).

    3.6  Surveys of blood lead concentrations

         The most extensive surveys of blood lead concentrations that have
    been carried out in the United States were the National Health and
    Nutrition Examination Surveys (Pirkle et al., 1994). In the second
    such survey, conducted between 1976 and 1980, a mean blood lead
    concentration of 13 g/dL was found in persons aged 1-74. In the third
    survey, conducted in 1988-91, a mean concentration of 2.8 g/dL was
    found. The decrease can be attributed to the drastic reduction in the
    use of lead in gasoline and in soldered cans during the intervening
    period.

         The concentrations of lead are widely distributed and generally
    appear to follow a log normal distribution which is skewed towards
    higher concentrations. As a result, many people are exposed to high
    concentrations of lead even when the mean concentration is low.
    Children of urban and low-income families are particularly likely to
    be exposed to high concentrations (Brody et al., 1994).

         Surveys of lead concentrations in other parts of the world
    suggest that exposure was generally lower than that in the United
    States before 1980 (WHO, 1995), and the concentrations have been
    lowered further as a a result of programmes to reduce exposure, even
    though the reductions were generally more modest than those in the
    United States.

    4.  QUANTITATIVE RISK ASSESSMENT

         The brief review presented above of current knowledge about the
    presence of lead in the environment and its toxicology is largely
    qualitative. Because the health effects associated with exposure to
    lead differ in degree, a quantitative description is given below, with
    a quantitative statement of the associated uncertainty to convey the
    limitations of current knowledge.

         As risk assessments are designed to assist in making decisions,
    the design of an assessment is influenced by the objectives of the
    decision. For a number of reasons, a single risk assessment cannot be
    used as the basis for all possible decisions. Many adverse health
    effects are associated with exposure to lead, all of which are
    potential subjects for a risk assessment. Most of the effects are
    associated with the levels of exposure found in occupational settings,
    whereas the present exercise is meant to assist decisions about
    exposure of the general population, who are exposed to lead mainly at
    relatively low concentrations in food. The assessment described below
    is focused on the effects of lead on the neurobehavioural development
    of children. The carcinogenic effects of lead are also considered
    briefly.

         An assessment of risk for the world population would be too broad
    to allow evaluations of the risks of particular segments of the
    population, whereas a risk assessment for a small population group
    would be inadequate for another, as exposure to lead varies widely
    throughout the world. In order to capture the range, risk assessments
    have been constructed for several population groups that vary in their
    diet and socioeconomic status.

         Two factors limit the scope of a risk assessment. The first is
    the availability of data to support particular theories or
    predictions, usually because the necessary experiments have not been
    or cannot be performed. This limits the level of detail of an
    assessment, and model uncertainty becomes an important element. A more
    vexing problem arises when the raw data exist but are not available
    for use in a risk assessment, for example, when they have not been
    published. This makes it difficult for other analysts to draw their

    own conclusions and to use the data to answer questions other than
    those addressed by the investigators. Many of the analyses of the
    relationship between exposure to lead and the neurobehavioural
    development of children are based on tests of the statistical
    significance of an association. In the absence of the raw data, it is
    difficult to use such studies to evaluate mathematical models.

         A second consideration is that risk assessments require much time
    and effort. Formal, detailed risk assessments are generally worth
    undertaking only for serious problems. The fact that one of the
    Committee's initial quantitative risk assessments addresses exposure
    to lead may be attributed to the fact that lead is generally
    considered to be the most serious environmental contaminant.

         Because of these limitations, the quantitative risk assessment
    presented below is relatively simple; however, a number of ways in
    which the assessment could be developed further are discussed.

    4.1  Exposure assessment

    4.1.1  Population estimates of dietary intake of lead

    4.1.1.1  Frequently consumed foods

         Since lead is a chronic poison, estimates of long-term exposure
    are required. As individuals consume many samples of a particular food
    over time, their lead intake is proportional to the arithmetic mean of
    the distribution of the concentrations of lead in the commodity. In
    such circumstances, the lead intake of the population can be estimated
    by multiplying the distribution of consumption of the food by the
    arithmetic mean of the lead concentration. The net intake from
    multiple studies can be obtained by summing the distributions in a
    Monte-Carlo simulation.

