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

    First draft prepared by Dr G. Gibbs, Canada (Chapter 2), Mr B.J. Pigg,
    USA (Chapter 3), Professor W.J. Nicholson, USA (Chapter 4),
    Dr A. Morgan, UK and Professor M. Lippmann, USA (Chapter 5),
    Dr J.M.G. Davis, UK and Professor B.T. Mossman, USA (Chapter 6),
    Professor J.C. McDonald, UK, Professor P.J. Landrigan, USA and
    Professor W.J. Nicholson, USA (Chapter 7), Professor H. Schreier,
    Canada (Chapter 8).

    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.

    World Health Organization                    Geneva, 1998

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
    Environment Programme (UNEP), the International Labour Organisation
    (ILO), and the World Health Organization (WHO).  The overall
    objectives of the IPCS are to establish the scientific basis for
    assessment of the risk to human health and the environment from
    exposure to chemicals, through international peer review processes, as
    a prerequisite for the promotion of chemical safety, and to provide
    technical assistance in strengthening national capacities for the
    sound management of chemicals.

         The Inter-Organization Programme for the Sound Management of
    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
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    field of chemical safety.  The purpose of the IOMC is to promote
    coordination of the policies and activities pursued by the
    Participating Organizations, jointly or separately, to achieve the
    sound management of chemicals in relation to human health and the

    WHO Library Cataloguing in Publication Data

    Chrysotile Asbestos.

         (Environmental health criteria ; 203)

         1.Asbestos, Serpentine - adverse effects
         2.Asbestos, Serpentine - toxicity
         3.Environmental exposure   4.Occupational exposure 
         I.International Programme on Chemical Safety   II.Series

         ISBN 92 4 157203 5             (NLM Classification: WA 754)
         ISSN 0250-863X

         The World Health Organization welcomes requests for permission to
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    Applications and enquiries should be addressed to the Office of
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    will be glad to provide the latest information on any changes made to
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    (c) World Health Organization 1998

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         The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar nature
    that are not mentioned. Errors and omissions excepted, the names of
    proprietary products are distinguished by initial capital letters.






    1. SUMMARY

         1.1. Identity, physical and chemical properties, sampling and
         1.2. Sources of occupational and environmental exposure
         1.3. Occupational and environmental exposure levels
         1.4. Uptake, clearance, retention and translocation
         1.5. Effects on animals and cells
         1.6. Effects on humans
         1.7. Environmental fate and effects on biota


         2.1. Identity
              2.1.1. Chemical composition
              2.1.2. Structure
              2.1.3. Fibre forms in the ore
              2.1.4. Fibre properties
              2.1.5. UICC samples
              2.1.6. Associated minerals in chrysotile ore
         2.2. Physical and chemical properties
              2.2.1. Physical properties
              2.2.2. Chemical properties
         2.3. Sampling and analytical methods
              2.3.1. Workplace sampling
              2.3.2. Sampling in the general environment
              2.3.3. Analytical methods
                 Fibre identification
                 Measurement of airborne fibre
                 Lung tissue analysis
                 Gravimetric analysis
         2.4. Conversion factors
              2.4.1. Conversion from airborne particle to
                        fibre concentrations
              2.4.2. Conversion from total mass to fibre
                        number concentrations


         3.1. Natural occurrence
         3.2. Anthropogenic sources
              3.2.1. Production
              3.2.2. Manufacture of products
              3.2.3. Use of products


         4.1. Occupational exposure
              4.1.1. Mining and milling
              4.1.2. Textile production
              4.1.3. Asbestos-cement
              4.1.4. Friction products
              4.1.5. Exposure of building maintenance personnel
              4.1.6. Various industries
         4.2. Non-occupational exposure
              4.2.1. Ambient air
              4.2.2. Indoor air


         5.1. Inhalation
              5.1.1. General principles
              5.1.2. Fibre deposition
              5.1.3. Fibre clearance and retention
                 Fibre clearance and retention in humans
                 Fibre clearance and retention in
                                  laboratory animals
              5.1.4. Fibre translocation
                 Fibre translocation in humans
                 Fibre translocation in animal models
              5.1.5. Mechanisms of fibre clearance
         5.2. Ingestion


         6.1. Introduction
         6.2. Effects on laboratory mammals
              6.2.1. Summary of previous studies
              6.2.2. Recent long-term inhalation studies
              6.2.3. Intratracheal and intrabronchial injection studies
              6.2.4. Intraperitoneal and intrapleural injection studies
              6.2.5. Ingestion studies
         6.3. Studies on cells
              6.3.1. Genotoxicity and interactions with DNA
              6.3.2. Cell proliferation
              6.3.3. Inflammation
              6.3.4. Cell death and cytotoxicity
              6.3.5. Liberation of growth factors and other response of
                        cells of the immune system


         7.1. Occupational exposure

              7.1.1. Pneumoconiosis and other non-malignant respiratory
              7.1.2. Lung cancer and mesothelioma
                 Critical occupational cohort studies -
                 Comparisons of lung cancer
                                  exposure-response - critical studies
                 Other relevant studies
              7.1.3. Other malignant diseases
                 Critical occupational cohort studies
                                  involving chrysotile
                 Other relevant studies
              7.2. Non-occupational exposure


         8.1. Environmental transport and distribution
              8.1.1. Chrysotile fibres in water
              8.1.2. Chrysotile fibres in soil
         8.2. Effects on biota
              8.2.1. Impact on plants
              8.2.2. Impact on terrestrial life-forms
              8.2.3. Impact on aquatic biota


         9.1. Introduction
         9.2. Exposure
              9.2.1. Occupational exposure
              9.2.2. General population exposure
         9.3. Health effects
              9.3.1. Occupational exposure
                 Lung cancer
              9.3.2. General environment
         9.4. Effects on the environment







         Every effort has been made to present information in the criteria
    monographs as accurately as possible without unduly delaying their
    publication.  In the interest of all users of the Environmental Health
    Criteria monographs, readers are requested to communicate any errors
    that may have occurred to the Director of the International Programme
    on Chemical Safety, World Health Organization, Geneva, Switzerland, in
    order that they may be included in corrigenda.

                                 *     *     *

         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
    356, 1219 Châtelaine, Geneva, Switzerland (telephone no. + 41 22 -
    9799111, fax no. + 41 22 - 7973460, E-mail irptc@unep.ch).

                                 *     *     *

         This publication was made possible by grant number 5 U01 ES02617-
    15 from the National Institute of Environmental Health Sciences,
    National Institutes of Health, USA, and by financial support from the
    European Commission.

