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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY







    ENVIRONMENTAL HEALTH CRITERIA 3





    Lead








    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of either the World Health Organization or the United Nations
    Environment Programme

    Published under the joint sponsorship of
    the United Nations Environment Programme
    and the World Health Organization

    World Health Organization
    Geneva 1977

    ISBN 92 4 154063 X

    (c) World Health Organization 1977

        Publications of the World Health Organization enjoy copyright
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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR LEAD

    1. SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

         1.1. Summary
              1.1.1. Analytical problems
              1.1.2. Sources and pathways of exposure
              1.1.3. Metabolism
              1.1.4. Experimental studies on the effects of lead
              1.1.5. Clinical and epidemiological studies on the effects
                      of lead. Evaluation of health risk to man from
                      exposure to lead

         1.2. Recommendations for further research
              1.2.1. Analytical methods
              1.2.2. Sources of lead intake
              1.2.3. Epidemiological studies
              1.2.4. Interactions of lead with other environmental
                      factors
              1.2.5. Significance of biological effects

    2. PROPERTIES AND ANALYTICAL METHODS

         2.1. Physical and chemical properties of lead and its compounds

         2.2. Analytical procedures
              2.2.1. Sampting
              2.2.2. Analytical methods for lead
              2.2.3. Methods for the measurement of some biochemical
                      effects of lead

    3. SOURCES OF LEAD IN THE ENVIRONMENT

         3.1. Natural occurrence
              3.1.1. Rocks
              3.1.2. Soils
              3.1.3. Water
              3.1.4. Air
              3.1.5. Plants
              3.1.6. Environmental contamination from natural sources

         3.2. Production of lead
              3.2.1. Lead mining
              3.2.2. Smelting and refining
              3.2.3. Environmental pollution from production

         3.3. Consumption and uses of lead and its compounds
              3.3.1. Storage battery industry
              3.3.2. Alkyllead fuel additives
              3.3.3. Cable industry
              3.3.4. Chemical industry
              3.3.5. Miscellaneous
              3.3.6. Environmental pollution from consumption and uses of
                      lead

         3.4. Waste disposal

         3.5. Miscellaneous sources of environmental pollution

    4. ENVIRONMENTAL TRANSPORT AND DISTRIBUTION

    5. ENVIRONMENTAL LEVELS AND EXPOSURES

         5.1. Exposure of the general population
              5.1.1. Air
              5.1.2. Water
              5.1.3. Food
              5.1.4. Miscellaneous

         5.2. Exposure of infants and young children
              5.2.1. Soil, dust, and taint
              5.2.2. Miscellaneous

         5.3. Occupational exposures
              5.3.1. Lead mining, smelting and refining
              5.3.2. Electric storage battery manufacturing
              5.3.3. Shipbreaking and welding
              5.3.4. Printing
              5.3.5. Alkyllead manufacture
              5.3.6. Other industrial exposures

         5.4. Blood lead concentrations of various populations
              5.4.1. Adult populations
              5.4.2. Children

    6. METABOLISM OF LEAD

         6.1. Absorption
              6.1.1. Absorption by inharation
                      6.1.1.1  Human studies
                      6.1.1.2  The relationship of air lead to blood lead
                               in the general population
                      6.1.1.3  The relationship of air lead to blood lead
                               in occupational exposure
                      6.1.1.4  Animal studies

              6.1.2. Absorption of lead from the gastrointestinal tract
                      6.1.2.1  Human studies
                      6.1.2.2  The relationship of oral intake of lead to
                               blood lead levels in man
                      6.1.2.3  Animal studies

         6.2. Distribution and retention
              6.2.1. Human studies
              6.2.2. Studies in animals

         6.3. Elimination of lead
              6.3.1. Human studies
              6.3.2. Animal studies

         6.4. "The metabolism of alkyllead compounds

    7. EXPERIMENTAL STUDIES ON THE EFFECTS OF LEAD

         7.1. Animal studies
              7.1.1. Haemopoietic system
              7.1.2. Nervous system
                      7.1.2.1  Inorganic lead
                      7.1.2.2  Alkyllead compounds
              7.1.3. Renal system
              7.1.4. Gastrointestinal tract
              7.1.5. Cardiovascular system
              7.1.6. Respiratory system
              7.1.7. Reproductive system
              7.1.8. Endocrine organs
              7.1.9. Carcinogenicity
                      7.1.9.1  Inorganic lead compounds
                      7.l.9.2  Alkyllead compounds
              7.1.10. Mutagenicity
              7.1.11. Teratogenicity

         7.2. Acquisition of tolerance to lead

         7.3. Factors influencing lead toxicity
              7.3.1. Age and sex
              7.3.2. Seasonal variations
              7.3.3. Nutrition
              7.3.4. Intercurrent disease, alcohol, and other metals

         7.4. Human studies

    8. EFFECTS OF LEAD ON MAN--EPIDEMIOLOGICAL AND CLINICAL STUDIES

         8.1. Retrospective studies of lead-exposed populations
              8.1.1. Epidemiology of lead poisoning in industry

              8.1.2. Epidemiology of lead poisoning in the general adult
                      population
              8.1.3. Epidemiology of lead poisoning in infants and young
                      children

         8.2. Clinical and epidemiological studies of the effects of lead
              on specific organs and systems
              8.2.1. Haemopoietic system
                      8.2.1.1  delta-aminolevulinic acid dehydratase (ALAD)
                      8.2.1.2  Free erythrocyte porphyrins (FEP)
                      8.2.1.3  delta-aminolevulinic acid excretion in urine
                               (ALA-U)
                      8.2.1.4  Coproporphyrin excretion in urine (CP-U)
                      8.2.1.5  Effects of lead on cell morphology
                      8.2.1.6  Effects of lead on erythrocyte survival
                      8.2.1.7  Effects of lead on haem synthesis
                      8.2.1.8  Relationship between lead exposure and
                               anaemia
              8.2.2. Nervous system
                      8.2.2.1 Central nervous system
                      8.2.2.2 Peripheral nervous system
              8.2.3. Renal system
              8.2.4. Gastrointestinal tract
              8.2.5. Liver
              8.2.6. Cardiovascular system
              8.2.7. Reproduction
              8.2.8. Endocrine organs
              8.2.9. Carcinogenicity
              8.2.10. Effects on chromosomes
              8.2.11. Teratogenicity

         8.3. Factors influencing lead toxicity
              8.3.1. Acquisition of tolerance to lead
              8.3.2. Age
              8.3.3. Seasonal variation
              8.3.4. Nutrition
              8.3.5. Intercurrent disease, alcohol, and other metals

    9. EVALUATION OF HEALTH RISKS TO MAN FROM EXPOSURE TO LEAD AND ITS
         COMPOUNDS

         9.1. Relative contributions of air, food, water and other
              exposures to total intake
              9.1.1. Adult members of general population groups
              9.1.2. Infants and children
              9.1.3. Occupationally exposed population groups

         9.2. Evaluation of haematological effects

         9.3. Dose-effect relationships

         9.4. Dose-response relationships

         9.5. Diagnosis of lead poisoning and indices of exposure and/or
              effects for epidemiological studies
              9.5.1. Concentration of lead in blood (Pb-B)
              9.5.2. Aminolevulinic acid dehydratase (ALAD)
              9.5.3. Aminolevulinic acid (ALA) and coproporphyrin (CP)
                      excretion in the urine
              9.5.4. Lead excretion in the urine
              9.5.5. Haematological changes (stippled cells, anaemia)
              9.5.6. Lead in tissues (teeth and hair)
              9.5.7. Some practical aspects
                      9.5.7.1  General population studies
                      9.5.7.2  Occupationally-exposed persons
                      9.5.7.3  Reliability of the sampling and analytical
                               methods
         9.6. The problem of alkyllead compounds

    REFERENCES
    

    NOTE TO READERS OF THE CRITERIA DOCUMENTS

        While every effort has been made to present information in the
    criteria documents as accurately as possible without unduly delaying
    their publication, mistakes might have occurred and are likely to
    occur in the future. In the interest of all users of the environmental
    health criteria documents, readers are kindly requested to communicate
    any errors found to the Division of Environmental Health, World Health
    Organization, 1211 Geneva 27, Switzerland, in order that they may be
    included in corrigenda which will appear in subsequent volumes.

        In addition, experts in any particular field dealt with in the
    criteria documents are kindly requested to make available to the WHO
    Secretariat any important published information that may have
    inadvertently been omitted and which may change the evaluation of
    health risks from exposure to the environmental agent under
    examination, so that that information may be considered in the event
    of updating and re-evaluating the conclusions contained in the
    criteria documents.

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR LEAD

    Geneva, 29 April-5 May 1975

    Participants

    Professor M Berlin, Department of Environmental Health, University of
        Lund, Sweden

    Professor A. David, Centre of Industrial Hygiene and Occupational
        Diseases, Institute of Hygiene and Epidemiology, Prague,
        Czechoslovakia  (Vice-Chairman)

    Dr. F. A. Fairweather, Division of Chemical Contamination of Food and
        Environmental Pollution, Department of Health and Social Security,
        London, England

    Professor R. A. Goyer, Department of Pathology, University of Western
        Ontario, London, Ontario, Canada  (Chairman)

    Dr. L. Graovac-Leposavic, Institute of Occupational and Radiological
        Health, Belgrade, Yugoslavia

    Dr. R. J. M. Horton, Environmental Protection Agency, Research
        Triangle Park, NC, USA

    Dr. C. H. Nordman, Institute of Occupational Health, Helsinki, Finland
         (Rapporteur)

    Dr. H. Sakabe, Department of Industrial Physiology, National Institute
        of Industrial Hygiene, Kawasaki, Japan

    Professor H. W. Schlipkter, Institute of Air Hygiene and Silicosis,
        Dsseldorf, Federal Republic of Germany

    Professor N. Ju. Tarasenko, First Moscow Medical Institute, Moscow,
        USSR

    Professor R. L. Zielhuis, Coronel Laboratory, Faculty of Medicine,
        University of Amsterdam, Amsterdam, Netherlands

     Representatives of other agencies

    Dr. A. Berlin, Health Protection Directorate, Commission of the
        European Communities, Centre Louvigny, Luxembourg

    Professor R. Bourdon, International Union of Pure and Applied
        Chemistry, Commission on Toxicology, Laboratoire de Biochimie-
        Toxicologie, Centre Anti-Poison de l'Hpital Fernand Widal, Paris,
        France

    Dr. D. Djordjevic, Occupational Safety and Health Branch,
        International Labour Office, Geneva, Switzerland

    Dr. R. Morf, International Union of Pure and Applied Chemistry,
        Liaison Officer with WHO, 8311 Kyburg Zh, Switzerland

     Secretariat

    Professor Paul B. Hammond, Department of Environmental Health,
        University of Cincinnati, The Kettering Laboratory, Cincinnati,
        Ohio, USA  (Temporary Adviser)

    Dr. Y. Hasegawa, Medical Officer, Control of Environmental Pollution
        and Hazards, Division of Environmental Health, World Health
        Organization, Geneva, Switzerland

    Dr. J. E. Korneev, Scientist, Control of Environmental Pollution and
        Hazards, Division of Environmental Health, World Health
        Organization, Geneva, Switzerland

    Dr. V. Krichagin, Scientist, Promotion of Environmental Health, WHO
        Regional Office for Europe, Copenhagen, Denmark

    Dr. B. Marshall, Medical Officer, Occupational Health, Division of
        Environmental Health, World Health Organization, Geneva.

    Professor L. A. Timofievskaja, Institute of Occupational Health,
        Moscow, USSR  (Temporary Adviser)

    Dr. V. B. Vouk, Chief, Control of Environmental Pollution and Hazards,
        Division of Environmental Health, World Health Organization,
        Geneva  (Secretary) 

    List of abbreviations

    ALA       delta-aminolevulinic acid

    ALA-U     delta-aminolevulinic acid in urine

    ALAD      porphobilinogen synthase (EC 4.2.1.24), delta-aminolevulinate
              dehydratase, delta-aminolevulinic acid dehydratase

    ALAS      delta-aminolevulinate synthase (EC 2.3.1.37), aminolevulinic
              acid synthetase

    CP        coproporphyrins

    CP-U      coproporphyrin in urine

    CPG       coproporphyrinogen III

    EDTA      ethylenediaminetetraacetic acid

    FEP       free erythrocyte porphyrins

    Hb        haemoglobin

    LD50      median lethal dose

    PP        protoporphyrin IX

    PBG       porphobilinogen

    Pb-B      lead in blood

    Pb-U      lead in urine

    RBC       red blood cells

    SGOT      aspartate aminotransferase (EC 2.6.1.1), serum glutamic
              oxaloacetic transaminase

    ENVIRONMENTAL HEALTH CRITERIA FOR LEAD

        A WHO Task Group on Environmental Health Criteria for Lead met in
    Geneva from 29 April to 5 May 1975. Dr B. H. Dieterich, Director,
    Division of Environmental Health, opened the meeting on behalf of the
    Director-General. The Task Group reviewed and revised the second draft
    criteria document and made an evaluation of the health risks from
    exposure to lead and its compounds.

        The first and second drafts were prepared by Professor Paul B.
    Hammond of the Department of Environmental Health, The Kettering
    Laboratory, University of Cincinnati, Ohio, USA. The comments on which
    the second draft was based were received from the national focal
    points for the WHO Environmental Health Criteria Programme in
    Bulgaria, Czechoslovakia, Federal Republic of Germany, Greece, Japan,
    The Netherlands, New Zealand, Poland, Sweden, USA, and the USSR, and
    from the United Nations Educational, Scientific and Cultural
    Organization (UNESCO), Paris, from the United Nations Industrial
    Development Organization (UNIDO), Vienna, from the Centro Panamericano
    de Ingenieria Sanitaria y Ciencias del Ambiente (CEPIS) at Lima, Peru,
    and from the Health Protection Directorate of the Commission of the
    European Communities (CEC), Luxembourg. Comments were also received,
    at the request of the Secretariat from: Professor R. Goyer and
    Professor H. Warren, Canada; Professor J. Teisinger, Czechoslovakia;
    Dr S. Hernberg, Finland; Dr K. Cramer and Dr B. Haeger-Aronsen,
    Sweden; Dr D. Barltrop, Professor B. Clayton, Professor R. Lane, and
    Professor P. J. Lawther, United Kingdom; Dr J. J. Chisholm, Professor
    H. L. Margulis, and Dr G. Ter Haar, United States of America; and Dr
    D. Djuric and Professor K. Kostial, Yugoslavia.

        Valuable comments were received on the third draft, resulting from
    the task group, from: Mr Joseph E. Faggan, Director of Petroleum
    Chemicals Research, Ethyl Corporation, Ferndale, Michigan, USA, and
    from Mr R. L. Stubbs, Director-General, Lead Development Association,
    London and Chairman, Statistical Committee, International Lead and
    Zinc Study Group.

        The collaboration of these national institutions, international
    organizations, WHO collaborating centres, and individual experts is
    gratefully acknowledged. Without their assistance this document would
    not have been completed. The Secretariat wishes to thank, in
    particular, Professor Hammond for his continued help in all phases of
    the preparation of the document, and Dr H. Nordman of the Institute of
    Occupational Health, Helsinki, who assisted the Secretariat in the
    final scientific editing of the document.

        This document is based primarily on original publications listed
    in the reference section. However, several recent publications broadly
    reviewing health aspects of lead and its compounds have also been

    used. These include publications by Kehoe (1961), NAS-NRC (1972), NRC-
    Canada (1973), Goyer & Rhyne (1973), WHO Working Group (1973), Inter-
    Department Working Group on Heavy Metals (1974), SCEP (1974),
    Nordberg, ed. (1976). In addition, the document draws on comprehensive
    and useful data from the proceedings of several symposia and meetings,
    e.g. the "International Symposium on Environmental Aspects of Lead",
    Amsterdam, 1972, arranged by the Commission of the European
    Communities and the US Environmental Protection Agency; the
    "International Symposium on Recent Advances in the Assessment of the
    Health Effects of Environmental Pollution", Paris, 1974, jointly
    organized by the Commission of the European Communities, US
    Environmental Protection Agency, and the World Health Organization;
    the University of Missouri's Annual Conferences on Trace Substances in
    Environmental Health, Columbia, Missouri, 1967-1975; and the
    "International Symposium on Environmental Lead Research", Dubrovnik,
    1975, organized by the Institute for Medical Research and Occupational
    Health, under the auspices of the Yugoslav Academy of Sciences and
    Arts.

        Details of the WHO Environmental Health Criteria Programme,
    including some of the terms frequently used in the documents, may be
    found in the introduction to the publication "Environmental Health
    Criteria 1-Mercury", published by the World Health Organization,
    Geneva, in 1976.

    1.  SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

    1.1  Summary

    1.1.1  Analytical problems

        The procurement of environmental and biological samples requires
    careful consideration of the special problems relating to the
    particular material to be analysed. In air sampling, it is most
    important to ensure that the sampler is placed at the breathing zone
    of the population group under study. For all sampling procedures and
    particularly for blood, external contamination is a major problem.

        The most successful analytical method in recent years has been
    atomic absorption spectroscopy. It has proved to be versatile and
    sufficiently sensitive for most purposes, but reliable results,
    particularly for biological specimens such as blood, can be obtained
    only after considerable experience has been acquired.

        Determinations of haem intermediates and of porphobilinogen
    synthase (EC 4.2.1.24) (ALAD)a,b activity in blood are important
    methods for estimating the biological consequences of overexposure to
    lead. There is a great need for standardization of both these methods
    and of ways of expressing the results.

    1.1.2  Sources and pathways of exposure

        The major sources of lead in the environment that are of
    significance for the health of man, arise from the industrial and
    other technological uses of lead. The major dispersive non-recoverable
    use of lead is in the manufacture and application of alkyllead fuel
    additives. Because of current legislative actions with respect to the
    maximum permissible concentration of lead in gasoline, the consumption
    of lead for the production of alkyllead additives decreased from 1973
    to 1975 and a further decline for the latter half of the 1970s may
    occur as more cars equipped with catalysts which require lead-free
    gasoline will come into use.

              

    a  "In the first instance, enzymes are named according to the 1972
       recommendations of the Commission on Enzyme Nomenclature but
       throughout the rest of the document the more familiar names or
       abbreviations are used.

    b  Formerly known as delta-aminolevulinate dehydratase or
       delta-aminolevulinic acid dehydratase.

        From a mass balance point of view, the transport and distribution
    of lead from stationary or mobile sources is mainly  via air.
    Although large amounts are probably also discharged into soil and
    water, lead tends to localize near the points of such discharge. Lead
    that is discharged into the air over areas of high traffic density
    falls out mainly within the immediate metropolitan zone. The fraction
    that remains airborne (about 20%, based on very limited data) is
    widely dispersed. Residence time for these small particles is of the
    order of days and is influenced by rainfall. In spite of widespread
    dispersion, with consequent dilution, there is evidence of lead
    accumulation at points extremely remote from human activity, e.g. in
    glacial strata in Greenland.

        The biota acquires lead both by surface deposition and by
    secondary transfer from soil to plants and from plants to animals.
    However, the impact of man-made lead pollution on the lead content of
    plants and animals is not perceptible except in localized areas of
    intense air pollution, e.g. around smelters and in the immediate
    vicinity of roads with heavy traffic.

        The concentration of lead in air varies from 2-4 g/m3 in large
    cities with dense automobile traffic to less than 0.2 g/m3 in most
    suburban areas and still less in rural areas. The concentration of
    lead in drinking water is generally less than 10 g/litre, but in some
    areas where the water is soft (low in calcium and magnesium) and
    where, at the same time, lead pipes and lead-lined water storage tanks
    are used, the concentration may reach 2000-3000 g/litre. At this
    concentration (and even at concentrations of several hundred g/litre)
    a perceptible rise in the body burden of lead occurs, which is
    reflected in elevated values of lead in the blood (Pb-B).

        The contribution of food to man's exposure to lead is highly
    variable. Some recent studies in the USA have estimated the daily oral
    intake in food and beverages to be about 100 g whereas earlier
    studies and some recent European studies indicated the intake to be in
    the range of 200-500 g/day. However, a recent Swedish study reported
    volumes of the order of 20 g/day. No specific category of food has
    been identified as being especially high in lead content other than
    wine and foods that are stored in lead-soldered cans or lead-glazed
    pottery. Processed milk contains considerably more lead than fresh
    cow's milk which has a similar concentration to human milk. The
    reported lead concentrations range from less than 5 g/litre to
    12 /litre. If this information is correct, milk could be a
    significant source of lead for infants.

        Various miscellaneous sources of lead have been identified as
    being highly hazardous. These include lead-glazed ceramics used for
    beverage storage, illicitly-distilled whisky, and discarded automobile
    battery casings when used for fuel.

        In certain countries, gross overexposure of some infants and young
    children has been recorded. The major sources are lead-based paint in
    old houses and in the soil surrounding these homes, and the soil
    surrounding lead smelters. Lead in street dust due to atmospheric
    fallout, and miscellaneous lead-containing objects chewed or eaten by
    children are other possible sources of exposure, but their relative
    importance is not clear.

        The highest exposure occurs in workers who come into contact with
    lead during mining, smelting, and various manufacturing processes
    where lead is used. The major pathway of exposure is inhalation. The
    concentration of air lead in the working environment of smelters and
    storage battery factories often exceeds 1000 g/m3. For other
    industries, data are either not available or indicate a lower level of
    exposure.

        Extensive surveys have been made on blood concentrations in both
    adults and young children. Such data are useful indicators of overall
    exposure to lead.

    1.1.3  Metabolism

        A number of studies have been made which indicate that 35% of the
    lead inhaled by man is deposited in the lungs. The relative importance
    of the mucociliary escalator mechanism and of direct absorption from
    pulmonary deposition is poorly understood and the contribution of
    airborne lead to total daily intake cannot be estimated from metabolic
    data. But when sustained Pb-B is used as a measure of lead absorption,
    it can be assumed from human data that continuous exposure to 1 g of
    lead per m3 of air would contribute lead levels of about
    1.0-2.0 g/100 ml of blood.

        About 10% of lead taken in from food and beverages is absorbed.
    However, using data from several sources, the dietary contribution to
    Pb-B can only be roughly estimated as 6-18 g of lead per 100 ml of
    blood per 100 g of dietary lead intake.

        From both animal and human studies, the general features of lead
    distribution and excretion are fairly clearly defined. The body burden
    of lead can be subdivided into a large, slow-turnover compartment and
    a smaller more rapidly-exchanging compartment. Anatomically, the
    larger compartment is mainly located in bones. The amount of lead in
    this compartment increases throughout life. The smaller compartment
    consists of the soft tissues and includes the blood. Lead levels in
    soft tissues and in blood continue to increase up to early adulthood
    and then change little. Elimination of lead from the body is mainly by
    way of the urine (about 76%) and the gastrointestinal tract (about
    16%). The other 8% is excreted by miscellaneous routes (sweat,
    exfoliation of the skin, loss of hair) about which little is known.

        Alkyllead compounds (tetraethyllead and tetramethyllead) are
    dealkylated both to trialkyl derivatives and to inorganic lead.
    Details of alkyllead metabolism have been learned from animal studies
    and have not been defined in man.

    1.1.4  Experimental studies on the effects of lead

        The extensive animal studies that have been conducted concerning
    the biological effects of lead indicate that, with rare exceptions,
    the toxic phenomena that have been observed in man have also been
    successfully reproduced in animals. Although animal studies have
    provided a more profound understanding of the effects of lead than
    could be learned from studies of man himself, they have not been of
    much use in the elucidation of dose-effect and dose-response
    relationships in man.

        Major differences that have been noted are as follows: (1) benign
    and malignant tumour induction has occurred in rats and mice exposed
    to lead acetate and in rats exposed to lead subacetate and lead
    phosphate but carcinogenic effects have not been seen in man; (2)
    clear-cut reductions in fertility have been observed in experimental
    animals but not in man, although data have been reported which suggest
    that this might be so; (3) hyperactivity and other behaviourial
    disturbances have been observed in rats, mice, and sheep without prior
    encephalopathy. This is especially important because of current
    suspicions that widespread, slight brain damage occurs in young
    children with relatively low exposure not preceded by encephalopathy.
    Evidence also exists for compensatory increases in ALAD in animals
    with continuing exposure to lead whereas all human studies to date
    have been negative in this respect.

    1.1.5  Clinical and epidemiological studies on the effects of lead:
           Evaluation of health risk to man from exposure to lead

        Studies of the effects of lead on man may be divided into two
    general types. The first type is the retrospective study of the causes
    of mortality in lead-exposed populations in contrast with those in
    matched control groups. Several studies showed that at high exposure
    levels (Pb-B>80 g/ 100 mla), a slightly higher number of deaths
    occurred due to cerebrovascular disease and chronic nephritis. In one
    study, where the mortality rate due to cancer was observed, no
    statistically significant differences were found between the
    industrially exposed workers and the control group.

              

    a  In this document, the concentrations of lead in blood are
       expressed in g/100 ml although in some original papers the values
       are given in g/100 g. For practical purposes, the difference of
       about 5% can be neglected.

        The second type of study concerns morbidity rates due to the
    effects of lead on specific organs and systems. In some cases, it has
    been possible to estimate the level of the exchangeable body burden
    (expressed as Pb-B) at which a given intensity of effect (dose-
    response relationship) has been observed in certain sections of a
    selected group. For other effects it has only been possible to specify
    the Pb-B level at which no effect was observed in reasonably large
    groups of people (no-detected-effect level).

        The haematopoietic system shows effects at lower Pb-B levels than
    any other system. The effects are, in order of sensitivity: inhibition
    of erythrocyte ALAD, elevation of erythrocyte protoporphyrin IX (FEP),
    rise in urinary delta-aminolevulinic acid (ALA) and coproporphyrin
    (CP) excretion, inhibition of erythrocyte sodium-potassium adenosine
    triphosphatase (EC 3.6.1.3) (Na-K-ATP'ase), and fall in haemoglobin
    level. A fall in haemoglobin level is clearly an indication of adverse
    effects. The no-detected-effect level for this effect is a Pb-B
    concentration equivalent to 50 g/100 ml in adults and 40 g/100 ml in
    children.

        The effects of inorganic lead on the central nervous system have
    been under intensive investigation in recent years, particularly with
    regard to subtle effects on behaviour, mainly in children, but also to
    some extent in adults. Substantial doubts remain as to the validity of
    some of the studies because the relationship between the exposure to
    lead at the time the damage occurs and at the time the effects are
    first observed is not known. Nevertheless, a no-detected-effect level
    has been specified that is lower than for classical lead
    encephalopathy. The no-detected-effect level is estimated to be at
    Pb-B values of about 60-70 g/100 ml for adults and of about
    50-60 g/100 ml for children.

        The renal effects of lead are of two general types. The first is
    tubular, characterized by the Fanconi triad of aminoaciduria,
    hyperphosphaturia, and glycosuria. It occurs with relatively short-
    term exposure and is reversible. The second type of renal effect is
    characterized anatomically by sclerotic changes and interstitial
    fibrosis. Functionally, filtration capacity is reduced. These changes
    are of a progressive nature and may lead to renal failure. It is
    probable that exposures leading to this type of nephropathy are rarely
    encountered even in industry today. A no-detected-effect level cannot
    be specified.

        The problem of the toxic effects of alkyllead is almost entirely
    restricted to workers who are occupationally exposed. There is very
    little information concerning dose-effect and dose-response
    relationships and even the frequency of occurrence of toxic effects
    and their relation to specific work activities is not well documented.

    1.2  Recommendations for Further Research

    1.2.1  Analytical methods

        One of the major needs is for the standardization of analytical
    methods, particularly with regard to the haem intermediates, ALAD, and
    erythrocyte Na-K-ATP'ase. At the present time, it is often impossible
    to compare studies conducted in one laboratory with those of another.
    This is particularly true for enzymatic methods that give different
    results depending on pH, oxygen tension, and the presence or absence
    of other factors, e.g. other metals that can influence the action of
    lead. It is of equal importance that a standard mode of expressing
    results be introduced in order to achieve valid interlaboratory
    comparisons. Thus, measurements involving urine should be expressed
    per unit of creatinine excreted per unit time; this would probably
    take body mass into consideration.

        In view of the highly variable results that have been obtained in
    the interlaboratory comparisons conducted to date, more cooperative
    efforts should be undertaken and maintained on a continuous basis. It
    is recommended that all published data include interlaboratory
    comparison results for the methods used. International standard
    specimens of the commonly investigated biological media with reliably
    determined concentrations of lead should be developed and made
    available to investigators.

        Finally, standardized methods of statistical treatment of
    analytical data should be adopted and adhered to.

    1.2.2  Sources of lead intake

        It is apparent that the estimations of lead in the diet of man
    vary greatly. Future studies should include specifications concerning
    the characteristics of the individuals for whom lead consumption data
    are being reported, including sex, age, weight, and physical activity.
    Since the ultimate purpose of food studies is to evaluate the
    contribution made to the total dose, it is important that future
    reports also include the observed Pb-B levels and, preferably, other
    indices, such as delta-aminolevulinic acid in urine (ALA-U), PP and
    ALAD in erythrocytes. Food studies should also include estimates of
    the lead concentration of various components of the total diet. Only
    with such studies will it be possible to arrive at decisions regarding
    the control of lead in foods.

        More precise information is available concerning the contribution
    of airborne lead to Pb-B and although this seems to be a minor
    contributor to Pb-B for the general population compared with diet,
    additional studies are needed both in occupational situations, and for
    the general population. The studies should be of a relatively long-

    term nature and should be done, as far as possible, with personal air
    samplers maintained in operation continuously throughout the day
    during the period of study.

        There is a great need to study the sources of lead affecting
    infants and young children including the contributions of food, milk
    and other beverages, and air, and also miscellaneous sources, e.g.
    paint, soil, and dust.

    1.2.3  Epidemiological studies

        Prospective studies are needed of the health effects of both
    inorganic and organolead compounds, with particular reference to a
    more thorough estimation of the nature of the lead exposure, Pb-B
    levels, and measurable effects. It would seem particularly useful to
    make further studies on occupational groups, beginning at the time of
    their entry into the high lead environment.

    1.2.4  Interactions of lead with other environmental factors

        In both epidemiological studies and in experimental studies on
    animals, not enough emphasis has been placed on the environmental
    variables that can affect man's response to lead. The list of such
    variables is long and is documented in this report. Particular
    attention should be paid to the influence of other metals, air
    pollutants, and the nutritional status of the subjects, since these
    factors have been identified as interacting with lead either in regard
    to its deposition in the body or in regard to its biological effects
    in target organs.

    1.2.5  Significance of biological effects

        Numerous abnormalities have been identified, the toxic
    significance of which is obscure, e.g. elevated free erythrocyte PP
    and marginal erythrocyte ALAD inhibition. There is an urgent need to
    study the significance of these findings in relation to human health.

    2.  PROPERTIES AND ANALYTICAL METHODS

    2.1  Physical and Chemical Properties of Lead and its Compounds

        Lead (atomic number, 82; atomic weight, 207.19; specific gravity,
    11.34) is a bluish or silvery grey soft metal. The melting point is
    327.5C and the boiling point at atmospheric pressure 1740C. It has
    four naturally occurring isotopes (208, 206, 207, and 204 in order of
    abundance), but the isotopic ratios for various mineral sources are
    sometimes substantially different. This property has been used to
    carry out non-radioactive-tracer environmental and metabolic studies.

        Although lead has four electrons in its valence shell, only two
    ionize readily. The usual oxidation state of lead in inorganic
    compounds is therefore + 2 rather than + 4. The inorganic salts of
    lead (II), lead sulfide, and the oxides of lead are generally poorly
    soluble. Exceptions are the nitrate, the chlorate and, to a much
    lesser degree, the chloride (Table 1). Some of the salts formed with
    organic acids, e.g. lead oxalate, are also insoluble.

        Under appropriate conditions of synthesis, stable compounds are
    formed in which lead is directly bound to a carbon atom.
    Tetraethyllead and tetramethyllead are well-known organolead
    compounds. They are of great importance owing to their extensive use
    as fuel additives. Both are colourless liquids. Their volatility is
    lower than for most gasoline components. The boiling point of
    tetramethyllead is 110C and that of tetraethyllead is 200C. By
    contrast, the boiling point range for gasoline hydrocarbons is
    20-200C. Thus evaporation of gasoline tends to concentrate
    tetraethyllead and tetramethyllead in the liquid residue.

        Both tetramethyllead and tetraethyllead decompose at, or somewhat
    below, the boiling point. Analysis of automobile exhaust gases shows
    that the ratio of tetramethyllead to tetraethyllead increases as the
    engine warms up, indicating that tetramethyllead is more thermostable
    than tetraethyl-lead (Laveskog, 1971). These compounds are also
    decomposed by ultraviolet light and trace chemicals in air such as
    halogens, acids, or oxidizing agents (Snyder, 1967).

    2.2  Analytical Procedures

    2.2.1  Sampling

        Particular attention should be paid to the cleanliness of the
    instruments and the purity of chemicals to prevent the appearance of
    artifacts due to the secondary contamination by lead, especially in
    the sampling of foods and biological media.


        Table 1.  Some physical and chemical data on lead and selected lead compoundsa
                                                                                                                                                

                                                                                          Solubility
    Name               Synonym and          Molecular  Melting             Boiling        in cold           Soluble in
                       formula              weight     point (C)          point (C)     water (g/litre)
                                                                                                                                                

    lead               Pb                   207.19      327.502            1740           insoluble         HNO3; hot concentrated H2SO4
      acetate          Pb(C2H3O2)2          325.28      280                --             443               hot water; glycerine; alcohol
                                                                                                              (slightly)
      azide            Pb(N3)2              291.23                         explodes 350     0.23            acetic acid; hot water 
                                                                                                              (0.9 g/litre)
      carbonate        cerrusite PbCO3      267.20      315 (decomposes)                    0.0011          acid; alkali; decomposes in 
                                                                                                              hot water
      chlorate         Pb(ClO3)2            374.09      230 (decomposes)                  very soluble      alcohol
      chloride         cotunite PbCl2       278.10      501                950              9.9             NH4 salts; slightly in dilute
                                                                                                              HCl and in NH3; hot water
                                                                                                              (33.4 g/litre)
      chromate         crocoite, chrome     328.18      844                decomposes       0.000058        alcohol; alkali
                         yellow PbCrO4
      nitrate          Pb(NO3)2             331.20      470 (decomposes)                  376.5             alcohol; alkali; NH3; hot water
                                                                                                              (1270 g/litre)
      ortophosphate    Pb3(PO4)2            811.51     1014                                 0.00014         alkali; HNO3
      oxalete          PbC2O4               295.21      300 (decomposes)                    0.0016          HNO3
      oxide: di-       plattnerite PbO2     239.19      290 (decomposes)                  insoluble         dilute HCl; acetic acid (slightly)
             mono-     litharge PbO         223.19      888                                 0.017           HNO3; alkali; NH4Cl
             red       mioium Pb3O4         685.57      500 (decomposes)                  insoluble         HCl; acetic acid
             sesqui-   Pb2O3                462.38      370 (decomposes)                  insoluble         decomposes in acid and hot water
      stearate         Pb(C18H35O2)2        774.15      115.7                               0.5             hot water (0.6 g/litre); ether
                                                                                                            (0.05 g/litre)
      sulfate          anglesite PbSO4      303.25     1170                                 0.0425          NH4 salts; concentrated H2SO4
                                                                                                              (slightly)
      sulfide          galena PbS           239.25     1114                                 0.00086         acid
                                                                                                                                                

    Table 1.  (Cont'd)
                                                                                                                                                

                                                                                          Solubility
    Name               Synonym and          Molecular  Melting             Boiling        in cold           Soluble in
                       formula              weight     point (C)          point (C)     water (g/litre)
                                                                                                                                                

    tetraethyllead     Pb(C2H5)4            323.44     -136.80             200            insoluble         benzene; petroleum; alcohol; ether
                                                                           decomposes;
                                                                           91
    tetramethyllead    Pb(CH3)4             267.3      -27.5               110            insoluble         benzene; petroleum; alcohol; ether
                                                                                                                                                

    a  Adapted from Weast, R. C., ed. Handbook of Chemistry and Physics, 55th edition, Cleveland, Ohio, Chemical Rubber Company, 1974.
    

        In air sampling, high-volume samplers are preferable for accuracy
    (when it is necessary), but the low-volume technique is also useful
    for obtaining extensive data. As in all sampling for suspended
    particulate matter, the accuracy of volume meters should be checked
    periodically. The size of the pores of filters for collecting lead-
    containing particles should be small, possibly less than 0.2 m for
    glass-fibre filters (Lee & Goransen, 1972). Liquid scrubbers
    containing iodine monochloride and solid scrubbers with activated
    carbon, cristobalite, or iodine crystals have been used for sampling
    organic lead compounds in air, in the range of about 1 g/m3 or less
    (Snyder, 1967; ASTM, 1970; Laveskog, 1971; Coleville & Hickman, 1973;
    Purdue et al., 1973) up to 10 g/m3 (Harrison et al, 1974).

        Depending on the purpose of sampling, care should be taken to
    select the appropriate site for sampling devices and to achieve the
    best possible sampling conditions by:

    --  estimating the required amount of particulates before deciding on
        the sample volume and the sampling procedure;

    --  placing the sampling devices in the appropriate position (e.g.
        breathing air level, level of inlet tubes of house ventilators,
        window level in the case of a traffic-laden town street, at a
        reasonable distance from the highway in uninhabited zones, etc),

    --  taking the samples at appropriate rates and volumes (e.g. daily
        breathing volumes, daily ventilating capacities of installations)
        and for a sufficient time to make possible the estimation of the
        average concentration (e.g. during a work shift, or a 24-hour or
        longer period for general population exposure);

    --  taking into account the use of appropriate areas (cattle grazing,
        recreational zones, children's playgrounds etc.)

