INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES
    AND CONTAMINANTS



    WHO FOOD ADDITIVES SERIES NO. 13






    The data contained in this document were examined by the
    Joint FAO/WHO Expert Committee on Food Additives*
    Rome, 3-12 April 1978




    Food and Agriculture Organization of the United Nations
    World Health Organization



    * Twenty-second Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Geneva, 1978, WHO Technical Report Series No. 631

    LEAD

    Explanation

         Lead as a food contaminant was evaluated for provisional
    tolerable weekly intake for man (adult) by the Joint FAO/WHO Expert
    Committee on Food Additives in 1972. Additional data have become
    available and are summarized below.

    Absorption and retention by animals

         In short-term, 48-hour, feeding studies with groups of six
    weanling rats lead absorption from the diet was increased by high fat,
    low mineral, low protein, and high protein diets. Low fat, low fibre,
    high fibre, low vitamin, and high vitamin diets had no effects on lead
    absorption (Barltrop and Khoo, 1975).

         The retention and tissue distribution of 210Pb were studied on
    10-day-old, 150-day-old, and adult Macaca fascicularis monkeys,
    each age-group comprising four animals (Willes et al., 1977). Lead
    nitrate, 10 micrograms lead/kg body weight, containing 10 
    micro-Ci210Pb/microgram Pb was administered by gavage after a 12-hour 
    fast. The 210pb excreted in urine and faeces was monitored for 96 
    hours. All monkeys were necropsied 96 hours after dosing and the 210Pb
    contents of various tissues was determined. The data demonstrate that 
    infant monkeys retain significantly more lead than adults.

         Blood 210Pb levels 96 hours after dosing did not vary
    significantly between age-groups, and of the 210Pb contained in blood
    98-99% was found in the cells, and 1-2% in the plasma. In the cells,
    5-8% of the 210Pb was bound to the cell membranes. The distribution
    between blood components did not vary significantly with age.

         The percentage of the lead dose excreted in urine did not vary
    significantly between age-groups. Both the tissue Pb concentrations,
    and tissue-blood Pb ratios were significantly higher in the bone
    structures of the young animals than in the adults. The brain:blood Pb
    ratio in the infants was significantly higher than in the older
    groups.

         Radioactive lead was administered intravenously to beagle dogs
    (11-26 micro-Ci/dog), and whole-body gamma-ray counting and
    measurement of the excreta was continued for about two years. The
    effective half-lives for the slowest time constant component was 815
    days, based on the in vivo counting results, and 1940 days, based on
    the analysis of the excreta. The longer half-life given by the data
    from the counting of the excreta is considered more reliable. In the
    whole-body counting system the progressive burying of the radioactive
    lead in the bony skeleton would gradually increase the absorption of

    the weak gamma-rays simulating a loss of lead. The observed half-life
    of 1940 days (equal to 5.3 years), can be extrapolated to man, using a
    factor of 4, yielding a figure of 21.2 years (Hursh, 1973). This
    compares with the estimate based on stable lead measurements performed
    on man indicating a biological half-life of 16.8 years (Holzman et
    al., 1968, cited by Hursh, 1973).

    Biochemical effects of lead in man

         In a recant study Kuhnert et al. (1976, 1977) have determined the
    ALAD activity, and the lead level in the blood of 47 urban mothers,
    and in the cord blood of their infants. In addition the activated ALAD
    activity was also determined: this was done in the presence of a
    chelating agent which removes the lead from the enzyme. These were
    signs of enzyme inhibition avon at the lowest lead levels, below
    20 micrograms/100 mL red blood cells. There was a close correlation
    between maternal and infant blood lead levels, and maternal and infant
    ALAD activities.

    Metabolism of lead - relationship in man of oral intake and blood
    levels

         In most epidemiological studies, the actual exposure is not
    accurately known. In a recent study male volunteers were given known
    amounts of lead acetate via the oral route for seven weeks; the doses
    were designed to maintain a blood lead level of 400 ppb. Various
    biochemical parameters were determined weekly. Increases in blood
    lead levels were accompanied by decreases in the activity of
    delta-aminolaevulinic acid dehydratase (ALAD) in the blood to levels
    of 45-70% of the initial values by the end of exposure. Free
    erythrocyte porphyrins (FEP) were increased after a latent period of
    0-21 days from the beginning of lead exposure. The rate of increase of
    FEP and the latent period were influenced by the percentage absorption
    of the lead from the gastrointestinal tract, the distribution of
    absorbed lead within the body and the rate of release of new
    erythrocytes from the bone marrow into the peripheral blood (Cools et
    al., 1976).