    Environmental Health Criteria



         In 1973 the WHO Environmental Health Criteria Programme was
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           environmental pollutants and human health, and to provide
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         The first Environmental Health Criteria (EHC) monograph, on
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         The original impetus for the Programme came from World Health
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    Selection of chemicals

         Since the inception of the EHC Programme, the IPCS has organized
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         If an EHC monograph is proposed for a chemical not on the
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         The draft document, when received by the RO, may require an
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    FIGURE 1



    Professor J.M. Dement, Duke Occupational Health Services, Duke
         University, Durham, NC, USA  (Vice-Chairperson)a

    Professor J.Q. Huang, Shanghai Medical University, Shanghai,

    Professor M.S. Huuskonen, Institute of Occupational Health,
         Helsinki, Finlandb

    Professor G. Kimizuka, Department of Pathobiology, School of
         Nursing, Chiba University, Chiba, Japan

    Professor A. Langer, Environmental Sciences Laboratories,
         Brooklyn College of the City University of New York, Brooklyn,
         New York, USA  (Co-Rapporteur)

    Ms M.E. Meek, Priority Substances Section, Environmental Health
         Directorate, Health Protection Branch, Health Canada, Ottawa,
         Ontario, Canada  (Chairperson)c

    Ms M. Meldrum, Health and Safety Executive, Toxicology Unit,
         Bootle, United Kingdom  (Co-Rapporteur)

    Dr H. Muhle, Fraunhofer Institute for Toxicology and Aerosol
         Research, Hanover, Germany

    Professor M. Neuberger, Institute of Environmental Hygiene,
         University of Vienna, Vienna, Austria

    Professor J. Peto, Section of Epidemiology, Institute of Cancer
         Research, Royal Cancer Hospital, Sutton, Surrey, United Kingdom

    Dr L. Stayner, Risk Analysis and Document Development Branch,
         Education and Information Division, National Institute for
         Occupational Safety and Health, Morgantown, West Virginia, USA


    a  Professor J.M. Dement chaired the meeting sessions when
    discussions on Chapters 9, 10 and 11 were held. These sessions were
    held  in camera without the presence of observers. He also chaired
    the final session when the whole document was adopted.
    b  Not present at the last session
    c  Not present at the discussions on Chapter 10.

    Dr V. Vu, Health and Environmental Review Division, US
         Environmental Protection Agency, Washington, D.C., USA


    Mr D. Bouige, Asbestos International Association (AIA), Paris,

    Dr G.W. Gibbs, Committee on Fibres, International Commission on
         Occupational Health, Spruce Grove, Alberta, Canadab


    Dr Paolo Boffetta, Unit of Environmental Cancer Epidemiology,
         International Agency for Research on Cancer, Lyon, France

    Dr I. Fedotov, Occupational Safety and Health Branch, International
         Labour Office, Geneva, Switzerland

    Mr Salem Milad, International Registry of Potentially Toxic
         Chemicals, United Nations Environment Programme, Geneva,

    Professor F. Valic, IPCS Scientific Adviser, Andrija œtampar
         School of Public Health, Zagreb University, Zagreb, Croatia
         (Responsible Officer and Secretary of Meeting)

     Resource persons

    Professor J. Corbett McDonald, Department of Occupational and
         Environmental Medicine, National Heart and Lung Institute,
         London, United Kingdomb

    Professor W.J. Nicholson, Department of Community Medicine,
         Mount Sinai School of Medicine, New York, NY, USA


    a  Present only during first two days of the meeting (i.e. before the
    discussions on Chapters 9, 10 and 11 were held)
    b  Not present during the discussions on Chapters 9, 10 and 11, which
    were held  in camera


         A Task Group on Environmental Health Criteria for Chrysotile
    Asbestos met at WHO Headquarters, Geneva, Switzerland, from 1 to 6
    July 1996. Dr M. Mercier, Director IPCS, opened the Meeting and
    welcomed the participants on behalf of the heads of the three
    cooperating  organizations of the IPCS (UNEP/ILO/WHO). The Task Group
    reviewed and revised the third draft of the monograph, made an
    evaluation of the risks for human health and the environment from
    exposure to chrysotile asbestos, and made recommendations for health
    protection and further research.

         The first drafts were prepared by Dr G. Gibbs, Canada
    (Chapter 2), Mr B.J. Pigg, USA (Chapter 3), Professor W.J. Nicholson,
    USA (Chapter 4), Dr A. Morgan, UK and Professor M. Lippmann, USA
    (Chapter 5), Dr J.M.G. Davis, UK and Professor B.T. Mossman, USA
    (Chapter 6), Professor J.C. McDonald, UK, Professor P.J. Landrigan,
    USA and Professor W.J. Nicholson, USA (Chapter 7), Professor H.
    Schreier, Canada (Chapter 8).

         In the light of international comments, the second draft was
    prepared under the coordination of Professor F. Valiœ, Croatia.
    Chapter 8 was modified by a group of experts in risk assessment
    (Professors J. Hughes, USA, J. Peto, UK, and J. Siemiatycki, Canada).

         Professor F. Valiœ was responsible for the overall scientific
    content of the monograph and for the organization of the meeting, and
    Dr P.G. Jenkins, IPCS Central Unit, for the technical editing of the

         The efforts of all who helped in the preparation and finalization
    of the monograph are gratefully acknowledged.


         ACM      asbestos-containing material
         AOS      activated oxygen species
         ATEM     analytical transmission electron microscopy
         BAL      bronchoalveolar lavage
         BP       benzo (a)pyrene
         CI       confidence interval
         EDXA     energy-dispersive X-ray analyser
         f        fibre
         FGF      fibroblast growth factor
         LDH      lactate dehydrogenase
         mpcf     millions of particles per cubic foot
         mpcm     millions of particles per cubic metre
         NHMI      N-nitrosoheptamethyleneimine
         OR       odds ratio
         p        particle
         PCOM     phase contrast optical microscopy
         PDGF     platelet-derived growth factor
         PMR      proportional mortality ratio
         RR       relative risk
         SAED     selected area electron diffraction
         SEM      scanning electron microscopy
         SMR      standardized mortality ratio
         TEM      transmission electron microscopy
         TPA      12-O-tetradecanoylphorbol-13-acetate
         TWA      time-weighted average
         UICC     Union Internationale Contre le Cancer (reference
                  asbestos samples)


         As early as 1986 the International Programme on Chemical Safety
    (IPCS) published the Environmental Health Criteria (EHC 53) on the
    health effects of natural mineral fibres with particular emphasis on
    asbestos (IPCS, 1986). During the next 7 years, efforts were focused
    on possible reduction of environmental asbestos exposure (IPCS, 1989;
    WHO/OCH, 1989), including the evaluation of a number of possible
    substitute fibres such as man-made mineral fibres (IPCS, 1988), and
    selected organic synthetic fibres (IPCS, 1993).

         In 1992, four WHO Member States invited the Director-General of
    WHO to request the IPCS to update that part of EHC 53 concerning the
    health effects of chrysotile asbestos. The Director-General accepted
    the request and instructed the IPCS to develop an EHC specifically for
    chrysotile asbestos taking into consideration that (a) the
    International Labour Organisation had recommended the discontinuation
    of the use of crocidolite asbestos; (b) amosite asbestos was, for all
    practical purposes, no longer exploited; and (c) there was still
    wide-spread production and use of chrysotile asbestos in the world.

         A number of reputable scientists (selected solely on the basis of
    their contributions to the open scientific literature) were approached
    with the request to develop individual scientific chapters for the
    first draft. Chapters 5, 6 and 7 were drafted by two or three authors
    independently. On the basis of these texts a coherent draft was
    prepared by the IPCS.