        In addition, whenever possible, a procedure should be used that
    makes it possible to evaluate particle-size distribution and the
    physico-chemical properties of the lead compounds involved, including
    the shape of the particles and the state of their aggregation.

        Stationary samplers can provide general indices of the exposure of
    individuals within a certain area. For estimating exposure through
    inhalation, personal samplers are highly desirable (Azar et al.,
    1973).

        Techniques for sampling water are less complex than for air. The
    major question is whether or not the water should be filtered before
    analysis since it is known that lead occurs in water both in the
    particulate fraction and in solution. For most purposes at least, it
    is reasonable to sample water without any fractionation of the
    material collected.

        However, in some cases it may be necessary to determine the
    biological availability for absorption of the various forms of lead
    that occur in water, and in soil. The latter is a dust source and may
    be a food contamination source as well.

        The preparation of soil and soil dust samples for lead analysis
    usually involves drying (at 100c), homogenization by grinding, and
    sieving (Thornton & Webb, 1975; Bolter et al., 1975).

        For the study of lead in foods, two general methods have been
    used. These are the duplicate portions technique and the equivalent
    composite technique (theoretical diet). These two general techniques
    and others have been reviewed recently with reference to their
    advantages and disadvantages (Pekkarinen, 1970). The duplicate
    portions technique involves the collection for analysis of duplicates
    of the meals actually consumed by the individual. When carried out
    over a long enough period, the technique has the advantage of defining
    variability in consumption. Kehoe (1961) used this method for the
    daily determination of lead consumption over long periods.
    Considerable variation in lead consumption was found in individuals
    even when consumption was averaged for four- or eight-week collection
    periods. The disadvantages of the method are the expense and the
    exacting nature of the method of collecting samples; these factors
    tend to limit the numbers of individuals included in such studies.

        The equivalent composite technique consists of formulating the
    ingredients of meals typical for subpopulations and analysing them.
    The advantages are economy and ease of collection. This approach may
    or may not include the cooking process. The disadvantage is
    uncertainty as to how typical or representative the formulation is.
    Even when the cooking process is included, there may be significant
    differences in the manner of preparation for the study in comparison
    with that carried out under actual home conditions.

        The main problem in the sampling of body fluids and tissues for
    lead analysis is potential secondary contamination with lead. Special
    precautions must be taken to ensure that all blood-collecting and
    blood-storage materials are as free from lead as possible. All glass
    equipment involved in blood collection and storage should be made of
    lead-free silicate glass, rinsed first in mineral acid, then with
    copious amounts of glass-distilled or deionized water. Polypropylene
    syringes have been recommended (NAS-NRC, 1972). Needles should be of
    stainless steel with polypropylene hubs. Blood is often drawn directly
    from the needle into vacuum tubes. It is wise to confirm periodically
    the absence of significant amounts of lead in the anticoagulant used
    in the blood container, although this has not been reported as a
    problem.

        New analytical techniques make it possible to determine lead
    concentrations in microlitre quantities of blood. The trend towards
    the procurement of micro-samples of blood by skin prick increases the

    hazard of secondary contamination of the blood. Only one systematic
    investigation on the significance of this problem has been reported.
    Mitchell et al. (1974) describe a procedure whereby sample
    contamination appears to be avoided. This is achieved by spraying
    collodion over the cleansed skin before lancing. The correlation
    between the concentration of lead in micro-samples and in macro-
    samples obtained by venipuncture was fairly good (r = 0.92). The same
    general precautions must be taken in the collection of urine samples
    as in the collection of blood samples.

        Ceramic surfaces are analysed to determine the quantity of lead
    likely to be leached by different foods and beverages. In all cases
    acetic acid solutions are used but the concentrations vary from 1 to
    4%. The temperature of the tests ranges from 20 to 100C and the
    duration from 30 minutes to more than 24 hours (Laurs, 1976; Merwin,
    1976).

    2.2.2  Analytical methods for lead

        The analytical methods currently in use for the estimation of lead
    content are of two general types, destructive and non-destructive. In
    the former, the sample is first oxidized to destroy all organic
    matter. The ash is then usually dissolved in an aqueous medium, either
    for further preparative steps or for direct instrumental analysis.
    Non-destructive methods are of more recent origin and are still too
    complicated for routine studies. They include X-ray fluorescence
    analysis and fast neutron activation. In selecting methods,
    consideration must be given to the cost of the equipment and the time
    involved in performing the analyses.

        The oldest and best known of the general methods currently in wide
    use are those based on the formation of the red complex that lead
    forms with dithizone (diphenylthiocarbazone). Numerous specific
    procedures have been developed based on the spectrophotometric
    determination of lead dithizonate. A typical example is the "US Public
    Health Service" method commonly used for the determination of lead in
    biological materials (NAS-NRC, 1972). The method has evolved over many
    years. A study of its reliability was reported by Keenan et al.
    (1963). An interlaboratory comparison was made of analyses of blood
    and urine with and without the addition of lead. Ten laboratories
    participated in the study. For blood, the concentration of lead
    calculated in the principal laboratory was 20 g/100 ml. The average
    reported by the participating laboratories was 26 g/100 ml with a
    standard deviation of  0.82 g/100 ml. For samples of blood to which
    lead was added, the average result was right on the mark,
    70 g/100 ml  0.78. For "spiked" urine, determined by the primary
    laboratory to contain 750 g/litre, the average reported result was
    679  5.5 g/litre.

        Perhaps no method of instrumental analysis for lead has enjoyed
    such a rapid acceptance in recent years as atomic absorption
    spectroscopy. In conventional atomic absorption spectroscopy, the
    source of heat is a flame into which the sample solution is aspirated.
    More recently, various procedures have been developed whereby the
    receptacle containing the sample is heated electrically. This type of
    modified procedure is termed flameless atomic absorption spectroscopy.
    The main advantage of this approach is that sample size is reduced
    from the millilitre to the microlitre range with no commensurate loss
    of sensitivity. Another advantage is that the heated receptacle can be
    used for ashing the sample immediately prior to the spectrophotometric
    analysis. Numerous reports have appeared describing various kinds of
    flameless instrumentation and their application in the analysis of the
    lead content of blood and other materials (Cernik, 1974; Delves, 1970;
    Ediger & Coleman, 1973; Matousek & Stevens, 1971; Kubasik et al.,
    1972; Hwang et al., 1971; Sansoni et al., 1973; Schramel, 1973;
    Schramel, 1974). It has been reported that the analytical capabilities
    of this method for determining lead in whole blood are comparable with
    that of the conventional flame atomic absorption method (Kubasik et
    al., 1972; Hicks et al., 1973).

        Electroanalytical methods have also been found useful for lead
    determinations. These include polarography and, more recently, anodic
    stripping voltametry. The polarographic method was developed
    specifically for lead by Teisinger (1935). The low sensitivity of the
    method as applied to lead in blood and urine required working close to
    the detection limits. This is obviously a disadvantage when
    determining the normal levels of lead in blood and urine. Various
    modifications of the original method have been used for the evaluation
    of industrial exposures (Weber, 1947; Baker, 1950; Brezina & Zuman,
    1958). This method found wide application until more effective masking
    procedures were developed to increase the specificity of the dithizone
    method. Anodic stripping voltametry is gaining in popularity for lead
    analysis. Results have been compared using a dithizone method, an
    atomic absorption method, and anodic stripping voltametry (Matson,
    1971). Generally, there was good agreement between all three methods
    in the estimation of the lead contents of blood and urine. In another
    study, anodic stripping voltametry was compared with atomic absorption
    spectroscopy and polarography for the analysis of lead in blood and
    urine (Horiuchi et al., 1968). The authors concluded that there were
    no significant differences between the results obtained by the various
    methods. Anodic stripping voltametry has also been compared with
    conventional and flameless atomic absorption spectroscopy and with
    potentiometric determination using ion-specific electrodes to estimate
    the lead content of water (Kempf & Sonnenborn, 1973).

        Two non-destructive methods for lead analysis have been under
    investigation in recent years. These are neutron activation and X-ray
    fluorescence. The first of these is not likely to find wide
    application for lead analysis in the near future because of the cost

    and the need for access to a fast neutron source. Its advantage is
    that the concentration of many elements can be determined
    simultaneously.

        X-ray fluorescence is also theoretically capable of detecting,
    non-destructively, all elements in a substance. A major obstacle to
    the wide application of this method is the profound matrix effect of
    the substances being analysed. Another problem is the backscatter from
    the exciting source. These design problems and approaches to their
    solution have been discussed recently by Kneip & Laurer (1972). Lead
    analysis by means of X-ray fluorescence with proton excitation has
    been successfully used with biological samples (Mller et al., 1974).
    It has also been used as the standard method for the determination of
    lead on filters from air sampling equipment by the Warren Springs
    Laboratory in the United Kingdom. In the USA, the most extensive
    application of X-ray fluorescence for lead analysis has been for
    estimating the concentration and amount of lead on the walls of
    houses. For this purpose, several portable units have been designed
    and are being used in surveys of dwellings for hazardous
    concentrations of lead. Since the instruments in question scan
    surfaces, instrument response is in terms of lead detected per unit
    area and not per unit weight or volume of paint film. This creates
    difficulties, since the thickness of the total paint film varies
    depending on how many times a surface has been painted. Ordinances
    should perhaps be revised to specify tolerances based on surface area.
    The accuracy of these instruments is severely limited. These factors
    have been studied using one of the commercially available instruments
    (Spurgeon, 1973). In another report from the US National Bureau of
    Standards (Rasberry, 1973), four commercial instruments were tested as
    received from the manufacturer. It was found that all the instruments
    had a detection limit below 1 mg/cm2, but that between 1 and
    6.6 mg/cm2, errors as large as 30-50% occurred. It is difficult to
    evaluate the adequacy of such instruments since it is not at all clear
    where the cut-off is between hazardous and non-hazardous amounts of
    lead per unit area of paint film. Thus, if the cut-off were known to
    be at or above 1 mg/cm2, the instruments would clearly be useful.

        The accuracy and precision of various methods for the lead
    analysis of biological materials have been appraised in a number of
    interlaboratory comparison programmes both at the national (Keppler et
    al., 1970; Donovan et al., 1971) and international levels (Berlin et
    al., 1973). In general, these published studies have indicated that
    the accuracy of the measurements is unsatisfactory, with less than
    half of the laboratories performing adequately. More recently, in a
    programme involving sixty-six European laboratories, it was observed
    that even when only the laboratories that measured lead in blood and
    urine with a precision of greater than 10% were selected, the
    interlaboratory variability still remained high. It is possible that

    the performance could be improved by rapid distribution of the sample
    and by improved sample preparation techniques, e.g. by subjecting
    blood samples to ultrasonic irradiation prior to despatch to
    participating laboratories.

        The paper punch disc microtechnique (Cernik & Sayers, 1971;
    Cernik, 1974) was used in a population survey of blood lead content
    performed in Western Ireland (Grimes et al., 1975). Over 400 duplicate
    samples were analysed double-blind by one laboratory. The assay showed
    a satisfactory agreement with the results obtained by other
    laboratories using various techniques.

        Comparisons have also been reported of the agreement between
    results obtained by the same investigator using different analytical
    methods. Yeager et al. (1971) compared the results obtained using a
    standard dithizone procedure and flame atomic absorption spectroscopy.
    The results from common digests of the same material were compared.
    The materials included blood, urine, tissue, faeces, food, and bone.
    Since the two methods are based on entirely different analytical
    principles, a straight line with a slope equal to 1 and an intercept
    equal to 0, obtained when the results of atomic absorption
    spectroscopy analyses were plotted against the results of the
    dithizone method, suggested that the two methods were equally
    accurate.

        These studies show that blood sample preparation is important to
    ensure sufficient homogeneity for microanalytical techniques.

    2.2.3  Methods for the measurement of some biochemical effects of lead

        The classic method for the urinary delta-aminolevulinic acid (ALA)
    determination was developed by Mauzerall & Granick (1956). The major
    procedural difficulty was separation from interfering substances. A
    number of modifications and simplifications have been made by several
    authors (Davis & Andelman, 1967; Grabecki et al., 1967; Williams &
    Few, 1967; Sun et al., 1969; Tomokumi & Ogata, 1972).

        The original Mauzerall & Granick method does not discriminate
    between ALA and aminoacetone, a fact that these authors were careful
    to point out. This is probably not very important when ALA excretion
    is greatly increased due to lead exposure, but for marginal
    elevations, it may be a serious problem. In healthy humans on a normal
    diet, the urinary excretion of ALA and that of aminoacetone are nearly
    equal (Marver et al., 1966). These authors and also Urata & Granick
    (1963) separated ALA from aminoacetone by chromatography.

        One interlaboratory comparison study of ALA methods has been
    reported (Berlin et al., 1973). The methods used by the laboratories
    were those of Mauzerall & Granick (1956), Davis & Andelman (1967) and
    of Grabecki et al. (1967). The results using the Grabecki method were

    significantly higher than those using the Mauzerall & Granick method.
    Results with the Davis & Andelman method gave a mean value
    intermediate between the other two. The coefficients of variation were
    quite high: 33%, Grabecki; 28%, Mauzerall & Granick; and 49%, Davis &
    Andelman. It should also be noted that in the case of the Grabecki
    method, the colorimetric reaction was influenced by various
    interfering substances in the individual urine samples. This source of
    error was not considered in the interlaboratory comparison (Mappes,
    1972).

        Comparisons have also been reported between these different
    techniques by Roels et al. (1974) who evaluated the critical factors
    in the urine preparation which affected the different methods. The
    ionic strength and pH of the urine can affect the results of some of
    the methods.

        In the methods used for the determination of ALAD activity, the
    amount of porphobilinogen (PBG) formed per unit time by a standard
    amount of enzyme source is measured. Limited data indicate that ALAD
    in blood is stable for several hours, even at room temperature
    (Hernberg et al., 1970); however, storage at lower temperatures
    improves the stability. The major variables reported to influence the
    activity of the enzyme are pH (Nikkanen et al., 1972), oxygen tension
    (Gibson et al., 1955), the nature of the anticoagulant (Collier,
    1971), and the presence or absence of activators (Bonsignore et al.,
    1965; Collier, 1971; Granick et al., 1973; Hapke & Prigge, 1973).
    Measurement of ALAD activity in erythrocytes is a relatively simple
    procedure that can be conducted without sophisticated equipment. This
    makes it attractive as a measure of the haematological effects of
    exposure to lead. A number of investigators have shown it to be fairly
    specific for lead.

        In its simplest and most frequently used form, the method of
    Bonsignore et al. (1965) requires the incubation of a mixture of
    blood, ALA, and water under aerobic conditions at 38C. However, many
    investigators have modified the procedure and results from different
    laboratories are not necessarily comparable. In a recent
    interlaboratory comparison (Berlin et al., 1973), nine participants
    used various modifications of the Bonsignore method. Thus, it was only
    possible to compare the activity ratios between different blood
    samples. For two blood samples this ratio showed a coefficient of
    variation of only 13%.

        Recently a "European standardized method" has been developed,
    tested in a collaborative study, and agreed upon by nineteen
    laboratories. The results of these tests compare very favourably with
    blood lead determinations. The interlaboratory coefficient of
    variation for ALAD was 10% (Berlin et al., 1974).

        Porphyrins exhibit intense fluorescence when excited by light at
    approximately 400 nm (Soret band). They may be quantitatively
    determined either by measurement of light absorption in the Soret band
    region or by the measurement of fluorescence (Sassa et al., 1973;
    Chisolm, 1974).

        A number of methods have been reported for the measurement of
    protoporphyrin IX. Some of these methods discriminate between
    different porphyrins, measuring specifically the concentration of
    protoporphyrin IX in erythrocytes (Schwartz & Wikoff, 1952; Wranne,
    1960; Schlegel et al., 1972; Granick et al., 1972; Sassa et al.,
    1973). Other methods measure the total concentration of free
    erythrocyte porphyrins including copro- and uro-porphyrins (Kammholtz
    et al., 1972; Piomelli, 1973; Schiele et al., 1974b). It is, however,
    scarcely necessary to make a distinction between the two kinds of
    procedure as over 90% of the free erythrocyte porphyrins are made up
    of protoporphyrin IX (Baloh, 1974). A particular advantage of the more
    recently developed procedures for the measurement of FEP is that they
    can be performed on microcapillary samples of blood (Kammholz, 1972;
    Granick et al., 1972; Sassa et al., 1973: Piomelli, 1973; Schiele et
    al., 1974a). The Piomelli procedure utilizes two successive
    extractions into ethylacetate-acetic acid with subsequent transfer of
    porphyrins into hydrochloric acid. The procedure of Granick et al.
    (1972) is simpler. Ethylacetate-acetic acid and hydrochloric acid are
    successively added to the sample of blood. In both procedures the
    ethylacetate serves to remove and retain interfering impurities in the
    blood. The data obtained by these two methods are not strictly
    comparable.

        All the methods described measure protoporphyrin in the free base
    form. Lamola & Yamane (1974) have recently demonstrated that the
    protoporphyrin IX associated with iron deficiency and lead
    intoxication is present as a zinc chelate. This is not so in the case
    of erythropoietic porphyria. On the basis of these observations they
    developed a fluorimetric method for zinc chelate (Lamola et al.,
    1975). The major advantage of this method is its simplicity and
    rapidity. Microlitre samples are analysed fluorimetrically, after
    dilution, without any extraction steps.

        The measurement of coproporphyrins in urine is generally done by
    extraction of the porphyrins into either ethylacetate-acetic acid
    (Sano & Rimington, 1963) or diethyl ether (Askevold, 1951) followed by
    transfer into hydrochloric acid. Absorbance is then measured at 401 nm
    with the corrections recommended by Rimington & Sveinsson (1950). The
    method is apparently specific, since uroporphyrins, the most likely
    source of interference, are not extracted into the organic phase under
    these conditions (Rimington & Sveinsson, 1950). An alternative method
    has been reported whereby the fluorescence of the hydrochloric acid
    extract is measured after adsorption on to magnesium hydroxide
    (Djuric, 1964). Certain precautions are necessary if urine is to be

    analysed for coproporphyrins. Coproporphyrins are unstable in acid
    urine and, furthermore they are light-sensitive (Schwartz et al.,
    1951). They may be stored safely in the dark at 4C if the pH is
    maintained between 6.5 and 8.5.

    3.  SOURCES OF LEAD IN THE ENVIRONMENT

    3.1  Natural Occurrence

    3.1.1  Rocks

        Lead occurs naturally in the earth's crust in the concentration of
    about 13 mg/kg. As with all elements, there are some areas with much
    higher concentrations including the lead ore deposits scattered
    throughout the world.

        The most important sources of lead are igneous and metamorphic
    rocks, with lead concentrations in the range of 10-20 mg/kg (Wedepohl,
    1956, Vinogradov, 1956, 1962; Turekian & Wedepohl, 1961). The
    concentration of lead in sedimentary rocks is of the same order of
    magnitude. The lead content of carbonaceous shales from the United
    States of America and Europe ranges from 10mg/kg to 70mg/kg (Wedepohl,
    1971; Davidson & Lakin, 1962). The lead contents of shale and
    sandstone are similar but that of phosphate rocks is higher, and may
    exceed 100 mg/kg (Sheldon et al., 1953). Unconsolidated sediments in
    bodies of freshwater and in shallow marine areas have a similar lead
    content to shales. Deep marine sediments have quite a high lead
    content by comparison, commonly containing 100-200mg/kg (Riley &
    Skirrow, 1965).

        The lead content of coal is relatively low. However, when
    expressed on an ash-weight basis, the concentration is generally
    higher than that of igneous, metamorphic, and sedimentary rocks, but
    not more than ten-fold (Abernethy et al., 1969).

    3.1.2  Soils

        Surface soils are in direct contact with the contemporary
    environment; thus, special care must be taken to distinguish between
    soils that acquire lead only from natural sources and soils that are
    polluted by man. Acidic soils generally have a lower lead content than
    alkaline soils. The nature of the organic matter in soil also has a
    considerable influence on its lead content. Some organic matter is
    rich in chelating components, and it binds lead, either promoting its
    movement out of the soil or fixing the metal, depending on the
    solubility properties of the complex. Although all of these factors no
    doubt play a role in determining the lead content of specific soils,
    the concentrations usually encountered in areas, remote from human
    activity, are similar to concentrations found in rocks, with an
    average range of 5-25 mg/kg (Swaine, 1955). More recent data from
    various parts of the world have confirmed this estimate.

    3.1.3  Water

        Analyses of groundwater have revealed lead concentrations varying
    from 1 to 60 g/litre (Kehoe et al., 1933, 1944; Bagchi et al., 1940).
    Most data refer to water that has been filtered to remove particulate
    matter. Colloidal lead is only partially removed by filtration and to
    different degrees. Water that is pumped from the ground is usually not
    filtered prior to analysis. The content of colloidal material is
    probably insignificant in such samples owing to natural filtration
    which removes colloidal particles fairly effectively.

        There have been a large number of investigations concerning the
    concentration of lead in natural surface waters. From the data
    available, Livingstone (1963) estimated that the global mean lead
    content in lakes and rivers is 1-10 g/litre. Although this estimate
    includes man-made pollution, it probably still represents a fair
    approximation of natural conditions since water flowing through the
    ecosystems has a considerable self-cleaning capacity.

        The concentration of lead in sea water has been found to be lower
    than in freshwaters. Tatsumoto & Patterson (1963) report
    0.08-0.4 g/litre in seawaters off the coast of California. In deep
    waters the concentration was even lower. According to Chow (1968)
    surface waters off Bermuda, which are free from continental
    influences, have lead concentrations averaging 0.07g/litre, while
    central Atlantic waters contain an average of 0.05 g/litre. Although
    there seem to be somewhat higher lead concentrations in the surface
    waters of the Pacific and the Mediterranean, compared with the central
    Atlantic, the concentrations at depths below the 1000-m level are very
    similar, i.e. around 0.03-0.04 g/litre (Chow, 1968).

    3.1.4  Air

        The atmospheric concentration of lead measured at points most
    remote from civilization is of the order of 0.0001-0.001 g/m3
    (Jernigan et al., 1971; Chow et al., 1969; Egorov et al, 1970;
    Murozumi et al., 1969). The sampling sites in these studies were
    mainly over remote areas of oceans and over Greenland. Patterson
    (1965) estimated from geochemical data that the concentration of lead
    in air of natural origin is about 0.0006 g/m3. If that is a correct
    estimate, even the air over uninhabited, remote, continental areas may
    be contaminated by human activities. For example, Chow et al. (1972)
    reported that the concentration of lead in the air over remote,
    uninhabited mountains of southern California had a concentration of
    0.008 g/m3.

    3.1.5  Plants

    Lead occurs naturally in all plants, as well as in soil, air, and
    water. Extremely variable concentrations of lead in plants have been
    reported but nevertheless, certain generalizations have been made.
    Warren & Delavault (1962) have concluded that the normal concentration
    of lead in leaves and twigs of woody plants is 2.5 mg/kg on a dry
    weight basis. For vegetables and cereals they estimated normal
    concentrations to be 0.1-1.0 mg/kg dry weight. Mitchell (1963) found
    that the usual concentration of lead in pasture grasses was 1.0 mg/kg
    dry weight. These figures should be multiplied by a factor of 20 to
    convert concentration on a dry weight basis to an ash weight basis.

    3.1.6  Environmental contamination from natural sources

        The contribution of natural sources of lead to lead concentrations
    in the environment is small. As regards exposure of man, these sources
    are negligible. Through various breakdown processes, rocks yield lead
    which is transferred to the biosphere and the atmosphere and
    ultimately back to the earth's crust in the form of sedimentary rocks.
    Soluble lead has for thousands of years entered the oceans with river
    discharges, and the amount has been estimated by Patterson (1965) at
    some 17 000 tonnes per year. Sources contributing to airborne lead are
    silicate dusts, volcanic halogen aerosols, forest fires, sea salts
    aerosol, meteoric and meteoritic smoke, and lead derived from the
    decay of radon. The last mentioned source generates the lead isotope
    210Pb in trace amounts, the mean air residence time of which has
    been calculated to be about four weeks; the radioactive half-life is
    22 years (Hill, 1960).

    3.2  Production of Lead

    3.2.1  Lead mining

        Lead is produced from ores and recycled lead products. Lead occurs
    in a variety of minerals the most important of which are galena (PbS),
    cerrusite (PbCO3) and anglesite (PbSO4). Galena is by far the most
    important source of primary lead. It occurs mostly in deposits
    associated with other minerals, particularly those containing zinc.
    Mixed lead and zinc ores account for about 70% of total primary lead
    supplies. Ores containing mainly lead account for about 20% and the
    remaining 10% is obtained as a by-product from other deposits, mainly
    zinc and copper-zinc deposits (Federal Institute for Minerals Research
    and German Institute for Economic Research, 1972). The proportions of
    various metals may differ in the ores of different countries. Silver
    is the most important of the other metals frequently present in lead
    deposits but copper may also be present in concentrations high enough
    to be commercially important. Other minor constituents of lead ores
    are gold, bismuth, antimony, arsenic, cadmium, tin, gallium, thallium,

    indium, germanium, and tellurium. The lead content of ores is
    comparatively low, i.e. 3-8%, but even ores with lower lead contents
    may be commercially valuable.

        The level of world mine production of lead concentrates from ores
    has increased in recent years. According to the International Lead and
    Zinc Study Group and the World Bureau of Metal Statistics, the world
    mine production of lead (lead content) was about 3.6 million tonnes in
    1975, as compared with about 2.6 million tonnes in 1965. These figures
    include production estimates for socialist countries with a planned
    economy made by the World Bureau of Metal Statistics. The most
    important lead mining countries, producing over 100 000 tonnes each in
    1975, were Australia (10% of the total world output), Bulgaria (3%),
    Canada (9.6%), China (3.8%), Mexico (4.5%), Peru (5.5%), United States
    of America (16%), USSR (14.5%), and Yugoslavia (3.5%). In addition,
    some other countries had a production of over 2% of the world total,
    e.g. Ireland, Japan, Democratic People's Republic of Korea, Morocco,
    Poland, Spain, and Sweden. There are about 40 countries producing only
    small amounts each, making together only some 12% of the world
    production. One estimate of proven lead reserves of the world is 93
    million tonnes of lead metal content. (Federal Institute for Minerals
    Research and German Institute for Economic Research, 1972.)

    3.2.2  Smelting and refining

        Smelting and refining is classified as primary or secondary, the
    former producing refined lead from concentrates (primary lead); the
    latter recovering lead from scrap (secondary lead). The raw materials
    for secondary lead are process (new) scrap arising during
    manufacturing processes, and recycled (old) scrap which arises when
    lead-containing manufactured goods are discarded. Old material makes
    up the bulk of the scrap, the most important source being storage
    batteries, which account for 70-80% of the total supply of scrap.

        Secondary lead accounts for about half the consumption in the
    United States of America and it has been estimated that about 35% of
    the total world lead supply comes from secondary sources (Federal
    Institute for Minerals Research and German Institute for Economic
    Research, 1972). Table 2 gives the production of lead ore, the total
    metal production, and the consumption of some industrialized
    countries.


        Table 2.  Lead production and consumption in some industrialized countries (kilotonnes)a
                                                                                                                      

    Country                 Lead ore production              Metal production                Consumption
                            (metal content)                                                  (refined metal)
                                                                                                                     
                            1973      1974     1975b         1973      1974     1975b        1973      1974     1975b
                                                                                                                      

    EUROPE                  1134      1134      1069         2054      2115      1871        2118      2125      1831
        Belgium                -         -         -           98        95       103          52        64        54
        Bulgaria             105       110       108          100       105       108          80        85        91
        Denmark                -         -         -           13        15        13          19        23        20
        France                25        24        22          186       178       150         214       199       188
        Germany, Federal
        Republic of           40        35        37          300       319       260         290       260       210
        Ireland               53        34        55            -         -         -           1         3         2
        Italy                 27        24        27          100       112        70         234       242       200
        Netherlands            -         -         -           25        26        20          38        41        38
        Poland                70        70        72           68        70        66          87        90        40
        Spain                 64        65        58          120       102        85         121       116        90
        Sweden                74        73        69           42        41        37          34        36        32
        UK                     -         -         -          265       277       229         282       266       238
        USSR                 570       590       504          640       660       600         600       620       544
        Yugoslavia           106       109       117           97       115       130          66        80        84
                                                                                                                      

    AFRICA                   223       183       178          116       117        93          65        66        75
        Morocco               90        86         -            1         1         -           -         -         -
        South Africa          63        55        53           64        64        49          27        31        39
                                                                                                                      

    AMERICA                 1430      1412      1379         1666      1677      1565        1718      1706      1339
        Canada               388       314       348          187       127       172          69        63        55
        Mexico               168       169       163          177       204       179          88        83        74
        Peru                 199       201       185           83        80        72          10         9        10
        USA                  570       616       575         1100      1128      1008        1423      1374      1027
                                                                                                                      

    Table 2.  (Cont'd)
                                                                                                                      

    Country                 Lead ore production              Metal production                Consumption
                            (metal content)                                                  (refined metal)
                                                                                                                     
                            1973      1974     1975b         1973      1974     1975b        1973      1974     1975b
                                                                                                                      


    ASIA                     273       284       291          413       423       395         457       412       386
        Democratic Republic
          of Korea            90       100       100           60        65        60          20        20        20
        Japan                 53        44        51          228       228       195         267       217       186
        People's Republic
          of China           130       140       140          125       130       140         170       175       180
                                                                                                                      

    OCEANIA                  396       360       384          221       225       191          82        79        75
        Australia            396       360       384          221       225       191          74        72        68
                                                                                                                      

    Other countries           55        53        48          102       108        88         189       203       233
                                                                                                                      

    TOTALS                  3617      3569      3497         4642      4723      4260        4883      4882      4154
                                                                                                                      

    a  Sources: International Lead, Zinc Study Group, and World Bureau of Metal Statistics.
    b  Estimated.
    

    3.2.3  Environmental pollution from production

        Mining, smelting, and refining, as well as the manufacture of
    lead-containing compounds and goods, can give rise to lead emissions.
    According to a study of the industrial sources of air pollution by
    lead in the USA, Davis (1973) reported that 9% of the total of 18 000
    tonnes generated from such sources was attributable to the production
    of primary lead.

        Smelters of lead ores are well known to create pollution problems
    in local areas. Their influence on the surrounding air and soil
    depends to a large extent on the height of the stack, the trapping
    devices in the stacks, the topography, and other local features. The
    emissions can cover a considerable area. The zone of air pollution for
    one large smelter in the USA extended to approximately 5 km from the
    smelter while soil contamination extended as far as 10 km (Landrigan
    et al., 1975b). The larger area of the zone of soil pollution compared
    to the zone of air pollution probably was due to the fact that current
    emission control devices are more effective than earlier ones used to
    be. The opposite situation was found around the Mezica mine and
    smelter in Yugoslavia (Djuric et al., 1971; Kerin, 1972, 1973). In
    this case, the zone of air pollution extended as far as 10 km from the
    smelter stack. Soil was grossly contaminated (>200 mg/kg) as far away
    as 7 km. There was also heavy pollution of water courses through
    effluents.

        Secondary smelters producing lead from scrap are comparatively
    small, numerous, and frequently situated close to human settlements.
    Several studies showed that pollution in the surroundings of such
    smelters had been severe enough to produce an increase in the intake
    of lead by people living nearby (section 5.1.1).

    3.3  Consumption and Uses of Lead and its Compounds

        Figures for the consumption of lead are available for most
    industrialized countries. The estimated total world consumption of
    lead in 1975 was about 4.1 million tonnes (Table 2). The use of lead
    is greatly influenced by the growth of the automobile industry which
    in 1974 took about 56% of total consumption. Table 3 is compiled from
    statistics of lead consumption for the Federal Republic of Germany,
    France, Italy, Japan, the United Kingdom, and the United States of
    America. There has been a notable increase in the consumption for
    batteries over the period 1969-1974.

    3.3.1  Storage battery industry

        The manufacture of electric storage batteries is responsible for
    the largest consumption of lead (Table 3). This industry uses both
    metallic lead in the form of a lead-antimony alloy, and lead oxides in
    about equal proportions. The metallic lead is in the grids and lugs,

    while the oxides, litharge (PbO), red lead (Pb304), and grey oxide
    (PbO2), are used in the active material that is pasted on the
    plates. The demand for lead batteries decreased in 1974 and 1975
    concomitantly with the decline in total consumption (Table 2) as a
    result of the economic recession in several of the major lead-
    producing countries. However, the fall in the demand for batteries has
    also been attributed to the longer life-time of batteries, (Stubbs,
    1975) which in 1967 was considered to be about 29 months (US Bureau of
    Mines, 1969) but according to Stubbs is, at present, close to 4 years.
    The battery industry also constitutes the major source of lead for
    secondary lead production. It has been estimated that up to 80% of the
    lead in storage batteries is recovered at secondary smelters
    (Ziegfeld, 1964).

    Table 3.  Percentage of total lead consumption by different
              industries in six major industrial countries
                                                              

    Industry                 1969a          1974b
                                                              

    Batteries                35.9           44
    Alkyllead                12.0           12.0
    Cable sheathing          10.9            9.2
    Chemical pigments        10.9           12.0
    Alloys                    8.1           10.8
    Semi-manufacturers       16.5           12.0
                                                              

    a  Federal Institute for Minerals Research and German Institute
       for Economic Research, 1972.
    b  Based on data provided by Stubbs, R. L., Lead Development
       Association, London.


        The lead battery is likely to retain its position as a convenient
    source of electricity in the foreseeable future. The nickel-cadmium
    battery does offer some advantages but is about three times more
    expensive. Better battery design, improvements in the electrical
    systems in cars and lower mileages because of higher gasoline costs
    are factors that may retard the growth rate for lead consumption by
    the battery industry. New applications for batteries may, on the other
    hand, increase demand.

    3.3.2  Alkyllead fuel additives

        Alkyllead compounds have been in use as anti-knock additives in
    gasoline for almost 50 years. Use of these compounds (almost
    exclusively tetraethyllead and tetramethyllead) increased steadily up
    to 1973 (Table 4). In 1973, the world consumption of refined lead for

    the manufacture of lead additives was about 380 000 tonnes
    (International Lead and Zinc Study Group, 1976). The moderate decrease
    in consumption in 1974 was almost entirely attributable to a decrease
    of 22 000 tonnes in the use of lead for gasoline additives in the USA.
    A further decline in the consumption was estimated in the USA in 1975,
    amounting to some 50 000 tonnes (Table 4); thus, the consumption in
    1975 declined by 30% in comparison with the 1973 consumption (Stubbs,
    1975). In the USA, the manufacture of alkylleads is, after batteries,
    the largest lead consuming industry. By comparison, lead additives
    make up only 6% of the European market for lead (International Lead
    and Zinc Study Group, 1973). The decrease in the use of lead for fuel
    additives is likely to continue in the latter half of the 1970s as
    more cars fitted with catalysts requiring lead-free gasoline will come
    into use, The regulations on the maximum permissible concentrations of
    lead in gasoline will further affect the consumption of lead in fuels.
    The US Environmental Protection Agency's reduction programme aiming at
    0.13 g of lead per litre of gasoline by 1 January 1979 was ratified in
    March 1976 by the US Court of Appeals. The maximum permissible level
    in the Federal Republic of Germany has been 0.15 g of lead per litre
    since 1 January 1976, and in Japan has been, 0.31 g of lead per litre
    since July 1971. Some European countries introduced limits of 0.4 g of
    lead per litre (e.g. Austria, Norway, Sweden, Switzerland) but most
    European governments have deferred their decision because of the
    economic implications of lowering the lead content (International Lead
    and Zinc Study Group, 1976).

    Table 4.  Consumption of refined lead for the manufacture of
              alkylleads (kilotonnes)a
                                                                     

    Country                          1972    1973     1974     1975b
                                                                     

    USA                               253     249      227       175
    Europe: (total)                  (87)    (89)     (89)      (91)
      France                           13      14       14        14
    Germany, Federal Republic of        9       9       10         9
      Italy                            15      12       10        10
      United Kingdom                   50      54       56        58
    Others                          n.a.b     40b      40b       35b
                                                                     

    Total                             340     378      357       301
                                                                     

    a  From: International Lead and Zinc Study Group, 1976
    b  Estimated data; n.a.=not available.

    3.3.3  Cable industry

        The relative importance of the cable industry as a lead consumer
    has declined considerably (Table 3), mainly owing to the introduction
    of plastic sheathing/insulation. However, the total amount of lead
    used is still notable (Table 5). The use of lead in cable production
    is comparatively greater in Europe and several developing countries
    than in the United States of America. Alloys used for cable sheathing
    contain small amounts of many other elements including cadmium,
    tellurium, copper, antimony, and arsenic.

    3.3.4  Chemical industry

        Although a wide range of lead pigments are still produced they are
    increasingly being substituted by other, less toxic, pigments. Red
    lead (minium) is used extensively in the painting of structural steel
    work and lead chromate is often used as a yellow pigment. The use of
    lead for pigment manufacture in 1974 is given in Table 5.

        Lead arsenate was, at one time, an important insecticide but is
    now little used and current consumption figures are not available.