         The number of food categories included varies according to the
    quality of the data available. A simple model and simulation are shown
    in Table 5. This simulation is based on estimates of mean intakes in
    the United States converted to distributions by assuming that they
    follow a standard form: a log normal distribution with a geometric
    mean equal to 0.76 times the arithmetic mean and a geometric standard
    deviation of 0.76. Since they are based on data for the United States,
    they do not reflect any geographic difference in lead concentrations.
    Simply summing distributions will not, however, account for
    correlations in the consumption of particular foods, in that high
    consumption of one food may tend to be accompanied by high consumption
    of another. Such correlations can be represented by introducing
    statistical correlation models to relate the foods to one another or
    by closely tying the simulation to data from consumption surveys.
    Either approach will require access to raw data on consumption, which
    are not usually published.

        Table 5. Estimates of population exposure to lead (g/day) in different regions
                                                                                  

    Statistic    Middle Eastern   Far Eastern   African   Latin American   European

                                                                                  

    0.05         7.1              7.0           7.1       7.1              6.8
    0.5          11.4             11.2          11.5      11.5             11.3
    0.95         20.5             20.0          20.3      21.1             21.5
    0.99         29.1             25.8          28.8      26.9             32.4
                                                                                  
    
    4.1.1.2  Infrequently consumed foods

         If a dietary source of very high concentrations of lead is
    consumed infrequently, it may be important to simulate long-term
    intake. An estimate for an individual can be obtained by averaging the
    number of samples of the food expected to be consumed by that
    individual over a given time. For example, the intake of an individual
    who eats the food at four meals per year would be calculated from four
    samples.

    4.1.2  Simulations of the effect of a commodity with a high
           concentration of lead

         To portray the impact of a food commodity with unusually high
    concentrations of lead, a simulation was run for a situation in which
    the concentrations in grain were 10 times higher than usual (Table 6).
    A log normal distribution with a geometric mean of 0.25 and a standard
    deviation of 0.6 was used to represent exposure from non-dietary
    sources. Although the distribution is represented in terms of dietary
    intake, it should be considered to be dietary equivalents since
    absorption rates from other media may differ. The values could be
    altered to reflect national distributions of blood lead
    concentrations. Although they are plausible, these are hypothetical
    distributions anddo not apply in any particular case. The effect of
    intervention was also simulated for a Middle Eastern diet with two
    putative levels of intervention: the first reduced exposure by one
    half, while the second resulted in 'normal' concentrations (Table 7).

    4.1.3  Relation of dietary lead to blood lead

         The blood lead concentrations resulting from a given dietary
    intake can be estimated from simple empirical models or from more
    complex pharmacokinetic models. The former require fewer assumptions
    and are simpler to use. They are reasonably accurate as long as the
    data on which they are based are derived under conditions that are
    comparable to those for which the predictions are made, but they may
    be inadequate in several circumstances.

        Table 6. Estimates of population exposure (g/day) to a commodity that 
    contains high concentrations of lead and to other sources of lead
                                                                                

    Statistic   Middle Eastern   Far Eastern   African   Latin American  European
                                                                                

    0.05        34               31            31        35              25
    0.5         73               62            58        62              52
    0.95        170              144           124       127             142
    0.99        257              238           172       170             247
                                                                                

    Table 7. Estimates of the effects on population
    exposure (g/day) of reducing exposure in a
    Middle Eastern diet to a commodity with unusually
    high concentrations of lead
                                                      

    Statistic   Intervention
                                                      
                None        Reduction       Reduction 
                            by one half     to 'normal'
                                                      

    0.05        37.2        29.3            20.4
    0.5         74.1        56.1            38.3
    0.95        176.1       110.6           80.1
    0.99        233.3       155.7           112.0
                                                      
    
         First, significant exposure to lead may occur from other sources,
    and the impact of that source on blood lead concentrations must be
    estimated separately. It may also be necessary to evaluate the mutual
    effect of several sources of lead on blood concentrations, which may
    require a pharmacokinetic model, such as that designed by the United
    States Environmental Protection Agency.

         Second, if the levels of exposure result in blood concentrations
    outside the range of 10-25 g/dL that has usually been measured, the
    model used to represent the relationship between dietary intake and
    blood lead (linear or nonlinear) become critical and must be evaluated
    critically, perhaps using more than one model to represent the source
    of uncertainty. 