         The drafts of chapters 5, 6 and 7 were sent for preliminary
    review to a limited number of recognized experts proposed by IPCS
    participating institutions. The full draft of the document was
    submitted to the standard IPCS worldwide evaluation procedure by
    circulating it for comments to more than 140 IPCS Contact Points.

         Taking into account all the relevant comments, a second draft was
    developed by the IPCS. Chapter 7, drafted independently by three
    authors, was modified by a working group of experts and focuses on
    lung cancer and mesothelioma risks in populations exposed almost
    exclusively to chrysotile. The discussion in this chapter has been
    restricted primarily to direct observation from epidemiological

         The third draft was submitted for evaluation, modification and
    finalization to a Task Group of experts appointed by WHO. None of the
    primary authors was appointed to be a member of the Task Group.

    1.  SUMMARY

    1.1  Identity, physical and chemical properties, sampling and analysis

         Chrysotile is a fibrous hydrated magnesium silicate mineral that
    has been used in many commercial products. It is widely used in global
    commerce today. Its physical and chemical properties as a mineral are
    observed to vary among the exploited geological deposits. The minerals
    that accompany the fibre in ores are many, and among these may be some
    varieties of fibrous amphibole. Tremolite is thought to be especially
    important in this respect; its form and concentration range greatly.

         Analysis of chrysotile in the workplace currently entails the use
    of light and electron microscopes. Various instruments and devices
    have been previously used to monitor environments for the presence and
    concentration of both total dust and fibres. The membrane filter
    technique and phase contrast optical microscopy are commonly used
    today for workplace assay (expressed as fibres per ml air); and the
    transmission electron microscopy is also employed. Environmental
    assays require the use of transmission electron microscopy. Tissue
    burden studies have been employed to improve information regarding
    exposures. Depending on the degree of attention to detail in these
    studies, inferences regarding mechanisms and etiology have been drawn.

         Gravimetric and thermal precipitator and midget impinger
    techniques were previously used for workplace characterization, and
    these dust (not fibre) values are the only early exposure indices
    available for gauging exposure-response relationships. There have been
    many attempts to convert these values to fibres per volume of air, but
    these conversions have had very limited success. Conversion factors
    have been found to be industry-specific and even operation-specific;
    universal conversion factors carry high variances.

    1.2  Sources of occupational and environmental exposure

         Low concentrations of chrysotile are found throughout the crustal
    environment (air, water, ice caps and soil). Both natural and human
    activities contribute to fibre aerosolization and distribution.
    Anthropogenic sources include dusts from occupational activities,
    which cover ore recovery and processing, manufacturing, application,
    usage and, ultimately disposal.

         Production occurs in 25 countries, and there are seven major
    producers. Annual world production of asbestos peaked at over 5
    million tonnes in the mid-1970s but has since declined to a current
    level of about 3 million tonnes. Manufacturing of chrysotile products
    is undertaken in more than 100 countries, and Japan is the leading
    consumer country. The current main activities resulting in potential
    chrysotile exposure are: (a) mining and milling; (b) processing into
    products (friction materials, cement pipes and sheets, gaskets and
    seals, paper and textiles); (c) construction, repair and demolition;
    (d) transportation and disposal. The asbestos-cement industry is by
    far the largest user of chrysotile fibres, accounting for about 85% of
    all use.

         Fibres are released during processing, installation and disposal
    of asbestos-containing products, as well as through normal wear of
    products in some instances. Manipulation of friable products may be an
    important source of chrysotile emission.

    1.3  Occupational and environmental exposure levels

         Based on data mainly from North America, Europe and Japan, in
    most production sectors workplace exposures in the early 1930s were
    very high. Levels dropped considerably to the late 1970s and have
    declined substantially to present day values. In the mining and
    milling industry in Quebec, the average fibre concentrations in air
    often exceeded 20 fibres/ml (f/ml) in the 1970s, while they are now
    generally well below 1 f/ml. In the production of asbestos-cement in
    Japan, typical mean concentrations were 2.5-9.5 f/ml in 1970s, while
    mean concentrations of 0.05-0.45 f/ml were reported in 1992. In
    asbestos textile manufacture in Japan, mean concentrations were
    between 2.6 and 12.8 f/ml in the period between 1970 and 1975, and
    0.1-0.2 f/ml in the period between 1984 and 1986. Trends have been
    similar in the production of friction materials: based on data
    available from the same country, mean concentrations of 10-35 f/ml
    were measured in the period between 1970 and 1975, while levels
    0.2-5.5 f/ml were reported in the period between 1984 and 1986. In a
    plant in the United Kingdom in which a large mortality study was
    conducted, concentrations were generally above 20 f/ml in the period
    before 1931 and generally below 1 f/ml during 1970-1979.

         Few data on concentrations of fibres associated with the
    installation and use of chrysotile-containing products are available,
    although this is easily the most likely place for workers to be
    exposed. In the maintenance of vehicles, peak concentrations of up to
    16 f/ml were reported in the 1970s, while practically all measured
    levels after 1987 were less than 0.2 f/ml. Time-weighted average
    exposures during passenger vehicle repair in the 1980s were generally
    less than 0.05 f/ml. However, with no controls, blowing off debris
    from drums resulted in short-term high concentrations of dust.

         There is potential for exposure of maintenance personnel to mixed
    asbestos fibre types due to large quantities of friable asbestos in
    place. In buildings with control plans, personal exposure of building
    maintenance personnel in the USA, expressed as 8-h time-weighted
    averages, was between 0.002 and 0.02 f/ml. These values are of the
    same order of magnitude as typical exposures during telecommunication
    switchwork (0.009 f/ml) and above-ceiling work (0.037 f/ml), although
    higher concentrations were reported in utility space work (0.5 f/ml).
    Concentrations may be considerably higher where no control plans have
    been introduced. In one case, short-term episodic concentrations were
    1.6 f/ml during sweeping and 15.5 f/ml during dusting of library books
    in a building with a very friable chrysotile-containing surface
    formulation. Most other 8-h time-weighted averages are about two
    orders of magnitude less.

         Based on surveys conducted before 1986, fibre concentrations
    (fibres > 5 µm in length) in outdoor air, measured in Austria,
    Canada, Germany, South Africa and the USA, ranged between 0.0001 and
    about 0.01 f/ml, levels in most samples being less than 0.001 f/ml.
    Means or medians were between 0.00005 and 0.02 f/ml, based on more
    recent determinations in Canada, Italy, Japan, the Slovak Republic,
    Switzerland, United Kingdom and USA.

         Fibre concentrations in public buildings, even those with friable
    asbestos-containing materials, are within the range of those measured
    in ambient air. Concentrations (fibres > 5 µm in length) in buildings
    in Germany and Canada reported before 1986 were generally less than
    0.002 f/ml. In more recent surveys in Belgium, Canada, the Slovak
    Republic, United Kingdom and USA, mean values were between 0.00005 and
    0.0045 f/ml. Only 0.67% of chrysotile fibres were longer than 5 µm.

    1.4  Uptake, clearance, retention and translocation

         The deposition of inhaled chrysotile asbestos is dependent upon
    the aerodynamic diameter, the length and the morphology of the fibre.
    Most airborne chrysotile fibres are considered respirable because
    their fibre diameters are less than 3 µm, equal to an aerodynamic
    diameter of about 10 µm. In laboratory rats, chrysotile fibres are
    deposited primarily at alveolar duct bifurcations.