    Table 5.  Consumption of lead in cables and pigments in five
              industrial countries in 1974 (kilotonnes)a
                                                             

    Country                          Cable         Pigments
                                                             

    France                             40             32
    Germany, Federal Republic of       52             80
    Italy                              50             47
    Japan                              21             50
    United Kingdom                     44             35
                                                             

    Total                             205            244
                                                             

    a  Data from International Lead Zinc Study Group statistics.


        The use of lead for the manufacture of alkyllead additives was
    discussed in section 3.3.2. The petroleum industry also uses a small
    amount of litharge dissolved in sodium hydroxide solution to remove
    sulfur compounds in the refining of petroleum.

    3.3.5  Miscellaneous

        Industries producing semi-manufactured components account for an
    important proportion of the total consumption. The surface of lead
    oxidises readily and is then very resistant to corrosion. The building
    and construction industries use lead sheet for roofing and other
    flashings, wall cladding, and sound insulation. Lead also forms alloys
    readily and is used in solder, bearing metals, brasses, type metal,
    collapsible tubes, and for radiation shielding. The ammunition
    industry is another major consumer of lead. There are many minor uses
    of lead compounds but these account for only a very small proportion
    of total lead consumption.

    3.3.6  Environmental pollution from consumption and uses of lead

        The combustion of alkyllead additives in motor fuels accounts for
    the major part of all inorganic lead emissions. The consumption of
    lead for the manufacture of alkylleads was estimated at 380 000 tonnes
    in 1973 and 300 000 tonnes in 1975 (section 3.3.2). Of this amount,
    over 70% is like to enter the environment immediately after
    combustion, the rest being trapped in the crank case oil and in the
    exhaust system of the vehicles (Davis, 1973; Huntzicker et al., 1975).
    Moreover, part of the lead retained in the lubricating oil will enter
    the environment through different pathways (section 3.4). The degree
    of pollution from the combustion of alkyllead naturally differs from
    country to country, depending on the car density. The importance of
    alkyllead combustion is exceptionally high in the USA, where 20% of
    the total lead consumed is for the manufacture of alkyllead compounds,
    the corresponding values in 1969 being only 5% for France and 11% for
    Italy and the United Kingdom. The estimated total world emissions from
    this source were, according to the figures mentioned above, at least
    266 000 tonnes in 1973 and 210 000 tonnes in 1975.

        In the study by Davis (1973) on lead emissions into the air from
    industrial sources in the USA, 11% (1900 tonnes) was attributed to the
    processing of alkyllead additives. The manufacture of storage
    batteries emitted smaller amounts (480 tonnes) and emissions were
    still smaller in the production of lead oxide, lead pigments, type
    metal, solder, etc. The amounts of effluent from these industries were
    not studied. The dispersion of lead through the exhausts of workrooms
    should also be considered. These emissions although not very large may
    still contribute significantly to the pollution of the surrounding
    areas. The possibility of contamination of the home environment
    through working clothes should be borne in mind.

        The magnitude of the pollution arising from the vast number of
    lead containing items that are subjected to weathering or are
    decomposed in the course of time is difficult to appraise. According
    to one estimate, about 50% of paint is removed from surfaces protected
    by lead pigments in a period of about seven years before re-painting

    (Patterson, 1965). Heavy contamination of the dust and soil around
    houses painted with lead paints has been consistently reported (Ter
    Haar & Aranow, 1974).

        Only an unknown, but probably small fraction of the lead used in
    metallic form for the production of sheeting, cable, printing metal,
    etc. is ever released into the environment. Contamination of domestic
    water supplies, foods, and beverages resulting from the use of lead
    pipes, PVC pipes, glazed ceramics, and from cans with lead containing
    solders may under certain conditions be hazardous to man's health
    (sections 5.1.2 and 5.1.4).

        The lead content in tobacco has been attributed to lead residues
    present in the soils of tobacco fields as a result of the former use
    of lead arsenate as an insecticide (section 5.1.4).

    3.4  Waste Disposal

        A substantial part of lead wastes are remelted in secondary
    smelters (see section 3.2.2).

        Municipal incinerators have recently been investigated for lead
    emissions. An unknown proportion of the non-recycled, lead containing,
    consumer products, e.g. collapsible tubes, bottle caps, cable scrap,
    battery casings, and products painted with lead pigments, are
    incinerated. Depending on the type of furnace and on purification
    devices, these emissions may be considerable (Davies, 1973; Mattsson &
    Jaakkola, 1974).

        Waste lubricating oil has been contaminated through the combustion
    of lead alkyls. Over 50% of the oil is dumped or used as road oil. In
    1970, the total amount of waste oil generated in the USA was about
    2400 million litres. Waste crankcase oil contains about 1% lead. Thus,
    the estimated amount of lead discharged into the environment from this
    source in the USA was nearly twice the amount originating from, for
    instance, the production of primary lead (Davis, 1973).

        The extent of environmental pollution by lead arising from the
    incineration of sewage and sludge is not known.

    3.5  Miscellaneous Sources of Environmental Pollution

        When studying all industrial sources emitting lead into air, Davis
    (1973) reported that out of a total of 18 000 tonnes, copper smelting
    accounted for 8% and the production of steel and iron another 8%.
    Smaller amounts were generated in the production of primary zinc and
    also in the production of cement.

        Coal contains small amounts of lead with a wide range of
    concentrations in different coals. Concentrations found by Abernethy
    et al. (1969) in coal from various districts in the USA ranged from
    0.6 to 33.1 mg/kg. According to Patterson (1965) about 5% of the ash
    leaving boilers as stable fly-ash aerosols is made up of small
    particles of a few micrometres. This silicate matter contains about
    100 mg of lead per kg. Large quantities of coal are burnt to produce
    steam in power stations, steel works, and in manufacturing industries.

        Small amounts of lead are generated from burning oil, which also
    has a very broad range of lead concentrations. The average
    concentrations in oil appear to be below 0.5 mg/kg (Davis, 1973). The
    possible future use of sewage sludge as fertilizer is discussed in
    section 4.

    4.  ENVIRONMENTAL TRANSPORT AND DISTRIBUTION

        From a mass-balance point of view, the transport and distribution
    of lead from stationary or mobile sources into other environmental
    media is mainly through the atmosphere. Large discharges may also
    occur directly into natural waters and on to the land but, in such
    cases, lead tends to localize near the points of discharge owing to
    the very low solubility of the compounds that are formed upon contact
    with soil and water. The mass transfer of lead from air to other media
    is as yet poorly defined and the various mechanisms involved in the
    removal of lead from air are not fully understood. Although some data
    indicate that an important proportion of the lead may be removed
    through sedimentation (Atkins, 1969) the most efficient clearing
    mechanism is probably rain (Ter Haar et al., 1967). In a study of the
    concentration of lead in rainfall at 32 stations in the United States
    of America the average was 34 g/litre (Lazrus et al., 1970). Most of
    these data were collected in areas with a high population density.
    Over rural areas of the USA the concentration was found to be
    approximately 18 g/litre (Ter Haar et al., 1967).

        Lead is rapidly removed from water when it passes through soil and
    bottom sediments. This is due to the high capacity of organic matters
    to bind the lead firmly. Because of this clearing mechanism, lead
    concentrations in both natural waters and water supplies are generally
    low (section 5.1.2).

    Table 6.  Distribution of lead from motor vehicles in the Los
              Angeles basina
                                                        

    Environmental area             Fractional 
                                     fallout
                                                        

    Retained in car                    0.25
    Near fallout                       0.40
    Far fallout                        0.08
    Airborne                           0.24
    Unaccounted for                    0.03
                                                        

    a  Adapted from Huntzicker et al., 1975.


        An attempt was made to account for the lead emitted by automobiles
    in the Los Angeles Basin (Huntzicker et al., 1975) which is an area of
    exceptionally dense motor traffic. Limited environmental monitoring
    data tended to confirm the approximate correctness of the
    calculations. The transport pattern was classified as "near fallout",
    "far fallout" and "airborne". "Near fallout" was defined as the
    deposition in the immediate vicinity of roadways. "Far fallout" was

    defined as the fallout away from roadways, but within the basin, and
    "airborne" designated small particles carried away from the basin and
    ultimately deposited elsewhere. The data are shown in Table 6 and
    indicate that most of the emission was deposited within the basin. The
    fallout figures are calculated from the estimated behaviour of the
    airborne particles based on particle size distribution. If these
    results are approximately valid for other metropolitan areas, soil and
    water pollution from automobile emission fallout is predominantly
    limited to the immediate metropolitan area. The particles carried away
    from the area by air transport are probably widely dispersed and
    diluted since the atmospheric retention time of small particles is
    probably fairly long. It has been estimated that the residence time of
    airborne particles ranges from 6 days to 2 weeks in the lower
    troposphere and from 2 to 4 weeks in the upper troposphere (SCEP,
    1970). Residence time will vary with a number of factors such as wind
    currents and rainfall. Yamamoto et al. (1968) demonstrated that
    atmospheric turbidity varied inversely with rainfall, owing to the
    washout effect of rain.

        In spite of the great dilution of airborne lead that occurs during
    transport from centres of human activity, there is evidence indicating
    that a long-term global accumulation of lead has occurred. This long-
    term accumulation has been studied in glacial ice and snow deposits.
    Studies in Greenland showed that ice formed in about 1750 had lead
    concentrations 25 times greater than ice estimated to have been formed
    in about 800 B.C. From 1750, the concentration increased steadily to
    about 1940. From 1940 to the present day, the rate of increase has
    risen even more sharply. The most recent ice layers examined (about
    1968) had a concentration 400 times greater than the natural
    background. Similar studies in the region of the Antarctic have also
    shown a rise, but it has not been so dramatic (Murozumi et al., 1969).
    Jaworowski (1968) conducted studies of Polish glaciers similar to
    those conducted in Greenland. He observed an approximate 16-fold
    increase in the lead concentration over the past 100 years.
    Chronological increases in the lead content of Swedish mosses have
    also been reported from 1860 to 1968 (Ruhling & Tyler, 1968). These
    increases, about 4-fold in the past hundred years, were thought to
    reflect first the increase in coal combustion and later the
    introduction of leaded gasoline.

        The transfer of air lead to the biota may be direct or indirect.
    For plants, the fallout contribution may be direct via the above
    ground parts, or it may be indirect by way of the soil. The pattern
    and degree of lead accumulation appears to be substantially influenced
    by the state of growth. Mitchell & Reith (1966) found that the lead
    content of certain plants increased 10-fold or more from the period of
    active growth to the time when growth ceased in the late fall. Some
    trees apparently have the capacity to accumulate high concentrations
    of lead. Kennedy (1960) reported that the tips of larches, firs, and
    white pines contained 100 mg of lead per kg dry weight, when grown in

    the lead mining areas of Idaho where the soil lead concentration was
    20 000 mg/kg. The total concentration of lead in soil does not
    correlate well with the concentration in the plant but a correlation
    does exist when adjustment is made for the degree to which the soil
    lead can be brought into an aqueous solution of ammonium lactate and
    acetic acid (Kerin et al., 1972).

        Thus, there is no doubt that plants acquire lead from the soil and
    air, but interspecies differences are prominent (Dedolph et al.,
    1970). It does not seem likely, however, that lead deposited on the
    leaves of plants transfers readily to other parts. Thus, Ter Haar
    (1970) showed in greenhouse studies that atmospheric lead at
    1.45 g/m3 did not influence the lead content of tomatoes, beans,
    carrots, potatoes, wheat, and cabbage heads, but did have an effect on
    the lead content of lettuce and bean leaves.

        Transfer of lead from plants to animals is not well-defined.
    However, the concentration of lead in meat and eggs is quite similar,
    on a wet weight basis, to the concentration found in vegetables and
    grains (Schroeder et al., 1961). There is no evidence of biological
    accumulation proceeding from plants to animals.

        Much remains to be learned about the environmental transport and
    distribution of lead. The potential pathways of lead from air to man
    are indicated in Fig. 1. Special attention should be given to the
    potential transfer of the fallout lead in cities that is washed into
    the sewage systems. Sewage sludge is currently being considered for
    use as fertilizer. Most cities have dual sewage system, i.e., storm
    and sanitary sewers, and it was shown in the report of the US
    Environmental Protection Agency Office of Research and Monitoring
    (1972) that storm runoff is far from being clean and probably warrants
    being treated in many instances. However, lead is not currently viewed
    as a hazard in this case because sludges have a high phosphate content
    which tends to minimize the bio-availability of the lead for plants
    (Chaney, 1973).

        Little information exists with regard to the biotransformation of
    lead by microorganisms in the environment. However, Wong and his
    collaborators (1975) have reported that microorganisms in lake
    sediments can transform certain inorganic and organic lead compounds
    into volatile tetramethyllead. The authors were not able to explain
    completely the pathways of this transformation. A possible mechanism
    for the conversion of trimethyllead acetate into tetramethyllead in
    anaerobic systems was presented by Jarvie et al. (1975), who proposed
    that this takes place through the formation of an intermediate sulfide
    which decomposes into tetramethyllead. There is need for further
    research along these lines.

    FIGURE 1

    5.  ENVIRONMENTAL LEVELS AND EXPOSURES

        In the preceding chapter the general pattern of the environmental
    transport and distribution of lead was described. This chapter is more
    specifically concerned with the different circumstances under which
    people are exposed to lead to a degree that may be hazardous to their
    health.

    5.1  Exposure of the General Population

        The general population is exposed to lead by ingestion of food,
    and water, and by inhalation. In addition, children are exposed by
    eating non-food items, and those working in the lead industries suffer
    exposure over and above their exposure as members of the general
    population. These categories of exposure will be considered
    separately.

    5.1.1  Air

        The highest concentrations of lead in ambient air are found in
    dense population centres. The larger the city, the higher the ambient
    air lead concentration. As one moves away from the centre of the city,
    the concentration falls progressively. For urban stations, an average
    concentration of 1.1 g/m3 has been reported; for non-urban stations
    (near the city) the average was 0.21 g/m3; for stations somewhat
    farther removed it was 0.10 g/m3, and for remote areas,
    0.02 g/m3 (McMullen et al., 1970). Air over streets with heavy
    traffic contained more lead than air over streets with light traffic,
    and considerably more than the ambient air over rural areas.

        There is a clear pattern in this picture, the non-urban sites
    showing less than 0.5 g/m3, while the urban sites have values
    ranging from 1 to 5-10 g/m3. The highest levels have been recorded
    on highways during rush hours, 14-25 g/m3 (WHO Expert Committee,
    1969).

        The results of continuous monitoring for 1971-72, in 27 European
    cities, by 43 uniform sampling stations are summarized in Table 7
    (Commission of European Communities, 1973).

        The ambient air lead levels at 15 national sampling stations in
    Japan in 1973 were 0.30 g/m3 for the average 24-hour value,
    2.72 g/m3 for the maximum 24-hour value, and 0.01 g/m3 for the
    minimum (Environment Agency, Japan, 1975).


        Table 7.  Air lead concentrations in some cities of the European Community (1971-72)a
                                                                                                            

    Location                  Continuous measurements                Traffic-hour measurements
                                                                                                            

    Non-urban                 monthly averages      < 0.5 g/m3      -
                              daily maxima          < 1   g/m3      -
                                                                                                            

    Small cities
       residential areas      monthly averages      < 1 g/m3        -
                              daily maxima          < 2 g/m3
       traffic areas          -                                      monthly averages            < 3 g/m3
                                                                     individual measurements     < 8 g/m3
                                                                                                            

    Metropolitan areas
       residential areas      monthly averages      < 2 g/m3        individual measurements     < 4 g/m3
                              daily averages
                                up to                 8 g/m3
       traffic areas          monthly averages                       monthly averages            < 10 g/m3
                                up to                 6.5 g/m3
                              daily values up to     10 g/m3        single measurements
                                                                       up to                       20 g/m3
                                                                                                            

    a  Data from the Commission of the European Communities (1973).
    

        People who live in close proximity to dense automobile traffic are
    exposed to appreciably higher concentrations than others. In Los
    Angeles, California, where general ambient air levels are unusually
    high, the monthly mean concentration near traffic was as high as
    6.4 g/m3 (US Department of Health, Education and Welfare, 1965).
    This is in contrast to the general ambient air level of 2-4 g/m3
    reported for that city (Tepper & Levin, 1972). There is also a diurnal
    pattern whereby the concentration rises and falls in approximate
    proportion to the vehicular traffic activity (US Department of Health,
    Education and Welfare, 1965; Lahmann, 1969; Heller & Kettner, 1969;
    Chovin et al., 1973). Most studies report that a seasonal variation
    also occurs (Tepper & Levin, 1972; Georgii & Jost, 1971).

        Nearly all air lead measurements in communities have been made
    outdoors. Only a small number of indoor concentration studies are
    available (e.g. Fugas et al., 1973; Yocom et al., 1971; Daines et al.,
    1972). Indoor levels vary from slightly lower than, to about 1/3 of,
    comparable outdoor levels. Higher indoor levels are found only in lead
    industry environments. In the absence of specific data, reference
    should be made to the much more voluminous literature available on the
    penetration of undifferentiated particulate pollution into buildings.
    This was reviewed by Benson (1972). In general, very small particles
    enter buildings readily, and exist there at levels similar to those
    outside. Larger particles, near stationary sources and very close to
    roadways, penetrate buildings less readily.

        Studies of air lead concentrations over a number of years or even
    a decade, at the same or similar locations, have produced quite
    variable results. Occasionally air lead levels have declined as in
    Cincinnati, Ohio (US Department of Health, Education and Welfare,
    1965). This was attributed to greatly decreased coal consumption. The
    US National Air Surveillance Network, which has most of its stations
    in city centres, has shown little change in large cities and variable
    behaviour in smaller cities (NAS-NRC, 1972). Tepper & Levin (1972) and
    Chow & Earl (1970) have shown considerable increases in air lead
    levels at a number of stations in large cities. In 1967, Ott et al.
    (1970) developed a predictive model of increasing automotive pollution
    based on carbon monoxide emission patterns. Since air lead comes
    largely from vehicular sources, this report should be considered when
    changes in air lead with time are evaluated.

        The respiratory uptake of lead from air depends on total lead
    concentration, particle size distribution, particle shape, chemical
    composition, physicochemical properties, and respiratory volume
    (section 6.1.1).

        The particle size distribution of lead in ambient air has been
    studied by a number of investigators. As regards pulmonary deposition
    and absorption, the mass median equivalent diametera rather than the
    microscopic particle size is considered appropriate. Robinson & Ludwig
    (1967) reported a mass median equivalent diameter of 0.25 m, with 25%
    of the particles smaller than 0.16 m and 25% larger than 0.43 m.
    These data were representative of a variety of areas in Los Angeles,
    the San Francisco Bay area, Cincinnati, Chicago, and Philadelphia.
    There was little variation from one city to another. Other studies
    conducted in the United States of America gave similar results
    (Mueller, 1970; Robinson et al., 1963). More recently Lee et al.
    (1972) have reported mass median equivalent diameters of 0.42-0.69 m
    for six United States cities. Jost et al. (1973) reported that 50% of
    particles had mass median equivalent diameters of less than 0.4 m and
    20% of more than 0.5 m.

        Not much is known about the chemical form in which general ambient
    air lead occurs. Ter Haar & Bayard (1971) studied the composition of
    airborne lead particulates with an electron microprobe analyser. They
    studied particulates collected directly from the exhaust pipe of a car
    and also from air at various distances from a busy highway. Their
    results (Table 8) indicate that car exhaust lead is initially composed
    of halides that are converted to oxides, sulfates, and carbonates with
    aging.

        Alkyllead vapours occur in ambient air because some of the
    alkyllead in gasoline escapes combustion. Purdue et al. (1973) have
    recently reported on the organic lead concentration in an underground
    parking garage and in the general ambient air of six major cities in
    the USA. In the parking garage, the total air lead level was
    11.7 g/m3, of which 16.7% was organic lead. In the six major
    cities, the organic lead concentration was about 10% of total lead.
    There is some uncertainty as to the accuracy of the organic lead data
    since the concentrations found approached the detection limit of the
    method. In another study in Los Angeles, using a different method for
    trapping organic lead, approximately 2% of the lead was found to be
    organic (Snyder, 1967). Differences found in the concentration of
    organic lead relative to particulate lead can perhaps be explained in
    part by differences in proximity to the emitting source. Laveskog
    (1971) made repeated studies over several months on the presence of
    organic lead in the air at a number of locations in Stockholm. The

              

    a  Mass median equivalent diameter = equivalent diameter above and
       below which the weights of all larger and smaller particles are
       equal.

    levels were uniformly low (under 10% of the total lead) except for 2
    brief periods. These occurred near a gasoline station, and were
    attributed to the evaporation of spilled fuel. Colwill & Hickman
    (1973) verified this concept in similar studies near gasoline handling
    installations.

        The air in the vicinity of lead smelters may be appreciably
    polluted and thus can affect the general population. A detailed study
    has recently been made of the environmental impact of a large ore
    smelter near El Paso, Texas (Landrigan et al., 1975b). The annual mean
    concentration in 1971 was approximately 80 g/m3 in the immediate
    vicinity of the smelter and fell off rapidly, attaining a near-
    background level of 1 g/m3 about 5 km away. Approximately 42% of
    the particle mass had an aerodynamic diameter of less than 2 m. In a
    similar study conducted near a smelter and a mine in the Meza Valley,
    Yugoslavia, the air lead concentration, 10 km away, ranged from 1.3 to
    24.0 g/m3 (Djuric et al., 1971). Five air sampling stations were
    located at various distances within 10 km of the smelter stack. About
    45% of the particles had a diameter equal to or less than 0.3 m and
    an additional 25% were in the range of 0.31-0.8 m. Although not
    specified, it is probable that these particle sizes were expressed as
    aerodynamic diameters, since the authors refer to this range as being
    of optimum size for absorption. The extensive pollution in some
    directions was probably due to the topography. The Meza Valley is only
    a few hundred metres wide and depending on wind direction, the lead
    particles can be conveyed long distances.

        Roberts et al. (1974) reported the lead levels in air, dust, soil,
    and in the blood of children living near two secondary smelters in
    totonto. Monthly mean air lead levels (1.0-5.3 g/m3) were about
    twice those encountered in other parts of the city, but were subject
    to greater daily variation. Lead levels in dustfall of
    200-1500 mg/m2/month, and soil levels of 16 000-40 000 mg/kg of soil
    near the smelter declined to background levels within 300-400 m of the
    stacks. From 13 to 30% of the children living within 300 m of the
    stacks had blood lead levels of over 40 g/100 ml.

        Pollution of the surrounding country by a secondary lead smelter
    has been reported to have affected the lead absorption of adults
    living 1-4 km from the main emitter (Nordman et al., 1973). Air lead
    concentrations were not reported. The dustfall lead concentrations
    ranged from 10 mg/m2/month (4 km from the chimney) to
    200 mg/m2/month (200 m from the chimney). There was a correlation
    between blood lead concentration and degree oferythrocyte ALAD
    inhibition on the one hand and the proximity of habitation to the
    smelter on the other. A correlation between Pb-B values and monthly
    dustfall lead was also demonstrated.

        Table 8.  Composition of airborne lead particles by electron microprobe analyser.a
                                                                                        

                                       Percentage of total
                                        particles counted

    Sample           PbCl2     PbBr2    PbBrCl      Pb(OH)     Pb(OH)    (PbO)2    (PbO)2
                                                    Cl         Br        PbCl2     PbBr2
                                                                                        

    Exhaust pipe
      Zero time       10.4      5.5      32.0         7.7       2.2       5.2        1.1
      18 h             8.3      0.5      12.0         7.2       0.1       5.6        0.1

    Eight Mile Road
      Near road       11.2      4.0       4.4         4.0       2.0       2.8        0.7
      400 yards       10.5      0.7       0.6         8.8       1.1       5.6        0.3

    Rural site         5.4      0.1       1.6         4.0       -         1.5        -
                                                                                        

                                       Percentage of total
                                        particles counted

    Sample           (PbO)2    PbCO3    Pb3         PbOx       (PbO)2    PbO       PbSO4
                     PbBrCl             (PO4)2                 PbCO3     PbSO4
                                                                                        

    Exhaust pipe
      Zero time       31.4      1.2       -           2.2       1.0       -          0.1
      18 h             1.6     13.8       -          21.2      29.6       0.1        -

    Eight Mile Road
      Near road        2.0     15.6       0.2        12.0      37.9       1.0        2.2
      400 yards        0.6     14.6       0.3        25.0      21.3       4.6        6.0

    Rural site         1.0     30.2       -          20.5      27.5       5.0        3.2
                                                                                        

    a  From: Ter Haar & Bayard (1971).
    
    5.1.2  Water

        Man's exposure to lead through water is generally low in
    comparison with exposure through air and food (WHO Working Group,
    1973). The lead concentration in the water supplies of most of the 100
    largest American cities, as determined in 1962, ranged from a trace to
    62 g/litre (Durfor & Becker, 1964). Since 1962, continuous monitoring
    of American water supplies has indicated that the US Public Health
    Service prescribed limit of 50 g/litre has not been exceeded (NAS-
    NRC, 1972). In another study, only 41 out of 2595 samples of tap water
    contained more than 50 g/litre, and 25% contained no measurable
    amount of lead (McCabe, 1970).

        Under some circumstances, the concentration of lead in drinking
    water can become extremely high. Gajdos & Gajdos-Trk (1973)
    described two cases of severe clinical lead poisoning attributable to
    a municipal water supply that contained lead levels of 2.6 mg/litre.
    In another case, in rural Scotland, four people developed clinical
    lead poisoning and others showed biochemical evidence of grossly
    elevated lead exposure (Goldberg, 1974). The concentration of lead in
    the domestic water supply was 2-3 mg/litre. In this case, the reason
    for the extreme contamination was that the water was stored in lead
    tanks. In another study, conducted in Glasgow, Scotland, it was shown
    that lead pipes in the plumbing of homes can also result in high
    concentrations of lead in soft water (water low in calcium and
    magnesium) (Beattie et al., 1972a). Homes with both lead-lined water
    storage tanks and lead pipes had the highest concentration. The
    plumbo-solvency of water standing in lead pipes is influenced
    significantly by several factors. The solvency increases about four-
    fold with increasing acidity over the pH range from 6 to 4. Increases
    of a somewhat lesser degree were also noted with increasing alkalinity
    over the range of pH from 8 to 10 (Moore, 1973). The same author also
    pointed out the increasing plumbo-solvency of water with increasing
    temperature and with decreasing calcium concentration. Quite recently
    it was shown that lead concentrations in tap water were highly
    dependent on the volume of water flushed through the system before
    sampling. The concentrations were also considerably lower when a 95/5
    (tin/lead) solder had been used in the copper piping instead of the
    50/50 or 60/40 solders (Wong & Berrang, 1976).

        When water was left standing overnight in plastic pipes, some
    degree of leaching of lead into the water was observed (Heusgem &
    DeGraeve, 1973). The source of lead in this case was probably lead
    stearate which is used as a stabilizer in the manufacture of polyvinyl
    plastics. The problem of plastic pipes has been discussed recently
    (Schaller et al., 1968; Packham, 1971). Packham did not feel that
    there was a hazard associated with the use of such material in
    domestic water supply systems. But more study is needed, particularly
    of situations in which water stands in the pipes for prolonged
    periods.

        Lead levels in surface and ground waters were recently reviewed by
    a WHO Working Group (1973). Natural surface waters have been reported
    to contain usually less than 0.1 mg/litre (Kopp & Kronen, 1965). In
    unpolluted areas the concentrations are of the order of 1 g/litre or
    less (Zukovickaja et al., 1966). Some rivers in France were recently
    analyzed by Servant (1973) who found that, in the Midi-Pyrenees
    region, the mean concentration of dissolved lead varied from 6.7 to
    10.4 g/litre.

    5.1.3  Food

        The contribution of food to man's exposure to lead has been under
    study for many years, beginning with the study of Kehoe et al. (1933)
    who found lead in every item of food in both industrial and primitive
    societies. The concentration of lead in various items of food is best
    described as highly variable. In fact, there seems to be about as much
    variation within specific items of food as between different
    categories of foods. For example, Schroeder et al. (1961) found that
    the range was 0-1.5 mg/kg for condiments, 0.2-2.5 mg/kg for fish and
    seafood, 0-0.37 mg/kg for meat and eggs, 0-1.39 mg/kg for grains, and
    0-1.3 mg/kg for vegetables.

        Estimates of actual consumption of lead in food and beverages have
    been made using two general approaches. Some investigators have used
    the duplicate portions sampling method. Others have derived
    theoretical intakes based on nutritional tables and known
    concentrations of lead in the dietary components (composites
    technique, see section 2.2.1). The results of studies using the two
    methods are given in Table 9. In general, the composites technique
    appears to yield somewhat higher mean values for adults than the
    duplicate portion technique. There are considerable differences in the
    daily intakes reported from different countries. Whether these
    differences are real or due to factors associated with the methods
    used remains to be assessed. Inadequacies in sampling and in the
    analytical methods used may account for a considerable part of the
    differences; few of the studies cited present any evidence of
    interlaboratory quality control of the analytical assays. Most
    estimates do not specify the age, sex, or level of physical activity
    assumed in arriving at the estimates. These are very important
    determinants of dietary intake. Thus, the calorie requirement for a
    25-year-old male in the United States of America is approximately 2900
    calories, whereas it is only 1900 calories for women, age 35-55
    (Altman & Dittmer, 1968). Horiuchi et al. (1956) were quite aware of
    the vast differences in food intake among different categories of
    adults and between adults and children. They made an effort to take
    these factors into account in developing their estimates of lead
    intake from dietary sources.

        Daily faecal lead excretion can also be used as a means of
    estimating daily lead ingestion, since only approximately 10% of
    dietary lead is absorbed (Kehoe, 1961). This approach, which was used


        Table 9.  Dietary lead intake.
                                                                                                                    

    Method         Age            Sex         Activity      Lead/day (g)           No. of     References
                                                                                   subjects
                                                            range        average
                                                                                                                    

    Duplicate      adult          male        sedentary     120-350      218            9      Kehoe, 1961
      portions     adult          male        sedentary     74-216       113           17      Coulston et al., 1972b
                   21-30 years    4 male      -             237-306      274            5      Thompson, 1971
                                  1 female
                   adult          -           -             4.8-83.0     17.8           -      Schtz et al., 1971
                   adult          male        medium-       119-360      231           35      Nordman, 1975
                                              heavy
                   adult          female      medium        89-305       178           36      Nordman, 1975

                   3 months-                                -            40-210b        8      Alexander et al, 1973
                   8.5 years

    Composites     adult          male        heavy work    -            455            -      Horiuchi et al., 1956
      technique    adult          male        medium        -            299            -      Horiuchi el al., 1956
                   10 years       male                      -            254            -      Horiuchi et al., 1956
                   10 months      male                      -            126            -      Horiuchi et al., 1956
                   18 years       male        medium        -            57-233a        -      Kolbye et al., 1974
                   adult          male        medium        -            139            -      NRC (Canada), 1973
                   adult          male        medium        -            518            -      Lehnert et al., 1969
                   adult          male        medium        -            505            -      Zurlo at al., 1970
                                                                                                                    

    a  See page 52
    b  Ranging from 40 g in a breast-fed infant to 210 g in an 8-year-old child, as calculated using ICRP
    

    by Tepper & Levin (1972) (section 6.1.2.2), presents some uncertainty
    regarding actual absorption and neglects contributions to faecal lead
    from gastrointestinal secretion, which cannot be estimated.

        A factor that is usually ignored is the occurrence of lead in
    various foods at concentrations below the practical detection limits.
    Thus, Kolbye et al. (1974) arrived at different estimates based on the
    assumptions they made regarding whether or not lead was present in all
    items eaten. There was uncertainty as to how to cope with the problem
    of lead concentrations reported as "zero" or "trace" in certain
    samples. When "zeros" and "traces" were accepted as meaning absolutely
    no lead, the estimated daily lead intake was 57.4 g for an 18-year-
    old man. This seemed unduly low, particularly in the light of the fact
    that the faecal lead excretion of normal American women is
    90-150 g/day (Tepper & Levin, 1972). Certain assumptions were
    therefore made regarding the "zeros" and "traces". If it was assumed
    only that "traces" really represented 0.09 mg/kg, the calculated
    intake became 159 g/day. When the additional assumption was made that
    "zero" had a finite value of 0.05 mg/kg, the calculated daily intake
    of an 18-year-old male became 233 g. Another source of error in
    establishing how much is consumed relates to food preparation. Lead
    may be either added to the diet or removed in the course of
    preparation. Both Horiuchi et al. (1956) and the report from the
    British Ministry of Agriculture, Fisheries and Foods (1972) took
    special pains to explain how this problem was handled.


        Published reports on lead levels in wine (Truhaut et al., 1964;
    Zurlo & Griffini, 1973) show that important variations occur from
    sample to sample. Considering ordinary wines there does not seem to be
    any significant difference between white, red, and ros (Truhaut et
    al., 1964). Average lead concentrations of 130-190 g/litre could be
    calculated (range 60-255 g/litre), but even higher mean values
    (299 g/litre) have recently been reported (Boudene et al., 1975).
    Wine therefore is likely to be a substantial source of lead for some
    people, and may account for part of the differences in Pb-B levels
    (section 5.4) and in daily dietary lead intake between various
    countries.

        The concentration of lead in milk is a matter of special concern
    because milk is a major dietary constituent for infants. Human breast
    milk has been reported to contain 12 g/litre (Murthy & Rhea, 1971)
    and <5 g/litre (Lamm & Rosen, 1974). Cow's milk has been reported to
    have a similar concentration, when taken directly from cows for
    analysis; 9 g/litre (Hammond & Aronson, 1964). The concentration of
    lead in processed cow's milk is higher than in human milk or in milk
    obtained directly from cows. The types of processing vary considerably
    as does the degree of apparent lead contamination. Thus whole milk
    concentrations are only moderately elevated. Mitchell & Aldous (1974)
    reported an average of 40 g/litre in whole bulk milk and Kehoe (1961)

    reported 20-40 g/litre for local USA market milk. By contrast,
    evaporated milk and formulas have still higher concentrations.
    Mitchell & Aldous (1974) reported an average of 202 g/litre for
    evaporated milk. Somewhat higher values were reported by Murthy & Rhea
    (1971) (330-870 g/litre) and somewhat lower by Lamm & Rosen (1974)
    (110  11 g/litre).

        A major contribution to the lead content of processed milk as well
    as of other food products appears to be lead solder used in the seams
    and caps of cans. It has been shown that foods preserved in such cans
    frequently have much higher concentrations of lead than do the same
    items packed in glass containers (Mitchell & Aldous, 1974).

        Although plants do not take lead up from the soil readily, fruits
    and vegetables grown in areas exposed to smelter emissions may be
    appreciably contaminated. Kerin (1972) determined lead in the total
    diet of peasants near a smelter and found that the daily ingestion of
    lead with food was 670-2640 g.

    5.1.4  Miscellaneous

        The intake of lead in food, air, and water is a major concern as
    regards the general population because of the pervasive nature of
    these exposures. Another frequent exposure source, smoking, probably
    makes a small contribution to the lead burden (section 5.4.1 ).
    However, surprisingly little information is available concerning the
    concentration of lead in smoking tobacco. Cogbill & Hobbs (1957)
    reported the concentration of lead in two separate brands of
    cigarettes and in a composite sample of five brands. Concentrations
    were 19, 80, and 39 mg/kg at 58%, relative humidity or 21, 84, and
    41 g per cigarette. The amount of lead transferred to mainstream
    smoke was 1.0, 3.3, and 1.9 g per cigarette which represented 4.8,
    3.9, and 6% transfer. Arsenic/lead ratios found in the tobacco
    indicated that the source of lead was probably lead arsenate. At one
    time lead arsenate was used extensively as an insecticide in American
    tobacco fields but other pesticides rapidly replaced it shortly after
    World War II. Residues of lead arsenate have probably persisted in the
    fields and could contaminate plants externally. More recently,
    Szadkowski et al. (1969) reported 0.483  0.267 g of lead per
    cigarette in the total smoke for eight brands of cigarette. This
    represented 19%, of the total lead in the tobacco or 2.6 g per
    cigarette. No distinction was made between mainstream and side-stream
    smokea. Untabulated data from a study by Menden et al. (1972)
    indicated that only about 2% of lead in non-filter types of cigarettes
    was transferred to the mainstream smoke. The average content of lead
    in commercial cigarettes was given as 10.40-12.15 g/cigarette

              

    a  "i.e. the smoke which drills off the burning end of cigarette
       between puffs.

    (Petering & Menden, private communication). Most of the lead was found
    in the ash; the lead content of the sidestream of individual
    cigarettes varied considerably with a maximum value of 16%. Assuming
    an average lead content ranging from 2.5 to 12.2 (Lehnert et al.,
    1967; Szadkowski et al., 1969; Rabinowitz, 1974; Petering & Menden,
    private communication) and a 2% transfer to the mainstream smoke
    (Menden et al., 1972) are fair estimates, and without taking into
    account the possible contribution from the sidestream smoke, a crude
    assessment of the direct inhalation intake of lead from smoking 20
    cigarettes a day would be about 1-5 g.

        Certain other sources of exposure are important. These sources do
    not affect any major segment of the population but collectively they
    no doubt account for the majority of the cases of clinical lead
    poisoning in the general population.

        The presence of high concentrations of lead in illicitly distilled
    whisky occurs commonly in the USA and causes poisoning in adults. The
    condensers used in homemade stills are often discarded automobile
    radiators. These contain substantial amounts of lead in the soldered
    joints. The concentration of lead in the final product frequently
    exceeds 10 mg/litre. The problem of lead poisoning from this source
    exists predominantly in the southeastern parts of the USA where
    illicit whisky production is most common.