         Third, the exposure may not be in a steady state. Most of the
    available data refer to relatively constant exposure to lead, usually
    due to contamination of drinking-water from lead plumbing. If exposure
    to lead is infrequent or occurs at high concentrations for short
    periods of time, use of the O'Flaherty pharmacokinetic model
    (O'Flaherty, 1991, 1993, 1995) is clearly warranted.

         Fourth, other dietary components or atypical physiological states
    may alter the rate of absorption of lead from the intestine into the
    blood. In particular, iron and calcium can compete for the active
    transport of lead into the blood. As a result lead uptake is greater
    when other minerals are not present, for instance when water is drunk
    on an empty stomach. Calcium deficiency, which may be triggered by
    pregnancy, can lead to up-regulation of the calcium transport
    mechanism with a concomitant increase in lead uptake.

         The present exercise is limited to simple empirical models. 

    4.1.3.1  Drinking-water and blood lead concentrations in bottle-fed
             infants

         The best study for evaluating the relationship between dietary
    intake of lead and blood lead values in infants is that of Lacey et
    al. (1985), in which the concentrations of lead in water and blood
    were measured for a population of Scottish infants. The individual
    values were published and were thus available for further analysis.
    Since the infants in this study who were exposed to low concentrations
    in drinking-water still generally had blood lead concentrations > 10
    g/dL, they would appear to have been exposed other than in the diet.
    The data were fit into several models, all of which were based on the
    assumption of a linear relationship between dietary intake and blood
    lead but with different population models (see Figures 1-3 and Table
    8). The models all yielded an intercept of roughly 15 g/dL which may
    reflect exposure from dust or air (leaded gasoline) or maternal
    exposure before birth. The models also all yielded a slope of roughly
    0.05 g/dL per g/L in drinking-water, so that the relation to dietary
    intake depends on the amount of water consumed by the infants in the
    study. As infants typically consume 500-1000 ml of formula per day
    (Ershow & Cantor, 1989), the slope attributable to dietary intake
    corresponds roughly to 0.05-0.1 g/dL per g/day, or a change of 1
    g/dL per 10-20 g/day in an infant diet, where the range reflects the
    uncertainty in the relationship.

         The population variation reflected in the models comes from
    several sources, including other exposures to lead, the amount of
    formula consumed, and the change in blood attributable to dietary
    exposure. In the present exercise, only the latter source of variation
    represents true population variation, while the other sources
    contribute to the uncertainty of the measure.

    4.1.3.2  Drinking-water and blood lead concentrations in adults

         The report of a study by Sherlock et al. (1982) does not present
    data for individuals but does include a table of the numbers of
    persons with blood lead concentrations in specified ranges stratified
    by the concentrations of lead in drinking-water. These data are given
    in Table 9 after conversion from absolute numbers to percentiles and
    are plotted in Figure 4.

    FIGURE 3

    FIGURE 4

    FIGURE 5

    FIGURE 6

        Table 8. Linear models for the relationship between dietary and 
    blood lead concentrations in bottle-fed infants
                                                                         

    Population model      Intercept     Slope                  Variance
                          (g/dL)       (g/dL per mg/day)
                                                                         

    Log normal            14.67         0.054                  0.36 (GSD)
    Normal                15.59         0.052                  8.04 (SD)
    Normal, fractional    15.43         0.052                  0.37 (FSD)
                                                                         

    Parameters for linear models fit to the data of Lacey et al. (1987).
    The variance parameters are not directly comparable since they reflect
    different assumptions about the shape of the population distribution.
    GSD, geometric standard deviation; SD, standard deviation; FSD,
    fractional standard deviation (standard deviation as a fraction of
    the mean)

    Table 9. Relationship between concentrations of lead in drinking-water
    and in the blood of adults
                                                                          

    Concentration   Concentration in drinking-water (g/L)
    in blood
    (g/dL          < 10   < 100   < 300   < 500   < 1000  < 1500   > 1500
                                                                          

    < 10            0.62   0.26    0.00    0.00    0.00    0.00     0.00
    < 15            0.92   0.63    0.11    0.11    0.00    0.00     0.13
    < 20            1.00   0.79    0.54    0.26    0.16    0.00     0.13
    < 25            1.00   1.00    0.86    0.63    0.42    0.00     0.13
    < 30            1.00   1.00    0.93    0.84    0.63    0.25     0.13
    < 35            1.00   1.00    1.00    0.89    0.74    0.50     0.50
    > 35            1.00   1.00    1.00    0.95    0.79    0.63     0.63
                                                                          

    Data from Sherlock et al. (1982)
    Cumulative population percentiles from a Scottish village for a
    series of blood lead concentrations with varying concentrations
    of lead in drinking-water. The percentiles are cumulative with
    respect to blood lead, so that each percentile reflects the percentage
    of the population in each lead-water grouping with a lower blood
    lead concentration.
    