         In the nasopharyngeal and tracheobronchial regions, chrysotile
    fibres are cleared via mucocilliary clearance. At the alveolar duct
    bifurcations the fibres are taken up by epithelial cells. Fibre length
    is an important determinant of alveolar clearance of chrysotile
    fibres. There is extensive evidence from animal studies that short
    fibres (less than 5 µm long) are cleared more rapidly than long fibres
    (longer than 5 µm). The mechanisms of the relatively more rapid
    clearance of chrysotile fibres compared to those of amphiboles are not
    completely known. It has been hypothesized that short chrysotile
    fibres are cleared through phagocytosis by alveolar macrophages, while
    long chrysotile fibres are cleared mainly by breakage and/or
    dissolution. To what extent chrysotile fibres are translocated to the
    interstitium, pleural tissue and other extrathoracic tissues is not
    fully understood.

         Analyses of human lungs of workers exposed to chrysotile asbestos
    indicate much greater retention of tremolite, an amphibole asbestos
    commonly associated with commercial chrysotile in small proportions,
    than of chrysotile. The more rapid removal of chrysotile fibres from
    the human lung is further supported by findings from animal studies
    showing that chrysotile is more rapidly cleared from the lung than are
    amphiboles including crocidolite and amosite.

         Available data from studies in humans and animals are
    insufficient to evaluate the possible uptake, distribution and
    excretion of chrysotile fibres from ingestion. Available evidence
    indicates that, if penetration of chrysotile fibres across the gut
    wall does occur, it is extremely limited. One study indicated an

    increased level of chrysotile fibres in the urine of workers
    occupationally exposed to chrysotile.

    1.5  Effects on animals and cells

         Various experimental samples of chrysotile fibres have been shown
    in numerous long-term inhalation studies to cause fibrogenic and
    carcinogenic effects in laboratory rats. These effects include
    interstitial fibrosis and cancer of the lung and pleura. In most
    cases, there appears to be an association between fibrosis and tumours
    in the rat lung. Fibrogenic and carcinogenic effects have also been
    found in long-term animal studies (mainly in rats) using other modes
    of administration (e.g., intratracheal instillation and intrapleural
    or intraperitoneal injection).

         Exposure/dose-response relationships for chrysotile-induced
    pulmonary fibrosis, lung cancer and mesothelioma have not been
    adequately investigated in long-term animal inhalation studies.
    Inhalation studies conducted to date, mainly using a single exposure
    concentration, show fibrogenic and carcinogenic responses at airborne
    fibre concentrations ranging from 100 to a few thousand fibres/ml.
    When data from various studies are combined, there appears to be a
    relationship between airborne fibre concentrations and lung cancer
    incidence. This type of analysis, however, may not be scientifically
    sound as different experimental conditions were used in available

         In non-inhalation experiments (intrapleural and intraperitoneal
    injection studies), dose-response relationships for mesothelioma have
    been demonstrated for chrysotile fibres. Data from these types of
    studies, however, may not be suitable for the evaluations of human
    risk from inhalation exposure to fibres.

         Tremolite asbestos, a minor component mineral of commercial
    chrysotile, has also been shown to be carcinogenic and fibrogenic in a
    single inhalation experiment and an intraperitoneal injection study in
    rats. Exposure/dose-response data are not available to allow direct
    comparison of the cancer potency of tremolite and chrysotile.

         The ability of fibres to induce fibrogenic and carcinogenic
    effects appears to be dependent on their individual characteristics,
    including fibre dimension and durability (i.e. biopersistence in
    target tissues), which are determined in part by the physico-chemical
    properties. It has been well documented in experimental studies that
    short fibres (shorter than 5 µm) are less biologically active than
    long fibres (longer than 5 µm). It is still uncertain, however,
    whether short fibres have any significant biological activity.
    Furthermore, it is not known how long a fibre needs to remain in the
    lung in order to induce preneoplastic effects, since the appearance of
    asbestos-related cancer generally occurs later in the animal's life.

         The mechanisms by which chrysotile and other fibres cause
    fibrogenic and carcinogenic effects are not completely understood.
    Possible mechanisms of fibrogenic effects of fibres include chronic
    inflammation process mediated by production of growth factors (e.g.,
    TNF-alpha) and reactive oxygen species. With regard to fibre-induced
    carcinogenicity, several hypotheses have been proposed. These include:
    DNA damage by reactive oxygen species induced by fibres; direct DNA
    damage by physical interactions between fibres and target cells;
    enhancement of cell proliferation by fibres; fibre-provoked chronic
    inflammatory reactions leading to prolonged release of lysozymal
    enzymes, reactive oxygen species, cytokines and growth factors; and
    action by fibres as co-carcinogens or carriers of chemical carcinogens
    to the target tissues. It is likely, however, that all these
    mechanisms contribute to the carcinogenicity of chrysotile fibres, as
    such effects have been observed in various  in vitro systems of human
    and mammalian cells.

         Overall, the available toxicological data provide clear evidence
    that chrysotile fibres can cause fibrogenic and carcinogenic hazard to
    humans. The data, however, are not adequate for providing quantitative
    estimates of the risk to humans. This is because there are inadequate
    exposure-response data from inhalation studies, and there are
    uncertainties concerning the sensitivities of the animal studies for
    predicting human risk.

         Chrysotile fibres have been tested in several oral
    carcinogenicity studies. Carcinogenic effects have not been reported
    in available studies.

    1.6  Effects on humans

         Commercial grades of chrysotile have been associated with an
    increased risk of pneumoconiosis, lung cancer and mesothelioma in
    numerous epidemiological studies of exposed workers.

         The non-malignant diseases associated with exposure to chrysotile
    comprise a somewhat complex mixture of clinical and pathological
    syndromes not readily definable for epidemiological study. The prime
    concern has been asbestosis, generally implying a disease associated
    with diffuse interstitial pulmonary fibrosis accompanied by varying
    degrees of pleural involvement.

         Studies of workers exposed to chrysotile in different sectors
    have broadly demonstrated exposure-response or exposure-effect
    relationships for chrysotile-induced asbestosis, in so far as
    increasing levels of exposure have produced increases in the incidence
    and severity of disease. However, there are difficulties in defining
    this relationship, due to factors such as uncertainties in diagnosis
    and the possibility of disease progression on cessation of exposure.

         Furthermore, some variation in risk estimates are evident among
    the available studies. The reasons for the variations are not entirely
    clear, but may relate to uncertainties in exposure estimates, airborne
    fibre size distributions in the various industry sectors and
    statistical models. Asbestotic changes are common following prolonged
    exposures of 5 to 20 f/ml.

         The overall relative risks for lung cancer are generally not
    elevated in the studies of workers in asbestos-cement production and
    in some of the cohorts of asbestos-cement production workers. The
    exposure-response relationship between chrysotile and lung cancer risk
    appears to be 10-30 times higher in studies of textile workers than in
    studies of workers in mining and milling industries. The relative
    risks of lung cancer in the textile manufacturing sector in relation
    to estimated cumulative exposure are, therefore, some 10-30 times
    greater than those observed in chrysotile mining. The reasons for this
    variation in risk are not clear, so several hypotheses, including
    variations in fibre size distribution, have been proposed.