        Another source of poisoning is improperly glazed earthenware
    vessels. Improper glazing results in the leaching of lead into the
    vessel, particularly when the contents are acidic. Cases of poisoning,
    both fatal and non-fatal, have been recorded from the use of
    improperly glazed pottery. Klein et al. (1970) reported two cases (one
    fatal) in which apple juice stored in the incriminated vessel for 3
    days contained 1300 mg/litre. In another case the ceramic mug
    responsible was used for drinking colaa, pH 2.7 (Harris & Elsea,
    1967). After two hours of standing in the mug, the cola contained lead
    levels of 6.8 mg/litre. It was estimated that this patient drank 3.2
    mg of lead per night in this fashion for two years. Other cases have
    been reported from Yugoslavia (Beritic & Stahuljak, 1961) and from the
    United Kingdom (Whitehead & Prior, 1960). The problem involves the
    storage of acid materials in the vessels. In a test of the leaching of
    lead from commercial and handcrafted pottery, Klein et al. (1970)
    found that 4% acetic acid allowed to stand at room temperature in the
    vessels for 18 hours often acquired concentrations of lead in excess
    of 100 mg/litre. In fact, in more than half of the cases, the
    concentration of lead exceeded 7 mg/litre.

              

    a  A popular carbonated non-alcoholic beverage.

        Another source of lead poisoning in the general population is the
    use of discarded storage battery casings for fuel. There is some
    uncertainty as to whether the cases of poisoning that have been
    recorded (Williams et al., 1933; Gillet, 1955) were due to inhalation
    of lead fumes or to hand-to-mouth transfer of fallout material. The
    prevalence of children in the number of recorded cases supports the
    argument for hand-to-mouth transfer.

        Because of the wide variety of applications of lead, additional
    potential hazards are still being identified. For example, the use of
    lead wire core wicks in candles was only recently called to the
    attention of the USA authorities (Bridbord, unpublished results,
    1973).

    5.2  Exposure of Infants and Young Children

    5.2.1  Soil, dust, and paint

        The young child of pre-school age is exposed to special hazards
    from environmental sources of lead. This is because such children
    frequently exhibit the habit of licking, chewing, or actually eating
    foreign objects. Lead-based paints have long been considered the major
    source of excessive lead intake in young children. Thus, Sachs (1974)
    reported that 80% of patients seen because of evidence of excessive
    lead absorption had a history of eating paint or plaster and in
    another 10% X-ray examination revealed paint in the abdomen. The
    author also was of the opinion that if X-ray examinations had been
    repeated at each visit to the clinic, evidence of paint ingestion
    would have appeared in all patients. A similar view was expressed by
    Chisholm & Harrison (1956). In their series of 105 children whose
    homes were investigated, 102 of the homes contained at least one
    source of paint containing 5% lead or more. Of even greater
    significance was the fact that the painted surfaces identified as
    sources were flaking.

        Other investigators have attempted to assess the importance of
    paint as a source of excessive lead exposure. Griggs et al. (1964)
    found a positive correlation between the presence of elevated urinary
    lead or coproporphyrin and the presence of flaking paint in the homes.
    Nonetheless, in many instances the homes of children with abnormal
    urine had no flaking paint indoors. Unfortunately data were not given
    as to the number of children with abnormal urine and no evidence of
    flaking paint indoors or outdoors. Guinee (1973) reported that in an
    extensive survey of the homes of children having blood lead
    concentrations equal to or greater than 60 g/100 ml, 75% of the homes
    had at least one surface in which the paint contained more than 1%
    lead. Furthermore, children with elevated blood lead concentrations
    were more likely to live in homes where the painted surfaces were
    cracked than children with low blood lead values.

        All of these studies indicate that lead in painted surfaces in
    houses is almost certainly the major source of lead for infants and
    young children. Some other studies suggest that the issue is not that
    clear-cut. Greenfield et al. (1973) reported that, in one study, 18
    out of 19 rural children with elevated blood lead concentrations lived
    in homes having at least one accessible painted surface containing 1%
    or more of lead, whereas paint containing 1% or more of lead could be
    found on accessible surfaces in only 60% of the homes of inner city
    children with excessive lead exposure. The implication is that sources
    of lead other than paint were often responsible for the exposure of
    city children. Two equally rational interpretations are that an
    insufficient number of surfaces were tested in the children's homes or
    that children often spend time in several homes, some of which might
    not have been tested for lead-based paint.

        Studies of sources of lead all too often ignore the fact that
    painted surfaces on the outside of houses are a potential source of
    lead or, for that matter, that the soil surrounding the houses may
    have accumulated substantial concentrations of lead from the
    weathering of outer walls. With regard to the latter, Fairey & Gray
    (1970) reported that the concentration of lead in the soil near homes
    where paediatric lead poisoning had occurred was over 1000 mg/kg in 27
    out of 30 cases. By contrast, only 30 out of 170 soil samples taken
    from yards selected at random (and not associated with cases of lead
    poisoning) had concentrations of lead in excess of 1000 mg/kg.
    Bertinuson & Clark (1973) have reported extremely high soil lead
    values close to residences in the older section of Cincinnati. In one
    case, because the distance across the yard from the base of the house
    to a road with heavy traffic was sufficient, it was possible to assess
    the relative contributions of lead from car exhaust and lead from the
    weathering of the house. The gradient ranged from 12 000 mg/kg
    adjacent to the house, down to 400 mg/kg, about 10 m from the road.
    This suggested that weathering of painted surfaces of the house could
    have been the major source of soil lead in this instance. Although the
    high concentrations of lead in the soil in the vicinity of houses may
    be due to weathering of lead-based paint, it is possible that in many
    cases it is also due to the accumulation of combusted alkyllead from
    car exhaust. In this connexion, recently-reported data of Ter Haar &
    Aranow (1974) are particularly informative. They surveyed the profile
    of lead in soil, extending from the base of 36 urban residences out to
    the street gutters. Eighteen of the residences were of brick
    construction and 18 were of frame construction. In summary form, their
    data were as shown in Table 10. The data reflect the likelihood of the
    major contribution of weathered lead-based paint to soil lead. But
    they also strongly suggest that vehicular sources make a significant
    and sometimes very substantial contribution to soil lead near the
    sidewalks.

    Table 10.  Lead in dirt in Detroit (mg/kg dry dirt)a
                                                                        

    Location                  Painted frame houses     Brick houses
                                                                        
                              Mean   Range             Mean   Range
                                                                        

    Within 0.6 m of house
      front                   2349   (126-17 590)     351   (78-1030)
      back                    1586   (162-4951)       501   (72-2350)
      sides                   2257   (140-7284)       426   (91-1160)
                              1846   (104-7000)       595   (40-2290)

    3 m from house
      front                    447   (58-1530)        156   (39-316)
      back                     425   (149-1410)       200   (72-480)

    Near sidewalk              627   (152-1958)       324   (86-1130)
      curb                     572   (320-1957)       612   (147-2420)
      gutter                   966   (415-1827)      1213   (304-3170)
                                                                        

    a  Adapted from Ter Haar & Aronow (1974)


        Street dust has also been found to contain high concentrations of
    lead. Using recent data from 77 midwestern cities in the USA, it was
    calculated that the concentration of lead averaged 1636 mg/kg dust in
    residential areas, 2413 mg/kg in commercial areas, and 1512mg/kg in
    industrial areas (Hunt et al., 1971).

        In order for soil or street dust to be a significant source of
    lead for man, it is of course, necessary that it be ingested and/or
    inhaled. Evidence regarding the likelihood that young children would
    ingest soil or street dust is extremely fragmentary. However, in a
    recent study of 58 children with increased lead burdens, it was found
    that 37 had a history of eating dirt and sand, compared with 34 eating
    plaster, 20 eating paint flakes, 15 chewing on furniture, 14 chewing
    window sills, and 7 eating wallpaper (Pueschel et al., 1972). Further
    inferential evidence as to the possible significance of soil and dust
    as a source of lead is to be found in the recent Smeltertown episode
    near El Paso, Texas, referred to earlier (Landrigan et al., 1975b).
    This town is the site of a large smelter which processes lead ores,
    among others. The young children in the town have high blood lead
    concentrations. In a sample of 14 children of 1-5 years of age,
    78.6-100% were found to have lead concentrations equal to or greater
    than 40 g/100 ml blood. The concentration of lead in the surface soil
    of Smeltertown has a median value of 3700 mg/kg. One is tempted to

    conclude that the blood lead levels of these young children increased
    owing to ingestion of this soil. However, the picture is somewhat
    confounded by the fact that older children also showed a high
    incidence of elevated blood lead concentrations but to a lesser
    degree; and older children are not generally considered to exhibit
    pica. Smeltertown adults had normal blood lead concentrations. Intake
    of lead by inhalation would probably have affected adults as well as
    children. Thus, it is likely that lead intake by the children was by
    direct oral intake. The painted surfaces in the residences were seldom
    in a flaking condition and were not found to be more than two or three
    layers thick, in contrast to the multiple layers usually found in city
    slum areas where lead poisoning is prevalent. The information
    available therefore suggests that the sources of lead were soil and
    dust. Indeed, there was a highly significant correlation between the
    concentration of lead in the blood of the children and the
    concentration of lead in household dust.

        The presence of high concentrations of lead in soil is not
    necessarily hazardous. Thus, children living on soils containing lead
    levels of up to 8000 mg/kg showed only minimal elevations in blood
    lead concentration (Barltrop et al., 1974). This was found to be so
    even among the children with pica for soil. Perhaps climatic
    differences are important. Smeltertown in Texas is extremely dry and
    dusty whereas the region studied by Barltrop and coworkers was in
    England, where the soil is presumably not as accessible to children
    owing to the relatively heavy cover of vegetation. The play behaviour
    of children also determines to a certain extent their exposure to lead
    (Einbrodt et al., 1974).

        Since dust and dirt occur indoors as well as outdoors, some
    attention has been directed recently to the significance of indoor
    dust. Transfer of lead-bearing house dust to the hands of young
    children has recently been demonstrated (Sayre et al., 1974). The
    house dust of inner city old houses contained far more lead than the
    dust of newer, suburban houses. Furthermore, the hands of the children
    in inner city houses were heavily contaminated with lead, whereas the
    hands of suburban children were not. It is not at all certain that the
    source of lead in the house dust was fallout from car exhaust. New
    housing in the inner city had very little lead in dust. The inference
    is that the lead was probably from the painted surfaces, since the
    paint in old houses has high concentrations of lead whereas the paint
    in new houses in the same area generally has a low lead content. But
    even the presence of lead-containing dust on children's hands provides
    little information concerning hazard since the critical question is
    how much is actually transferred from the hands to the digestive
    tract.

    5.2.2  Miscellaneous

        Facial cosmetics have long been a source of lead poisoning in
    Oriental countries. Kato (1932) discussed the problems encountered in
    Japan. Face powders, pastes, and liquids were found to contain as much
    as 67% lead. Exposure of children was considered to be by inhalation
    of powders, or ingestion of powders and other formulations. More
    recently, there have been several reports of infant poisoning from a
    mascara-like cosmetic used by Indian and Pakistani women (Warley et
    al., 1968; Alexander & Delves, 1972). This substance may contain as
    much as 88% lead sulfide.

        Another source of lead exposure for young children is coloured
    newsprint (Hankin et al., 1973). It has been found that the coloured
    inks used in magazine illustrations contain extremely high
    concentrations of lead. Coloured pages were found to have lead
    concentrations of 1140-3170 mg/kg.

        Children and other family members may be exposed to lead
    contamination at home by work clothing being worn at home or brought
    home for cleaning, or by small pieces of metal which may be brought in
    (InterDepartmental Working Group on Heavy Metals, 1974).

    5.3  Occupational Exposures

        It is among the workers who smelt, refine, and use lead in
    manufacturing items of commerce that the highest and most prolonged
    exposures are found. Lead poisoning among these people was common at
    one time. Today, workers, management, and physicians are generally
    aware of the danger of lead and know how to handle the problem; so,
    the incidence and severity of poisoning have decreased substantially
    in recent years. However, much still remains to be done to eliminate
    lead poisoning completely as an occupational disease. The major hazard
    today seems to be in small enterprises (Engel et al., 1971) and in
    some large industries where adequate industrial hygiene programmes do
    not exist or are difficult to implement, or where awareness of the
    existence of hazardous circumstances may be lacking.

        A recent WHO study of occupational health problems in the Andean
    countries (El Batawi, unpublished results, 1974) showed that, in Chile
    for instance, among 580 workers exposed to lead, 21.9% had an
    increased level of ALA in the urine. In Colombia, 3370 workers exposed
    to lead were examined, of whom 4.30% were considered to be suffering
    from lead poisoning.

        The major route of lead exposure in industry is by inhalation. The
    generation of lead-bearing dusts and fumes is inevitable. The workers'
    clothes may also be an important source of exposure. Even the lesser
    problem of oral intake of lead is really a consequence of the
    generation of airborne dusts which settle out from the air on to food,

    water, or other objects that are transferred to the mouth in one
    fashion or another. Thus, good housekeeping and, above all, good
    ventilation have a strong impact on exposure. An industrial process
    may be quite safe in one factory and quite hazardous in another solely
    because of differences in ventilation engineering or because of
    differences in housekeeping practices and worker education.

    5.3.1  Lead mining, smelting, and refining

        The lead mining hazards depend, to some extent, on the solubility
    of the lead from the ores. The lead sulfide (PbS) in galena is
    insoluble and absorption through the lung is slight. However, in the
    stomach, some lead sulfide may be converted to slightly soluble lead
    chloride which may then be absorbed in moderate quantities.

        The process of lead smelting and refining probably has the
    greatest potential for hazardous exposure of all the lead industries.
    The most hazardous operations are those in which molten lead and lead
    alloys are brought to high temperatures, resulting in the vaporization
    of lead. This is because condensed lead vapour has, to a substantial
    degree, a small (< 5 m), respirable particle size range. Thus,
    although the total air lead concentration may be greater in the
    vicinity of ore proportioning bins than it is in the vicinity of a
    blast furnace in a primary smelter, the amount of particle mass in the
    respirable size range may be much greater near the latter.

        As an example, we can consider the processes involved in the
    preparation of lead bullion in typical primary lead ore smelters in
    Salt Lake City, Utah. The various processes are essentially grinding
    and smelting. The main operations are: (1) ore proportioning; (2)
    nodulizing and sintering; (3) blast furnace; (4) drossing and
    reverberation. Air lead concentrations have been determined using
    personal monitors worn by workers at the various stations. These data
    are summarized in Table 11. Similar data for primary lead smelters
    elsewhere are not available. However, it is evident that lead exposure
    in primary smelters may be extremely high. The hazard to the workers
    in the example cited would be extremely serious were it not for the
    fact that the use of respirators is mandatory in these particular
    smelters.

        Comparable data are not available for exposures in secondary
    smelters. Secondary smelters are to be found in or near most large
    cities. They depend on the local supply of lead scrap in the form of
    discarded electric storage batteries, cable casings, pipes, and other
    materials for their supply of lead. The nature of the operation is
    similar to the one described for primary smelters, except that no ore-
    processing is involved. Tola (1974) has recently reported on hazards
    in secondary lead smelters in Finland. The work practices involved
    were not described. Thus, it was not indicated whether or not these

        Table 11.  Air lead concentrations in three primary lead smelters (g/m3)a
                                                                                     

    Smelter   Year      Locationb    Meansc                      Mean     Range
                                                                 of       (all values)
                                                                 means
                                                                                     

    A         1972-75     (1)        610, 1930,  2860            1800       250-3670
                          (2)        970,  470,   450             630       250-1380
                          (3)        860,  950,   320             710       200-1700
                          (4)       1220,  350,   950             840       260-1640
    B         1973-74     (1)       1310, 2330,  4720            2790       370-5160
                          (2)       2740, 3460,   770            2320       310-7570
                          (3)        860,  140,   530             510       120-1560
                          (4)       1270,  540,  5730, 4050      2900        60-7220
    C         1973-74     (1)           -                           -              -
                          (2)       3850, 8740,   830            4470    < 10-31 200
                          (3)       1320,  230                    780        90-1340
                          (4)         80                           80
                                                                                     

    a  Data provided by M. Varner, American Smelting and Refining Co.,
       Salt Lake City, Utah, U.S.A.
    b  Locations: (1) Ore proportioning; (2) nodulizing and sintering;
       (3) blast furnace; (4) drossing and reverberation.
    c  Determined with personal monitors on separate occasions.
       Each sampling period was 5-7 hours.
    

    workers wore respirators on the job. But whatever the work practices
    may have been, they were not adequate. Out of 20 smelters and
    founders, 16 had blood lead concentrations equal to or greater than
    70 g/100 ml.

        Foundries in which molten lead is alloyed with other metals have
    also been sources of high atmospheric exposure. In one such operation
    the concentration of lead was 280-290 g/m3 (Berg & Zenz, 1967).

    5.3.2  Electric storage battery manufacturing

        The electric storage battery industry has been studied fairly
    carefully with reference to the nature and degree of lead exposure.

        Within the manufacturing process, there are numerous specific
    operations that are hazardous by virtue of the resultant high air lead
    concentrations. Plate casting is a molten metal operation. The hazard
    here is from spillage of dross, resulting in dusty floors. Mixing of
    lead oxide paste runs parallel to grid casting. Here, as in subsequent
    operations, the major hazard is from lead oxide dust, particularly
    when loading the mixer with lead oxide powder. Ventilation is needed
    during loading and frequent clean-up is necessary to prevent the
    accumulation of dust. Pasting of the plates follows, either by hand or
    by machine. In either case the hazard is from dust which accumulates
    as the paste dries. The plates are then cured, oven dried and removed
    for the forming process. Although the plates must be welded into
    circuits, the temperature is not high enough to generate significant
    concentrations of lead fumes. Once more, the main problem is lead
    oxide dust, although the amount of handling involved generally does
    not require ventilation. After another drying process, the plates are
    stacked to make elements, either by hand or machine. In both cases the
    process is dusty and ventilation is needed, but particularly with
    machine stacking. The stacks are then burned to weld together the
    positive and negative lugs. This is done in a ventilated burning box.
    Final assembly and finishing are low-hazard operations that do not
    require ventilation if conducted with care.

        Reports have appeared concerning the air lead concentrations
    associated with the various phases of battery manufacture. The data
    summarized in Table 12, show that oxide mixing is probably the most
    hazardous occupation, followed by machine pasting, assuming that the
    same accumulative time is spent at each activity. This conclusion is
    borne out by the result of a recent study. The blood lead
    concentration was found to be most elevated and the erythrocyte ALAD
    activity was most depressed among men engaged in oxide mixing and
    pasting (Tola et al., 1971).

        The data cited above for air lead concentrations in the lead
    smelting and refining industry and in the electric storage battery
    industry may not of course be wholly representative of these
    industries. But they are sufficiently alarming to suggest that
    respirators must be worn in most of these operations, as indeed they
    were in the case of the smelters from which the data were gathered.

    5.3.5  Shipbreaking and welding

        Any process in which lead-containing metals are heated with
    torches to high temperatures are potentially hazardous. This is due to
    the formation of lead fumes with a high fraction of the airborne mass
    existing in the respirable particle size range. As an example, steel
    structures are coated with lead-based paint prior to final assembly.
    Thus, Tabershaw et al. (1943) found the average air lead concentration
    in the breathing zone of welders of structural steel to be
    1200 g/m3. Welding can also be a hazard on occasion, when the
    coating is so-called zinc silicate, since zinc silicate can contain


        Table 12.  Air lead concentrations (g/m3) in electric storage battery manufacturing
                                                                                                  

    Operation           Elkins,   Tsuchiya &               Williams, et al.,   Engels &
                        1950a     Harashima, 1965a         1969b               Kuhnen, 1973c,d
                                                                                                  
                        mean      mean      range          mean      S.E       mean     range
                                                                                                  

    Oxide mixing        730       2000      250-13 000     -         -         5400     180-21 600
    Plate casting       260       500       200-620        50        3         -        -
    Pasting, hand       750       -         -              150       29        710      100-2700
    Pasting, machine    -         -         -              220       25        1100     80-13 500
    Forming             -         -         -              130       13        220      30-2200
    Stacking and
     breaking           500       -         -              -         -         880      110-1500
                                                                                                  

    a  Air sampling time not stated.
    b  Personal air samplers worn for full work shift for 2 weeks
    c  Air sampling time 40-60 minutes.
    d  Approximations derived by collation of various sub-categories from authors' data
    

    substantial concentrations of lead. Welding of zinc silicate-coated
    steel can give rise to breathing zone concentrations of lead far in
    excess of 150 g/m3, the current threshold limit value in the USA
    (Pegues, 1960). Even the welding of galvanized steel creates
    concentrations of 400-500 g/m3. These high values were recorded
    under conditions of poor ventilation. With good ventilation, welding
    of zinc silicate-coated steel resulted in lead concentrations of
    180 g/m3 near the welder's nose and 70 g/100 ml in his blood.

        The recovery of scrap metal from the dismantling of ships requires
    extensive cutting of steel plates with electric torches. These plates
    are heavily coated with lead-based paint. Consequently, the evolution
    of lead fumes and their inhalation by the shipbreakers commonly
    results in lead intoxication. Air samples collected near the breathing
    zone of shipbreakers show that lead concentrations of as much as
    2700 g/m3 are attained, even in the open (Rieke, 1969).

    5.3.4  Printing

        The hazard in a printing establishment is probably in direct
    proportion to the dispersion of lead oxide dust, secondary to the
    remelt operation. An early study was reported by Brandt & Reichenbach
    (1943) in which melting pots were located in a variety of places where
    used type was discarded. These pots were maintained at temperatures
    ranging from 318C to 477C. The highest air lead concentration
    recorded was 570 g/m3, and the i highest average concentration for
    any room was 200 g/m3. Although working methods and industrial
    hygienic conditions have probably changed considerably since this
    report was published, a marginal degree of hazard still prevails.
    Tsuchiya & Harashima (1965) reported a range of lead levels of
    30-360 g/m3 at breathing level in several printing shops in Japan.

        Biological monitoring of workers in the printing industry has been
    reported. It was found that four of those engaged in smelting had
    blood lead concentrations greater than 50 g/100 ml (Hernberg et al,
    1969). There was only one blood lead value greater than 70 g/100 ml
    among the 28 workers studied.

    5.3.5  Alkyllead manufacture

        Tetraethyllead was first distributed as an additive to automobile
    fuel in 1923. Tetramethyllead was introduced in 1960. Today, the
    annual production of these two alkyllead compounds accounts for
    approximately 12% of total lead consumption by industry (see 3.3).
    Inevitably, workers engaged in the manufacture of these compounds are
    exposed to both inorganic and alkyllead. Some exposure also occurs at
    the petroleum refineries where tetraethyllead and tetramethyllead are
    blended into gasoline.

        The process of tetraethyllead manufacture consists of reacting a
    sodium-lead alloy with ethyl chloride. The alloy is made by combining
    molten lead with elemental sodium. The alloy is then transported to
    the autoclaves in hoppers. After the autoclave has been charged, ethyl
    chloride is added over several hours. The reaction takes place at
    about 75C for a further period of 30-60 minutes. Steam distillation
    is then applied to remove residual ethyl chloride. The lead sludge is
    recovered, purified by smelting and re-used. The process generally in
    use for the manufacture of tetramethyllead is basically the same as
    for tetraethyllead. The final step is blending with dyes and
    scavengers. The product is shipped either in drums or tanker lorries.

        Although there is a potential hazard from skin absorption of
    tetraethyl and tetramethyllead, this is guarded against by the use of
    protective clothing. In a recent study, a good correlation was found
    between the organic air lead concentration in a plant and the rate of
    lead excretion in the urine (Linch et al., 1970). The average
    concentration of organic lead was 0.179 mg/m3 for the tetramethyl
    lead operation and 0.120 mg/m3 for the tetraethyllead operation. The
    somewhat higher level registered for tetramethyllead was probably
    because the reaction between the organic reagent and the lead alloy
    takes place at a somewhat higher temperature and pressure than that
    employed in tetraethyllead production. Categories of hazard have been
    established based on the frequency with which workers are removed from
    exposure because of excessive urinary lead excretion (Table 13).

    Table 13.  Degree of hazard from lead exposure in the alkyllead
               industrya
                                                                         

    High                        Moderate                Low
                                                                         

    1. smelting furnaces        1. drumming plant       1. blending
    2. charging autoclaves      2. steam distillation   2. pressure vessel
    3. unloading and movement   3. alloying                  inspection
         of lead pigs
    4. lead recovery            4. autoclave area
    5. maintenance
                                                                         

    a  Data provided by: M. R. Zavon, Medical Director, Ethyl
       Corporation, Ferndale, Michigan, USA.


        No exposure data are available for the blenders who mix
    tetraethyllead and tetramethyllead with gasoline at the refineries,
    but some exposure is likely to occur. Even at the filling stations
    where gasoline is pumped into cars, the concentration of organic lead
    in the vicinity of the pumps is appreciably greater than in the

    ambient air. Organic lead concentrations of 0.2-1.5 g/fm3 were
    found in the vicinity of pumps (Colwill & Hickman, 1973; Harrison et
    al., 1974), and the concentration of tetraalkyllead emitted from the
    exhaust pipe of cars varied from 50 to 1000 g/m3 when the engine
    was idling (Laveskog, 1971).

    5.3.6  Other industrial exposures

        The diversity and extent of the industrial applications of lead
    makes it impossible to consider all cases. Furthermore, in most
    instances the actual exposure levels have not been assessed. Some
    technological applications of lead are too recent to have provided
    much industrial hygiene experience. For example, the use of lead
    stearate as a stabilizer in the manufacture of poly(vinylchloride) is
    emerging as a new hazard. In the 1971 Annual Report of the British
    Chief Inspector of Factories, the number of reported cases of lead
    poisoning in the plastics industry was second only to that in the lead
    smelting industry (HM Chief Inspector of Factories, 1973). Other
    individual cases have been reported in recent years (Scarlato et al.,
    1969; Maljkovic, 1971). Lead stearate is milled and mixed with the
    poly(vinylchloride) and the plasticizer, to the extent of about 1-3%.
    It seems probable that the source of the problem is the dust that is
    generated in the mixing process. It appears too, that lead exposure
    occurs in the rubber tire industry (Sakurai et al., 1974), probably as
    a result of using lead dithiocarbamate as an accelerator in rubber
    manufacture.

        Drawing from his own experiences and knowledge of the field,
    Hernberg (1973) has provided a classification of hazard for common
    industrial activities where lead is used (Table 14).

    5.4  Blood Lead Concentrations of Various Populations

        Under certain conditions, blood lead levels (Pb-B) are a useful
    indicator of exposure and are therefore discussed in this section
    dealing with environmental levels and exposures (see also section
    6.1.1.2).

    5.4.1  Adult populations

        A great deal of data is available on the blood lead levels of
    adult populations. By far the major proportion of these studies have
    reported that Pb-B mean values for occupationally unexposed, rural,
    and urban, populations range from 10 to 25 g/100 ml (Hofreuter et
    al., 1961; US Department of Health, Education and Welfare, 1965; Butt
    et al., 1964; Holmquist, 1966; Lehnert et al., 1970; Horiuchi, 1970;
    Tepper & Levin, 1972; McLaughlin et al., 1973; Tsuchiya et al., 1975).
    Studies relating to populations from northern Italy have consistently
    revealed somewhat higher mean values, ranging from 24 to 35 g/100 ml
    (Zurlo et al., 1970; Secchi et al., 1971; Secchi & Alessio, 1974). 

        Table 14.  Relative hazard of lead poisoning in some occupations or operationsa
                                                                                              

    High hazard                                                 Moderate or slight hazard
                                                                                              

    Primary and secondary lead smelting                         Lead mining

    Welding and cutting of lead-painted metal constructions     Plumbing

    Welding of galvanized or zinc silicate coated sheets        Cable making

    Shipbreaking                                                Wire parenting

    Nonferrous foundries                                        Lead casting

    Storage battery manufacture: pasting, assembling,           Type founding in printing shops
      welding of battery connectors                             Stereotype setting

    Production of lead paints                                   Assembling of cars

    Spray painting                                              Automobile repair

    Mixing (by hand) of lead stabilizers into poly(vinyl        Shot making
      chloride)

    Mixing (by hand) of crystal glass mass                      Welding (occasionally)

    Sanding or scraping of lead paint                           Lead glass blowing

    Burning of lead in enamelling workshops                     Pottery/glass making

    Repair of automobile radiators
                                                                                              

    a  From: Hernberg, 1973.
    

    Similar Pb-B levels were also reported from rural and urban population
    groups in France (Boudene et al., 1975). In contrast, relatively low
    values (8.5 g/100 ml) have been reported for 50 women from southern
    Sweden (Haeger-Aronsen et al., 1971). These are consistent with
    recently reported values for the Finnish female general population,
    ranging from 7.9 (rural), to 9.7 (urban) g/100 ml (Nordman, 1975).

        As a rule, the Pb-B levels of urban populations, and of people
    heavily exposed to automobile exhausts, have been found to be higher
    than those of rural populations or of populations living in areas with
    less traffic (Hofreuter et al., 1961; US Department of Health,
    Education and Welfare, 1965; Lehnert et al., 1970; Tepper & Levin,
    1972) (Table 15). In one recent study, Pb-B levels were determined
    among adults before and after the opening of a motorway interchange
    with a high traffic density. Pb-B levels were found to be considerably
    higher among men and women living in the immediate vicinity of the
    interchange after it was opened than before (Waldron, 1975). In the
    evaluation of the results of this study, allowance must be made for
    the facts that no control group was studied, the procedure of drawing
    blood samples was changed after opening the interchange, the sampling
    took place at different times of the year and no data were given
    pertaining to the control of the analytical method used (atomic
    absorption spectroscopy). Thus, the possibility of systematic errors
    cannot be ruled out. On the other hand, Stopps (1969) found that the
    Pb-B levels of people living in various places remote from
    civilization had group means of 12-23 g/100ml, values not
    significantly different from group means reported for people living in
    urban areas of highly industrialized countries. No information was
    given in the report concerning procedures or quality control of the
    analytical methods.

        A distinct increase in the lead absorption has been recorded in
    people living in the vicinity of lead smelters (Secchi et al., 1971;
    Nordman et al., 1973; Martin et al., 1975; Graovac-Leposavic et al.,
    1973).

        Men have higher Pb-B levels than women (NAS-NRC, 1972). This
    difference does not appear to be totally attributable to the higher
    haematocrit values of men (Tepper & Levin, 1972; Nordman, 1975). At
    least part of the difference is likely to be accounted for by the
    higher food consumption of men.

        No association has been established between Pb-B levels and age in
    adults (NAS-NRC, 1972; Tepper & Levin, 1972; Nordman, 1975).

        The influence of cigarette smoking is not fully evaluated; some
    researchers have reported higher Pb-B levels for smokers than for non-
    smokers (Hofreuter et al., 1961; US Department of Health, Education
    and Welfare, 1965; Tepper & Levin, 1972), while others have been
    unable to confirm such an association (Lehnert et al., 1967; Jones et
    al., 1972; McLaughlin & Stopps, 1973; Nordman, 1975; Tsuchiya et al.,
    1975).

        Table 15.  Summary of concentration of lead in blood of selected
               groups of males, USAa
                                                                               

    Mean           No. of       Identity of groups
    (g/100 ml)    subjects
                                                                               

       11              9        Suburban nonsmokers, Philadelphia
       12             16        Residents of rural California county
       13             10        Commuter nonsmokers, Philadelphia
       15             14        Suburban smokers, Philadelphia
       19            291        Aircraft employees, Los Angeles
       19             88        City employees, Pasadena
       21             33        Commuter smokers, Philadelphia
       21             36        City Health Dept. employees, Cincinnati
       21            155        Policemen, Los Angeles
       22             11        Live and work downtown, nonsmokers, Philadelphia
       23            140        Post Office employees, Cincinnati
       24             30        Policemen, nonsmokers, Philadelphia
       25            191        Firemen, Cincinnati
       25            123        All policemen, Cincinnati
       25             55        Live and work downtown, smokers, Philadelphia
       26             83        Police, smokers, Philadelphia
       27             86        Refinery handlers of gasoline, Cincinnati (1956)
       28            130        Service station attendants, Cincinnati (1956)
       30             40        Traffic police, Cincinnati
       30             60        Tunnel employees, Boston
       31             17        Traffic police, Cincinnati (1956)
       31             14        Drivers of cars, Cincinnati
       33             45        Drivers of cars, Cincinnati (1956)
       34             48        Parking lot attendants, Cincinnati (1956)
       38            152        Garage mechanics, Cincinnati (1956)
                                                                               

    a  From: US Department of Health, Education and Welfare, 1965.
    

    5.4.2  Children

        European studies of Pb-B levels in children indicate that, in
    general, the values are similar to or possibly even lower than those
    in adults. Pb-B levels of 200 children aged 4-13 years in rural
    western Ireland have been reported to be below 13 g/100ml with 45% of
    the results below 10 g/100ml (Grimes et al., 1975). A group of 363
    children aged from 8 days to 8 years was surveyed in the
    Nuremberg/Erlangen area. The children displayed a mean Pb-B level of
    3.3  2.6 p.g/100 ml in the first year of life; the Pb-B level
    increased year by year and reached a mean of 11.5  4.9 g/100 ml at

    the age of 6-8 years (Haas et al., 1972a). However, most of the
    available data on Pb-B levels in children have been obtained as a
    result of case-finding programmes conducted in the USA. In one study,
    the average blood level of 230 children, aged 1-5 years, in two rural
    counties was found to be 22.8 + 11.0 g/100 ml (Cohen et al., 1973).
    An upward correction was made for all haematocrit values below 40%;
    more than half of the children lived in older houses (more than 25
    years old) one-quarter of which had flaking paint or holes in the
    plaster.

        There has been great concern in the USA that a very large number
    of inner city children have abnormally elevated Pb-B levels. The
    concern is for children in the blood lead range of 40-80 g/100 ml.
    Thus, Blanksma et al. (1969) reported that in 1967, and 1968, 8%, and
    3.8%, respectively, of Chicago slum children had Pb-B concentrations
    in excess of 49 g/100 ml. This study involved 68 744 children, the
    majority of whom were between 1 and 6 years of age. The problem is not
    limited to large cities. Fine et al. (1972) reported on a survey of 14
    Illinois communities with populations ranging from 9641 (Robbins) to
    126 963 (Peoria). Of a total of 6151 children, 18.6% had Pb-B levels
    higher than 39 g/100 ml and 3.1% had levels higher than 59 g/100 ml.
    Some of the communities were in the Chicago urban complex, but a
    considerable number were not. There did not appear to be any great
    difference in the percentage of children having an excessive
    concentration of lead among the Chicago urban communities as compared
    with the downstate and western Illinois communities. The findings are
    certainly not unique to Illinois. In a recent survey, 34% of 343
    children in an impoverished area of Boston had Pb-B levels in excess
    of 39 g/100ml and 12% were over 49 g/100ml (Pueschel et al., 1972).
    Similar data have been gathered recently in New York City and
    elsewhere.

    6.  METABOLISM OF LEAD

    6.1  Absorptiona

        The absorption of lead from environmental sources is not solely
    dependent on the amount of lead presented to the portals of entry per
    unit time. It is also dependent on the physical and chemical state in
    which the metal is presented and it is influenced by host factors such
    as age and physiological status. The amount of food eaten and the
    amount of air breathed, with the proportionate ingestion or inhalation
    of lead, are functions of metabolic activity. Men engaged in heavy
    work breathe more air and eat more food than sedentary individuals of
    the same weight, and children eat almost as much food and breathe
    almost as much air as middle-aged adults.

    6.1.1  Absorption by inhalation

        A large amount of information has accumulated regarding the
    factors that determine the degree of deposition and retention of
    inhaled aerosols in general (Task Group on Lung Dynamics, 1966). With
    appropriate knowledge of the aerodynamic characteristics of lead
    aerosols, it would be possible to make reasonable predictions from the
    lung model developed by the ICRP Task Group on Lung Dynamics,
    concerning the fractional deposition that would occur in the human
    airways. It would also be possible to predict the pattern of regional
    deposition in the airways. Unfortunately, the knowledge necessary for
    making accurate predictions is not available, particularly in the case
    of industrial exposure.

        The ICRP lung model would predict that approximately 35% of the
    lead inhaled in general ambient air would be deposited in the airways,
    since the aerodynamic diameterb of the lead particles is
    approximately 0.1-1.0 m (see section 5.1.1). The lung model would
    also predict that regional deposition would be predominantly in the
    alveolar bed and in the deeper regions of the tracheobronchial system.
    Furthermore, it would predict that fractional deposition of lead dusts
    generated in an industrial environment would be greater than it would
    be for lead in general ambient air, however, the deposition would be

              

    a  In this document, absorption and uptake are used synonymously.
    b  Aerodynamic diameter = diameter of a unit density sphere with the
       same settling velocity as the particle in question (Task Group on
       Lung Dynamics, 1966).

    mainly in the nasopharynx rather than in the pulmonary bed or
    tracheobronchial region, owing to the larger particle size. Industrial
    lead fumes, such as those generated in the process of cutting metals
    with electric torches, would be of small particle size and would
    behave accordingly. But even the lead aerosols breathed by the general
    population are not well enough characterized to predict deposition.
    This is particularly true for the very small particles (<0.1 m)
    which are largely deposited by diffusion (Lawther, 1972).

        The adequacy of the ICRP lung deposition model is open to
    question, at least for small particles. The model predicts a total
    airway deposition of 40-50% for 0.5-m particles, whereas a study in
    human volunteers indicated a deposition of only 6-16% depending on the
    rate and depth of respiration (Muir & Davies, 1967).