    Effects on children

         The relationship of blood lead and mental development was
    investigated by Kotok et al. (1977). The high lead group consisted of
    31 children with a mean blood lead level of 79.6 micrograms/100 mL,
    range 61-200 micrograms/100 mL. The control group of 36 children
    with a mean lead level of 28.3 micrograms/100 mL (range 11-40
    micrograms/100 mL). The parameters measured were social maturity,
    spatial relationships, spoken vocabulary, comprehension, visual
    attention and auditory memory. This study did not reveal significant
    differences in the cognitive functions of the lead and control groups.

         In another study three groups of children were compared. One
    group consisted of 31 mentally-retarded children, in whom the etiology
    of their condition was unknown. The second group was composed of 33
    mentally retarded, with a known probable etiology. The last group
    was a control sample of 30 normal children. The mean lead level
    of the mentally retarded unknown etiology group was 25.5 ± 9.1
    micrograms/100 mL, whereas in the control groups the mean values were
    18.7 ± 6.5 and 18.8 ± 7.3 micrograms/100 mL, a significant difference
    (David et al., 1976).

    Epidemiology of lead poisoning in infants, young children and adults

         The signs of lead poisoning are well documented and there are
    many well known sources of contamination such as ceramic glazes,
    decorations on cocktail glasses, etc. However, there have been recent
    reports of lead poisoning from some unexpected sources. In one case,
    powdered horse bone, prescribed for dysmenorrhoea, was found to
    contain 190 ppm of lead (Crosby, 1977). In another case, a young child
    in Hong Kong showed signs of acute lead poisoning after treatment with
    various Chinese herbal medicines (Chan et al., 1977). The risk of lead
    poisoning from herbal medications has also been reported in America
    where haematological and neurological symptoms ascribed to lead
    poisoning resulted from the ingestion of certain herbal pills
    (Lightfoote et al., 1977).

         There is a well-documented history of lead poisoning in
    Queensland, where a high incidence of cerebellar calcification has
    been reported to occur. These findings at autopsy are confined to
    people born in Queensland, or who have lived there for long periods of
    time. There is definite statistical correlation between cerebellar
    calcification and raised lead levels in cranial bone and it is also
    noted that the lesion occurs in almost all cases of lead nephropathy.
    However, the lesion is not present in all cases with raised lead
    levels in bone and it is therefore thought that a brief, though
    severe, episode of poisoning might result in brain injury whilst a
    more sustained exposure might be necessary to produce renal damage
    (Tonge et al., 1977).

         Blood lead levels in some pre-school children (approximately two
    years old), living near a lead battery manufacturing works, were found
    to be elevated and especially if the father was employed at the works.
    In a follow-up to this study, certain children were re-examined three
    years later for developmental and behavioural functions. There were no
    significant differences in any of the tests employed between the
    "high" lead group (> 35 µg/100 ml) and the "moderate" lead group
    (<35 µg/100 ml). Nevertheless, The "high" lead group consistently
    did "slightly less well" than the "moderate" lead group. The
    difficulties of determining actual lead exposure over several years,
    and thus the allocation into "high" or "moderate" lead exposure were
    noted (Ratcliffe, 1977).

    Effect of lead on chromosomes of man

         Chromosome analyses have been carried out on children living in a
    town with a lead smelter plant where there were indications of
    increased lead exposure (shown by increased blood lead levels,
    decreased delta-aminolaevulinic acid dehydratase or increased free
    erythrocyte porphyrins). There was no evidence of a higher number of
    cells with structural chromosome aberrations or of an increased
    aberration yield (Bauchinger et al., 1977).

    Lead intake and blood-lead levels

         Very few estimates exist in which total lead intakes are
    correlated with blood-lead levels. Goyer and Mushak (1977) evaluated
    several recent data and deduced that every 100 micrograms of lead
    present in the daily diet would contribute about 10 micrograms of lead
    per 100 mL blood. They estimated also that with blood levels in the
    normal range of 20-30 micrograms/100 mL, environmental air-lead levels
    contribute only a small fraction of this blood-lead level. For
    children such estimates are more difficult and less well established.
    In the United States of America, children of one to three years of age
    consume about 100 micrograms of lead per day. Since absorption from
    the gastrointestinal tract may be as high as 50%, their diet may
    contribute more to the blood-lead level.