         Several simple three-parameter models were fit to these data
    (shown in Figure 5), all of which showed quantitatively similar fits
    of the data. Each had consistent deviations from some part of the data
    set. The linear model deviated at very high and very low lead
    concentrations, whereas the log linear model fit fairly well at low
    doses but fit poorly at high doses and predicted higher than observed
    blood concentrations at a lead concentration of 100 g/L. When
    concentrations in drinking-water below 300 g/dL were fit separately,
    a linear model with a log normal population distribution produced a
    very good fit (see Figure 5). Since this value covers the typical
    range of dietary intake, it is suitable for assessing dietary exposure
    to lead. The parameters for the model are a slope of 0.035 g/dL per
    g/L in drinking-water and a geometric standard deviation (reflecting
    population variation) of 0.31.

         In order to apply this model to general dietary intake, the
    amount of tapwater consumed by the individuals in the study must be
    estimated. For a range of 0.5-1.5 L/day, the range of slopes
    (reflecting uncertainty) from which blood concentrations can be
    calculated is 0.023-0.07 g/dL per g/day. The slope for conversion
    from dietary intake to blood lead concentration is not greatly
    different: the conversion factor for infants is only two to four times
    greater than that for adults. Blood lead concentrations for a given
    level of exposure are therefore not proportional to body weight,
    perhaps because of the greater uptake of lead by bone during growth in
    children.

    4.2  Dose-response assessment

    4.2.1  Designing an analysis

         Existing analyses of the relationship between exposure to lead
    during gestation or childhood and neurobehavioural performance during
    childhood have a number of problems, some of which are discussed
    below.

         First, most of the analyses are of individual studies. Since
    there have been many studies with somewhat disparate results, it is
    difficult to draw general conclusions. In order to do so, it would be
    necessary to obtain the original data from the authors of the studies,
    assimilate them into a common format, and design models to accommodate
    all the variables included.

         Second, the conclusions drawn from large epidemiological studies
    with many potential confounding variables often depend on the model
    used, and it is difficult to compare studies in which different models
    were used. Furthermore, insufficient information may be provided to
    select the relevant model. For example, it may be impossible to
    ascertain whether an effect is due to lead or to some other variable
    whose presence correlates with that of lead. This can be an important
    source of uncertainty in a risk assessment.

    FIGURE 5

         Third, different tests may be used to measure different
    end-points. While tests are standardized in terms of normal variation,
    they may not be scaled to a common performance standard, and if they
    are standardized for different populations at different ages, they may
    be standardized in terms of anticipated adult variation. It may be
    desirable to recalibrate scales to direct them to particular
    performance measures. In particular, measures of cognitive and motor
    performance might be preferable to a general measure of IQ.

         Fourth, most of the analyses have been performed in order to
    establish a relationship between exposure to lead and behavioural
    performance rather than to evaluate the quantitative relationship
    between exposure to lead and outcome. The analyses are therefore often
    based on tests of statistical significance that involve comparisons of
    groups with high and low exposure to lead rather than a critical
    evaluation of the dose-response relationship.

    4.2.2  Dose-response models for blood lead and IQ

         Because a comprehensive model is beyond the scope of this
    analysis, relatively simple models are used to relate blood lead
    concentration to IQ. The analysis with the fewest of the potential
    flaws discussed above was conducted by Schwartz (1993). This analysis
    relies on the results of Bellinger et al. (1991) and relates blood
    lead to IQ as measured by the McCarthy scales (see Figure 6). When 13
    confounding variables were modelled, a change of one IQ point was seen
    for every 2-4 g/dL change in blood lead concentration, with a steeper
    slope (a greater effect) at higher blood lead concentrations than at
    lower ones.

         Schwartz (1993) also conducted a meta-analysis of seven studies,
    relying on the reported regression coefficients (six positive and one
    negative) for the dose-response relationship and t statistics to
    estimate the variance. This analysis indicated that an increase in
    blood lead concentration from 10 to 20 g/dL results in a change of
    approximately 2.5 IQ points.