        Predictions concerning the characteristics of airway clearance of
    lead aerosols using the ICRP lung model are even more difficult to
    make than predictions regarding deposition. The lung model would
    predict that the fate of lead deposited in the airways would vary
    greatly depending on its solubility characteristics and on the
    inherent toxicity of the particles to the clearance mechanism (lung
    macrophages and cilia). The chemical forms of lead in air are both
    numerous and variable, depending on the source and on residence time
    in the air (see section 5.1.1). In many types of industrial exposure,
    lead is probably mainly in the form of lead oxide.

    6.1.1.1  Human studies

        Actual studies on the fractional deposition of particles in the
    respiratory tract of man have not been extensive, especially in the
    case of lead. Kehoe (1961) studied the deposition of lead in human
    volunteers with an air lead level of 150 g/m3. The source of lead
    was combusted tetraethyllead which produced lead (III) oxide
    (Pb2O3) in the air. Subjects breathed air containing particles
    with an average diameter of 0.05 m viewed under the electron
    microscope, with 90% ranging from 0.02-0.09 m. A diameter of 0.05 m
    for lead (III) oxide as seen under the electron microscope represents
    a mass median equivalent diameter of approximately 0.26 m (NAS-NRC,
    1972). Subjects also breathed air containing particles having an
    average diameter of 0.9 m (mass median equivalent diameter = 2.9 m);
    36% of the smaller particles, and 46% of the larger particles, were
    deposited.

        Nozaki (1966) also reported on lung deposition of inhaled lead in
    man. Lead fumes were generated in a high-frequency induction furnace
    and were inhaled at a concentration of 10 000 g/m3. Particle size
    was closely controlled according to the method of Homma (1966). The
    results (see Table 16) were similar to those of Kehoe (1961) and were
    reasonably consistent with the ICRP lung deposition model (Task Group
    on Lung Dynamics, 1966).

        These data suggest that an estimate of 30  10% deposition is
    reasonable for the usual general ambient air situation and that lead
    oxide deposition characteristics will vary considerably, depending on
    the particle size and on the depth and frequency of respiration.

        However, one cannot predict the contribution of airborne lead to
    the body burden of lead on the basis of deposition studies alone.
    Regional deposition probably varies greatly from one exposure
    situation to another, that is, the industrial setting  versus the
    ambient environment. Also, the nature of lung clearance is unknown and
    is difficult to study. Nevertheless, it is possible to determine
    short-term lung clearance by carrying out gamma ray lung scans
    following inhalation of 212Pb. Such a study in man has been reported
    (Hursh & Mercer, 1970) but its relevance to the rate of clearance of
    the chemical and physical forms of lead usually inhaled by man is
    highly questionable. Such radioactive lead studies involve the
    adsorption of 212Pb atoms on carrier aerosol particles. The
    desorption of lead atoms from aerosol nuclei under these artificial
    circumstances may be quite significant, and the estimated rate may be
    totally unlike the clearance rate for ambient air lead particles.

        Kehoe (1961) has reported that when a subject breathed large-
    particle aerosols of lead (III) oxide (approximately 2.9 m mass
    median equivalent diameter) for many weeks at 150 g/m3 a very
    substantial increase in faecal excretion occurred, probably reflecting
    the fact that the particles were largely trapped in the nasopharynx
    and swallowed. When the same subject inhaled air with a lead
    concentration of 150 g/m3, with the lead in small particles
    (approximately 0.26 m mass median equivalent diameter), only a small
    rise in faecal lead excretion was observed.

        During inhalation of particulate air pollutants, the lead dust
    comes into contact with lung cells, which are primarily responsible
    for phagocytosis. It must be remembered that alveolar macrophages are
    damaged  in vitro by inorganic lead compounds (Beck et al., 1973),
    and that similar effects have been demonstrated  in vivo in rats and
    guinea-pigs (section 6.1.1.4). It seems possible, therefore, that the
    lung defence mechanisms are, to some extent, impaired in an
    environment with a high air lead concentration, and that the rate of
    absorption of inhaled particles under such circumstances is affected.

        In summary, studies of airway deposition and clearance of lead in
    man have not, as yet, provided any clear indication of the daily
    absorption to be expected under realistic conditions. They have only
    emphasized the necessity to consider other kinds of data to obtain
    this information.

        Since the concentration of lead in the blood is thought to reflect
    current and recent lead exposure, the degree of lead intake from air
    should be reflected in this factor.

        Table 16.  Deposition of lead fumes in the airways of human subjectsa
                                                                                       

    10 respirations/min: 1350 cm3 tidal air      30 respirations/min: 450 cm3 tidal air
                                                                                       
    Particle diameterb   % Deposition            Particle diameterb    % Deposition
    (m)                                         (m)
                                                                                       

       1.0               63.2                    1.0                   35.5
       0.6               59.0                    0.6                   33.5
       0.4               50.9                    0.4                   33.0
       0.2               48.1                    0.2                   29.9
       0.1               39.3                    0.1                   27.9
       0.08              40.0                    0.08                  26.5
       0.05              42.5                    0.05                  21.0
                                                                                       

    a  Adapted from Nozaki, 1966.
    b  Mass median equivalent diameter.
    

    6.1.1.2  The relationship of air lead to blood lead in the general
             population

        The risk to man from lead in air has become a matter of
    considerable concern in recent years. Studies of lead deposition and
    retention in the airways of man have not been very enlightening. A
    more indirect but nonetheless useful approach to the problem starts
    from the assumption that the concentration of lead in the blood is
    proportional to the concurrent level of total uptake by way of the
    several portals of entry. It follows that each environmental source
    (mainly air, food and water) would contribute to the blood lead
    concentration in direct proportion to its contribution to the total
    daily lead uptake. Up to the present time, such a relationship has
    never been rigorously demonstrated. Goldsmith & Hexter (1967)
    developed a linear regression plot of log Pb-B  versus log lead
    concentration in air. The air lead samples were not necessarily taken
    at the same time and place as the blood samples. Thus, the regression
    line was calculated on the basis of rather imprecise information.
    However, data from experimental human subjects breathing known high
    concentrations of lead oxide were found to fit the regression line
    rather well. A cogent criticism is the fact that the validity of the
    air lead data as applied to the specific blood lead data is very
    uncertain. The contribution of air lead to blood lead, as inferred
    from the Goldsmith-Hexter curve, is about 1.3 g of lead per 100 ml of

    blood per 1 g of lead per m3 of air. Other epidemiological studies
    have been made of the relationship between air lead and blood lead.
    Azar et al. (1973) monitored the inhaled air of 150 individuals using
    personal air samplers continuously, 24 hours per day. The air lead
    exposure ranged from 2 g/m3 to 9 g/m3. There was a significant
    correlation between log air lead level and log blood lead level, when
    data from all the cities involved were pooled. The contribution of air
    lead to blood lead was found to be somewhat less (approximately 1.0 g
    of lead per 100 ml of blood per 1 p.g of lead per m3 of air over the
    range of air lead concentrations studied), than was estimated from the
    Goldsmith-Hexter curve.

        Another recent epidemiological investigation which examined the
    relationship between air lead and blood lead levels was the Seven
    Cities Study (Tepper & Levin, 1972). No significant correlation was
    found between air lead and blood lead levels over an air lead range of
    0.17-3.39 g/m3. A major deficiency was the fact that the air data
    were obtained from fixed outdoor sampling stations in the 11 cities
    involved.

        Two studies have been reported recently in which the relationship
    between blood lead and air lead levels was investigated in human
    volunteers. In one study, 14 male volunteers were exposed to a lead
    oxide aerosol for 23 hours per day at an average concentration of
    10.9 g/m3 for up to 17 weeks. Blood lead concentrations and other
    parameters were measured before, during, and following the exposure
    period. A plateau of blood lead concentration was attained during the
    exposure, and a return to pre- or near pre-exposure levels was
    observed during the post-exposure period. The air contribution to the
    Pb-B levels was approximately 1.4 g of lead per 100 ml blood per 1 g
    of lead per m3 of air (Coulston et al., 1972b). In another study,
    male volunteers inhaled an air lead concentration of 3.2 g/m3. The
    blood lead level increased from 18 g to 25 g/100 ml, that is
    approximately 2 g of lead per 100 ml blood per 1 g of lead per m3
    (Coulston et al., 1972c). Rabinowitz (1974) reported a study of a
    single volunteer using stable lead isotope tracers in which the sudden
    removal of the normal lead in air by filtration resulted in a
    reduction of the blood lead concentration from approximately
    14.5 g/100ml to approximately 11.3 g/100 ml over a period of 40 days
    (Fig. 2). The average air lead levels were estimated taking into
    account measurements made indoors and outdoors, and the time spent in
    both locations. Prior to the experiment (day 109), the average air
    lead concentration was 1.6 g/m3 and during the experiment (day
    109-148) it was 0.2 g/m3. In calculating the contribution of air
    lead to blood lead at day 148, allowance should be made for the fact
    that the concentration of lead of normal isotopic composition was
    decreasing prior to the removal of lead from the air. If this is taken
    into account the contribution of air lead to blood lead at day 148
    would be about 1.7 g of lead per 100 ml of blood per 1.4 g of lead
    per m3 of air, or 1.2 g of lead per 100 ml of blood per 1 g of

    lead per m3 of air. It is unfortunate that it was not possible to
    follow the blood lead concentrations for a longer period of time after
    removal of lead from room air, since a new steady state had not been
    fully achieved. The study is also of limited value for application to
    the general population because only one individual was studied.

        On the other hand, the Coulston study was deficient in that the
    form of air lead breathed (lead (III) oxide) may be deposited in, and
    cleared from, the airways in a significantly different manner from
    lead, as it actually occurs in general ambient air.

        In conclusion it seems, that there is probably a perceptible
    effect of air lead on blood lead in the range of air lead
    concentrations applicable to the general population. The data
    available suggest that with blood lead levels in the range found in
    the general population, air lead levels may contribute from 1.0 to
    2.0 g of lead per 100 ml of blood per 1 g/m3 of air.

    FIGURE 2

    6.1.1.3  The relationship of air lead to blood lead in occupational
             exposure

        There is very little precise information concerning the
    relationship between the concentration of lead in air (Pb-A) and Pb-B
    levels in subjects who are occupationally exposed. The air sampling
    technique used in the study of this relationship is of great
    importance. Personal monitors should be used since in most industrial
    situations the air lead concentrations to which individuals are
    exposed may be highly variable, depending on the particular tasks
    being performed and on the individual's work habits.

        Only one study has been reported in which the subjects wore
    personal monitors and in which the estimated individual Pb-A could be
    related to Pb-B and some biochemical tests (Williams et al., 1969). In
    this study, workers in various departments of an electric storage
    battery factory wore personal samplers for the full work shift for two
    weeks. There were considerable variations in the measured
    concentrations of air lead both among departments and among individual
    personal samples. Relevant data are presented in Table 17.

        Using the data reported by Williams et al. (1969) an attempt was
    made to estimate very crudely the potential contribution of Pb-A to
    Pb-B in subjects who were occupationally exposed to lead. Several
    arbitrary assumptions were made in this estimation:

    Table 17.  Means and standard errors of measured lead in air and
               Pb-B levels in different departments of an electric
               storage battery factorya
                                                                       

    Department            No.   Pb in air (g/m3)     Pb-B (g/100 ml)
                                                                       
                                mean     S.E.         mean     S.E.
                                                                       

    Machine pasting       6      218      25          74.2      4.7
    Hand pasting          8      150      29          63.2      9.2
    Forming               9      134      13          63.0      2.7
    Casting               6       52       3          -         -
    Plastics dept. A      5       12       0.8        27.2      1.4
    Plastics dept. B      5        9       0.8        29.1      1.6
                                                                       

    a  Adapted from Williams et al., 1969.

    (1) that the weekly time-weighted average concentration of lead in air
        (c) is a good measure of the effective inhalation exposure,
        irrespective of the probable differences in breathing rates during
        work hours. For a 40-hour working week  c = 0.24 (Pb-A)o + 0.76
        (Pb-A)a, subscripts  o and  a referring to the occupational
        and ambient concentration of lead in air.

    (2) that (Pb-A)a was 1 g/m3 and that it had contributed
        1.4 g/100 ml to the measured Pb-B values (see 6.1.1.2), and that
        for each further increase of Pb-A= 1 g/m3, the increase in Pb-B
        would be 1.4 g/100 ml in the range of Pb-A values up to about
        10 g/m3.

    (3) that the contributions of the occupational inhalation exposure,
        non-occupational inhalation exposure, and exposures from other
        sources (such as food) to the Pb-B levels are additive.

        A further oversimplification was that the probable differences in
    the chemical composition and physical characteristics of air-borne
    lead in occupational and non-occupational environments were completely
    neglected.

        The contribution, (Pb-B)F, of non-inhalation exposures such as
    food intake to the measured levels of lead in blood was assumed to be
    the same for all workers and constant over the two week period of
    observation. It was calculated from the data of Table 17 for the
    workers in plastics departments A and B used as control groups, by
    subtracting the estimated contribution of c to blood lead from the
    measured Pb-B values, and taking the mean, i.e. (Pb-B)F=[27.2-
    (3.6  1.4)+ 29.1 - (2.9  1.4)] = 23.6 g/100 ml. (Pb-B)o was then
    obtained by subtracting 23.6 from measured Pb-B values for all other
    departments.

        The results are shown in Table 18.

    Table 18. Estimation of blood lead levels potentially derived from
              effective inhalation exposure  c
                                                                     

    Department         Measured Pb-B   (Pb-B)o       c      (Pb-B)o/c
                       g/100 ml       g/100 ml    g/m3
                                                                     

    Machine pasting    74.2            50.6         53.1    0.96
    Hand pasting       63.2            39.6         36.8    1.1
    Forming            63.0            39.4         32.9    1.2
    Casting            --              --           13.2    --
    Plastics A         27.2            3.6           3.6    1.0
    Plastics B         29.1            5.5           2.9    1.5
                                                                     

        From these calculations it would appear that an increase of
    1 g/m3 in the weekly time-weighted average concentration of lead in
    air would correspond to an increase of approximately 1 g/100 ml in
    Pb-B.

        A similar but somewhat lower figure for the air lead contribution
    to Pb-B levels can be arrived at using data from a study, parts of
    which are reported in two different publications (Prpic-Majic et al.,
    1973; Fugas et al., 1973). From their data, they calculated that the
    time-weighted average concentration of respirable lead particles for
    52 workers in unspecified lead trades was 35 g/m3. Their average
    Pb-B level was 44.3 g/100 ml, while the Pb-B level of a control
    population living in an air environment of 0.2 g/m3 was
    22.4 g/100 ml. Assuming the Pb-B levels due to non-air sources to be
    the same for the two groups, i.e. 22.1 g/100 ml (total (22.4) minus
    the ambient air contribution to Pb-B (0.2  1.4 = 0.3)), the air
    contribution to the Pb-B level for the industrially exposed group
    would be 44.3-22.1 or 22.2g/100ml. Since the air lead concentration
    was 35 g/m3, 1 g of lead per m3 contributes 0.6 g of lead per
    100 ml of blood.

        Another possible method of estimating the contribution of Pb-A to
    Pb-B in the occupationally exposed subjects is to find first a
    functional relationship that fits the Pb-B data from Table 17 and
     c. A power function 1n  y= 1n 18.9 + 0.34 1n  c gives a good fit
    in the range of c = 10 to c = 50 (correlation coefficient
     r = 0.994), and enables the estimation of the increase in Pb-B per
    unit increase in  c. The results of these calculations are shown in
    Table 19. Although still a gross oversimplification, this method seems
    to give more realistic results because it reflects the fact that, at
    the higher Pb-A level, Pb-B does not increase linearly with Pb-A, and
    that therefore, the expected increase in Pb-B per unit increase in
     c (dy/d c, Table 19) gets smaller and smaller as Pb-A levels grow.

    Table 19.  Power curve fita to the plot of Pb-B against the
               time-weighted average concentration of lead in air  (c)
                                                                       
    Department             c      Measured Pb-B        y        dy /dc
                         g/m3    g/100 ml        g/100 ml
                                                                       

    Machine pasting      53.1     74.2               73.2       0.47
    Hand pasting         36.8     63.2               64.6       0.60
    Forming              32.9     63.0               62.2       0.64
    Casting              13.2     --                 45.6       1.09
    --                   (10)     --                 41.3       1.41
    Plastics A            3.6     27.2               29.3       --
    Plastics B            2.9     29.1               27.2       --
                                                                       

    a  " y = 18.9 c 0.34 = Pb-B calculated.

    6.1.1.4  Animal studies

        Animal studies have been useful in the development of the ICRP
    lung deposition and clearance models, but they have not contributed
    much to resolution of the specific questions concerning the fate of
    inhaled lead in man. However, observations made on the effects of
    inhaled lead on lung macrophages are of special interest. A pronounced
    reduction in the number of lung macrophages has been demonstrated in
    rats and guinea-pigs owing to inhalation of lead (III) oxide at both
    10 and 150 g/m3 (Bingham et al., 1968). Maximum reduction occurred
    within approximately one week. This phenomenon has also been reported
    by others (Beck et al., 1973; Bruch et al., 1973, 1975). These
    observations suggest that, with high air lead concentrations at least,
    the lung clearance mechanism may not be functioning as effectively in
    diverting lead deposited in the lower airways to the gastrointestinal
    tract as the ICRP lung clearance model predicts. Thus, Pott &
    Brockhaus (1971 ) reported that large doses of lead bromide solution
    and of lead oxide suspension administered intratracheally to rats
    (1.5 mg of lead oxide per dose on 8 successive days) were retained by
    the body as completely as intravenous doses. However, at  of this
    dose, retention was significantly less.

    6.1.2  Absorption of lead from the gastrointestinal tract

    6.1.2.1  Human studies

        The uptake of lead from the gastrointestinal tract has been
    studied fairly extensively, but as with the uptake of lead from air,
    the evidence concerning a number of important points is somewhat
    uncertain. Long-term balance studies conducted by Kehoe (1961) showed
    that the daily excretion of lead into the urine was a little less than
    10%, of the intake from food and beverages. He surmised that this
    fraction represented the amount absorbed from the gastrointestinal
    tract. In estimates made on this basis, the amount of urinary lead
    that could have originated from the air is disregarded, as well as the
    fact that some of the lead absorbed from the gastrointestinal tract is
    re-excreted into the bowel.

        Recent studies by Rabinowitz et al. (1974), using orally
    administered 204Pb, indicate that the absorption of lead
    incorporated into the diet is a little less than 10%, which is
    consistent with Kehoe's conclusions based on a different experimental
    approach.

        Attention has been directed recently towards the absorption of
    lead from the gastrointestinal tract in infants and young children. In
    a study of eight normal children, from 3 months to 8.5 years of age,
    Alexander et al. (1973) found a high degree of lead absorption (53%).
    There did not appear to be any significant reduction in fractional
    retention within the age range studied. This work is subject to

    criticism because of the large scatter of values and because the
    conclusions were based on 3-day balances, a period that is probably
    insufficient for reaching any reliable conclusions.

    6.1.2.2  The relationship of oral intake of lead to blood lead levels
             in man

        It would be of great interest to be able to relate oral intake of
    lead to blood lead levels. It is obvious that, as the intake of lead
    increases, blood lead levels will rise, but a quantitative expression
    of this relationship at any particular level of lead intake has not
    been determined. Table 20 compares daily oral lead intake (g/day) and
    Pb-B levels (g/100 ml) found in adult populations without known
    excessive exposure to lead, from several parts of the world.

        Table 20. Comparison of daily oral lead intake with Pb-B levels
                                                                                             

    Study design             Oral intake     Pb-Ba         Pb-B per   Reference
                             (g/day)        (g/100 ml)   100 g
                                                           oral Pb
                                                                                             

    Duplicate portion        113 (men)        20.7          18.3      Coulston et al., 1972b
    Faecal excretion         119b (women)     15.3          13.0      Tepper & Levin, 1972
    Duplicate portion        230 (men)        12.3           5.4      Nordman, 1975
    Duplicate portion        180 (women)       7.9           4.4      Nordman, 1975
    Composites technique     505 (men)        34.6           6.8      Zurlo & Griffini, 1973c
                                                                                             

    a  "Contributions of air to Pb-B levels are not reported in most of these studies and
       could not be subtracted from total Pb-B levels.
    b  Calculated from daily faecal excretion of 108 g of lead assuming gastrointestinal
       absorption of 10%.
    c  Pb-B levels from Secchi et al. (1971).
    

        From the data in Table 20 it is not possible to draw any reliable
    conclusions regarding the contribution of foods and beverages to Pb-B
    levels. The contribution is calculated to be greater in the two
    American studies than in the European ones. One of these two American
    studies (Tepper & Levin, 1972) was actually of faecal lead excretion,
    not of dietary lead. But even if this study were discounted, there
    remains a considerable discrepancy between the other American study
    (Coulston et al., 1972b) and the European studies, which cannot be
    explained.

        Each of these studies involved a different number of subjects and
    involved different analytical techniques. It is also probable that
    there was also exposure from other environmental sources.

        At levels of lead intake above 1000 g per day, the rise in blood
    lead level does not appear to increase linearly with dose, but, in
    fact, may fit a logarithmic function.

        From data published by Kehoe (1961) concerning balance studies on
    human volunteers, a single individual with a total daily lead intake
    of 600 g had blood lead levels in the range of 30-35 g/100 ml
    registered over several months, which is consistent with the
    relationships suggested in Table 20. However, individuals with larger
    daily additions of lead did not have proportionately higher blood lead
    levels. A single individual with oral lead intake of 3300 g per day
    had a blood lead level in the 50-60 g/100 ml range, again followed up
    for several months.

        For children, the dietary contribution to blood lead is more
    difficult to estimate than for adults. Because of the higher
    absorption of lead, particularly in infants, the contribution of
    dietary lead to blood lead levels may be higher than for adults.

    6.1.2.3  Animal studies

        The effect of age on gastrointestinal absorption of lead has been
    studied in experimental animals. The absorption of lead from food has
    been investigated in many animal studies. Values between 5 and 10% are
    usual (Port & Brockhaus, 1971; Schlipkoter & Pott, 1973; Horiuchi,
    1970).

        Kostial et al. (1971) demonstrated that 5-7 day old rats absorb at
    least 55% of single oral tracer doses of 203Pb. In an extension of
    these studies, Forbes & Reina (1972) observed that the
    gastrointestinal absorption of tracer doses of 212Pb, 85Sr and
    59Fe was high prior to weaning and decreased rapidly thereafter. In
    the case of lead, absorption which was 83% at 16 days, decreased
    gradually to 74% on the day of weaning (22 days) and rapidly
    thereafter to about 16% at 89 days. The addition of tracer doses of
    metals to the diet is, however, an artificial situation. Results might
    have been quite different had appreciable amounts of carrier lead been
    included. Nevertheless, these observations are consistent with those
    reported in young children.

        Certain dietary factors have also been shown to influence the
    gastrointestinal absorption of lead. Kello & Kostial (1973) have shown
    that milk enhances lead absorption in 6-week-old-rats. Fasting
    enhances lead absorption, at least as determined by Garber & Wei
    (1974) in mice. Low dietary levels of calcium and of vitamin D enhance
    lead absorption (Sobel et al., 1938b; Six & Goyer, 1970). It has also

    been demonstrated that rats on an iron-deficient diet accumulate more
    lead in their bodies than do rats on an iron-sufficient diet (Six &
    Goyer, 1972). This seems particularly significant in the light of the
    fact that young children in socially and economically deficient homes
    have a high incidence of anaemia and excessively high blood lead
    concentrations.

        The absorption of lead ingested in the form of paint has received
    attention because of the hazard of lead-based paint to young children.
    Recent data from experiments on rats indicate that lead chromate and
    lead naphthenate incorporated into dried paint films are substantially
    available for absorption, although to a somewhat lesser degree than
    lead naphthenate in oil or lead nitrate in aqueous solution (Gage &
    Litchfield, 1968, 1969).

    6.2  Distribution and Retention

        As with all substances entering the body, a single dose of lead
    distributes initially in accordance with the rate of delivery of blood
    to the various organs and systems. Redistribution then occurs to
    organs and systems in proportion to their respective affinities for
    lead. Under conditions of continuous intake over long periods of time,
    a near-steady state is achieved with respect to intercompartmental
    distribution.

        Perturbations in the pattern of distribution occur when large,
    short-term peaks of lead intake are superimposed on this well-defined
    pattern of long-term distribution.

    6.2.1  Human studies

        The kinetics of lead distribution and accumulation in man have not
    been well defined in man directly. However, from autopsy data, the
    general pattern of lead metabolism is clearly discernible. Above all,
    it is clear that lead has a strong tendency to localize and accumulate
    in bone. The accumulation of lead in the human body begins in fetal
    life (Horiuchi et al., 1959; Barltrop, 1969). Lead is readily
    transferred across the placenta and the concentration of lead in the
    blood of newborn children is similar to that of their mothers,
    indicating mother-fetus equilibration processes (Haas et al., 1972b;
    Hower et al., 1975). The distribution of lead in fetal tissue is quite
    similar to the distribution in adults (Barltrop, 1969).

        The total lead content of the body may reach more than 200 mg in
    men aged 60-70 years, but is lower for women. Barry & Mossman (1970)
    calculated that in non-occupationally exposed adults, 94-95% of the
    total body lead (body burden) was in the bones. A similar estimate was
    made by Schroeder & Tipton (1968), by Horiuchi et al. (1959), and by
    Horiguchi & Utsunomiya (1973). These recent reports serve to reaffirm
    the long-recognized affinity of lead for bone. They also provide the

    additional observation that the concentration of lead in bones
    increases throughout most of life. This is in contrast to soft
    tissues. Most soft tissues do not show a significant age-related
    change in lead concentration after the second decade of life (Barry,
    1975). This is also true of the concentration of lead in whole blood
    (US Department of Health, Education and Welfare, 1965; Horiuchi &
    Takada, 1954) and in blood serum (Butt et al., 1964). Thus, it appears
    that the skeleton is a repository for lead that reflects the long-term
    accumulative human exposure, whereas the body fluids and soft tissues
    equilibrate reasonably fast and therefore reflect current and recent
    exposure. Little is known as to whether the mobilization of lead lying
    inactive in the bones can occur so rapidly that signs of poisoning
    appear. There is need for more studies in this field.

        The concentration of lead in the blood is of prime importance in
    the evaluation of lead exposure. It is relied upon as an aid to the
    diagnosis of poisoning and as an index of exposure to assess hazardous
    conditions both in occupationally-exposed people and in the general
    population. It has long been known that lead circulating in the blood
    is mainly found in the erythrocytes (Cantarow & Trumper, 1944). The
    concentration of lead in erythrocytes is about 16 times greater than
    in plasma (Butt et al, 1964). The nature of the association of lead
    with the erythrocyte is not clearly understood. Numerous studies have
    been reported concerning the  in vitro addition of lead to
    erythrocytes suspended in plasma or saline solutions. But the validity
    of such studies is open to serious question. Thus, Clarkson & Kench
    (1958) found that lead added  in vitro was readily removed by EDTA,
    whereas residual lead present in the cells prior to the addition of
    lead could not be removed. This suggests a difference in regard to:
    (1) the degree of binding, (2) the site of binding in or on the cell,
    or (3) the type of binding of the lead. Recent studies indicate that
    lead is mainly bound to human erythrocyte protein, notably to
    haemaglobin, rather than to stroma (Barltrop & Smith, 1971, 1972).

        The rate of equilibration of lead in blood with sources of input
    and with other body compartments has been studied in man by Rabinowitz
    et al. (1973, 1974) using a stable lead isotope tracer (204Pb). The
    data reported indicate that with a constant daily oral input of
    204Pb, a virtually constant concentration of the tracer in the blood
    is achieved after approximately 110 days. Upon withdrawal of the
    tracer 204Pb from the diet, the 204Pb concentration in the blood
    disappears with a half-time of approximately 19 days. The kinetics of
    disappearance and accumulation suggest that first order rate processes
    of exchange are involved with regard to this relatively mobile
    compartment. Tola et al. (1973) also provided data which indicate that
    the concentration of lead in the blood rises fairly rapidly to a new
    steady state level when men are newly introduced into an occupational
    lead environment. The time required for the blood lead concentration
    to achieve a new plateau reflecting the new environment is about 60
    days.

        The body burden of lead increases from birth to old age (Schroeder
    & Tipton, 1968; Barry & Mossman, 1970; Barry, 1975). When data for
    various specific organs and systems are examined, it becomes evident
    that there are two general pools of lead within the total organism.
    The major one, in terms of total lead, consists of bone. This pool is
    clearly highly accumulative. As a consequence, lead in bone
    accumulates through most of the life span. Other organs and systems
    are much less accumulative and, to different degrees, tend to
    stabilize relatively early in adult life reflecting a greater turnover
    rate of lead compared with that in bone.

        There is good reason to make a distinction between total body
    burden and exchangeable body burden since the organs and systems
    comprising the exchangeable body burden are the ones having the
    greater toxicological significance. It is also extremely important to
    note that lead in whole blood is a part of the exchangeable fraction
    of the body burden. Among adults in the general population there is no
    age-related difference in regard either to the concentration of lead
    in whole blood or in blood serum. Thus, in a general way, the Pb-B
    level reflects the concentration of lead in soft tissues, and long-
    term changes in Pb-B levels with changes in exposure levels are
    probably accompanied by corresponding long-term changes in the rest of
    the exchangeable pool.

        Nuclear inclusion bodies containing lead have been found in man
    subjected to lead exposure (Cramer et al., 1974; Galle & Morel-
    Maroger, 1965; Richet et al., 1966) as well as in experimental animals
    (see section 7.1.3). Although most frequently reported to occur in the
    kidney, they have been found in other organs as well. There is a
    suggestion from limited data that inclusion bodies are associated with
    short-term lead exposure and not with long-term exposure (Cramer et
    al., 1974).

        The concentration of lead in deciduous teeth has received special
    attention because they are readily available from young children and
    because they provide a long-term record of lead exposure, much as is
    the case with bone. Dentine in the area adjacent to the pulp is
    particularly useful in this respect because it is laid down from the
    time of eruption to the time the tooth is shed. It has been reported
    that the concentration of lead in dentine is considerably lower in
    suburban schoolchildren than it is in children in areas of high lead
    exposure (Needleman & Shapiro, 1974).

        There has been some interest in the possible use of hair lead as
    an index of exposure. Unfortunately, there is no reliable information,
    as yet, to indicate just how hair analyses should be interpreted in
    relation to the frequency and degree of exposure.

    6.2.2  Studies in animals

        Animal studies have been particularly useful in defining more
    precisely the nature of the kinetics of lead distribution and removal
    from various tissues. Following administration of a single dose of
    lead to rats, the concentration of lead in soft tissues is relatively
    high and falls rapidly, mainly as a result of transfer into the bone
    (Hammond, 1971). The distribution characteristics of lead were found
    to be independent of the dose of lead over a wide range. The rate
    constants for the elimination of lead from various tissues in rats
    following a single dose of lead have been described by Castellino &
    Aloj (1964). The rate of elimination was much slower from bone than
    from other tissues. In studies on rats, Bolanowska et al. (1964) noted
    that the rate of elimination of a single dose of lead from the body by
    spontaneous excretion became slower with time, reflecting
    progressively decreasing mobility of the residual body burden. This is
    no doubt mainly due to the fact that as lead becomes progressively
    more deeply buried in the bone matrix, its exchangeability with other
    compartments and its availability for excretion decrease.

        Rather striking age-related differences have been observed
    concerning the distribution and retention of lead in rats (Momcilovic
    & Kostial, 1974). The rate of elimination of a single tracer dose of
    203Pb from the whole body, blood, and kidney was faster in adults
    than in sucklings. In the case of the brain, there was actually a
    slight increase in the 203Pb content of the brain of the sucklings
    while the content was falling in other soft tissues. Numerous animal
    studies have also demonstrated placental transfer of lead to the fetus
    (see Carpenter, 1974, for relevant literature).

        The intracellular distribution of lead has been studied in rat
    tissue, mainly by cell fractionation techniques (Castellino & Aloj,
    1969; Barltrop et al., 1971). Lead has an affinity for membranes of
    the cell, particularly mitochondria. These organelles undergo
    functional and ultrastructural changes in organs showing lead effects,
    e.g. renal tubular cells (Goyer & Krall, 1969). Little lead is found
    in lysosomes (Barltrop et al., 1971) in contrast with the
    intracellular distribution of many other metals, e.g. mercury, copper,
    iron.

        There are few studies indicating the concentration of lead in
    target organs that will produce effects. Formation of nuclear
    inclusion bodies is observed in rats with renal lead concentrations of
    about 10 mg/kg (wet weight) of kidney (Goyer et al., 1970a). Other
    effects of lead were found to occur at higher levels of organ
    concentration. Death in cattle is associated with lead levels of about
    50 mg/kg of kidney cortex (wet weight) (Allcroft & Blaxter, 1950).

        The concept of estimating the lowest level of metal accumulation
    that results in adverse effects in a target organ has not been well-

    explored in the case of lead. This is in contrast with cadmium where
    estimates have been made of the minimum concentrations of cadmium in
    the kidney cortex at which evidence of renal damage appears (Friberg
    et al., 1974).

    6.3  Elimination of Lead

        The elimination of lead from the body is thought to be mainly by
    way of the urine and the gastrointestinal tract. Little is known about
    the miscellaneous routes of excretion such as sweat, exfoliation of
    skin, and loss of hair.

    6.3.1  Human studies

        An approximation of the relative contributions of the various
    routes to lead excretion in man has been given by Rabinowitz et al.
    (1973). This study refers to only one non-occupationally exposed human
    subject. Excretions via the kidneys and the gastrointestinal tract
    were measured directly. Loss via other routes, e.g. hair, fingernails,
    and sweat, was estimated from data on the efflux of 204Pb from the
    blood compartment. Losses per day were as follows:

         urine                              38 g (76%)
         gastrointestinal secretions         8 g (16%)
         hair, nails, sweat, other           4 g (8%)

         The figure of 38 g for daily urinary excretion is consistent
    with the data of Teisinger & Srbova (1959). They reported an average
    daily urinary lead excretion of 31 g.

         The mechanism of urinary lead excretion in man is not well
    understood. However, the studies of Vostal (1966) provide strong
    evidence that the process of renal clearance of lead is essentially
    glomerular filtration. Extrapolation of a curve of glomerular
    filtration rate plotted against lead excretion rate resulted in zero
    lead excretion at zero filtration. The form of lead appearing in the
    urine has not been defined. One study suggests that the form in which
    lead appears in the urine depends on whether exposure to lead is
    normal or elevated. Thus, in lead workers with high urinary lead
    excretion, it has been found that only one-half to two-thirds of the
    urine lead can be precipitated with co-precipitating agents such as
    oxalate, phosphate, or carbonate. By contrast, virtually all the lead
    in the urine of people with normal lead exposure can be co-
    precipitated (Dinischiotu et al., 1960). This suggests that a stable
    lead chelate species arises with elevated exposure. Nuclear inclusion
    bodies or lead-protein complexes are found in the urine of children
    with acute lead poisoning (Landing & Nakai, 1959).

         The rate of biliary excretion of lead in man is not known.

         The biological half-time of lead is extremely difficult to
    estimate. The constantly decreasing availability of the major stores
    of lead in osseous tissue makes it virtually impossible to describe
    the rate of loss from the body in simple terms. It is at least clear
    that, in man, clearance of one-half of a body burden of lead would
    require a number of years.

    6.3.2  Animal studies

         Animal data on the routes of lead excretion suggest a
    considerable species variation. In rats (Castellino et al., 1966) and
    in sheep (Blaxter & Cowie, 1946) excretion by biliary and transmucosal
    routes is greater than urinary excretion. On the other hand, the ratio
    of urinary to gastrointestinal lead excretion in the baboon is 2:1
    (Eisenbud & Wrenn, 1970). Vostal (1966) studied the mechanism of lead
    excretion in dogs. In mild chronic intoxication, excretion was by
    glomerular filtration, without evidence of any tubular secretion or
    reabsorption. With more severe poisoning, there was evidence of renal
    tubular reabsorption. Evidence was also presented for a tubular
    secretory mechanism in the chicken.

    6.4  The Metabolism of Alkyllead Compounds

         The characteristic toxic effects of tetraethyllead and
    tetramethyllead are not caused by the tetraalkyl compounds themselves,
    but rather by the trialkyl derivatives formed by dealkylation in the
    liver (Cremer, 1959; Cremer & Callaway, 1961). Tetraethyllead is
    initially converted mainly to triethyllead and partly to inorganic
    lead (Bolanowska, 1968). The triethyllead concentration in organs then
    falls only slowly. Even after several days, there is no significant
    reduction. The behaviour of tetramethyllead is quite similar to the
    behaviour of tetraethyllead. Tetramethyllead is much less toxic
    probably because it is dealkylated to the trialkyl toxic form much
    more slowly than is the case with tetraethyllead (Cremer, 1965).