         Ziegler et al. (quoted by Mahaffey, 1977) conducted metabolic
    balance studies in young children from two to 25 months of age,
    consuming diets containing "usual" levels of lead. A lead intake of
    less than 50 micrograms/day (based on individual balance data) appears
    to be accompanied by negative lead balance.

    REFERENCES

    Barltrop, D. and Khoo, H. E. (1975) The influence of nutritional
    factors on lead absorption, Postgrad. med. J., 51, 795-800

    Bauchinger, M., Dresp, J., Schmid, E., Englert, N. and Krause, C.
    (1977) Chromosome analyses of children after ecological lead exposure,
    Mutation Res., 56, No. 1, 75-80


    Chan, H., Billmeier, C. J., jr and Evans, W. E. (1977) Lead poisoning
    from ingestion of Chinese herbal medicine, Clin. Toxicol., 10,
    No. 3, 273-281

    Cools, A., Sallé, H. J. and Verberk, M. M. (1976) Biochemical response
    of male volunteers ingesting inorganic lead for 49 days, Int. Arch.
    Occup. Environ. Health, 38, No. 2, 129-139

    Crosby, W. H. (1977) Lead-contaminated health food. Association with
    lead poisoning and leukemia, J. Amer. med. Ass., 237, No. 24,
    2627-2629

    David, O., Hoffman, S., McGann, B., Sverd, J. and Clark, J. (1976) Low
    lead levels and mental retardation, Lancet, 25 December, pp.
    1376-1379

    Goyer, R. A. and Mushak, P. (1977) Lead toxicity laboratory aspects.
    In: Goyer, R. A. and Mehlman, M. A. (1977) Advances in modern
    toxicology. Vol. 2 Toxicology of trace elements, New York, Wiley,
    pp. 41-77

    Hursh, J. B. (1973) Retention of 210pb in beagle dogs, Hlth Phys.,
    25, 29-35

    Kotok, D., Kotok, R. and Heriot, J. T. (1977) Cognitive evaluation of
    children with elevated blood lead levels, Amer. J. Dis. Child., 131,
    791-793

    Kuhnert, P.M., Kuhnert, B. R. and Erhard, P. (1976) Effect of lead
    on delta-aminolevulinic acid dehydratase activity in maternal and
    fetal erythrocytes, Symposium - Trace Substances in Environmental
    Health

    Kuhnert, P.M., Erhard, P. and Kuhnert, B. R. (1977) Lead and
    delta-aminolevulinic acid dehydratase in RBC's of urban mothers and
    fetuses, Environ. Res., 14, 73-80

    Lightfoote, J., Blair, J. and Cohen, J. R. (1977) Lead intoxication in
    an adult caused by Chinese herbal medication, J. Amer. med. Ass.,
    238, No. 14, 1539

    Mahaffey, K. R. (1977) Quantities of lead producing health effects in
    humans: sources and bioavailability, Environmtl. Hlth Persp., 19,
    285-295

    Ratcliffe, J. M. (1977) Brit. J. prev. soc. Med., 31, 258

    Tonge, J. I., Burry, A. F. and Seal, J. R. (1977) Cerebellar
    calcification: a possible marker of lead poisoning, Pathology.,
    9 No. 4, 289-300

    USEPA (1977) National ambient air quality standard for lead.
    Notice of proposed rulemaking, document 40 CFR Part 50, FRL 821-4

    Willes, R. F., Lok, E. Truelove, J. F. and Sundaram, A. (1977)
    Retention and tissue distribution of 210pb (NO3)2 administered
    orally to infant and adult monkeys, J. Tox. Environ. Health, 3,
    395-406

    World Health Organization (1972) Expert Committee on Food Additives.   
    Lead. Sixteenth Report, pp. 16-20, Geneva

    World Health Organization (1973) Expert Committee on Trace Elements in
    Human Nutrition, Lead, pp. 46-47, Geneva

    World Health Organization (1977) Environmental Health Criteria.
    3. Lead. Geneva

    Ziegler, E. E., Edwards, B. B., Jensen, R. L., Mahaffey, K. R. and
    Fomon, S. J. (1978) Absorption and retention of lead by infants,
    Pediat. Res., 12, No. 1, 29-34

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