         The principal shortcoming of this analysis for the purposes of
    risk assessment is that there is no statement of the relationship
    between dose and response for either population variation or
    uncertainty. The same effect may not be seen in all individuals
    because of the presence of identified and unidentified confounders.
    The analysis also does not indicate the uncertainty in the estimates
    that may result from measurement errors, sampling bias, or model
    selection. The degree of true variation can be judged to some extent
    by comparing the results of different studies, since the variation is
    due partly to variation in the magnitude of the effect in the
    individuals in each population; however, it is difficult to judge the
    extent or shape of the distribution precisely.

         In order to represent the uncertainty in the dose-response
    relationship, the Committee used three models of the relationship
    (linear, hockey stick, and Hill) and two models to represent
    population variation (normal and log normal). Probabilities were
    assigned to the models in relation to the weight of the evidence for
    each; thus, the three-parameter Hill model was given greater weight
    than the other two because it provides a better fit of the analysis by
    Schwartz (1993) of the effects of low doses of lead (see Figure 6)
    and, because it is sigmoidal, it can account for the apparently
    greater effect of lead at a blood concentration of 20 g/dL than at
    higher concentrations (National Research Council, 1993). It is also a
    biologically relevant model which is suitable for modelling saturable
    processes in which the effect is the result of reversible binding of
    the agent to the target site. The linear model is given some
    preference because it is simple, with only one parameter. The hockey
    stick model includes two parameters and provides an intermediate fit.

         Further uncertainty is represented by using triangular
    distributions for the model parameters, which are characterized by
    estimates of the minimum, most likely, and maximum values. These are
    presented in Tables 10 and 11. The estimates are based largely on the
    fits in the analysis of Schwartz (1993; see Figure 7) but were
    adjusted downwards by 40% to be more consistent with the other
    literature on lead (e.g. Yule et al., 1981; Schroeder et al., 1985;
    Hawk et al., 1986; Lansdown et al., 1986; Fulton et al., 1987; Winneke
    et al., 1990). The probability assignments in the model also reflect
    the analysis of Schwartz (1994), which suggests that a linear model
    may be more appropriate than a sigmoidal model. The behaviour of these
    models when assembled into a two-dimensional Monte-Carlo simulation is
    illustrated in Table 12.

         The populations in studies of the relationship between exposure
    to lead and performance on behavioural tests have had relatively
    constant exposure. In order to gauge the relative importance of
    shorter exposures, an equation was used that is based on the
    assumption that the net lifetime effect of lead on behavioural
    performance is proportional to the average exposure over the first
    5-15 years of life. This reflects the notion that sustained exposure
    to lead will have a greater effect on adult IQ than shorter exposure.
    When the dose received during a shorter exposure is distributed
    relative to a 10-year period, the equation for distributing exposure
    for the developmental effects of lead is:

                             actual dose  dose duration (years)
       Effective dose =                                         

                                period of development (years)

    where the period of development is an uncertain range of 5-15 years.


    FIGURE 6

    FIGURE 7


    4.2.3  A sample diet-response simulation

         The effect of a commodity containing high concentrations of lead
    on the IQ of an infant as a result of maternal exposure was simulated
    by using the exposure assessment described in Table 6. The functions
    described above were used to calculate blood lead concentrations, the
    expected change in IQ after lifetime exposure, and the expected effect
    on adults after a limited exposure of nine months. These results are
    presented in Table 13. 

        Table 10. Models of the dose-response relationship for exposure
    to lead and reduced IQ scores in children
                                                                                 

    Model          Probability    Parameter(s)           Representation
                                                                                 

    Linear         0.4            Slope (IQ per g/dL)   Triangular (0, 0.25, 0.4)
    Hockey stick   0.2            Slope (IQ per g/dL)   Triangular (0, 0.35, 0.6)
                                  Threshold              Triangular (0, 5, 15)
    Hill           0.4            KD (g/dL)             Triangular (18,22,33
                                  Maximum                Triangular(15,20,40)
                                  Power                  Uniform (2.0, 2.8)
                                                                                 

    The median value for the uncertainty distribution is the best fit and is
    plotted in Figure 6. The values for the KD (dissociation constant) and
    maximum parameters are correlated.