         Since both these compounds have toxic and biochemical effects
    unlike those of inorganic lead, it is not to be expected that the
    biochemical tests used in assessing inorganic lead exposure would have
    the same significance as in exposure to organic lead. Indeed, in
    severe cases of tetraethyllead poisoning, urinary coproporphyrins and
    ALA excretion are usually not elevated, and free erythrocyte
    porphyrins are only moderately and inconstantly elevated (Gutniak et
    al., 1964; Beattie et al., 1972b). These biochemical tests are
    therefore of little use in short-term exposure situations. But, in
    long-term exposure situations, it is possible that some of them may be
    useful. Indeed, Robinson (1974) has shown that in workers industrially
    exposed to tetraethyllead, the urinary excretion of ALA is increased,
    but not to the same degree as in workers exposed to inorganic lead who
    have equivalent levels of total urinary lead excretion (organic plus
    inorganic). This suggests that some portion of total urinary lead is

    reflecting alkyllead exposure. Bolanowska et al. (1967) demonstrated
    that, in three fatal cases of tetraethyllead poisoning, the ratio of
    inorganic lead to triethyllead ranged from 67:1 to 18:1 in the urine.
    But this ratio did not reflect the ratio of inorganic to triethyllead
    in tissues at all accurately. In tissues, including the brain, the
    ratios were approximately 1:1.

    7.  EXPERIMENTAL STUDIES ON THE EFFECTS OF LEAD

         The major part of published experimental work on animals
    describes or aims to explain pathological or pathophysiological
    changes caused by lead. It does not contribute much to the
    understanding of the relationship between the dose administered, its
    distribution in a period of time, and the biological effect. The doses
    used in most animal experiments have, as a rule, been far above the
    levels that can occur in environmental or occupational contact with
    lead, with the exception of accidental ingestion of soluble lead
    compounds.

    7.1  Animal Studies

    7.1.1  Haemopoietic system

         Experimental studies on the effects of lead on blood and
    haemopoiesis have been carried out essentially to study pathogenic
    mechanisms. There are few studies dealing with the relationship
    between the lead dose and blood changes.

         There is a great deal of evidence showing that lead inhibits
    several enzymes that participate in haem synthesis. Inhibition of
    these enzymes is invoked to explain the rises in haem intermediates
    that occur as a result of lead exposure. Thus, the rise in erythrocyte
    protoporphyrin is readily explained on the basis of the well known
    inhibitory effect of lead on the mitochondrial enzyme ferrochelatase
    (EC 4.99.1.1) (haem synthetase). This action was first proposed by
    Rimington (1938) as the probable explanation for the anaemia in lead
    poisoning. Numerous studies have since confirmed that lead is indeed a
    rather potent inhibitor of haem synthetase (Dresel & Falk, 1954;
    Goldberg et al., 1956; Klein, 1962).

         Although specific inhibition of the enzyme haem synthetase is
    usually invoked to explain the accumulation of protoporphyrin, it is
    also possible that the availability of iron for coupling with
    protoporphyrin is inhibited by lead. It has been shown that lead
    interferes with the transfer of iron from transferrin to human
    reticulocytes (see section 8.2.1). Further support for the idea that
    lead interferes with the availability of iron is to be found in
    studies showing that lead causes accumulation of iron as "ferruginous
    micelles" in developing erythrocytes (Bessis & Jensen, 1965).
    Mitochondrial damage was evident in these studies, suggesting the
    possibility that globin synthesis may be compromised, along with haem
    synthesis.

         The increased excretion of coproporphyrin III in urine is
    suggestive of an inhibition by lead of the enzyme coproporphyrinogen
    oxidase (EC 1.3.3.3), which converts coproporphyrinogen III to
    protoporphyrin IX (PP) (Goldberg, 1972). There is no supportive

    evidence showing a direct inhibitory effect on this enzyme. One would
    imagine that inhibition of coproporphyrinogen oxidase (EC 1.3.3.3)
    would result in decreased blood levels of protoporphyrin IX, however,
    the opposite is true. Perhaps the concurrent rise in erythrocyte
    protoporphyrin, ALA excretion, and excretion coproporphyrin III in
    urine can be explained on the basis of delta-aminolevulinate synthase
    (EC 2.3.1.37) (ALAS) stimulation. Stimulation of ALAS activity by lead
    acetate  in vivo has been demonstrated in the avian hepatocyte,
    probably due to impairment of haem synthesis (Strand et al., 1972). By
    contrast, Gajdos & Gajdos-Trk (1969) found no change in the ALAS
    activity of bone marrow or liver in experimental lead intoxication of
    rabbits.

         Animal studies have been reported concerning ALAD inhibition by
    lead in tissues concurrently with inhibition in the circulating
    erythrocytes. This has been shown in the blood, brain, and liver of
    suckling rats (Miller et al., 1970). After 3040 days of exposure,
    erythrocyte ALAD underwent an 80-90% reduction. The blood lead
    concentration in these rats is not given but can be estimated from
    data in the report. It is stated that a maximum of 3 ml of blood was
    obtained from each rat. It also appears that the blood specimens each
    contained about 4.5 g of lead. Therefore the blood lead concentration
    must have been at least 150 g of lead per 100 ml of blood, and was
    probably nearer to 200.

         In other studies, in which long-term lead exposure of rats
    resulted in about 50% inhibition of erythrocyte ALAD, there was no
    inhibition of brain or liver ALAD (Coulston et al., 1972a): this may
    be due to the fact that the exposure levels were lower in this study
    than in the others cited.

         The question of the significance of lead exposure in relation to
    haemoglobin formation has been studied in dogs by Maxfield et al.
    (1972). These authors were mainly concerned with the question of
    whether the depression of ALAD activity in the peripheral blood was in
    any way associated with depressed formation of haemoglobin. Dogs were
    given lead over a period and the ALAD activity fell to a very low
    level. But the ability of the dogs to regenerate haemoglobin after
    removal of half of the circulating blood volume remained essentially
    normal. Although this indicates that the inhibition of ALAD activity
    in peripheral blood may not be significant, it should be pointed out
    that the lead exposure was not sufficiently high to cause any
    substantial rise in ALA excretion in the urine. ALA excretion was only
    approximately two-three times the baseline level.

         There is evidence that the synthesis of globin is affected by
    lead in animals as well as in man. In an  in vitro study, it was
    shown that the incorporation of 14C-glycine into globin in duck
    erythrocytes was reduced by 25% by a lead concentration of
    5  10-4 M (Kassenaar et al., 1957). The reduction of 14C-glycine
    incorporation into haem was considerably greater.

         Relatively little is known about the effects of lead on the
    formation or activity of other haem-containing compounds in the body.
    There is some evidence, however, that lead can inhibit formation of
    cytochrome P-450, a haemoprotein intimately involved in the drug-
    metabolizing mixed function oxidase system of hepatic microsomes
    (Alvares et al., 1972). Long-term lead administration has also been
    shown to affect the activity of cytochrome  c oxidase (EC 1.9.3.1)
    (Makagev & Verbolovic, 1967; Verbolovic, 1965). The effects seen were
    of a mixed nature, involving first stimulation then depression of
    activity. A decrease was also observed in the myoglobin concentration
    of some muscle groups. It is not clear from these studies whether the
    effects were due to inhibition of haem synthesis or of protein
    synthesis.

         Administration of lead to rats (over a period of 6 months) in
    doses of 2-4 g per rat, resulted in a change in cytochrome  c oxidase
    (EC 1.9.3.1) activity and in the amount of haemoglobin. The magnitude
    of the change increased with larger doses (Verbolovic, 1965). Dogs
    were given a solution of lead acetate over a 2-year period resulting
    in a reduction in the activity of cytochrome  c oxidase (EC 1.9.3.1)
    that was in proportion to the dose of lead administered (Makagev &
    Verbolovic, 1967).

         By means of electron microscopy, Pernis et al. (1964) showed
    grossly swollen mitochondria in the erythrocytes of lead-poisoned
    guinea-pigs, diverse vacuolar formations, and aggregates of molecules
    of ferritin. Electron microscopy of erythrocytes of rabbits receiving
    an intravenous dose of 20 mg/kg of 2% lead acetate solution showed
    vacuolization of the cytoplasm and swelling of the plasma membrane. An
    intensive vacuolization in thrombocytes and a reduction in the
    quantity of organelles, particularly those containing serotonin, also
    took place. In addition, a swelling of mitochondria after the complete
    disruption of cristae was noted (Hacirov, 1972). An experiment on rats
    showed ultramicroscopic changes of mitochondria in the red bone marrow
    cells in the early stages of poisoning.

    7.1.2  Nervous system

    7.1.2.1  Inorganic lead

         In view of recent concern about subtle impairments of cerebral
    function at sub-encephalopathic levels of lead exposure, there has
    been a renewed interest in lead and its toxic effects. High doses of
    lead will produce encephalopathy; this has been reported in cats (Aub
    et al., 1926) and dogs (Staples, 1955).

         The brains showed histopathological features similar to those
    described in human encephalopathy. Others have since reproduced this
    syndrome in the rat (Thomas et al., 1971; Michaelson, 1973; Clasen et
    al., 1974) and in the mouse (Rosenblum et al., 1968; Silbergeld &

    Goldberg, 1974). The effects may be explained on the basis of
    retardation of brain development (Michaelson, 1973; Krigman et al.,
    1974).

         Paraplegia was reported in suckling rats by Pentschew & Garro
    (1966). The disease was produced by transfer of lead from the mother's
    milk until weaning, with subsequent post-weaning feeding of lead to
    the young.

         Behavioural abnormalities such as excessive self-grooming and
    aggressiveness occur, even when the lead intake is reduced to a point
    where paraplegia no longer occurs (Michaelson & Sauerhoff, 1974). It
    was estimated that the minimum daily lead intake causing behavioural
    effects (Michaelson & Sauerhoff, 1974) rose from 0.08 mg/kg body
    weight at birth to 3 mg/kg at day 16 as a result of suckling. Post-
    weaning, this minimum intake rose from 50 mg/kg at day 20 to 60 mg/kg
    at day 28. From day 16 to day 20, intake was difficult to estimate
    since the infant rats were eating and suckling to different degrees.
    Other studies in rats (Snowdon, 1973) and sheep (Carson et al., 1974)
    indicate that offspring of mothers exposed to lead during pregnancy
    show learning defects. Older animals are refractory to this type of
    effect (Brown et al., 1971).

         Future behavioural studies should probably be extended to include
    sub-human primates since it has been shown that the histological and
    clinical features of lead encephalopathy can be produced in both
    infant and adult baboons (Cohen et al., 1972; Hopkins & Dayan, 1974).

         Studies of lead neuropathy in animals indicate that demyelination
    and axonal degeneration are more consistent findings than neuronal
    damage in the anterior horn cells or dorsal root ganglia of the spinal
    cord (Lampert & Schochet, 1968; Schlaepfer, 1969; Fullerton, 1966).
    This is consistent with findings in man. The slowing of nerve
    conduction found in man has also been produced experimentally in the
    guinea-pig (Fullerton, 1966).

         It is known that lead interferes in some manner with synaptic
    transmission in the peripheral nervous system and that the effects can
    be reversed by calcium (Kostial & Vouk, 1957). But, in addition, an
    increased frequency of miniature end-plate potentials has been
    reported (Manalis & Cooper, 1973). Neuromuscular blockade has also
    been demonstrated in the rat phrenic nerve-hemidiaphragm preparation
    (Silbergeld et al., 1974). Again, as in the other studies, the effect
    was antagonized by calcium. The significance of these findings with
    regard to the central nervous system remains to be determined.

         Studies at the biochemical level have been very limited. It has
    been shown, using the "Pentschew model", that incorporation of
    14C-glucose carbon into dicarboxylic amino-acids of the brain is
    reduced (Patel et al., 1974a, 1974b). These results were interpreted
    to indicate delayed brain maturation.

         Recent work in dogs (Stowe et al., 1973) has mapped the variation
    in lead concentrations in different parts of the brain of lead-
    poisoned dogs. The studies show a relationship between areas of the
    most marked histological change and high lead concentration. Male pups
    from the same litter were fed a purified diet, low in calcium and
    phosphorus, with and without 100 mg/kg of lead as lead acetate from
    the age of 6-18 weeks. The concentration of lead in the various brain
    segments is given in Table 21.

    Table 21.  Distribution of lead in the brains of control and
               lead-intoxicated dogsa
                                                               

    Brain segment       Lead concentration (mg/kg of wet tissue)
                                                               
                        Control              Lead intoxicated
                                                               

    Cerebellum          0.160  0.052        0.587  0.113
    Medulla             0.155  0.007        0.713  0.112
    Frontal white       0.053  0.027        0.920  0.156
    Thalamus            <0.10                1.023  0.142
    Occipital white     0.020  0.012        1.030  0.115
    Caudate             0.120  0.083        1.613  0.345
    Frontal grey        0.033  0.015        1.767  0.254
    Occipital grey      0.080  0.071        2.357  0.181
                                                               

    a  "Adapted from Stowe et al., 1973.


    7.1.2.2  Alkyllead compounds

         Unlike the case with inorganic lead, intoxication by
    tetraethyllead in juvenile or adult rats caused a characteristic
    encephalopathy, involving restlessness, ataxia, combativeness
    progressing to convulsions, coma, and death (Davis et al., 1963). In
    dogs there was extensive muscular tremor and twitching, which
    progressed to convulsions, coma, and death.

         Biochemical studies of the respiration of brain slices incubated
    with inorganic lead compared with triethyllead (the active metabolite
    of tetraethyllead) have substantiated the fundamental difference in
    the action of alkyllead compounds on the brain (Cremer, 1959). The
    toxic moieties in tetraethyllead and tetramethyllead poisoning are the
    trialkyl metabolites and not the inorganic lead ion.

         Essentially there is no qualitative difference between the toxic
    effects of tetramethyllead and tetraethyllead. However, there is a
    quantitative difference in that the inhalation LC50 for
    tetramethyllead (8870 mg/m3) is about 10 times higher than that for

    tetraethyllead (850 mg/m3) (Cremer & Callaway, 1961). The
    intravenous LD50 for tetraethyllead is about 10 mg of lead per kg of
    body weight in the rat (Cremer, 1959). This is in contrast to the
    intravenous LD 50 for inorganic lead, which is approximately 70 mg/kg
    in the rat (Fried et al., 1956). The precise manner in which the
    trialkyllead ion acts to cause altered brain function is not clearly
    known but the mechanism may involve inhibition of amine oxidase
    (flavin-containing) (EC 1.4.3.4) (monoamine oxidase) (Galzigna et al.,
    1964). In rabbits, administration of toxic doses of tetraethyllead
    results in a loss of copper, iron, and zinc in certain areas of the
    brain (Niklowitz & Yeager, 1973), suggesting that triethyllead may act
    by displacing certain essential trace metals from metalloenzymes in
    the brain.

         Tetramethyllead injected into rats in overtly neurotoxic doses
    did not depress ability to learn a simple task (Bullock et al., 1966).

    7.1.3  Renal system

         Animal studies have contributed to an understanding of the order
    of appearance of the various manifestations of renal toxicity in lead
    exposure. The spectrum and train of events as related to the exposure
    time and to the dose of lead have recently been reviewed (Goyer &
    Rhyne, 1973). In the earliest stage of renal response to lead
    exposure, reversible tubular effects occur. These include the
    appearance of intranuclear inclusion bodies, which is probably a
    mechanism for sequestration of lead. These bodies have been isolated
    and found to be composed of a lead-protein complex. The protein is
    insoluble in physiological solutions and is rich in acidic amino
    acids. It has not been characterized further (Moore & Goyer, 1974).
    The intranuclear inclusion bodies appear to have a high and specific
    affinity for lead compared with that for calcium, iron, zinc, copper
    or cadmium and about 90% of the lead in the kidney is associated with
    them (Goyer et al., 1970a; 1970b).

         The appearance of these bodies is accompanied by amino aciduria,
    glycosuria, and hyperphosphaturia. Morphological and functional
    changes in tubular epithelial cells also occur at this stage,
    including impaired respiratory and phosphorylative ability.

         After further lead administration, more severe changes occur in
    the renal tubular epithelium such as hyperplasia and cystic changes.
    There is a progressive increase in interstitial fibrous tissue and
    atrophy of tubular cells. These are irreversible changes that lead to
    a third stage of renal failure, manifested by azotaemia and
    hyperuricaemia. Sclerotic glomeruli appear, but the hypertension seen
    in some cases of chronic lead nephropathy in man has not been
    reproduced in experimental animals. The sequence described above in
    animals is probably generally valid for man.

    7.1.4  Gastrointestinal tract

         The effects of lead on the gastrointestinal tract have been
    studied in some detail in the guinea-pig (Mambeeva & Ahmiedova, 1967).
    Spastic contractions occurred from the stomach to the jejunum.
    Inhibitory effects were also noted, accounting for the frequent
    constipation seen to accompany lead colic.

    7.1.5  Cardiovascular system

         Experimental animal data on the question of hypertension are
    conflicting. Among rats given 70 mg of lead acetate per day orally,
    only a few survived 40 days and all were hypertensive (Griffith &
    Landauer, 1944). Hypertension has also been produced in the rabbit
    (Beckmann, 1925). Others have not seen hypertension with lead exposure
    in rats (Padilla et al., 1969) or dogs (Fours & Page, 1942). From all
    the above animal studies it seems that hypertension can occur with
    heavy lead exposure.

         There are conflicting reports regarding whether lead can cause
    atherosclerosis in experimental animals. Sroczynski et al. (1967)
    observed increased serum lipoprotein, cholesterol, and cholesterol
    deposits in the aortas of both rats and rabbits receiving large doses
    of lead. On the other hand, Prerovska (1973) did not produce
    atherosclerotic lesions in rabbits using similar doses of lead given
    over an even longer period of time.

         Cardiac myopathy has also been shown experimentally in lead-
    intoxicated rabbits (Kosmider & Sroczynski, 1961). The mechanism for
    this effect is not known.

         Kuz'minskaja (1964) and Mironcik & Timofeeva (1974) observed that
    rabbits receiving lead after a cholesterol load showed more intense
    sclerotic changes in the aorta and myocardium than rabbits on a normal
    diet without lead, or than rabbits given cholesterol alone.

         Makasev & Krivdina (1972) observed a phased change in the
    permeability of blood vessels (first phase-increased permeability;
    second phase-decreased permeability) in rats, rabbits and dogs, that
    received a solution of lead acetate. A phased change in the content of
    catecholamines in the myocardium and in the blood vessels was observed
    in subacute lead poisoning in dogs (Mambeeva & Kobkova, 1969). This
    effect appears to be a link in the complex mechanism of the
    cardiovascular pathology of lead poisoning.

    7.1.6  Respiratory system

         Alveolar macrophages from guinea-pigs are damaged  in vitro by
    inorganic lead compounds (3 g/1  106 cells) thus releasing a
    rapidly occurring lysis and a slowly developing, coarsely blistered
    vacuolization. More than 90% of the cells are damaged within 20 hours
    (Beck et al., 1973).

         Similar effects seem to occur in the organism, since in rats that
    had inhaled 10 g lead/m3 for 3-12 months, the number of macrophages
    that could be flushed from the lungs was reduced by 60% (Bingham et
    al., 1968).

         Electron microscope investigations of the lungs of rats that had
    been exposed for 14 days to concentrations of 100-200 g of lead
    oxide/m3 revealed toxic effects in the alveolar macrophages and the
    type I alveolar epithelial cells. The structures of the endoplasmatic
    reticulum and mitochondria were changed (Bruch et al., 1973).

         In the lungs, the alveolar macrophages have the capacity to
    degrade noxious substances and are important for other defence
    reactions. The ability of alveolar macrophages of guinea-pigs that had
    inhaled concentrations of 70-170 g of lead per m3 of air for four
    days, to degrade benzopyrene was distinctly decreased, the benzopyrene
    3-monooxygenase (1.14.14.2) activity being only about 10% of the
    original value. The activity returned to normal after three days
    without any lead exposure (Bruch et al., 1975). The elimination of
    bacteria from the lungs was also reduced, when rats were exposed to
    70 g of lead per m3 of air (Schlipkoter et al., 1977).

    7.1.7  Reproductive system

         Animal studies support the contention that behavioural
    deficiencies can occur in infants and newborn as a result of
    intrauterine exposure to lead via their mothers (see section 7.1.2).
    Others have shown a reduction in the numbers and size of offspring
    (Dalldorf & Williams, 1945; Puhae et al., 1963). Data in rabbits (Cole
    & Bachhuber, 1914), guinea-pigs (Weller, 1915), and rats (Stowe &
    Goyer, 1971) indicate that paternally-transmitted effects can occur,
    including reductions in litter size, weights of offspring, and in
    survival rate. Several investigators have reported that oral
    administration of lead to animals even at doses in the microgram per
    kilogram range can cause changes in spermatogenesis (Egorova et al.,
    1966; Golubovid et al., 1968), and an increase in testicular RNA and
    DNA content (Golubovic & Gnevkovskaja, 1967; Golubovic et al., 1968).

    7.1.8  Endocrine organs

         The effects of lead on thyroid function that have been reported
    in man have also been demonstrated experimentally in rats (Zel'tser,
    1962; Sandstead, 1967).

    7.1.9  Carcinogenicity

    7.1.9.1  Inorganic lead compounds

         The carcinogenic risk to man of lead salts and the relevant
    studies in animals have recently been discussed in an IARC publication
    (IARC, 1972).

         The induction of benign and malignant renal neoplasms has been
    observed in both Swiss mice and rats fed on diets containing 100 or
    1000 mg of basic lead acetate (Pb(C2H302)2. 2Pb(OH)2) per kg
    of diet (Van Esch & Kroes, 1969; Van Esch et al., 1962; Mao & Molner,
    1967; Azar et al., 1973). Similar results were observed in rats fed
    1000mg of lead acetate (Pb(C2H302)2. 3H20) per kg of diet
    (Boyland et al., 1962). In addition to renal neoplasms, tumours of the
    testes, the adrenal, thyroid, pituitary, and prostrate glands and of
    the brain have been reported in rats fed lead acetate or basic lead
    acetate, but the results await confirmation (Zawirska & Medras, 1968;
    Oyasu et al., 1970). Rats given intraperitoneal or subcutaneous
    injections of lead phosphate also developed renal tumours. Total doses
    of 120-680 mg of lead were effective (Zollinger, 1953; Roe et al.,
    1965). No kidney tumours were reported in hamsters fed 100 or 500 mg
    of basic lead acetate per kg of diet for up to 2 years (van Esch &
    Kroes, 1969).

         In Syrian golden hamsters given a combination of lead oxide and
    benzo[a]pyrene intratracheally once weekly for 10 weeks, lung adenomas
    occurred in 11/26 animals within 60 weeks. One adenocarcinoma of the
    lung was also observed. Such tumours did not occur in animals given
    the same dose of lead oxide or benzo[a]pyrene alone (Kobayashi &
    Okamoto, 1974).

    7.1.9.2  Alkyllead compounds

         Epstein & Mantel (1968) reported that subcutaneous injection of
    0.6 mg of tetraethyllead (given as 4 equally divided doses) to Swiss
    mice between birth and 21 days of age produced malignant lymphomas in
    1/26 males and 5/41 females, compared with 1/39 and 0/48 controls. In
    treated females, the tumours were observed between 36 and 51 weeks
    after the first injection. The significance of this finding in female
    mice is difficult to assess since this tumour occurs frequently and
    with variable prevalence in untreated mice of this strain.

    7.1.10  Mutagenicity

         Chromosomes from leukocyte cultures from mice fed 1% lead acetate
    in the diet showed an increased number of gap-break type aberrations
    (Muro 8,: Goyer, 1969). These changes involved single chromatids,
    suggesting that injury followed DNA replication.

    7.1.11  Teratogenicity

         There have not been any adequate animal studies to provide
    evidence to support the suggestion that lead may have a teratogenic
    effect.

    7.2  Acquisition of Tolerance to Lead

         Although human studies suggest that there is no acquired
    tolerance in regard to haem-synthesis mechanisms, there may be for
    other toxic effects. In this regard, it is interesting to note that
    the blood lead level at which cattle develop severe encephalopathy
    from eating paint is often less than 80 g/100 ml (Hammond et al.,
    1956). However, in cattle receiving 5-6 mg of lead per kg per day
    orally, the concentration of lead in the blood exceeded 100 g/100 ml
    within 2-4 months and remained at about that level for as long as four
    years with continuous administration, without any apparent harm to the
    animals (Allcroft, 1951). In these studies, haemoglobin did not fall
    until a terminal illness developed. Hapke (1974) found that in cattle
    and sheep the sensitivity to acutely toxic amounts of lead was reduced
    by a pretreatment with lead for 5 months. Goyer et al. (1972) have
    suggested from their studies on rats that the intranuclear inclusion
    bodies that develop during lead exposure serve as a protective
    mechanism by binding lead in the kidney, making it less toxic. But in
    the recent study of Cramer et al. (1974) (see section 7.1.3) it was
    shown that renal intranuclear inclusion bodies are present only in
    workers exposed to lead for a relatively short period of time. Thus,
    if inclusion bodies serve some protective function, it is only during
    a limited period of exposure. The formation of the cadmium-binding
    protein, metallothionein, which appears to have a protective role in
    cadmium exposure, is induced by a number of metals but not by lead
    (Webb, 1972).

    7.3  Factors Influencing Lead Toxicity

    7.3.1  Age and sex

         It has recently been reported that the intraperitoneal lethal
    dose of lead in rats is significantly lower for adult male rats than
    for adult female rats (Kostial et al., 1974). In the same study, it
    was observed that the lethal dose in mg/kg body weight for 3-week-old
    rats was about the same as for adult females.

    7.3.2  Seasonal variations

         The same seasonal pattern of high incidence of poisoning has been
    reported in dogs belonging to urban families as has been reported in
    children (Zook et al., 1969). It has also been shown experimentally in
    rats and mice (Baetjer, 1959; Baetjer & Horiguchi, 1963) and in
    rabbits (Blackman, 1937; Horiuchi et al., 1964) that susceptibility is
    greater at high ambient temperatures than at normal temperatures.

    7.3.3  Nutrition

         Experimental studies have shown that nutritional factors may
    influence the absorption of lead from the gastro-intestinal tract and
    thus alter susceptibility to the toxic effects of lead (Goyer &
    Mahaffey, 1972). Low phosphorous and calcium in the diet (Sobel et
    al., 1938b; Six & Goyer, 1970), high vitamin D (Sobel et al., 1938a),
    and low iron (Mahaffey, 1974) all enhance lead absorption. The amount
    and the composition of dietary protein may also influence lead
    toxicity. Low protein diets appear to increase the susceptibility to
    lead intoxication as compared to high protein diets (Baernstein &
    Grand, 1942; Goyer & Mahaffey, 1972).

         The significance of these findings for the susceptibility of
    people to lead poisoning has not been established. However, many
    children, even in developed countries like the USA, have sub-optimal
    dietary intakes of calcium, iron, and other nutrients (US Department
    of Health, Education and Welfare, cited by Mahaffey, 1974). This may
    have a bearing on the problem of increased lead absorption frequently
    found in children in poor, urban areas.

    7.3.4  Intercurrent disease, alcohol, and other metals

         High lead exposure increases the susceptibility of mice to
     Salmonella typhimurium infection (Hemphill et al., 1971). Lead
    administration also increases the susceptibility of rats (Filkins &
    Buchanan, 1973; Selye et al., 1966; Erve & Schumer, 1972), mice
    (Clercq de & Merigan, 1969), and baboons (Hoffman et al., 1974) to
    endotoxin shock, but such studies have been performed using extremely
    large intravenous doses of lead simultaneously with the endotoxin.

         Administration of ethanol (10%  ad libitum in drinking water)
    had no effect on the toxicity of lead to rats as measured by urinary
    ALA excretion, renal weight, or lead concentration in the kidneys,
    liver, or bones (Mahoffey, 1974).

         Very little is known about metal interactions and how they might
    affect the toxicity of lead, except at the nutritional level (see
    section 7.3.3). Beyond that, a synergistic effect has been noted
    between lead and cadmium with regard to experimental teratogenesis
    (Ferm, 1969). It was also found that zinc, given in the diet with
    lead, protected horses against the toxic effects of lead. Probably,

    this effect was not due to inhibition of lead absorption. Zinc
    supplementation actually caused an increase in the lead content of
    liver and kidney, but a decrease in the lead content of brain and bone
    (Willoughby et al., 1972). It might be inferred that zinc displaced
    lead from lead-inhibited enzymes that are zinc-dependent, such as ALAD
    (Cheh & Nellands, 1973). A dose-dependent effect of zinc, antagonistic
    to the depression of ALAD by lead, has recently been shown  in vivo
    and  in vitro as well as an  in vitro antagonism of zinc on the
    cytotoxic effect of lead on macrophages (Schlipkter et al. 1975;
    Ruiter de et al. 1977).

    7.4  Human Studies

         Planned experimental studies on the effects of lead in man are
    sparse. Kehoe (1961), in his famous experimental studies, in which
    human volunteers were exposed to a known amount of lead over various
    periods of time, confined himself to studying the lead balance only,
    and did not report on the effects of lead.

         Three subjects ingested 1 and 3 mg of lead daily, in the form of
    lead (II) nitrate, for 33 weeks. The ALA-U, CP-U, and erythrocyte
    protoporphyrin IX were measured regularly while Pb-B and Pb-U
    measurements were performed at irregular intervals (Schlegel et al.,
    1973). Exposure from food and ambient air was not controlled during
    the experiment. A rise in FEP was obtained with both doses and a rise
    in ALA-U and CP-U only with the 3 mg dose. Evaluation of the results
    obtained in this study is difficult, partly because of the small
    number of subjects studied and partly because the results were rather
    erratic.

         Coulston et al. (1972b; 1972c) conducted two exposure chamber
    experiments on male volunteers (see section 6.1.1.2). The volunteers
    were exposed to air lead concentrations with an average of 10.9 and
    3.2 g/m3 for up to 17 weeks. In the 10.9 g/m3 exposure study, 24
    volunteers participated, 6 of whom served as controls. In order to
    control dietary lead exposure, total diet for one full day was
    collected at intervals of eight days; the results indicated an average
    lead intake of about 110 g/day only. The variables measured were the
    Pb-B, ALAD, ALA-U, and CP-U. Blood lead levels increased in all of the
    exposed men and appeared to stabilize after about 2 weeks of exposure.
    The mean Pb-B level at that time was about double the pre-exposure
    mean, i.e., an increase from 19 to 37 g/100 ml. A concomitant
    increase of the urinary excretion of lead was reported; the faecal
    excretion remained unchanged however. The rise in blood lead levels
    was followed by a decrease in ALAD activity, which after 5 weeks of
    exposure was about 50% of the pre-exposure level. No change in ALA-U
    and CP-U was reported. Five months after the termination of the
    exposure, all but one of the participants had Pb-B values similar to
    those before exposure. The ALAD activity returned to normal almost
    immediately after cessation of exposure. No changes in the haemoglobin

    level were noted during the experiment. In the 3.2 g/m3 experiment
    a rise in the Pb-B level from 20 to 26 g/100 ml was obtained,
    followed by a slight decrease in ALAD activity, which after five weeks
    of exposure was about 85% of the pre-exposure level. Other changes
    were not reported.

         In a recent experimental study, a greater susceptibility to
    inorganic lead was demonstrated in females (Stuik, 1974; Stuik &
    Zielhuis, 1975). The volunteers were healthy male and female students
    aged 18-26 years. Groups of 5 males and 5 females received 20 g of
    lead per kg per day orally for 21 days. Lead was administered as lead
    acetate in glycerol.

         The control blood lead levels remained fairly constant at
    approximately 17 g/100 ml during the experiment. The exposed male
    subjects showed an increase from 20.6 g/100 ml to 40.0 g/100 ml at
    the end of the second week of exposure (40.9 g/100 ml in the third
    week). The blood lead in females rose from 12.7 g/100 ml to
    30.4 g/100 ml, the highest level being reached in the first part of
    the third week.

         The protoporphyrin IX content of the erythrocytes showed no
    change in either the control or the exposed male group. However, in
    the female group, it showed a rise beginning in the third week and
    rising to 48.0 g/100 ml erythrocytes. The findings were confirmed in
    a second experiment.

         It is suggested that the increase of the erythrocyte
    protoporphyrin IX was a result of interference in the use of iron in
    the formation of haemoglobin. The synergism of lead exposure and iron
    deficiency might be suggested as being responsible for the increased
    response of FEP in females but this will have to be tested further in
    experimental and epidemiological work.

    8.  EFFECTS OF LEAD ON MAN-EPIDEMIOLOGICAL AND CLINICAL STUDIES

         Two types of study characterizing the effects of lead on man have
    been reported:

    --   retrospective studies of the causes of mortality and morbidity in
         lead-exposed populations compared with unexposed populations, and

    --   studies of the effects of lead on specific organs and systems.

         The findings from these two types of study will be considered
    separately. In both cases, the main objective will be to establish, as
    far as possible, the dose of, or exposure to lead which is associated
    with specified effects, and the frequency of such effects.

         From the toxicological point of view, "the dose should be defined
    as the amount or concentration of a given chemical at the site of
    effect, i.e. where its presence leads to a given effect" (Nordberg
    ed., 1976). The application of this definition is difficult because
    the dose as defined above can rarely be measured directly and has to
    be estimated in various ways. In experiments, it is estimated from the
    amount injected or ingested or from dermal and other topical
    applications (using appropriate absorption factors and body
    distribution factors). In inhalation experiments it is estimated from
    the concentration as measured in air, the time of exposure, and the
    relevant deposition, retention, and absorption factors (if available).
    The same considerations apply for dose estimation from occupational
    exposure where, in addition to inhalation, the possible dermal
    exposure, ingestion during work-time, and exposure which workers are
    subject to as members of the general population, should be taken into
    account. The dose for the general population is estimated from
    inhalation of air, ingestion of food, water, and other beverages, and
    various other contacts, including drugs and consumer products,
    smoking, and in children, ingestion of soil, settled dust, and paint
    chips. A more direct way of estimating the dose is from measurements
    in body tissues and fluids such as blood, urine, faeces, sweat, or
    hair. Other organs, tissues, cells, and subcellular elements can be
    used for this purpose in animal experiments or in autopsy or biopsy
    material.

         Although the biological effects of lead on man have been
    characterized in some detail, the precise doses of lead responsible
    for the effects are rarely, if ever, known. With all its acknowledged
    shortcomings, the Pb-B level is the vital link between exposure and an
    effect. In section 6, an effort was made to define, as far as
    possible, the relationship between the lead in air and in the diet and
    Pb-B levels. The main objective of this section is to establish the
    relationship between Pb-B levels and biological effects. Only in this
    way is it possible to estimate the possible biological consequences of
    specific levels of lead in environmental media.

         Some biological effects of lead bear a close relationship to
    concurrent Pb-B levels, others do not. Thus, the degree of ALAD
    inhibition in peripheral blood rises and falls more or less
    concurrently with the Pb-B level, while some renal effects of lead are
    the consequence of an exposure to lead that may have occurred at a
    point remote in time and which is not reflected in the Pb-B level at
    the time the effect is first manifested clinically. The fidelity with
    which the Pb-B level reflects lead concentrations in target organs is
    subject to serious problems of analytical error as described in
    section 3.

         Beyond these considerations, there is the additional problem of
    variation in the inherent susceptibility of individuals, and the
    influence of co-existent variables that may modify this
    susceptibility, such as nutritional status, age, and presence or
    absence of diseases such as alcoholism. For all the above reasons, the
    Pb-B level cannot be used as a reliable indication of dose or exposure
    in dealing with individual patients. They should be used only in
    assessing population group exposures at which effects may occur in a
    certain proportion of individuals.

         Other tests for assessing dose have been proposed, e.g. lead
    excretion in response to chelating agents. Regardless of potential
    merits and special applications, most information relating health
    effects to dose has been obtained using Pb-B levels as an estimate or
    index of dose.

    8.1  Retrospective Studies of Lead-exposed Populations

    8.1.1  Epidemiology of lead poisoning in industry

         In many countries there has been a considerable improvement over
    the past forty years with respect to hygienic conditions in the lead-
    using industries. The exposure of workers to lead was considerably
    higher before 1930 than after. In the United Kingdom, the number of
    reported cases of poisoning fell dramatically in the decade 1920-30
    (Lane, 1964). Against this background, it is useful to consider the
    studies of Dingwall-Fordyce & Lane (1963). They found a higher than
    expected incidence of death due to cerebrovascular disease among men
    with past high lead exposure. The men studied retired from work
    between 1926 and 1960. All those studied had at least 25 years of
    service. Men in the heavy exposure category had an average urine lead
    concentration of 100-250 g/litrea over the last 20 years of

              

    a  100 g/litre corresponds to a Pb-B level of approximately
       60 g/100 ml and 250 g/litre corresponds to a Pb-B level of
       approximately 120 g/100 ml (Williams et al., 1969).

    employment. Men in the moderate exposure group had urine lead
    concentrations in the normal range. The third group had no exposure.
    As can be seen from Table 22, in the heavy exposure group deaths from
    cerebrovascular diseases (cerebral haemorrhage, thrombosis, and
    arteriosclerosis) were much higher than normal.

         The data also suggest that in this group the excessive death rate
    was most pronounced among men who retired prior to 1951 when exposure
    conditions were probably considerably worse than they were later. In
    the same study, it was found that the death rate from malignant
    neoplasms was not above the expected rate in any exposure grade.
    Unfortunately, the incidence of death due to chronic nephritis was not
    reported. A very similar survey was reported by Malcolm (1971) in
    which the subjects studied had, with few exceptions, been exposed to
    lead at moderate levels (average Pb-B level-65 g/100 ml). There was
    no statistically significant excess mortality in any of the following
    disease categories: heart disease, chest disease, cerebrovascular
    accidents, cancer, renal disease, and "miscellaneous".