         Estimation of the risk of mesothelioma is complicated in
    epidemiological studies by factors such as the rarity of the disease,
    the lack of mortality rates in the populations used as reference, and
    problems in diagnosis and reporting. In many cases, therefore, risks
    have not been calculated, and cruder indicators have been used, such
    as absolute numbers of cases and deaths, and ratios of mesothelioma
    over lung cancers or total deaths.

         Based on data reviewed in this monograph, the largest number of
    mesotheliomas has occurred in the chrysotile mining and milling
    sector. All the observed 38 cases were pleural with the exception of
    one of low diagnostic probability, which was pleuro-peritoneal. None
    occurred in workers exposed for less than 2 years. There was a clear
    dose-response relationship, with crude rates of mesotheliomas 
    (cases/ 1000 person-years) ranging from 0.15 for those with cumulative
    exposure less than 3530 million particles per m3 (mpcm)-years 
    (< 100 million particles per cubic foot (mpcf)-years) to 0.97 for
    those with exposures of more than 10 590 mpcm-years (> 300

         Proportions of deaths attributable to mesotheliomas in cohort
    studies in the various mining and production sectors range from 0 to
    0.8%. Caution should be exercised in interpreting these proportions as
    studies do not provide comparable data stratifying deaths by exposure
    intensity, duration of exposure or time since first exposure.

         There is evidence that fibrous tremolite causes mesothelioma in
    humans. Since commercial chrysotile may contain fibrous tremolite, it
    has been hypothesized that the latter may contribute to the induction
    of mesotheliomas in some populations exposed primarily to chrysotile.
    The extent to which the observed excesses of mesothelioma might be
    attributed to the fibrous tremolite content has not been resolved.

         The epidemiological evidence that chrysotile exposure is
    associated with an increased risk for cancer sites other than the lung
    or pleura is inconclusive. There is limited information on this issue
    for chrysotile  per se, although there is some inconsistent evidence
    for an association between asbestos exposure (all forms) and
    laryngeal, kidney and gastrointestinal tract cancers. A significant
    excess of stomach cancer has been observed in a study of Quebec
    chrysotile miners and millers, but possible confounding by diet,
    infections or other risk factors has not been addressed.

         It should be recognized that although the epidemiological studies
    of chrysotile-exposed workers have been primarily limited to the
    mining and milling, and manufacturing sector, there is evidence, based
    on the historical pattern of disease associated with exposure to mixed
    fibre types in western countries, that risks are likely to be greater
    among workers in construction and possibly other user industries.

    1.7  Environmental fate and effects on biota

         Serpentine outcroppings occur world-wide. Mineral components,
    including chrysotile, are eroded through crustal processes and are
    transported to become a component of the water cycle, sediment
    population and soil profile. Chrysotile presence and concentrations
    have been measured in water, air and other units of the crust.

         Chrysotile and its associated serpentine minerals chemically
    degrade at the surface. This produces profound changes in soil pH and
    introduces a variety of trace metals into the environment. This has in
    turn produced measurable effects on plant growth, soil biota
    (including microbes and insects), fish and invertebrates. Some data
    indicate that grazing animals (sheep and cattle) undergo changes in
    blood chemistry following ingestion of grasses grown on serpentine


    2.1  Identity

    2.1.1  Chemical composition

         Chrysotile, referred to as white asbestos, is a naturally
    occurring fibrous hydrated magnesium silicate belonging to the
    serpentine group of minerals. The chemical composition, crystal
    structure and polytypic forms of the serpentine minerals have been
    described by Langer & Nolan (1994).

         The composition of chrysotile is close to the ideal unit cell
    formula (Mg3Si2O5(OH)4); substitution by other elements in the
    crystal structure is possible. According to Skinner et al. (1988)
    substitution possibilities are:

              (Mg3-x-y Rx+2 Ry+3)(Si2-y Ry+3)O5 (OH)4,

         where R2+ = Fe2+, Mn2+ or Ni2+ and R3+=Al3+ or Fe3+.

    Results of a typical chemical analysis are shown in Table 1 of
    Environmental Health Criteria 53 (IPCS, 1986).

         Trace amounts of some other elements, such as Na, Ca and K, are
    probably due to the presence of other minerals admixed in the ore (see
    section 2.1.6).

    2.1.2  Structure

         Chrysotile is a sheet silicate with a basic building block of
    (Si2O5)n in which three of the oxygen atoms in each tetrahedron
    base are shared with adjacent tetrahedra in the same layer. The apical
    oxygens of the tetrahedra in the silica sheet become a component
    member of the overlying brucite layer (Mg(OH)2) (Speil & Leineweber,
    1969). As the dimensions of the cations in the silica and brucite
    sheets are different, strain is produced, which is accommodated by the
    formation of a scroll structure. Yada (1967) produced transmission
    electron micrographs that permitted visualization of this
    morphological feature. The curvature occurs with the brucite layer on
    the outer surface. The resulting capillaries are common to most
    specimens although solid cores have been found.

         When more than one structure occurs, they are called polytypes:
    orthochrysotile (orthorhombic structure), clinochrysotile (monoclinic
    structure) and parachrysotile (cylindrical or polygonal Povlen-type
    structures) (Wicks, 1979). Most chrysotile is a mixture of the ortho-
    and clino-polytypes in various proportions (Speil & Leineweber, 1969).

    2.1.3  Fibre forms in the ore

         Chrysotile can occur in the host rock as "cross-fibre" (fibre
    axes at right angles to the seam or vein), "slip-fibre" (fibre axes
    parallel to the seam) or massive fibre (in which there is no
    recognizable fibre orientation, as in the New Idria deposit in USA).

    2.1.4  Fibre properties

         Depending on the relative flexibility, fibres may be "harsh" or
    "soft". Chrysotile fibres generally occur with properties between
    these end-types (Badollet, 1948). While amphibole fibres are generally
    harsh, most chrysotile fibres are soft, although fibres displaying
    intermediate properties also occur. Harshness has been reported to be
    related to the water content of the fibre, i.e. the higher the water
    content the "softer" the fibre (Woodroofe, 1956), relative contents of
    clino- and ortho-chrysotile, and the presence of fine mineral
    intergrowth ( Speil & Leineweber, 1969).

         Harsh chrysotile fibres tend to be straighter and less flexible
    than the soft fibres. Inhalation of respirable straight fibres is
    reported to be associated with greater penetration to the terminal
    bronchioles than in the case of "curly" fibres (Timbrell, 1965, 1970).

         The fibres can be classified into crude chrysotile (hand-selected
    fibres in essentially native or unfiberized form) and milled fibres
    (after mechanical treatment of the ore). Fibre grades used for
    different products vary from country to country. The Canadian system
    has been described by Cossette & Delvaux (1979). The Canadian grading
    system is widely used internationally.