    Table 11. Models of the dose-response relationship between
    exposure to lead and effects in the population
                                                                            

    Model        Probability   Parameter(s)           Representation
                                                                            

    Normal       0.4           Fractional             Uniform
                               standard deviation     (5-15 % of mean effect)

    Log normal   0.6           Geometric              Uniform
                               standard deviation     (0.1-0.3)
                                                                            

    
    5.  COMMENTS

         The most widely used biomarker of exposure to lead is the
    concentration in blood (measured in g/dL). The most critical effect
    of lead at low concentrations is reduced cognitive development and
    intellectual performance in children. A number of studies in which

    various tests of behavioural performance were used have shown an
    association between blood lead concentration and reduced intelligence
    quotient (IQ) in children exposed pre-and postnatally. At blood
    concentrations below 10-15 g/dL, the effect of confounding variables
    and limits to the precision of analytical and psychometric
    measurements increase the uncertainty of any estimate of effect. If a
    threshold does exist, it is unlikely to be detected because of these
    limitations. However, there was some evidence of an association
    between cognitive deficits and exposure to concentrations even below
    10 g/dL.

    Exposure to lead

         Exposure to lead can occur as a result of ingestion in foodstuffs
    and water and from other sources, such as air. All three sources make
    important contributions. Although the current assessment was limited
    to dietary intake, a complete analysis would require addition of
    non-food sources of lead to the evaluation.

         The Committee reviewed data on lead intake in 25 countries and
    conducted several dietary assessments on the assumption that the WHO
    GEMS/Food regional diets contain 'typical' levels of lead in the food
    categories for which limits have been proposed by the Codex Committee
    on Food Additives and Contaminants. The WHO GEMS/Food diets have been
    used by the Codex Committee on Pesticide Residues and others to
    estimate intakes of pesticides and contaminants since 1987. The
    regional diets were used to estimate lead intake under three sets of
    assumptions about the concentrations of lead in food: all foods
    contain lead (1) at the limits currently proposed by the Codex
    Committee on Food Additives and Contaminants, (2) at a typical average
    concentration, and (3) at typical high levels found in foods. When the
    concentrations at the currently proposed Codex limits were used in the
    assessment, the estimated intakes were 13-20 g/kg bw per week. The
    typical average and high levels were derived from monitoring in the
    United States and were similar to those reported from other countries.
    The weekly intakes ranged from 1 to 2 g/kg bw per week for 'typical'
    lead levels and from 2 to 4 g/kg bw per week for 'high typical' lead
    levels. These narrow ranges in intake estimates reflect the fact that
    the monitoring data that were submitted to the Committee did not
    include foodstuffs that contained particularly high levels of lead,
    and no food group predominated. Virtually no data were submitted on
    foods with levels above the currently proposed Codex limit. The Expert
    Committee noted that similar intakes were obtained for the five
    different GEMS/Food regional diets with these models.

        Table 13. Estimated change in IQ after exposure to a commodity
    containing high concentrations of lead
                                                                                     

    Population     Intervention
    percentile                                                                       
                   None                 Reduction by one half    Reduction to 'normal'
                                                                                     

    0.05           0.008 (0.00, 0.06)   0.005 (0.000, 0.05)      0.003 (0.00, 0.04)
    0.5            0.018 (0.00, 0.1)    0.011 (0.00, 0.08)       0.006 (0.00, 0.06)
    0.95           0.042 (0.00, 0.16)   0.028 (0.00, 0.13)       0.02 (0.00, 0.10)
    0.99           0.051 (0.00, 0.19)   0.034 (0.00, 0.15)       0.02 (0.00, 0.12)
                                                                                     

    Estimates of the net change in IQ as result of exposure to lead in a commodity
    with high concentrations after two levels of intervention. The scenario on which
    the estimates are based presumes that exposure occurs as a result of maternal
    exposure only.
    
         The Committee reviewed data contained in the WHO GEMS/Food
    database and found that foods that were sampled in the 1980s contained
    much higher concentrations of lead than those seen presently and
    decided to base its conclusions on current data.

    Children

         The potential intake of lead by children was reported for seven
    countries on the basis of monitoring of the general food supply as
    well as infant formula and other foods commonly consumed by children.
    Several countries specifically provided intake levels of foods
    consumed by children. The estimated range of intake levels for
    children was 0.6-30 g/kg bw per week, which was generally two to
    three times the adult intake in the same country when evaluated on the
    basis of body weight.