         A recent American study is in general agreement with the
    conclusions of the British investigators concerning longevity and
    causes of death in the lead industries as they have operated over the
    last 25-30 years (Tabershaw & Cooper, 1974; Cooper & Gaffrey, 1975).
    The subjects were 1356 workers employed in the lead battery and
    smelter industries from 1946 to 1970. Both blood lead levels and
    urinary lead excretion were quite high. For example, 78.7% of 47
    smelter workers had Pb-B levels of 80 g/100 ml or more, from 1946 to
    1961. The figure was still 13.5% after 1965 (489 total workers
    sampled). The percentage of battery workers with Pb-B levels above
    this was somewhat lower. But for all the various categories of
    duration of employment and type of work, 81.5-95.7% of the Pb-B levels
    were equal to or greater than 40 g/100 ml. About 50% of the workers
    were employed for more than 10 years. The total mortality in this
    group was approximately the same as in the general population. The
    authors concluded that there was no evidence that work associated with
    lead increased the risk of death due to the major categories of
    cardiovascular and renal diseases. However, when chronic renal disease
    (chronic nephritis or other renal sclerosis) was segregated as a
    separate cause of death, there did appear to be a significant excess
    number of deaths. Thus, among smelter workers, the ratio of observed
    deaths to expected deaths was 7:2.8 and among the battery workers the
    ratio was 14:8.6. A similar association was found for a category of
    death classified as "other hypertensive disease": 7:1.9 among smelter
    workers and 13:6.3 among battery workers. For the two disease
    categories this adds up to 21 excess deaths out of 1267 for whom cause
    of death was listed. The authors emphasize that many of the workers in
    the study group were probably exposed to air lead concentrations
    considerably in excess of 0.15 mg/m3.


        Table 22.  Deaths from cerebrovascular disease in retired and employed workers from a lead industrya
                                                                                                                     

    Status         Year of        Grade of exposure
                   death                                                                                             
                                  None                          Medium                        Heavy
                                                                                                                     
                                  Expected       Observed       Expected       Observed       Expected      Observed
                                  incidence      incidence      incidence      incidence      incidence     incidence
                                                                                                                     

    Retired        1926-50        0.7            0              0.2            3              0.8            5
                   1951-61        7.2            6              3.2            3              8.5           19
                   1926-61        7.9            6              3.4            6              9.3           24b
    Employed       1946-61        3.2            3              3.1            3              5.6            9
                                                                                                                     

    a  Adapted from Dingwall-Fordyce & Lane, 1963.
    b   P <0.001.
    

         Although most epidemiological studies on occupational exposure
    have been carried out on industrial populations, one extensive study
    on orchard workers in the Wenatchee area of the state of Washington,
    has been reported (Neal et al., 1941). This study was somewhat
    complicated by the fact that exposure was to lead arsenate. In view of
    the known toxicity of arsenic, studies were included on the combined
    toxicities of lead and arsenic in animals. No synergism was found in
    these animal studies (Fairhall & Miller, 1941). The blood lead
    concentrations of the orchard workers and their families are
    summarized in Table 23.

         This study may have been crude in comparison to some more recent
    ones, but it had the rather unique merit of examining health effects
    not only in men, but also in women and children. Furthermore, the
    exposure levels, as reflected in the urine and blood data of Table 23,
    were only slightly higher than the approximate upper limit for people
    living in highly polluted cities today. The study was concerned with
    weight, blood pressure, diseases of the cardiovascular system, skin
    disorders, eye irritation, chronic nervous diseases, blood dyscrasias,
    kidney diseases, neoplastic diseases, and fertility. There was no
    evidence, based on data available at the time, that the health profile
    of these people was any different from that of the general population.

         In 1968, a follow-up study was undertaken of the people who had
    participated in the original study (Nelson et al., 1973). Over 97% of
    the original participants were successfully traced. There had been 452
    deaths among the 1231 original participants. A life table method of
    analysis of the standard mortality ratio was used. The overall
    mortality was less than the average for the state of Washington. The
    standard mortality ratios of exposed groups were not consistent with
    the exposure gradient. The mortality pattern for increasing duration
    of exposure was not consistent either.

    8.1.2  Epidemiology of lead poisoning in the general adult population

         Adequate studies of the relationship between lead exposure and
    health status in the general adult population have not been carried
    out. The limitations that apply to the epidemiological studies of
    occupational groups are magnified when applied to the general
    population. The range of exposure levels is smaller between sub-groups
    of the general adult population and their socioeconomic,
    physiological, and health profiles are probably more diverse.

    8.1.3  Epidemiology of lead poisoning in infants and young children

         There has been only one study reported of general mortality and
    disease-specific morbidity rate in children exposed to lead. The
    Wenatchee study referred to in section 8.1.1 included 146 children
    under the age of 15. As with the adults in this study, no abnormal
    pattern of disease incidence was noted. These children had moderately
    high lead exposure (see Table 23).


        Table 23.  Urine and blood lead content of persons in the Wenatchee study according to 
               severity of exposurea
                                                                                                      

    Group                    Urine lead content                     Blood lead content
                                                                                                      
                             No.          Average,     S.D.         No.          Average,    S.D.
                             analyses     g/litre     g/litre     analyses     g/100 ml   g/100 ml
                                                                                                      

    Low exposure
      men                      146           35          21          148           26          11
      women                    123           28          19          124           26          10
    Intermediate exposure
      men                      102           43          30          108           30          11
      women                     25           27          15           27           22          10
    High exposure
      men                      386           88          60          329           44          16
      women                     61           46          25           58           34          13
    Children under
        15 years
      boys                      81           53          39           17           37          15
      girls                     65           54          40           14           36          10
                                                                                                      

    a  "From Neal et. al., (1941).
    

    8.2  Clinical and Epidemiological Studies of the Effects of Lead on
         Specific Organs and Systems

         In the following discussion of the effects of lead on various
    organs and systems, consideration will be given to dose-effect and
    dose-response relationships. The word "dose" as used here will refer
    to Pb-B levels, as described in the introductory remarks of this
    chapter.

         The diversity of the effects of lead on haemoglobin formation and
    the complexity of the process itself make it difficult to determine
    which inhibitory effect is most sensitive and what is their relative
    importance at different levels of exposure (or dose).

         Dose-effect refers to the relationship between dose and the
    intensity of a specified effect in an individual, e.g. Pb-B level
     versus percentage inhibition of blood ALAD.

         Dose-response refers to the relationship between the dose and the
    proportion of a population showing a defined effect, specified as to
    the level of intensity, e.g. the proportion of a population showing
    more than 50% inhibition of blood ALAD at a Pb-B of 20 g/100 ml.

         Some effects of lead are not graded, for example, the effects on
    the kidney and the central nervous system are usually reported in all-
    or-none terms, i.e. a certain proportion of individuals in a
    population are reported to have shown the effect at a given range of
    Pb-B concentrations. With many effects of lead it is difficult to
    specify a dose-response or a dose-effect relationship because the
    available data are inadequate.

    8.2.1  Haemopoietic system

         The evidence for disturbances in haem synthesis is clearly shown
    in man by the appearance of abnormal concentrations of haem precursors
    in blood and urine. The levels of lead exposure at which these various
    manifestations of disturbed haem synthesis first appear have been
    studied extensively in man. The sequence of reactions affected by
    lead, and the consequences thereof, are shown in Fig. 5.

         Lead interferes with the biosynthesis of haem at several
    enzymatic steps, with the use of iron, and with globin synthesis in
    erythrocytes. Inhibition of ALAD and haem synthetase is well
    documented, and accumulation of the substrates of these enzymes (ALA
    and PP) is characteristic of human lead poisoning. Inhibition of ALAS
    is based on experimental evidence only. Whether there is enzymatic
    inhibition or whether other factors affect the conversion of
    coproporphyrinogen III (CPG) to protoporphyrin IX (PP) is not clear;
    nevertheless, increased urinary excretion of coproporphyrin III is

    FIGURE 3

    prominent in human lead poisoning. Minor increases in porphobilinogen
    (PBG) and uroporphyrins in urine are occasionally reported in severe
    lead poisoning. Although the  in vivo mechanisms are not clear,
    nonhaem iron (ferritin and iron micelles) accumulates in red blood
    cells with damaged mitochondria and other fragments not found in
    normal mature erythrocytes. Serum iron may be increased in persons
    with lead poisoning, but without iron-deficiency states. Globin
    synthesis in red blood cells is apparently impaired, although the
    mechanisms responsible for reduced globin synthesis remain unknown.

         The evidence available suggests that mild anaemia with a small
    reduction in blood haemoglobin may occur at, or slightly above, dose
    levels that are associated with minimal increases in urinary excretion
    of ALA, (Tola et al., 1973).

         Increased urinary excretion of ALA is accompanied by an elevation
    of the concentration in plasma in adults (Cramer et al., 1974) and in
    children (Chisolm, 1968a). This could indicate either an increased
    rate of ALA formation or a decrease in the rate of use of ALA. In view
    of the well-known inhibition of the enzyme ALAD, most authorities
    favour the view that elevated plasma levels reflect decreased use of
    ALA. The alternative possibility is that ALA formation is increased,
    presumably by increased formation or activity of the enzyme ALA-
    synthetase (ALAS). This may in fact be a significant factor. Berk et
    al. (1970) studied the rate of haem labelling in one case of lead
    poisoning with anaemia. They observed an increase in the rate of
    14C-glycine incorporation into the "early labelled peak" of
    stercobilin, and into haemin, indicating an increased rate of haem
    synthesis in response to an anaemia due to increased erythrocyte
    destruction. Coproporphyrin (CP) and ALA excretion were both elevated.
    This indicates that haem biosynthesis may be increased in lead
    poisoning in spite of increased excretion of haem precursors.

         It is also possible that the rate-limiting step in the
    pathogenesis of lead-induced anaemia may involve globin synthesis
    rather than haem synthesis. White & Harvey (1972) reported that the
    incorporation of 3H-leucine into alpha- and -chain globins of
    reticulocytes was differentially affected in a pair of 3-year-old
    twins with clinical lead poisoning accompanied by anaemia. The
    radioactivity associated with the different globin chains shifted
    systematically as the blood haemoglobin values of the children
    returned towards normal.

         The major effects of lead on haemopoiesis that are readily
    measured in man, are on the rate of excretion of ALA or CP in the
    urine, on the concentration of PP in the blood, and on the degree of
    inhibition of ALAD in the blood. None have been evaluated in relation
    to the fidelity with which they reflect the actual amount of lead
    absorbed per unit time, but they have been evaluated extensively with

    reference to their correlation with the concentration of lead in the
    blood. The literature since 1955, concerned with these
    interrelationships, has been reviewed recently by Zeilhuis (1971).

    8.2.1.1  delta-aminolevulinic acid dehydratase (ALAD)

         The effect of lead that most closely correlates with the
    concentration of lead in the blood is the inhibition of erythrocyte
    ALAD activity. Within the range of lead exposure encountered in the
    general population, the higher the concentration of lead in the blood,
    the lower the activity of the enzyme. Above this range, enzyme
    inhibition is almost complete and changes little with increasing dose.
    The relationship between Pb-B levels and ALAD activity was first
    reported by Makao et al. (1968) in a group of twelve men industrially
    exposed to lead. Later, Hernberg et al. (1970) reported on a much
    larger population of adults having a wide range of lead exposures.
    Granick et al. (1973) suggest the interesting possibility of
    correcting for individual variations in total ALAD by calculating the
    ratio of activity with,  versus activity without, enzyme reactivation
    using dithiothreitol as a reactivator. This calculation presumably
    expresses the inhibitory activity of lead for the particular sample.
    The normalization procedure improved the correlation between ALAD and
    blood lead. They found that the average no-effect Pb-B level for
    inhibitory effects in children, using this correction procedure, was
    about 15 g/100 ml. Tola (1973) reached a similar conclusion from his
    study of 1370 workers. His observations suggested that the average
    threshold was at a Pb-B level of 10-20 g/100 ml. However, a recent
    study on the Finnish general population puts the existence of a no-
    effect level into some doubt. In their study, Nordman & Hernberg
    (1975) obtained a statistically significant correlation between ALAD
    activity and Pb-B values not exceeding 10 g/100 ml (Pb-B mean value
    8.4 g/100 ml).

         Based on data concerning male workers and children, Zielhuis
    (1975) calculated a dose-response relationship for over 40% and over
    70% inhibition of ALAD (see Table 24).

    8.2.1.2  Free erythrocyte porphyrins (FEP)

         The most recently identified biochemical correlate of blood lead
    concentration is the erythrocyte protoporphyrin concentration. Some of
    the analytical methods in use (see section 2.2.3) measure the
    protoporphyrin IX concentration in erythrocytes, while others measure
    the free erythrocyte porphyrins, more than 90% of which, however,
    consists of protoporphyrin IX (Baloh, 1974). A correlation between FEP
    and Pb-B levels has been reported for industrial workers (Haeger-
    Aronsen, 1971). The dose-effect relationship is linear if log FEP is
    plotted against Pb-B. Two reports have appeared showing this
    relationship (Piomelli, 1973; Sassa et al., 1973). In both cases, the
    subjects were young children with a wide range of blood lead values.
    For the data reported by Sassa et al. (1973) the correlation of the
    logarithm of the protoporphyrin IX values and the blood lead
    concentrations was fairly good ( r = 0.72). When only the data for
    children having had a constant blood lead level for three months or

    Table 24.  Percentage of adults and children with more than 40% and
               70% inhibition of the mean ALAD activity found in control
               subjects with Pb-B < 14 g/100 mla
                                                                         

    Pb-B level     adults                      children
    (g/100 ml)                                                          

                   No.     > 40%     > 70%     No.     > 40%     > 70%

    14              --        --        --       9        11         0
    15-24           30        13         3      37        73         8
    25-34           26        62        12      24        88        13
    35-44           32        97        22      10        90        50
    45-54           53       100        68      --        --        --
    55-64           37       100        92      --        --        --
    65-74           43       100        95      --        --        --
                                                                         

                   221                          80
                                                                         

    a  "From Zielhuis (1975).


    longer were used, the correlation was much better ( r = 0.91). The
    point was made by the authors that the elevation of erythrocyte
    protoporphyrin IX reflected an inhibitory effect of lead on haem
    synthesis that occurs in erythroid cells in the bone marrow, whereas
    the absorption of lead by blood elements takes place both in
    circulating cells and in erythroid cells.

         In recent years, it has become evident that the increase of FEP
    occurs at lower Pb-B levels than the increase in ALA in the urine
    (Stuik, 1974; Roels et al., 1975). In addition, the same authors
    observed that women were more sensitive than men with regard to the
    effect of lead on erythrocyte protoporphyrin IX. In women the effect
    was evident at a lower Pb-B level than in men, and the rate of
    increase in erythrocyte protoporphyrin IX with increasing Pb-B was
    greater than in men. From the results of a recent preliminary survey,
    children appear to display an FEP response to lead resembling that of
    women (Roels et al., 1975). Based on these limited data, for 109 men,
    49 women, and for 219 children, Zielhuis (1975) calculated the dose-
    response relationship (see Tables 25, 26, and 27).

    Table 25.  Percentage of adult female subjects with
               FEP levels that exceeded those found in
               control subjects with Pb-B < 20 g/100ml.
                                                     

    Pb-B level       No.      % with FEP level
    (g/100 ml)               higher than normal
                                                     

    11-20            28               4
    21-30             9              33
    31-40             8              90
    41-50 )
    51-60 )           4             100
    61-70 )
                                                     

                     49
                                                     

    a  From: Zielhuis, 1975.


    Table 26.  Percentage of adult male subjects with
               FEP levels that exceeded those found
               in control subjects with Pb-B <20 pg/100 ml.
                                                     

    Pb-B level       No.      % with FEP level
    (pg/100 ml)               higher than normal
                                                     

    11-20            26               0
    21 30            43               7
    31-40            32              19
    41-50             4
    51-60             2             100
    61 70             2
                                                     

                     109
                                                     

    a  "From: Zielhuis, 1 975.

    Table 27.  Percentage of children with FEP
               levels that exceeded those found in
               control subjects with Pb-B < 20 g/100 ml.
                                                     

    Pb-B level       No.      % with FEP level
    (g/100 ml)               higher than normal
                                                     

    20               87               5
    21-30            72              21
    31-40            24              29
    41-50            14 )
    51-60            12 )            64
    61-70            10 )
                                                     

                    219
                                                     

    a  From: Zielhuis, 1975.


    8.2.1.3  delta-aminolevulinic acid excretion in urine (ALA-U)

         The rate of ALA excretion in urine has long been used as a
    measure of a biological effect of lead. The most recent studies of
    this relationship in industrially exposed subjects indicate that the
    logarithm of the ALA concentration in urine increases linearly with
    Pb-B levels from 40 g/100 ml (Selander & Cramer, 1970; Haeger-
    Aronsen, 1971; Soliman et al., 1973). Chisolm (1973) reported a good
    correlation in children of log ALA excreted in urine per 24 hours
    per m2 of body surface and Pb-B levels over a wide range of blood
    lead values. In occupational exposure, the excretion of ALA in urine,
    at a given Pb-B level was higher in women than in men (Roels et al.,
    1975).

         Using diagrams published by Haeger-Aronsen (1971) and by Selander
    & Cramer (1970) for 207 adult males, Zielhuis (1975) calculated the
    dose-response relationships for levels of ALA excretion greater than
    5 mg/litre and greater than 10 mg/litre (see Table 28). Some of the
    dose-response relationships shown in Tables 24-28 are illustrated in
    Fig. 4.

    8.2.1.4  Coproporphyrin excretion in urine (CP-U)

         Although there is some uncertainty, ALA-U is probably somewhat
    more sensitive to the effects of lead exposure than CP-U (Haeger-
    Aronsen, 1960; Djuric et al., 1966). ALA-U is also more lead-specific
    than CP-U. Data are insufficient for estimating dose-response
    relationships.

    FIGURE 4

    Table 28.  Percentage of male adults with ALA-U
               levels > 5 mg/litre and >10 mg/litre
               according to Pb-B level
                                                       

    Pb-B level       No.          ALA-U level (mg/litre)
    (pg/100 ml)                                        
                                      >5          >10
                                                       

    11-20             17               0            0
    21-30             27               0            0
    31-40             36              14            3
    41-50             55              33           11
    51-60             38              74           37
    61-70             34              88           50
                                                       

                     207
                                                       

    a  From: Zielhuis, 1975.

    8.2.1.5  Effects of lead on cell morphology

         Punctate basophilia occurs in lead poisoning, but a quantitative
    relationship between the number of stippled cells and Pb-B levels is
    not to be expected (Zielhuis, 1971). Too many variables are involved
    in the preparation of smears. The same is probably true of
    reticulocyte counts.

    8.2.1.6  Effects of lead on erythrocyte survival

         Increased rate of erythrocyte breakdown (decreased erythrocyte
    life) is often, but not consistently, seen in cases of anaemia due to
    lead poisoning. When erythrocytes are exposed to lead  in vitro, they
    exhibit increased osmotic resistance and increased mechanical
    fragility (Waldron, 1966). They also show inhibition of Na-K-ATPase
    with increased loss of intracellular potassium (Hasan & Hernberg,
    1966; Secchi et al., 1973). These effects have been cited to explain
    the fact that in many instances the anaemia in lead poisoning is
    accompanied by a shortening of the erythrocyte life span. It is
    presumed that one or more of these effects is responsible for the
    sensitivity of erythrocytes to spontaneous haemolysis. Erythrocyte
    survival time was reduced on the average by 20% in 17 occupationally-
    exposed workers, only 3 of whom showed clinical signs of poisoning
    (Hernberg, 1967). The author postulated that shortened cell life was
    due to the loss of membrane integrity secondary to Na-K-ATPase
    inhibition. Anaemia does not necessarily accompany a shortened red
    cell life span, and the correlation between blood haemoglobin and life

    span was not good in this particular study. The kinetics of
    disappearance of labelled cells indicated a shortening of life span by
    increased random destruction of cells of all ages. Leikin & Eng (1963)
    determined erythrocyte survival in 7 cases of lead poisoning in
    children. In 3 cases the erythrocyte survival time was shortened. All
    patients were mildly to moderately anaemic. It would seem from these
    and other studies that the anaemia in lead poisoning cannot be
    explained solely on the basis of reduced erythrocyte survival time.

    8.2.1.7  Effects of lead on haem synthesis

         The two general points of attack that have been identified are on
    haem synthesis and on globin synthesis. Of the two, the effects on
    haem synthesis are better understood. It is generally recognized, too,
    that manifestations of disturbed haem synthesis often occur in the
    absence of frank anaemia. These disturbances may also be significant
    for the numerous other haem-dependent enzymatic reactions essential
    for normal body functions. Thus, cytochromes, cytochrome  c oxidase
    (EC 1.9.3.1), and hydroperoxidases are all part of electron transfer
    systems requiring haem.

         Little is known about the effects of lead on the formation or
    activity of other haem-containing compounds. It has been reported that
    treatment with EDTA reversed the prolonged antipyrine half-life seen
    in two cases of clinical lead poisoning (Alvares et al., 1975). The
    authors suggested that in these cases, lead may have significantly
    inhibited the synthesis of cytochrome P-450.

    8.2.1.7  Relationship between lead exposure and anaemia

         It is well known that anaemia is a characteristic early toxic
    effect of lead in man. The Pb-B threshold level for this effect is
    still not certain. Williams (1966) reported that anaemia did not occur
    in industrial workers with Pb-B levels below 110 g/100 ml. Cooper et
    al. (1973) reported that the average haemoglobin level (Hb) was not
    decreased at Pb-B levels of up to 100 g/100 ml and Sakurai et al.
    (1974) did not observe any decrease of Hb or erythrocyte
    concentrations in workers at Pb-B levels of up to 50 g/100 ml. On the
    other hand, Tola et al. (1973) reported a slight effect of lead on Hb
    at an average Pb-B level of about 50 g/100 ml. This conclusion was
    drawn from analysis of the sequential change in Hb among workers newly
    introduced into an "industrial lead environment". This approach to the
    analysis of the effect of lead on Hb is certainly more sensitive for
    detecting an interaction between Pb-B levels and Hb than is a single
    Hb determination in a population of lead-exposed persons. Allowance
    must, however, be made for the possibility that sequential change in
    Hb may be due to seasonal effects independent of lead exposure
    (Coulthard, 1958).

         Children appear to be more sensitive to lead anaemia than adults.
    Thus, Betts et al. (1973) found a significant negative correlation
    between Hb and Pb-B levels; a decrease in Hb was evident in 36% of
    children with Pb-B levels from 37 to 60 g/100 ml, compared with only
    14% in children with Pb-B levels less than 37 g/100 ml. Pueschel et
    al. (1972) observed a curvilinear decrease in Hb between Pb-B levels
    of 40 and 130 g/100 ml in children between 1 and 6 years old. On the
    other hand, McNeil & Ptaznik (1975) found no anaemia in children with
    Pb-B levels considerably higher than 40 g/100 ml. Nutritional
    differences may explain the discrepancy. But this does not invalidate
    the proposition that for some groups of children a reduction in Hb may
    occur at a Pb-B level of approximately 40 g/100 ml.

    8.2.2  Nervous system

    8.2.2.1  Central nervous system

     Inorganic lead compounds. The effects of lead on the nervous system
    vary with the duration and intensity of exposure. Distinction must
    also be made between the effects on the central nervous system and the
    effects on peripheral nerves. Further questions have been raised
    concerning the inherent differences in the sensitivity of the nervous
    system of adults and the nervous system of infants and young children.
    There is no doubt that lead effects on the brain are much more
    commonly associated with childhood lead poisoning than with poisoning
    as it is seen in adults. But it is also possible that these
    differences are related to the intensity of exposure at the time the
    cases are identified rather than to any difference in inherent
    sensitivity.

         With chronic lead exposure, striking effects may occur referred
    to as lead encephalopathy. There are numerous detailed descriptions of
    adult lead encephalopathy (Crutcher, 1963; Whitfield et al., 1972;
    Teisinger & Styblova, 1961; Aub et al., 1926; Cantarow & Trumpet,
    1944). The major features are dullness, restlessness, irritability,
    headaches, muscular tremor, hallucinations, and loss of memory and
    ability to concentrate. These signs and symptoms may progress to
    delirium, mania, convulsions, paralysis, and coma. The signs and
    symptoms of encephalopathy in infants and young children are quite
    similar to those reported to occur in adults.

         The brain lesions in fatal cases of lead poisoning are cerebral
    oedema and changes in cerebral blood vessels. The normal convolutions
    of the cerebral hemispheres are often obliterated. Capillary
    endothelial cells are usually swollen (Pentschew, 1965). Extravasation
    of red blood cells and perivascular haemorrhage occur rather commonly
    and patchy neuronal loss, serous exudate, glial proliferation, and
    occasional areas of demyelinization are all characteristic of lead
    poisoning (Blackman, 1937; Okazaki et al., 1963; Whitfield et al.,

    1972). But not all deaths due to lead encephalopathy are accompanied
    by histological lesions of the central nervous system (Pentschew,
    1965).

         Neurological sequelae can occur in severe or repeated episodes of
    lead encephalopathy. The sequelae are no different qualitatively from
    those that occur following traumatic or infectious cerebral injury.
    The occurrence of permanent sequelae seems to be much more common
    among young children than among adults. Approximately one-fourth of
    the children who survived an attack of acute lead encephalopathy
    sustained permanent sequelae (Byers, 1959; Chisolm & Harrison, 1956;
    Smith, 1964). At least this was true prior to the introduction of
    current therapeutic practices such as those described by Chisolm
    (1968a). The incidence of sequelae appears to have been substantially
    reduced in recent years, but central nervous system sequelae may still
    occur if therapy is initiated only after the onset of encephalopathy
    (Chisolm, 1973). The most severe sequelae are cortical atrophy,
    hydrocephalus, convulsive seizures, and idiocy. More commonly, the
    sequelae are of a more subtle nature. Learning ability may be impaired
    due to motor incoordination, lack of sensory perception, or inability
    to concentrate. Such subtle disturbances have also been claimed to
    occur in children with high lead exposure, but in the absence of a
    history of encephalopathy (Byers & Lord, 1943; Cohen & Ahrens, 1959).

         The major concern today is that young children with elevated lead
    exposure, as reflected in Pb-B levels of 40-80 g/100 ml, may be
    experiencing subtle neurological damage without ever exhibiting
    classical signs of lead encephalopathy. Studies have been reported of
    the neurological status of children with Pb-B values in this range. In
    view of the possible long-term effects of lead on the brain,
    association between Pb-B and neurological status at the time of
    evaluation may give a false impression concerning the level of lead
    exposure when the damage was initiated. Exposure levels at the time of
    examination may be lower than at the time toxic effects occurred.
    Thus, the Pb-B level-effect association may underestimate the dose
    responsible for the effect.

         Burd de la et al. (1972) and Peuschel et al. (1972) observed
    dysfunction of the central nervous system (irritability, clumsiness,
    fine motor dysfunction, impaired concept formation, etc.) in 70 and 58
    children, respectively, whose Pb-B levels were always, in all cases,
    above 40 g/100 ml. Albert et al. (1974) studied the psychological
    profiles and educational performances of children, 5-15 years of age,
    who had histories of lead exposure early in childhood. Those who had
    been treated for lead poisoning, with or without encephalopathy,
    exhibited a higher incidence of diagnosed mental disorders and of poor
    school performance than those who had no such history, even when their
    history showed elevated lead exposure early in childhood.

         Kotok (1972) established that development deficiencies (using the
    Denver Development Screening test, which, according to the author is a
    somewhat insensitive measure of development) in a group of
    asymptomatic children with elevated lead levels (58-137 g/100 ml)
    were identical to those of a control group similar in age, sex, ethnic
    group, environment, neonatal condition, and presence of pica, but
    whose Pb-B levels were lower (20-55 g/100 ml). The deficiencies could
    be correlated with inadequacies in the children's environment. Klein
    et al. (1974) pointed out that in many studies, pica is not used as a
    controlled variable. In his view, pica may be part of a behavioural
    deficiency syndrome. In such a case the child would have the
    behavioural deficiency regardless of whether or not he ingested lead-
    containing objects. Indeed, there is evidence that among mentally
    subnormal children whose mental deficiency is unrelated to excessive
    lead absorption there is a high incidence of both pica and of
    moderately elevated Pb-B levels (Bicknell et al., 1968). In this
    study, 67% of the children, whose subnormal state antedated pica, had
    Pb-B levels from 39 to 88 g/100 ml, with a mean of 48 g/100 ml. By
    contrast, among the subnormal group without pica all but one had a
    Pb-B level of less than 36 g/100 ml. The study did not exclude the
    possibility that an excessive lead exposure could have aggravated the
    pre-existent subnormal state.

         Recently McNeil & Ptasnik (1975) published an initial evaluation
    of the long-term effects of elevated Pb-B levels in asymptomatic
    children, living in El Paso, USA. In 138 out of 206 children aged from
    21 months to 18 years (median 9 years), who volunteered (possibility
    of selection) to participate, the authors could not find any evidence
    of non-specific complaints, hyperactivity, or of abnormal psychometric
    testing values, if compared with a matched control group. There
    existed a significant difference in one personality test; however this
    was explained by geographic isolation and other factors and not by
    lead exposure. The average Pb-B levels were, respectively,
    50 g/100 ml (range 14-93) and 16 g/100 ml (range 10-28).

         More recently another psychological evaluation of the El Paso
    subjects was published by Landrigan et al. (1975a). Forty-six
    children, aged from 3 to 15 years, with Pb-B levels of 40-60 g/100 ml
    were compared with 78 ethnically and socioeconomically similar
    controls with Pb-B levels below 40 g/100 ml. The "Wechsler
    Intelligence Scale" showed that the age adjusted I.Q. was
    significantly lower in the first group. In addition, the lead exposed
    group also showed a significant slowing in the finger-wrist tapping
    test. The full-scale I.Q., verbal I.Q., and the behavioural and
    hyperactivity ratings did not differ. In this study, unfortunately,
    there were differences in age and sex between the study and control
    group which might account for the positive findings. It seems
    therefore that we have two studies of this situation that come to
    different conclusions regarding the possible effects of lead on
    neurological and psychological functions.

         Another approach has been to identify children with neurological
    or behavioural disorders of obscure etiology and to determine whether
    they show evidence of current or past elevated lead exposure (David et
    al., 1972; Moncrieff et al., 1964; Gibson et al., 1967).

         The work of David et al. (1972) is of particular interest because
    the neurological abnormality described was one that was reproduced
    experimentally in animals (see section 7.1.2). These workers reported
    occurrence of hyperactivity among children who had essentially normal
    blood lead concentrations, but who excreted abnormally large amounts
    of lead when treated with penicillamine. The children had no history
    of earlier lead encephalopathy. This study has been criticized because
    of statistical inadequacies (Bullpitt, 1972).

         Lansdown et al. (1974) examined a population of schoolchildren in
    London (less than 17 years of age); there was no relationship between
    Pb-B levels and intelligence (Wechsler test), reading (Butt test), and
    behaviour (e.g. hyperactivity as rated by the teachers). The authors
    suggested that social factors were more important than exposure to
    lead in determining mental development. The design of the study has
    also been criticized. Neither Landsown's nor David's study are
    conclusive.

         Morgan & Repko (1974) reported preliminary results of an
    extensive study of behavioural functions in 190 lead-exposed workers
    (Pb-B = 60.48  16.96 g/100 ml). In 68% of the subjects the Pb-B
    level was less than 80 g/100 ml. The majority of the subjects were
    exposed for between 5 and 20 years. The authors examined 36 non-
    independent measures of general performance. In addition, 44 measures
    of sensory, psychomotor, and psychological functions were obtained.
    Preliminary analysis suggested that Pb-B levels correlated with
    several reaction-time measures and ALAD correlated with measures from
    strength-endurance-recovery tasks. Both Pb-B levels and ALAD
    correlated with eye-hand co-ordination. This study, therefore,
    suggested that below a Pb-B level of 80 g/100 ml some behavioural
    changes did occur in adult workers. In addition, variability of
    performance increased with increasing Pb-B levels. Only during periods
    of high-demand performance did a worker's capacity decrease due to
    lead exposure. The authors themselves stressed that this preliminary
    analysis still has to be confirmed by further work.

     Alkyllead compounds. The encephalopathy of alkyllead intoxication is
    somewhat different from that due to inorganic lead exposure. In
    documented adult cases of poisoning the most frequent findings suggest
    a psychiatric problem. Hallucinations, tremor, delirium, insomnia,
    delusions, headaches, and violent mood swings are the most commonly
    reported symptoms (Boyd et al., 1957; Machie, 1935). The course of the
    intoxication runs from 1 to 10 weeks. Although alkyllead compounds are
    notorious for their high lethality, recovery is fairly complete among

    survivors (Akatsuka, 1973). Convulsions and coma apparently occur only
    in the most severe cases. There is insufficient information to
    establish dose-effect and dose-response relationships.

    8.2.2.2  Peripheral nervous system

         Inorganic lead has toxic effects on the peripheral nervous
    system. The older lead literature cites the frequent occurrence of
    lead palsy in occupational exposure to lead. The manifestations are
    mainly weakness of the extensor muscles, particularly those used most
    heavily. While motor function is mainly affected, hyperaesthesia,
    analgesia, and anaesthesia of affected areas have also been reported.

         Catton et al. (1970) found evidence of reduced nerve conduction
    velocity in about one-third of a group of 19 occupationally-exposed
    men of whom only one showed any other overt signs of lead toxicity.

         The most prominent finding of Seppalainen & Hernberg (1972) in
    lead workers (Pb-B levels 80-120 g/100 ml) without any clinical
    neurological signs was reduced motor conduction velocity of the slower
    fibres of the ulnar nerves; electromyographic changes included a
    diminished number of motor units on maximum contraction and
    fibrillations. Similar although less pronounced effects were reported
    by Sepplinen et al. (1975) in 26 workers whose Pb-B levels had never
    exceeded 70 g/100 ml (exposure time 13 months-17 years). Furthermore,
    in lead workers with Pb-B levels of 2-273 g/100 ml, Araki & Honma
    (1976) reported statistically significant negative correlations
    between nerve conduction velocity and Pb-B, ALAD, and lead
    mobilization test values, respectively. More recently, Sepplinen et
    al. (unpublished resultsa) reported a dose-response relationship
    between abnormally low conduction velocities, defined as values 2
    standard deviations below the mean of an unexposed reference group,
    and the highest Pb-B recorded during employment (2-20 years). The
    results indicate that nerve conduction impairment is induced in some
    workers at Pb-B's exceeding 50 g/100 ml.

    8.2.3  Renal system

         The effects of lead on the kidney have been studied extensively.
    Two general types of effect have been described. The first is rather
    clear-cut renal tubular damage characterized by generalized
    aminoaciduria, hypophosphataemia with relative hyperphosphaturia, and

              

    a  Reported at the Second International Workshop Permissible Levels
       for Occupational Exposure to Inorganic Lead, 21-23 September 1976.
       University of Amsterdam, The Netherlands. To be published shortly
       in  Int. Arch. Occup. Health.

    glycosuria, which has been studied in some detail in children with
    clinical lead poisoning (Chisolm, 1962). The condition is
    characterized by decreased tubular reabsorption of glucose and
    alpha-amino acids and therefore reflects proximal tubular damage.
    Aminoaciduria was seen more consistently in Chisolm's studies than the
    other two manifestations of tubular damage. Thus, the amino acid
    transport system is probably more sensitive to the toxic actions of
    lead than the transport systems for glucose and phosphate. Limited
    data indicate that aminoaciduria is terminated by chelation (Chisolm,
    1968b).

         In a group of children with slight lead-related neurological
    signs, generalized aminoaciduria was found in 8/43 children with Pb-B
    levels of 40-120 g/100 ml (Pueschel et al., 1972). A similar renal
    tubular syndrome has been reported to occur in industrially exposed
    adults (Clarkson & Kench, 1956; Goyer et al., 1972). In neither of
    these studies were Pb-B levels reported. However, Clarkson & Kench
    observed signs of lead poisoning (colic and punctate basophilia) in
    conjunction with aminoaciduria.

         In a group of 7 carefully studied lead-exposed workers,
    aminoaciduria was not present. Inulin clearance and renal blood flow
    were also normal at the time of examination. For these cases, the
    average Pb-B level was 100 g/100 ml and the minimum was 71 g/100 ml.
    These workers had been exposed for up to 20 years (Cramer et al.,
    1974). All had markedly elevated urinary ALA excretion. Interestingly,
    some of these workers with prolonged exposure had diffuse interstitial
    and peritubular fibrosis as determined by renal biopsy. These
    pathological findings are associated with quite a different kind of
    renal effect which is seen with prolonged lead exposure. It is
    commonly referred to as chronic lead nephropathy. Chronic nephropathy
    is characterized by slow development of contracted kidneys with
    arteriosclerotic changes, interstitial fibrosis, glomerular atrophy,
    and hyaline degeneration of the vessels. This progressive disease
    sometimes ends in renal failure. There is evidence that it occurs in
    industrially exposed workers, in long-term drinkers of lead-
    contaminated whisky, and among middle-aged people who had developed
    clinical lead poisoning much earlier in life. Currently, it is only
    rarely encountered in occupational exposure.

         This renal syndrome can develop and progress to renal failure
    long after abnormal lead exposure has terminated. As early as 1897, it
    was noted that deaths from chronic nephritis were much more frequent
    among people under 30 years of age in Queensland than in other
    sections of Australia. The first serious attempt to document a
    suspected relationship to earlier childhood lead poisoning was
    reported by Nye (1929). Further evidence of a causal relationship
    between chronic nephropathy and childhood lead exposure was provided
    later (Henderson, 1958). It was shown that people dying of chronic
    nephropathy in Queensland usually had a high concentration of lead in

    their bones (Henderson & Inglis, 1957). Emmerson (1963) later
    demonstrated abnormally elevated lead excretion in response to EDTA
    among surviving middle-aged cases of chronic nephropathy. Tepper
    (1963), however, was unable to find evidence of chronic nephropathy
    among young American adults with a history of childhood lead
    poisoning. The Americans had probably been exposed for a much shorter
    period of time than the Australians. Other unknown factors may also
    have played a role.