         At the turn of this century, the fibres of major commercial
    importance were several centimetres long. With time, as new
    applications developed, shorter fibres became important. This change
    is likely to have altered the nature of exposure in some

    2.1.5  UICC samples

         Two UICC (Union Internationale Contre le Cancer) standard
    reference samples of chrysotile asbestos were available for use in
    experimental work. One was from Zimbabwe (Chrysotile A) and the other
    was a composite sample of fibres from Canadian mines in the eastern
    townships of Quebec (Chrysotile B). The physico-chemical properties of
    these samples are well characterized and details of their composition
    and properties have been reported (Timbrell et al., 1968; Rendall,
    1970). These mixtures were artificial and did not reflect any one
    commercially available fibre.

    2.1.6  Associated minerals in chrysotile ore

         The mineral dusts to which miners or millers might be exposed are
    determined by the minerals associated with each of the chrysotile ore
    deposits. These depend on the composition of the original rock types
    and on the materials added or removed during geological events,
    surface weathering processes, etc. The spacial relationships among
    these components within ore bodies vary significantly from deposit to

         Iron is ubiquitous in chrysotile deposits derived from ultramafic
    rocks. In some of these, magnetite occurs in intimate association with
    the fibres (e.g., in Quebec). In other deposits types, e.g., in
    carbonate rocks, the iron content is low (e.g., in Arizona). Brucite,
    or nemalite (the fibrous form of brucite), is found in some deposits.
    Micas, feldspars, altered feldspars, talc and carbonate minerals may
    be present. Langer & Nolan (1994) listed minerals likely to be
    associated with ultramafic rocks in which chrysotile is found, and
    Gibbs (1971a) listed more than 70 minerals occurring in the Quebec
    chrysotile mining region. Minerals such as magnetite, calcite and
    zeolites may also occur in a fibrous form.

         Amphiboles may also be encountered, some in fibrous form. These
    latter minerals have been found in studies of lung tissues of exposed
    workers. Tremolite, ferro-tremolite, actinolite, anthophyllite and
    other amphibole minerals have been described. Their occurrence in ore
    bodies is both heterogeneous in distribution and variable in
    concentration. Addison & Davies (1990) found tremolite in 28 out of 81
    ore samples (34.6%) at concentrations (when detected) from 0.01 to
    about 0.6%. The average concentration was about 0.09%. The form of the
    amphibole, whether asbestos or massive, was not given. This
    information may be crucial in considering the mineral type as an agent
    of disease, especially for mesothelioma.

         Trace metals have been described in association with fibres,
    particularly chromium, cobalt, nickel, iron and manganese (Cralley et
    al., 1967; Gibbs, 1971a; Morgan & Cralley, 1973; Oberdörster et al.,
    1980). Concentrations in mills in the late 1960s were several times
    higher than those measured at textile plants at that time (Gibbs,

         Naturally occurring chrysotile has been shown to contain trace
    quantities of organic compounds, predominantly straight-chain alkanes
    (Gibbs, 1971b). Processed fibres may also contain organic compounds
    including polycyclic aromatic hydrocarbons (Gibbs, 1971a; Gibbs & Hui,
    1971). Concentrations of polycyclic aromatic hydrocarbons in the air
    of chrysotile mills were found to be lower than levels in urban areas
    (Gibbs, 1971a). Fibres can also be contaminated by alkanes and by
    antioxidants from storage in polyethylene bags (Commins & Gibbs, 1969;
    Gibbs & Hui, 1971).

         Radon concentrations in the Quebec chrysotile mines were reported
    to be below 0.3 Standard Working Level (Gibbs, 1971a). This has been
    rejected as an agent of disease among miners, especially for lung

    2.2  Physical and chemical properties

         The mineralogy and properties of chrysotile have been summarized
    by Wicks (1979), Pooley (1987), and Langer & Nolan (1994).

    2.2.1  Physical properties

         The physical properties of chrysotile, as they affect human
    health, have been described in Langer & Nolan (1986, 1994) and IPCS

         Harshness has been discussed in section 2.1.4.

         Heating of chrysotile fibre at 700°C for an hour converts it to
    an amorphous, anhydrous magnesium silicate material (Speil &
    Leineweber, 1969). Intensive dry grinding also destroys the structure
    of chrysotile. Analysis of wear debris from brake linings made with
    asbestos has shown that virtually all of the chrysotile fibre is
    converted to amorphous material, in association with the mineral
    forsterite (a recrystallization product). The conversion is explained
    by localized temperatures above 1000°C at the point of contact between
    the brake lining and the drum (Lynch, 1968; Rowson, 1978; Williams &
    Muhlbaier, 1982). The fibres found in the brake wear debris are
    predominantly (99%) less than 0.4 µm in length (Rohl et al., 1977;
    Williams & Muhlbaier, 1982). Rodelsperger et al. (1986) found less
    than 1% of fibres longer than 5 µm.

         Size and shape are the most important characteristics for
    defining the respirability of fibres. For workplace regulatory
    purposes a fibre has been defined most frequently as having an aspect
    ratio (ratio of fibre length to fibre diameter) of at least 3:1.
    Regulatory definitions usually impose a length of 5 µm or greater for
    workplace assay.

         Chrysotile bundles may be split longitudinally to form thinner
    fibres. The ultimate fibre is called a fibril. Yada (1967), by means
    of high resolution transmission electron microscopy, showed that basic
    spiral elements of chrysotile consist of 5 silica-magnesia units with
    approximately 10 silica-magnesia units forming the 0.007 µm wall of a
    single fibril. The diameter of the ultimate fibril is about 0.03 µm.

         The fibres of significance in health risk evaluation are those
    that can be inhaled. Timbrell (1970, 1973) showed that chrysotile
    fibres less than about 3.5 µm in diameter can enter the conducting
    airways of the lung. The radius of curvature of the chrysotile fibre
    may play a role in the ability of a fibre to penetrate to distant
    sites along the conducting airways.

         As it is possible to have long narrow fibres and short narrow
    fibres, descriptions of fibrous aerosols by "mean or median diameter",
    or "mean or median length" do not provide sufficient information.
    Comparisons of fibrous aerosols to which subjects are exposed may
    therefore be limited. The measurements of dimensions are
    time-consuming and complete data sets are scant.

         Results of most distributions reported are incomplete. Unless
    specific steps have been taken to evaluate very long fibres,
    transmission electron microscopy (TEM) will understate the number of
    long fibres (>20 µm). Because the proportion of very long fibres is
    low, random scanning rarely encounters them. Scanning electron
    microscopy (SEM) usually requires coating of the specimen. Most
    preparation techniques obscure single chrysotile fibrils. In addition,
    if chemical analysis of individual fibres is not made, other fibres
    may be erroneously reported as chrysotile.

         It has been noted that the vast majority of airborne chrysotile
    fibres are short, the percentage of fibres more than 5 µm long in
    mining and milling being about 1.3 and 4.1%, respectively (Gibbs &
    Hwang, 1980), while data show that up to 24% of fibres may be longer
    than 5 µm in certain textile spinning operations (Gibbs, 1994).
    Virtually all airborne fibres have a diameter of less than 3 µm and
    are thus respirable.