         Tap water is a significant potential source of lead, particularly
    for formula-fed infants; however, the data submitted were inadequate
    to permit estimation of the range of levels found in water.

    Quantitative risk assessment

    Exposure assessment

         Several simulation models were developed to estimate the
    distributions of dietary lead intake in regional diets. The first
    involved a scenario in which the regional populations covered by the
    WHO GEMS/Food database consumed food with lead concentrations
    corresponding to those found in a survey conducted in the United
    States. The second was designed to evaluate the impact of

    superimposition of a specific commodity from a source with a much
    higher distribution of lead on a background of other regional dietary
    and non-dietary exposures. In a third simulation, the impacts of
    several putative regulatory interventions on dietary intake were
    evaluated.

    Estimates of blood lead concentrations from dietary intake levels

         In order to predict the biological effects of changes in lead
    intake, a relationship must be derived between the concentration of
    lead in the diet and changes in the biomarker, the concentration of
    lead in blood. To do so, the Committee used simple empirical models to
    relate exposure to lead to concentrations in blood and other tissues.
    Most of the historical data refer to relatively constant exposure to
    lead, usually as a consequence of contamination of drinking-water by
    lead plumbing. These data have limited predictive value if the levels
    of exposure result in blood lead concentrations higher than 25 mg/dL.
    In addition, other dietary components or atypical physiological states
    may alter the rate of absorption from the intestine to the blood.

         In order to infer a relationship between ingestion of lead and an
    increase in the blood lead concentration in infants and young
    children, several models were fitted to data from studies of
    bottle-fed infants. Reasonable fits required the assumption that a
    zero dose in drinking-water corresponds roughly to a blood lead
    concentration of 15 g/dL, perhaps reflecting exposure from the
    environment or  in utero. The results, attributable to dietary intake
    of lead by infants, correspond roughly to a change in blood lead
    concentration of 0.05-0.1 g/dL per g of lead intake per kg bw per day. 
    For a 10-kg infant, this corresponds to a range of 0.5-1.0 g/dL per g 
    of lead in the diet per day.

         The Committee used data from another study to calculate the
    relationship between blood lead concentration and intake of lead from
    drinking-water by pregnant women. The sample size was large enough to
    allow characterization of population variation. When the raw data were
    fitted to several simple models, all resulted in poor fits. When
    concentrations in drinking-water below 300 g/L were fitted
    separately, a linear model with a log-normal population distribution
    produced a very good fit. A background blood lead concentration of
    roughly 9 g/dL was obtained, probably reflecting exposure from
    sources other than drinking-water. The model yielded a blood lead
    concentration of 0.035 g/dL per g of lead in 1 L of drinking-water.
    Because of uncertainty in the amount of water consumed by the
    individuals in the study, the variation around this value was wide,
    from 0.023 to 0.07 g/dL per g of lead intake per kg bw per day. 
    For a 60-kg person, this corresponds to a range of 1.4-4.2 g/dL per 
    g of lead in drinking-water per day.

    Dose-response assessments of neurobehavioural effects of lead in
    children

         The Committee noted a number of limitations in the available data
    on the effects of lead on neurobehavioural development in children.
    One problem was that raw data were not available for use in risk
    assessments or in evaluating mathematical models of the relationship
    between exposure to lead and performance in behavioural tests. Another
    problem was the somewhat disparate results obtained. Furthermore, it
    was difficult to compare the results of large epidemiological studies
    in which many potential confounding variables were analysed in
    different models. It is therefore not possible to ascertain whether
    any effect is due to lead or to some other variable. A further problem
    was that the same tests were not used in all studies, so that
    different end-points were measured. (Measures of cognitive and motor
    performance might be preferable to a general measure of IQ.) Finally,
    most of the analyses were based on tests of statistical significance
    between groups with high and low exposure to lead rather than a
    critical evaluation of the dose-response relationship.

         The analysis that had the fewest of these potential flaws showed
    a decrease of one IQ point for every 2-4 g/dL increase in blood lead
    concentration, with a greater effect at higher concentrations than at
    lower ones. A meta-analysis of seven studies showed that an increase
    in the blood lead concentration from 10 to 20 g/dL would result in a
    decrease of approximately 2.5 IQ points.