         The Australian cases involved childhood exposure with an apparent
    latency of 10-30 years for the development of renal insufficiency. But
    there is evidence that the same effect can result from continuous,
    prolonged high lead exposure among adults (Lilis et al., 1968; Richet
    et al., 1966; Danilovic, 1958; Morgan et al., 1966; Albahary et al.,
    1965; Albahary, 1964). In these cases, lead exposure was higher than
    is commonly encountered in industry today.

         In a series of 102 cases of lead poisoning studied by Lilis et
    al. (1968), 18 cases of clinically verified chronic nephropathy were
    found. For the whole series, the mean Pb-B level was approximately
    80 g/100 ml with a range of 42-141 g/100 ml. Nephropathy was more
    common among patients who had been exposed to lead for more than 10
    years than among those who had been exposed for less than 10 years.

         In the Danilovic (1958) study 7/23 cases had Pb-B levels of about
    100-200 g/100 ml. In the studies of Albahary et al. (1965) Pb-B
    levels were not reported. But exposure levels must have been quite
    high since the mean ALA excretion was about 37 mg/24 h for 29 workers.

         It seems likely, from all available evidence, that a prolonged
    high-level lead exposure is necessary, even in childhood, to produce
    this progressive chronic nephropathy.

         One interesting feature of this syndrome of chronic renal
    insufficiency is the frequent association with gout (Emmerson, 1963;
    Morgan et al., 1966). Although uric acid excretion is largely
    dependent upon tubular secretion, it is not at all certain that
    tubular secretion is inhibited. As a matter of fact, a study by
    Emmerson et al. (1971) of 13 cases of renal insufficiency due to lead
    nephropathy failed to reveal any alteration in uric acid secretion.
    The authors suggested an increased tubular reabsorption to account for
    the observed decreased clearance of uric acid.

         In summary, proximal tubular effects can occur in children and
    adults with subtle signs of lead poisoning.

         Prolonged exposure to lead leading to a Pb-B level of more than
    70 g/100 ml may give rise to chronic irreversible nephropathy.
    However, little is known about dose-effect relationships or about
    time-effect relationships for lead-induced chronic interstitial
    nephritis.

    8.2.4  Gastrointestinal tract

         As a symptom of lead poisoning, colic is a fairly consistent
    early warning of potentially more serious effects likely to occur with
    prolonged periods of exposure. It is most commonly encountered in
    industrial exposure. But it is probably also common in lead-poisoned
    infants and young children. The occurrence of colic at relatively low
    exposure levels in industry is well-known. Although it has been
    reported that 13/64 industrially exposed men with presumably lead-
    related colic and constipation had blood lead levels from somewhat
    less than 40 g to 80 g/100 ml (Beritic, 1971), it was also reported
    that in every case the diagnosis of lead colic was confirmed by the
    findings of high CP-U, excessive basophilic stippling,
    reticulocytosis, and various degrees of anaemia. This is consistent
    with the general observation that lead colic seems to be accompanied
    by other signs of poisoning. There are not enough data available to
    establish a dose-response relationship for this lead effect.

    8.2.5  Liver

         There is no definite evidence for the effects of lead on the
    liver. Dodic et al. (1971) reported signs of impaired liver function
    in 11 out of 91 patients hospitalized for lead poisoning. Liver damage
    was more frequent in cases of severe lead poisoning in 7 out of 18
    patients. However, the authors did not provide any information on Pb-B
    levels or on indices of disturbed porphyrin metabolism which would
    enable the assessment of the stage of lead poisoning. In a laboratory
    study of 301 workers in lead smelting and refining, Cooper et al.
    (1973) found 11.5% increased aspartate aminotransferase (EC 2.6.1.1),
    (SGOT)a values (above 50 U/litreb) in subjects with a Pb-B level
    below 70 g/100 ml, 20% in those with a Pb-B level of about
    70 g/100 ml, and 50% in workers with a Pb-B level above
    100 g/100 ml. The correlation between Pb-B levels and SGOT values was
    statistically significant. However, in the absence of information on
    the possible influence of diet, infections, or personal habits, the
    authors did not draw any definite conclusions concerning the etiology
    of these changes.

              

    a  Formerly known as serum glutamic oxaloacetic transaminase.
    b  = 50  1.67  10-5 mol/(m3.s)

    8.2.6  Cardiovascular system

         Increased capillary permeability occurs in acute lead
    encephalopathy (section 8.2.2.1). Under conditions of long-term lead
    exposure at high levels, arteriosclerotic changes have been
    demonstrated in the kidney (section 8.2.3). Dingwell-Fordyce & Lane
    (1963) reported a marked increase in the cerebrovascular mortality
    rate as compared with the expected rate among heavily exposed lead
    workers (section 8.1.1). This observation applied to men exposed to
    lead during the first quarter of this century, when working conditions
    were quite bad. There was no similar increase in the mortality rate
    for men employed more recently. Hypertension is an important element
    in the etiology of cerebrovascular deaths. Cramer & Dahlberg (1966)
    studied the incidence of hypertension in a population of 364
    industrially-exposed men, 273 of whom had a long-term exposure to
    lead. They subdivided these workers into "lead affected" and "non-
    lead-affected" groups, on the basis of the urinary coproporphyrin
    test. There was no statistically significant difference between the
    groups. Nor was the incidence higher than expected for non-exposed men
    in Sweden. This is contrary to the earlier findings of Vigdortchik
    (1935) and to the observations of Monaenkova & Glotova (1969). The
    disparity may have been due to differences in lead exposure. Other
    reports on the question do not show hypertension to be unduly
    prevalent among workers exposed to lead (Dressen et al., 1941; Lane,
    1949). It is not clear whether vascular effects of lead in man are the
    result of an action on blood vessels directly, or whether the effects
    are secondary to renal effects.

         There is a good evidence that signs of clinical lead poisoning
    sometimes include evidence of a toxic action on the heart. Cases have
    been described in adults and in children, always with clinical signs
    of poisoning. There is of course the possibility that the coexistence
    of lead poisoning and myocarditis is coincidental. But in many cases
    the electrocardiographic abnormalities disappeared with chelation
    therapy, suggesting that lead may have been the original etiological
    factor (Myerson & Eisenhauer, 1963; Silver & Rodriguez-Torres, 1968;
    Freeman, 1965). In a review of 5 fatal cases of lead poisoning in
    young children, heart failure was concluded to be the proximate cause
    of death in 2 cases (Kline, 1960). Kosmider & Petelenz (1962) examined
    38 adults over 46 years of age with chronic lead poisoning. They found
    that 66% had electrocardiographic changes, which was four times the
    expected rate for that age group. Orlova (1954) also reported
    electrocardiographic abnormalities in cases of lead poisoning.
    Dimitrova (1972) reported cardiac abnormalities in workers with
    undefined degrees of lead intoxication. There was a correlation of
    urinary excretion of lead with duration of systolic contraction and
    with isometric tension. Lead mobilization by EDTA accentuated these
    effects on the heart. No dose-effect relationships are apparent from
    the limited data available.

    8.2.7  Reproduction

         There is no epidemiological evidence of an effect of lead on the
    fertility of women or on  in utero fetal development, but there are
    numerous reports in the older literature of stillbirths and
    miscarriages among women working in the lead trade (Cantarow &
    Trumper, 1944; Oliver, 1914). These reports probably contributed to
    the promulgation of legislation forbidding the employment of women in
    the lead trades in many countries. Panova (1972) reported that women
    working in lead industries had a higher incidence, compared with a
    control group, of ovulatory dysfunction -- mainly an ovulatory cycles
    and cycles with luteal abnormality. A relationship was reported
    between ALA-U and the incidence of anovulatory cycles. The effect was
    seen at 8-10 mg ALA/litre of urine.

         There are not any reliable data to indicate that infertility in
    women results from exposure of the male partner to lead.

         Some of the early reports on lead poisoning (Oliver, 1914)
    suggested that reproductive failures such as sterility and
    miscarriages occurred even among the non-working wives of
    industrially-exposed men. The reproductive capability of 150
    occupationally exposed men was recently studied by Lancranjan et al.
    (1975). The results indicated that both lead poisoning and moderately
    increased lead absorption decreased the fertility of men. An increased
    frequency of asthenospermia, hypospermia, and teratospermia was found.
    No interference with the hypothalamopituitary axis was demonstrated;
    thus, hypofertility was thought to be due to the toxic effect of lead
    on the gonads.

    8.2.8  Endocrine organs

         Impairment of thyroid function and of adrenal function has been
    reported in cases of lead poisoning (Monaenkova, 1957; Sandstead et
    al, 1969; Sandstead et al., 1970; Pines, 1965).

         There is some evidence suggesting that lead may cause a
    derangement of tryptophan metabolism. This is based on the observation
    that urinary excretion of 5-hydroxyindoleacetic acid was increased in
    227 children living near a lead smelter (Ghelberg, 1966).
    Unfortunately, the 5-hydroxyindoleacetic acid determinations were not
    quantitative. Furthermore, blood lead values or other indices of
    exposure were not determined. Urbanowicz et al. (1969) noted a rise in
    5-hydroxyindoleacetic acid excretion in workers heavily exposed to
    lead (ALA-U--33.7 mg/litre of urine). The rise preceded the rise in
    ALA-U and CP-U. Dugandzic et al. (1973) also noted a rise in
    5-hydroxyindoleacetic acid excretion in moderately exposed workers
    (ALA-U--28.2  22.6 mg/litre of urine). More recently Schiele et al.
    (1974a), using another analytical method, reported that they were

    unable to find any significant elevation in 5-hydroxyindoleacetic acid
    excretion in workers with relatively high blood lead levels
    (88.5  16.1 g/100 ml).

    8.2.9  Carcinogenicity

         Dingwall-Fordyce & Lane (1963) did not find any evidence of an
    increased incidence of malignant diseases in their follow-up study of
    267 workers (section 8.1.1).

         In a more recent study of the causes of mortality among lead
    smelter and lead battery workers, it was concluded that while the
    incidence of malignant neoplasms was somewhat greater than expected,
    the difference was not statistically significant (Tabershaw & Cooper,
    1974; Cooper & Gaffey, 1975). This seems to support the conclusion of
    a IARC Working Group that there is no evidence to suggest that
    exposure to lead salts causes cancer of any site in man (IARC, 1972).

    8.2.10  Effects on chromosomes

         The literature is controversial as regards chromosomal
    abnormalities induced by exposure to lead. On the one hand,
    chromosomal aberrations have been reported to result from lead
    exposure corresponding to mean Pb-B values of 38-75 g/100 ml in
    various groups studied (Forni & Secchi, 1973; Schwanitz et al., 1970).
    Moreover, Deknudt et al. (1973) reported chromosomal aberrations in a
    group of 14 male workers with signs of lead poisoning. The authors
    concluded that, although the workers were exposed to zinc and cadmium
    as well as lead, the lead ought to be considered responsible for the
    aberrations. On the other hand, Schwanitz et al. (1975) were not able
    to corroborate their own findings among occupationally exposed workers
    and O'Riordan & Evans (1974) did not find any significant increase in
    chromosomal aberrations in shipbreakers with Pb-B values ranging from
    40 to over 120 g/100 ml. Schmid et al. (1972) did not find any
    evidence of lead-induced chromosome aberrations in a study on human
    peripheral lymphocytes  in vivo and  in vitro; furthermore,
    Bauchinger et al. (1972) did not find any abnormalities in the
    chromosomes of policemen with elevated Pb-B levels.

         In a recent report, Bauchinger et al. (1976) found that
    chromosomal aberrations were significantly increased in a group of 24
    male workers occupied in zinc electrolysis and exposed to zinc, lead,
    and cadmium. The workers had clearly elevated Pb-B and blood cadmium
    levels in comparison with a control group. The authors pointed out the
    similarity between this group and the group studied by Deknudt et al.
    (1973) as regards combined exposure. However, referring to studies
    indicating mutagenicity of cadmium (Oehlkers, 1953; Shiraishi et al.,
    1972; Shiraishi, 1975), Bauchinger and his colleagues were inclined to
    consider cadmium as being mainly responsible for the aberrations. They

    also emphasized the possibility of a synergistic effect of several
    metals on the chromosomes. Thus, the question as to whether
    chromosomal abnormalities occur as a result of lead exposure in man
    remains open. Furthermore, the human health significance of
    chromosomal abnormalities seen in lymphocyte cultures, as observed in
    some of these studies, is not yet known.

    8.2.11  Teratogenicity

         There is practically no information in the literature to suggest
    that lead is teratogenic for man (Wilson, 1973). Only one case has
    been reported of neuromuscular abnormalities and failure to grow in a
    child attributed to lead poisoning as a result of the consumption by
    the pregnant mother of illicit whisky (Palmisano et al., 1969).

    8.3  Factors influencing Lead Toxicity

    8.3.1  Acquisition of tolerance to lead

         Experience in industry does not suggest that, with continuous
    lead exposure, the human body becomes less reactive to lead. There
    have been two studies in which the biochemical parameters of lead
    exposure were followed for a long period after the initiation of
    industrial lead exposure. Tola et al. (1973) found that erythrocyte
    ALAD fell to a stable level in about 21 days, as the concentration of
    lead in the blood increased correspondingly. Then both blood lead and
    blood ALAD remained essentially stable for the next three months.
    There was no return toward normal values to suggest development of
    tolerance. Urbanowicz (1971) followed ALA-U and CP-U levels in 60
    workers for 24 months after they first became industrially exposed.
    There was a build-up of both biochemical effects for several months.
    But the levels then stabilized for the remainder of the two-year
    period. These studies suggest that the toxicologically-active fraction
    of the body burden during steady, long-term exposure remains
    essentially unchanged.

    8.3.2  Age

         Young children absorb lead more readily than older people. It
    also seems that children are more susceptible than adults in the sense
    that toxic effects occur at lower blood lead concentrations. The
    susceptibility of old people in comparison with younger adults has not
    been studied.

    8.3.3  Seasonal variations

         It has long been recognized that the incidence of severe lead
    intoxication in children is highest during the summer months (Baetjer,
    1959; NAS-NRC, 1972). The observation that urinary excretion of lead
    increases in late summer may have some bearing (Kehoe, 1961).

    8.3.4  Nutrition

         There are few reports of studies that point to nutritional
    variables as having a distinct effect on lead toxicity in man (NAS-
    NRC, 1972; Goyer & Rhyne, 1974). Iron deficiency and lead exposure
    both affect porphyrin metabolism at the point where protoporphyrin IX
    is converted to haem. An additive effect results.

    8.3.5  Intercurrent disease, alcohol, and other metals

         Little is known about the effects of intercurrent diseases on the
    toxicity of lead or about the effect of lead on the susceptibility of
    people to other diseases. People with haemoglobin and erythrocyte
    anomalies, such as sickle cell anaemia and thalassaemia, would
    probably be more sensitive to the effects of lead exposure, as would
    perhaps people with renal damage. It is also possible that an
    interaction may exist between lead exposure and infectious disease
    processes, although reliable human data are not available to prove the
    point.

         The effect of ethanol on lead toxicity is of some interest
    because the encephalopathy of illicitly-distilled whisky drinkers
    could conceivably involve an interaction of lead and the alcohol
    consumed. Furthermore, it has been suggested that heavy drinkers among
    industrially-exposed men may be more prone to lead toxicity than non-
    drinkers (Cramer, 1966; Candani & Farina, 1972).

    9.  EVALUATION OF HEALTH RISKS TO MAN FROM EXPOSURE TO LEAD AND
        ITS COMPOUNDS

         The evaluation of health risks to man from exposure to lead and
    its compounds involves the following considerations:

    (1)  the significance of different environmental sources of lead and
         of pathways of exposure;

    (2)  the probability of occurrence of biological effects at different
         levels and rates of lead intake;

    (3)  the significance for human health of the various known biological
         effects of lead;

    (4)  the validity and limitations of various indicators of lead
         exposure and of resultant effects.

         These considerations have been used in arriving at the
    conclusions which are summarized in this chapter.

    9.1  Relative Contributions of Air, Food, Water, and Other Exposures
         to Total Intake

    9.1.1  Adult members of general population groups

         For the general population, the major contribution of lead to the
    total daily intake is from food, but water and air may provide
    significant contributions under certain conditions. Separate
    consideration must be given to occupationally-exposed persons in whom
    both the total lead intake and the relative contributions of dietary
    and airborne lead are quite different.

         The inhalation of airborne lead contributes comparatively little
    to the Pb-B level in the general population. This follows from the
    fact that the lead concentration in ambient air seldom exceeds
    3 g/m3 when averaged over months and from the conclusions reached
    in section 6 that the contribution of airborne lead to Pb-B levels is
    probably within the range of 1.0 to about 2.0 g/100 ml for every
    1 g/m3 of air. Although deposition and retention of different forms
    of lead in air may vary, estimates of Pb-B levels from the
    concentrations of lead in air are similar for the ambient air and for
    the air in the work environment.

         Even if we assume a concentration of 1 g of lead per cubic metre
    of air contributes as much as 2.0 g/100 ml of blood, and that the
    ambient air concentration of lead is as high as 4.5 g/m3, the total
    contribution of airborne lead would not exceed 9.0 g/100 ml. This is
    still less than two-thirds of the value estimated by a WHO Expert
    Committee (1973). The discrepancy arises from the different approaches

    used in making the estimate. The WHO Expert Committee's estimate was
    based on lung deposition figures for lead obtained using the ICRP
    model (Task Group on Lung Dynamics, 1966). However, the ICRP lung
    model probably overestimates deposition for particles smaller than
    0.5 m (aerodynamic diameter) (Mercer, 1975), and the assumption that
    all the lead that is deposited is absorbed is probably also incorrect.

         Dietary intake of lead varies with eating habits and the lead
    content of water sources. The majority of estimates from various
    countries suggest that the daily oral lead intake from food by adults
    ranges from approximately 100 g to more than 500 g; most studies
    show lead intake from dietary sources to be 200-300 g/day. Relating
    blood lead levels to known daily oral lead intake suggests that each
    100 g of oral lead intake contributes about 6-18 g of lead/100 ml of
    blood. This source of lead therefore accounts for a very large
    fraction of the blood lead levels found in the general adult
    population with Pb-B values below 25 g/100 ml.

         The quantity of lead intake directly related to the lead content
    of drinking water is difficult to estimate. Assuming a lead
    concentration in drinking water of 50 g/litre (which is the upper
    limit generally found in the absence of lead pipes or other lead
    contributing factors) and a daily intake of one litre of water, 50 pg
    of total dietary lead could be attributed to water. This may be
    regarded as an upper limit but it must also be pointed out that lead
    in water ingested independently of food may be more readily absorbed
    and may provide a relatively greater contribution to the blood lead
    level than lead in food.

         In assessing the relative contributions of air and diet to Pb-B
    levels, attention is called to the possibility that air may be a
    significant source of dietary lead through fallout. However, there are
    no data to confirm this assumption.

         Improperly glazed pottery and illicit whisky have been cited as
    potential sources of excessive lead exposure for members of the
    general population.

         Smoking one packet of 20 cigarettes would result in the direct
    inhalation of about 1-5 g of lead but this only indicates the order
    of magnitude.

    9.1.2  Infants and children

         Infants and preschool children are a high-risk group with regard
    to lead intake and absorption. Relative contributions from food,
    water, and air are difficult to estimate because of the different diet
    (e.g. milk) and more active metabolic rate of young children. Also,
    intestinal absorption of lead by young children and, in particular, by
    infants may be greater than by adults. Tolerable intake of lead for

    preschool children should be less than the 3 mg/week recommended
    provisionally for adults by a WHO Expert Committee on Food Additives
    (1972).

         A special hazard for young children is the ingestion of non-food
    items, particularly lead-containing paint from surfaces in homes and
    lead-contaminated dust and soil.

    9.1.3  Occupationally exposed population groups

         Because of the variability of occupational exposure, no general
    conclusions are possible but precautions against excessive exposure
    must be exercised in view of the possibility of extremely high
    occupational lead exposures, as cited in section 5.

    9.2  Evaluation of Haematological Effects

         Based on information presented in section 8, the following
    conclusions have been reached concerning the significance of different
    effects on haematopoiesis.


     Inhibition of ALAD activity in erythrocytes. The health significance
    of decreased ALAD activity is still open to discussion. Although
    inhibition of ALAD in erythrocytes is to a certain extent paralleled
    by a decrease in other organs, e.g. liver and brain, no effect on
    health of this decrease has ever been established. Inhibition of ALAD
    is generally regarded as a good indicator of lead absorption but not
    of health impairment.

     Increased excretion of ALA and CP in urine, and increase of FEP are
    indicators of impaired haematopoiesis. Although at moderate levels of
    increase, no evidence has been brought forward to show that the vital
    functions of haematopoiesis are impaired, resulting, for example, in a
    reduced life-span of erythrocytes or anaemia, any increase should be
    regarded with suspicion and particularly so when it is more than twice
    the level found in non-exposed population groups. Because free
    erythrocyte protoporphyrins are also increased in the case of iron
    deficiency, this test may provide a better indication of impaired
    haematopoiesis in exposed iron deficient population groups (especially
    children) than the excretion of ALA and CP. Moreover, females and
    children appear to have an earlier and steeper increase of FEP than
    males for the same levels of Pb-B.

     Effects on erythrocyte membrane, as evidenced by shortened life-span
    and a decrease of Na-K-ATPase clearly can result in adverse health
    effects since anaemia may occur.  Anaemia, expressed by decreased
    haemoglobin level, may be regarded as a consequence of disturbed haem
    and globin synthesis and of the decreased life-span of erythrocytes
    and has clear adverse health consequences.

    9.3  Dose-Effect Relationships

         At present Pb-B levels are the best available indicator of the
    dose. It should, however, be recognized that Pb-B does not reflect the
    type of exposure. The dose-effect relationships based on Pb-B levels
    should generally be used for long-term exposure.

         As stated in section 8 (page 99) a dose-effect relationship
    refers in this report to the relationship between the dose as
    estimated by Pb-B levels and the intensity of a specified effect in
     individual subjects. For most effects, not enough data are available
    to present adequate dose-effect curves; however, for some effects,
    some points on the dose-effect curve can be tentatively estimated; for
    other effects, the data available only permit a statement referring to
    the Pb-B level below which such an effect has not been reported. This
    level is referred to as the no-detected-effect level. The degree of
    confidence that can be placed on such estimates will vary depending on
    the sample size and the number of studies reporting no effect.

     ALAD activity in erythrocytes. There is a negative linear
    relationship between the logarithm of ALAD and Pb-B levels. Increase
    in Pb-B levels is paralleled by a decrease in ALAD levels in the Pb-B
    range up to about 60 g/100 ml. For higher Pb-B values, the ALAD
    activity levels off at a very low level of enzyme activity. The no-
    detected-effect level for Pb-B is probably about 10 g/100 ml but may
    be even lower.

     ALA and CP in urine; PP in erythrocytes. There is a positive linear
    relationship between the logarithm of ALA (CP, FEP) and Pb-B levels;
    the no-detected-effect level for ALA and CP is about 40 g/100 ml; for
    FEP the no-detected-effect level in females is about 20-30 g/100 ml,
    in males it is about 25-35 g/100 ml; and in iron-deficient children
    in particular, it may be about 20-25 g/100 ml.

     Effects on the erythrocyte membrane start to occur at higher Pb-B
    levels, probably higher than 50-60 g/100 ml; a study by Secchi et al.
    (1974), on Na-K-ATPase, however, reports a lower no-detected-effect
    level of between 30 and 40 g/100 ml.

     Anaemia. Some authors maintain that the no-effect level in workers
    is above a Pb-B level of 100g/100ml; others, however, report a slight
    decrease in the haemoglobin level, at a mean level of Pb-B of about
    50 g/100 ml. In some population groups and particularly in iron-
    deficient children, the no-detected-effect level is at an approximate
    Pb-B level of 40 g/100 ml.

     Nervous system effects. The data on effects of lead compounds on the
    nervous system lead to the following tentative conclusions in regard
    to prolonged exposures:

    (1)  From Pb-B levels of approximately 40 g/100 ml, the probability
         of the occurrence of subclinical peripheral electrophysiological
         changes increases.

    (2)  From approximately 50 g/100 ml in children, the probability of
         noticeable brain dysfunction increases; in adults the level is
         probably somewhat higher (60-70 g/100 ml).

    (3)  From approximately 60 g/100 ml in children the probability of
         acute or chronic encephalopathy increases; in adults this level
         is higher, probably above 80 g/100 ml.

    (4)  The potential effects of lead on the nervous system constitute
         one of the main concerns, particularly in children. More
         carefully considered prospective studies should be carried out
         taking into account various interacting variables such as
         nutrition, socioeconomic status, and parental care in order to
         establish better founded dose-effect and dose-response
         relationships.

    (5)  No dose-effect or dose-response relationships can be established
         for alkyllead exposure on the basis of currently available
         information.

    The present no-detected-effect level for sub-clinical neuropathy
    appears to be a Pb-B value of 40-50 g/100 ml. For minimal brain
    dysfunction it is probably 50-60 g/100 ml in children and
    60-70 g/100 ml in adults, and for acute or chronic encephalopathy,
    60-70 g/100 ml in children, and over 80 g/100 ml in adults. The
    establishment of relationships between Pb-B levels and effect is
    especially difficult in children because the effect may be detected
    months or years after the critical exposure occurred.

     Renal function. Apparently prolonged exposure to Pb-B levels greater
    than 70 g/100 ml is necessary to produce nephropathy; a no-detected-
    effect level cannot be given. The problem is non-correspondence in
    time between the determination of Pb-B level and the detection of
    effect.

         Aminoaciduria, reflecting impaired amino acid transport through
    the renal tubules may occur in children and adults with increased lead
    absorption. The present data do not allow a no-detected-effect level
    to be estimated, but indicate that this effect is unlikely to be found
    in association with Pb-B levels below some 90-100 g/100 ml (Chisolm,
    1968b, Cramer et al., 1974).

     Changes in blood constituents such as calcium, phosphorus, glucose,
    cholesterol, total proteins, serum albumins, alkaline phosphatase
    (EC 3.1.3.1), lactate acid dehydrogenase, and urea nitrogen, could not
    be found in male workers with a median Pb-B level of 63 g/100 ml; 37%
    showed an effect with a Pb-B level greater than 70 g/100 ml (Cooper
    et al., 1973). There was an indication of increased bilirubin at a
    Pb-B level of about 70 g/100 ml. An increased pyruvate level after
    glucose administration was reported in 50% of children with Pb-B
    levels of 40-60 g/100 ml (Moncrieff et al., 1964).

     The general pattern of morbidity and mortality in workers does not
    appear to be affected if the Pb-B level never exceeds 70 g/100 ml.

         In assessing reported dose-effect relationships and no-detected-
    effect levels, one should take into account the fact that the
    available data are limited. Even from a theoretical viewpoint, the
    establishment of a definite no-effect level is not possible, because
    one can hardly ever expect to cover the whole range of susceptibility
    in human populations. Nevertheless, the available data suggest that
    the no-detected-effect levels given above are on the conservative
    side.

         Table 29 summarizes the no-detected-effect levels discussed. For
    some of these effects, it is possible to elaborate dose-response
    relationships. These cases are considered in section 9.4.

        Table 29.  No-detected effect levels in terms of Pb-B g of lead per 100 ml of blood)
                                                                                       

    No detected            Effect                             Population
    effect level
                                                                                       

    < 10                   Erythrocyte ALAD inhibition        adults, children
      20-25                FEP                                children
      20-30                FEP                                adult, female
      25-35                FEP                                adult, male
      30-40                Erythrocyte ATPase inhibition      general
      40                   ALA excretion in urine             adults, children
      40                   CP excretion in urine              adults
      40                   Anaemia                            children
      40-50                Peripheral neuropathy              adults
      50                   Anaemia                            adults
      50-60                Minimal brain dysfunction          children
      60-70                Minimal brain dysfunction          adults
      60-70                Encephalopathy                     children
    > 80                   Encephalopathy                     adults
                                                                                       
    
    9.4  Dose-response Relationships

         A dose-response relationship considers the observed relative
    frequency of occurrence of a specified  effecta in a group of
    subjects at a given dose level. As in the case of dose-effect
    relationships, the data available to evaluate a dose-response
    relationship are either limited or non-existent. The available
    information on dose-response relationships has been presented in
    section 8. In this section, attention is paid to the 5% response
    levels, i.e. that level of Pb-B at which not more than 5% of the group
    considered is expected to show the specified intensity of a specified
    effect. The 5% level has had to be stipulated, because not enough data
    are available to state the Pb-B levels for 0.5%, 1%, etc. Further
    investigations have to be carried out to enlarge the amount of data
    available. For further discussion see Zielhuis (1975). His review
    suggests the 5% response levels recorded in Table 30, which are in
    accordance with the data discussed in section 8. These response levels
    are also in agreement with those suggested by Hernberg (1975).

        Table 30.  Pb-B levels at which no more than 5% of the population will show
               the indicated intensity of effect
                                                                                    

    Biochemical effect     Intensity of effect        Population          Pb-B
                                                                          (g/100 ml)
                                                                                    

    ALAD inhibition        perceptible inhibition     adult, children     10
                           > 40% inhibition           adults              15-20
                           > 70% inhibition           adults              30
                           > 70% inhibition           children            25-30

    ALA-U                  perceptible increase       adults, children    40
                           > 10 mg/litre              adults, children    50

    FEP                    perceptible increase       adult males         30
                                                      adult females       25
                                                      children            20
                                                                                    

    a  From: Zielhuis, 1975.
    
              

    a  Graded effects may be specified in terms of their intensity.

    9.5  Diagnosis of lead Poisoning and Indices of Exposure and/or
         Effects for Epidemiological Studies

         For epidemiological studies and for the detection of the early
    effects of lead in occupational exposure of individuals, the following
    tests have been used:

    (1)  Lead levels in blood.

    (2)  Excretion of lead in urine spontaneously or after administration
         of chelating agents.

    (3)  Lead levels in tissues (teeth, bones, hair, etc.).

    (4)  Activity of ALAD in blood.

    (5)  Indices of disturbed porphyrin metabolism: ALA and/or CP in
         urine, Protoporphyrin IX in erythrocytes.

    (6)  Haematological indices such as basophilic stippling and
         haemoglobin levels.

    (7)  Early (sub-clinical) symptoms and signs of other damage (e.g. to
         the nervous system or the kidneys).

    (8)  Clinical evidence of poisoning.

         The criteria used by individual investigators correspond to the
    premises and purposes of their studies, for example, Pb-B for
    evaluating lead levels in the general population, and clinical signs
    of poisoning to assess morbidity caused by occupational exposure.

         The following considerations should be kept in mind when using
    and interpreting the results.

    9.5.1  Concentration of lead in blood (Pb-B)

         Pb-B reflects the current state of the dynamic equilibrium
    between the amounts of lead entering the organism, transported in the
    blood, and deposited in the tissues (including the bones). To date,
    insufficient information has been collected about the quantitative
    aspects of these processes, but from the data available, it may be
    stated that:

         (a) After a single inhalation of a soluble lead compound, the
    concentration of lead in the body will change in the same way as after
    an intravenous injection, i.e. there will be a rapid increase in Pb-B
    levels followed by a slower decrease; initially there will be a rapid
    elimination in the urine and a slow deposition in the tissues with
    subsequent redistribution according to the metabolism of lead in the
    various organs and systems.

         (b) During long-term exposure at a constant rate, an equilibrium
    between the amount of lead absorbed, deposited, and excreted develops
    over a long period (weeks to months, according to the daily doses
    received), which can be considered as a steady state.

         (c) There are only limited data as to how quickly this
    equilibrium (and Pb-B) changes when irregular variations in the dose
    of lead received (e.g. air lead concentrations) occur.

         A long-term steady state probably exists normally in non-
    occupationally exposed general adult populations, at least in the Pb-B
    level. However, no direct evidence for this assumption is available.

         In occupationally exposed persons, a steady state cannot be
    assumed because of the well known and marked variations of air lead
    concentrations in the working environment and of Pb-B levels in
    occupationally exposed individuals from one time to another and among
    the individuals in the same work place. Occasional exposure to a high
    lead concentration in the air could raise the Pb-B level for some time
    without contributing significantly to the body burden and to the
    biological effects.

         If Pb-B is to be used as an indicator of the degree of
    environmental lead exposure the above-mentioned facts must be taken
    into account, as well as the analytical method used and the
    limitations (accuracy, precision, sensitivity, limits of detection).

    9.5.2  Aminolevulinic acid dehydratase (ALAD)

         For ALAD the same conditions can apply as for Pb-B. The behaviour
    of ALAD activity will follow closely the level of Pb-B up to
    50-60 g/100 ml.

    9.5.3  Aminolevulinic acid (ALA) and coproporphyrin (CP) excretion
           in the urine

         ALA and CP in urine are not so dependent on the current state of
    lead exposure and absorption as the Pb-B, although their excretion
    diminishes relatively quickly when exposure ceases; they reflect more
    the average short-term level of lead exposure and have proved useful
    in this way. ALA and CP estimates have found broad recognition as
    indices of lead absorption and as indicators of early effects they
    reflect individual susceptibility to lead.

    9.5.4  Lead excretion in the urine

         An elevated rate of spontaneous lead excretion in the urine is
    indicative of high lead absorbed, but a normal rate of excretion does
    not serve as a reliable means of excluding the possibility of
    excessive absorption. Lead excretion in urine is dependent on the Pb-B

    level but is also influenced by other-mostly unknown-factors, so that
    no direct conclusions about exposure and the extent of absorption can
    be derived from lead levels in urine (even in a 24-hour sample).

         The excretion of lead provoked by chelating agents such as
    calcium disodium ethylenediamintetraacetate is thought to reflect the
    biologically active portion of the body burden. It is probably a more
    sensitive index of over exposure and excess absorption than the Pb-B
    level since clearly elevated values have been reported in cases of
    only marginally elevated Pb-B levels.

    9.5.5  Haematological changes (stippled cells, anaemia)

         These are not sensitive indices of over-exposure or excess
    absorption. They are not very useful for the early detection of
    possible health impairment.

    9.5.6  Lead in tissues (teeth and hair)

         These have been used as indicators of integrated long-term
    exposure and have the advantage that samples are easy to procure. As
    yet, the amount of information concerning the interpretation of the
    values obtained is inadequate for their evaluation as indices of
    exposure or dose.

    9.5.7  Some practical aspects

    9.5.7.1  General population studies

         The Pb-B level is the epidemiological index of choice, assuming
    that a reasonable approximation of a steady state exposure exists.
    ALAD activity estimates are equally useful for such studies or as
    epidemiological indices of lead absorption. The decision to use Pb-B
    or ALAD depends on the laboratory facilities available. Signs of lead
    effects other than ALAD inhibition are not to be expected at Pb-B
    levels below 20 g/100 ml. Lead in deciduous teeth and hair is
    potentially useful as an indicator of integrated exposure in infants
    but needs more study.

    9.5.7.2  Occupationally-exposed persons

         For screening the exposure of groups of workers, any method can
    be used that has the required sensitivity and specificity. Economic
    and time factors will determine the choice of test. When using the
    Pb-B level, the conditions of sampling must be well defined, taking
    into account the factors influencing the variations of the Pb-B
    concentrations. ALA and CP estimations in urine are widely used since
    they are simple, avoid the possibility of external contamination, and
    may provide a better picture of the integral exposure. ALAD activity
    is only useful at Pb-B levels below about 60 g/100 ml. For early
    detection of the signs of lead effects in individuals, ALA-U or CP-U

    tests are the best established screening methods. When abnormal values
    are found, further tests (including clinical and laboratory
    investigations) will have to be applied to evaluate the kind of
    disturbance and the degree of health risk (WHO Study Group, 1975).

    9.5.7.3  Reliability of sampling and analytical methods

         The evaluation of the pollution of the environment by lead and of
    the health effects on man which might result, depends on the
    reliability of sampling procedures and analytical methods used.

         The methods of sampling for different environmental media, and
    the possible exposure pathways of man have been discussed in section
    3. The great spatial and temporal variability of these environmental
    media and their diversity make the accurate assessment of total
    exposure a difficult task. Unless elaborate schemes are set up and
    extreme precautions are taken, the total exposure of a population
    group cannot be evaluated with an error of less than about 50%, taking
    into account tile analytical uncertainties.

         In the determination of the dose received or the effects on
    haematopoiesis observed, the sampling problem is relatively minor but
    the accuracy and precision of analytical techniques play an important
    role. An evaluation with up to 20% relative precision is seldom
    achieved under normal operational conditions.

    9.6  The Problem of Alkyllead Compounds

         The principal risk of alkyllead compounds is in occupational
    exposure, either by inhalation or by absorption through the skin.
    Acute toxicity results in an encephalopathy that differs greatly from
    the effects of inorganic lead on the central nervous system. Some
    components of the toxic effects are probably due to the alkyl compound
    as a whole rather than its lead component. Workmen at greatest risk
    are those involved in mixing fuel additives, although other workmen
    engaged in related occupations such as the cleaning of storage tanks
    where inhalation is possible, are also at high risk. Over-exposure of
    the general population to alkyllead compounds has not been documented.

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