         The cross-section of a chrysotile fibril is approximately
    circular (see figure in Yada, 1967). This is important in calculating
    the mass of individual fibres. Generally, the surface area depends on
    the degree of fibre openness. The New Idria (Coalinga) material has a
    surface area of about 78 m2/g and an average fibril diameter of
    0.0275 µm, while the Canadian 7R has a surface area of about 50 m2/g
    and an average fibril diameter of 0.0375 µm (Speil & Leineweber,
    1969). It has been suggested that surface area plays a role in
    imparting biological potential.

         Timbrell (1975) reported the magnetic properties of fibres.
    Chrysotile showed no preferred orientation in magnetic fields.

         It has been observed that industrial processing of fibres from
    different sources may affect total airborne dust concentrations.

    2.2.2  Chemical properties

         Chrysotile exhibits significant solubility in aqueous neutral or
    acidic environments (Langer & Pooley, 1973; Jaurand et al., 1977;
    Spurny, 1982). In contact with dilute acids or aqueous medium at pH
    less than 10, magnesium leaches from the outer brucite layer (Nagy &
    Bates, 1952; Atkinson, 1973; Morgan & Cralley, 1973). Magnesium loss
    has also been demonstrated  in vivo. The surface area of leached
    chrysotile is greatly increased (Badollet & Gannt, 1965). The
    solubility of the outer brucite layer of chrysotile in body fluids
    greatly affects bioaccumulation in lung tissues. The role of chemical
    properties in the biological behaviour of chrysotile has been recently
    discussed (Langer & Nolan, 1986, 1994).

         The adsorption of polar organic agents on the surface of
    chrysotile is reported to be higher than that of less polar or non-
    polar agents (Speil & Leineweber, 1969; Gorski & Stettler, 1974). The
    binding of carcinogens such as benzo (a)pyrene, nitrosonornicotine
    and  N-acetyl-2-aminofluorene to chrysotile has been studied by
    Harvey et al. (1984). Adsorption of components of cigarette smoke onto
    the surface of chrysotile fibres has been suggested to play a role in
    the etiology of lung cancer in fibre-exposed cigarette smokers. The
    fibre may act as a vehicle which transports polycyclic aromatic
    hydrocarbons across membranes of the target cells (Gerde & Scholander,

    2.3  Sampling and analytical methods

         The collection of samples from air, water, biological specimens,
    soils or sediments must follow an appropriate sampling strategy. A
    review of methods for sampling asbestos fibres has been published
    (IPCS, 1986).

         The most commonly used analytical methods involve phase-contrast
    optical microscopy (PCOM) (in the workplace) and transmission electron
    microscopy (TEM) (in the general environment). PCOM is
    resolution-limited and non-specific for fibre characterization. TEM
    overcomes both limitations (Dement & Wallingford, 1990).

    2.3.1  Workplace sampling

         The most widely used method for the last 20 years has been the
    membrane filter method. Several attempts have been made to standardize
    the method (CEC, 1983; ILO, 1984; AIA, 1988; NIOSH, 1989a; ISO, 1993).
    A recommended method for the determination of airborne fibre
    concentration by PCOM (membrane filter method) has been published
    (WHO, 1997).

         A known volume of air is drawn through a membrane filter on which
    the number of fibres is determined using a phase contrast microscope
    (see section Special attention should be given to flow
    rates, sampling time, face velocity through the filter, and where,
    when and how to sample. Preference should be given to assessing
    individual exposure by personal sampling. The sampling strategy should
    be selected to yield the best estimate of an 8-h time-weighted average
    concentration. Excursions may be evaluated for regulatory purposes. If
    the purpose of the measurement is evaluation of control measures,
    other methods may also be used.

    2.3.2  Sampling in the general environment

         Methods for sampling ambient air depend on the method of
    analysis, but generally involve filtering airborne particles from
    relatively large volumes of air using membrane filters. Strategies and
    sampling methods have been described by Rood (1991) and reviewed in
    detail in the Health Effects Institute study of asbestos in public
    buildings (HEI, 1991).

         For analysis of water, sample specimens are collected and
    filtered through polycarbonate filters. If there is much organic
    debris, this must be removed to improve particle detection. The fibres
    must be re-prepared before analysis. The instrumental method is the
    same as that used for air samples.

    2.3.3  Analytical methods

         Analyses are performed to identify the fibre or fibres present
    and to determine their concentrations.  Fibre identification

         Several methods have been developed to identify chrysotile
    asbestos using dispersion staining methods and polarization microscopy
    (Julian & McCrone, 1970; McCrone, 1978; Churchyard & Copeland, 1988;
    NIOSH, 1989a). NIOSH (1989b) described the procedure specifically for
    the analysis of asbestos bulk samples.

         The limit of visibility of fibres, depending on the microscope
    and light source used, is in the range 0.2-0.3 µm. With most high
    quality research microscopes, chrysotile fibres of 0.22 µm are
    generally reported as being observable. The experience and expertise
    of the microscopist and the quality of the laboratory set-up both
    influence the outcome.

         Fibres with diameters less than about 0.22 µm cannot be seen with
    a light optical microscope. When fibres with diameters less than this
    value need to be analysed, TEM is used. This method is generally
    applied to the identification and characterization of fibres in water
    and in ambient air (Chatfield, 1979, 1987; Rood, 1991; ISO, 1991; HEI,
    1991). The most reliable method of identifying chrysotile fibres is
    the combination of morphology, chemistry and electron diffraction
    (Skikne et al., 1971; Langer & Pooley, 1973). Several methods for the
    determination of amphibole fibres in chrysotile have been described
    (Addison & Davies, 1990).

         Analytical methods using scanning electron microscopy (SEM) have
    also been developed (AIA, 1984; WHO, 1985; ISO, 1992).  Measurement of airborne fibre concentrations

    a)  Workplace

         In the PCOM method, the membrane filter is dissolved or collapsed
    using a solvent with a refractive index which matches the refractive
    index of the filter medium, rendering it invisible. Fibres entrained
    on the filter are made readily visible.

         The number of fibres of specified length and diameter in a known
    area of the filter is counted at magnifications of 400 to 500. A
    graticule has been designed for this purpose. Development of the
    HSE/NPL slide (LeGuen et al., 1984), which permits laboratories to
    standardize the limit of visibility of their microscopes and
    microscopists, has improved the potential for interlaboratory
    agreement in counts.

         Improvements in the mounting techniques and counting strategy has
    resulted in higher fibre counts than those found using the same
    techniques in the early 1970s (HSE, 1979; Gibbs, 1994). This change
    was estimated in the United Kingdom to cause a two-fold increase in
    the reported fibre concentrations (HSE, 1979).

         Instrumentation for automatic counting has been developed (e.g.,
    Kenny, 1984) but has failed to receive wide international recognition.

    b)  Ambient air

         The diameter of most chrysotile fibres found in the
    non-occupational environment is below the resolution of the light
    optical microscope (Rooker et al., 1982).

         The most reliable method for determining the concentration of
    chrysotile fibres in ambient air is TEM. Most currently available
    transmission electron microscopes have a resolution of about 0.2 nm;
    in combination with an energy-dispersive X-ray analyser (EDXA), TEM
    can chemically characterize fibres down to a diameter of 0.01 µm. The
    disadvantage of TEM is the small area that can be scanned when
    employing very high magnifications. This makes analysis of the long
    fibres (>5 µm) more limited in accuracy (Coin et al., 1992). A review
    of the use of TEM and a comparison of direct and indirect methods of
    filter preparation have been published recently (HEI, 1991).