         This analysis does not include the possibility that the
    relationship between blood lead and IQ is nonlinear, in spite of some
    evidence that it may be. Furthermore, there is no expression of either
    population variation or uncertainty in the dose-response relationship.
    In order to address these concerns, probability trees and statistical
    distributions were included in the assessment of the dose-response
    relationship. Because raw data were not available, the values for the
    magnitude of the variation and uncertainty were chosen to be generally
    consistent with those available in the literature on the health
    effects of lead. As an example of the behaviour of the composite
    dose-response function generated, Table 14 gives estimates of the net
    decrease in IQ for the population median at four blood lead values,
    with a range of uncertainty for each estimate.

    Dose-response simulation

         A simulation model was developed in which a dose-response
    component was added to the exposure model described previously. This
    model was used to illustrate the net benefit of imposing limits on the
    levels of lead in food with respect to neurobehavioural development of
    children, given an anticipated reduction in exposure to lead.

         The studies that have related exposure to lead to performance in
    behavioural tests have been conducted in populations whose exposure to
    lead is relatively constant. In order to gauge the relative importance
    of shorter exposures, it was presumed that the net lifetime effect of
    lead on intellectual status (i.e. adult IQ) after a limited prenatal
    or postnatal exposure may be scaled relative to a period of 5-15
    years, the range representing the uncertainty associated with the
    adjustment.

         The model was based on consumption patterns from a WHO GEMS/Food
    Middle Eastern diet, assuming that the lead concentrations in food
    were typical of those in the United States, and non-dietary exposures
    corresponding roughly to those in the United States. In this
    hypothetical scenario, a decrement in IQ of 0.006 points (range,
    0-0.06) was estimated for the population mean of children as a result
    of maternal exposure for nine months. The procedure described above
    was used to adjust for the period of exposure. In a scenario in which
    the cereal grains in a regional diet contained 10 times higher lead
    levels, the estimated decrement in IQ points attributable to lead was
    0.02 (range, 0-0.1). A hypothetical intervention leading to a
    reduction in grain lead levels by one-half was estimated to reduce the
    decrement in IQ points to 0.011 (range, 0-0.08). Given the similarity
    in the estimates of exposure from the different regional diets,
    similar results would be anticipated if other WHO GEMS/Food regional
    diets were used in the scenario.

    Table 14. Net decrease in IQ associated with blood lead
    concentration
                                                         

    Concentration of          Median IQ decrement 
    lead in blood (g/dL)     (95% confidence interval)
                                                         

    5                         0.4 (0.0-1.5)
    10                        1.7 (0.5-3.1)
    15                        3.4 (1.1-5.0)
    20                        5.5 (1.6-6.9)
                                                         

         The Committee also estimated the effect on blood lead
    concentrations of long-term exposure to lead in the three models of
    regional diets used to illustrate the ranges of intake of lead under
    various assumptions. As a conservative estimate, the Committee assumed
    that a dietary intake of 1 g/kg bw per day (7 g/kg bw per week)
    would result in an increase in the lead concentration of blood of 1
    g/dL, the upper estimate for infants, and that this relationship was
    valid during the long-term exposure period (in utero + 10 years). This
    would correspond to an increase in blood lead concentration of 0.14
    g/dL per g lead per kg bw per week. Using this assumption in
    combination with the high values for estimated dietary intake, the
    Committee calculated that consumption of a diet containing lead at the

    currently proposed Codex limits would result in an increase in blood
    lead concentration of 3 g/dL. Consumption of diets with typical
    average lead concentrations or with typically high levels would result
    in increases in blood lead concentrations of 0.3 and 0.6 g/dL,
    respectively. Table 14, showing the decrements in IQ points predicted
    to be associated with various blood lead concentrations, provides
    confidence that the current concentrations of lead in foods would have
    very little impact on the neurobeha-vioural development of infants and
    children. However, the Committee stressed that a full risk assessment
    of dietary intake of lead should take other sources of exposures into
    account.

    6.  EVALUATION

         The Committee concluded that, overall, current dietary levels of
    lead have negligible effects on intellectual development but noted
    that foods with high lead contents remain in commerce. The simulation
    model presented here can be used to evaluate the effects of any
    planned interventions.

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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 (JECFA Evaluation)
       Lead (UKPID)