         SEM has been used in the measurement of chrysotile. Most SEMs
    have a resolution intermediate between that of TEM and PCOM.  Lung tissue analysis

         Several methods have been described (Langer & Pooley, 1973;
    Gaudichet et al., 1980; Rogers et al., 1991a,b). All methods use
    ashing or digestion of tissues, TEM, SAED and EDXA. International
    standardization of these methods has not as yet been carried out. For
    this reason comparison of results from different laboratories is often
    difficult to make.  Gravimetric analysis

         Gravimetric methods have been applied in some countries for the
    evaluation of workplace conditions and emissions (Rickards, 1973;
    Middleton, 1982). Relatively large samples of dust are needed and the
    methods do not distinguish between the fibres and non-fibrous dusts
    nor among mineral components of each group. In view of this and the

    current belief that counts of fibres better define the health risk,
    gravimetric methods are limited in application. However, it must also
    be recognized that bulk dust assay is a useful index for control
    evaluation and should be used if membrane filter techniques are

    2.4  Conversion factors

         The concentrations of airborne chrysotile fibres in the workplace
    are expressed as the number of fibres per millilitre (f/ml) of air,
    fibres per litre (f/litre) of air or fibres per cubic metre (f/m3) of
    air, or in milligrams per cubic metre (mg/m3) of air. Concentrations
    are expressed as number of fibres per cubic metre or nanograms per
    cubic metre (ng/m3) in the general environment.

         The number of fibres per millilitre, obtained by the method of
    membrane filtration and PCOM, is currently used by regulatory agencies
    in most countries for the workplace. It is for this reason that the
    conversion of results obtained by different methods into membrane
    filter equivalents has been performed. Critiques of such conversions
    have been published (Walton, 1982; Valiœ, 1993; Gibbs, 1994).

    2.4.1  Conversion from airborne particle to fibre concentrations

         In almost all epidemiological studies in which health effects
    have been related to exposure, concentration measurements were made
    using methods quite different from the membrane filter technique. The
    early instruments employed were the thermal precipitator in the United
    Kingdom, and the midget impinger in North America. Gravimetric
    measurements have also been used.

         Attempts to convert the midget impinger count to an equivalent
    membrane filter fibre count have shown that no single conversion
    factor applies. Large variations in the ratios of midget impinger to
    membrane filter counts occur in different industries, between jobs
    within a single industry, or at a single plant site (Ayer et al.,
    1965; Gibbs & Lachance, 1974). Similar conversion problems were
    encountered in other countries where attempts were made to convert
    konimeter or thermal precipitator results to membrane filter
    equivalents (DuToit & Gilfillan, 1979; DuToit et al., 1983; Valiœ &
    Cigula, 1992).

         Side-by-side study of conversion factors has shown the
    correlation between particle and fibre counts to be limited. Both
    industry and operation-specific correlations have been made but are
    only site-specific. Although some comparisons made for epidemiological
    studies have yielded valuable data, no universal factor has ever been
    found. High variance exists. Temporal change in dust conditions in
    plants may have also affected conversion factors (Dagbert, 1976). The
    range of conversion ratios between work sites has been large (Doll &
    Peto, 1985). For purposes of exposure-response studies, conversions
    based on industry- and operation-specific data have proven valuable in
    some instances.

    2.4.2  Conversion from total mass to fibre number concentrations

         The conversions from total mass concentrations of dust determined
    gravimetrically into the fibre number concentrations may also be
    generally subject to great errors (Pott, 1978; IPCS, 1986). However,
    in some specific industries a good correlation has been achieved (Fei
    & Huang, 1989; Huang, 1990).

         When measurements of airborne fibre concentrations are made using
    transmission electron microscopy, determination of fibre lengths and
    diameters are necessary. If chrysotile is split into fibrils,
    approximate mass can be calculated by determining the fibre dimensions
    and using fibre density in the calculation.


    3.1  Natural occurrence

         Chrysotile is present in most serpentine rock formations. As a
    result, chrysotile originating from serpentine rock is often found in
    air and water due to natural weathering (Nicholson & Pundsack, 1973;
    Neuberger et al., 1996).

         Workable deposits are present in over 40 countries. Twenty-five
    of these currently produce chrysotile. Canada, South Africa, Russia
    and Zimbabwe have 90% of the established world reserves (Shride,

         Chrysotile is emitted from both natural and industrial sources.
    No measurements concerning the extent of release of airborne fibres
    through natural weathering processes are available. A study of the
    mineral content of the Greenland ice cap showed that airborne
    chrysotile existed long before it was used commercially on a large
    scale. Ice core dating showed the presence of chrysotile as early as
    1750 (Bowes et al., 1977).

         Chrysotile is introduced into water by the weathering of
    chrysotile-containing rocks and ores, in addition to the effects of
    industrial effluents and atmospheric pollution (Canada Environmental
    Health Directorate, 1979). The largest concentrations of asbestos in
    drinking-water generally occur from erosion of asbestos deposits
    (Polissar, 1993; Neuberger et al., 1996). Millette JR ed. (1983) has
    attributed chrysotile in water supplies to erosion from natural
    sources in areas such as San Francisco, Sherbrooke and Seattle.
    Millette et al. (1980) have shown that in the USA asbestos in
    drinking-water is primarily chrysotile.

    3.2  Anthropogenic sources

         Chrysotile was at one time used in many applications, which
    included both friable and non-friable products (Shride, 1973).
    Currently, the human activities resulting in potential chrysotile
    exposure can be divided into broad categories: (a) mining and milling,
    (b) processing of asbestos into products (such as friction materials,
    cement pipe and sheet, gaskets and seals, paper and textiles), (c)
    construction and repair activities, and (d) transportation and,
    especially, disposal of chrysotile-containing waste products.

         Chrysotile is by far the predominant asbestos fibre consumed
    today, e.g., in the USA 98.5% asbestos consumption in 1992 was
    chrysotile (Pigg, 1994).

    3.2.1  Production

         Although there are 25 countries currently producing chrysotile,
    seven countries account for the major part of world production
    (Brazil, Canada, China, Kazakhstan, Russia, South Africa and Zimbabwe)
    (US Department of Interior, 1993).

         World production of asbestos increased 50% between 1964 and 1973
    when it reached 5 million tonnes (US Department of Interior, 1991),
    but production has generally declined since the mid-1970s to its
    current level of 3.1 million tonnes. Table 1 shows the yearly
    production levels by countries between 1988 and l992.

         Table 2 shows the decline in major asbestos uses in the USA
    during the period 1977-1991 (US Department of Interior, 1986, 1991).

         Chrysotile ore is usually mined in open-pit operations. Possible
    sources of emissions are drilling, blasting, loading broken rock and
    transporting ore to the primary crusher or waste sites. Subsequently,
    the ore is crushed and emissions may result during unloading, primary
    crushing, screening, secondary crushing, conveying and stockpiling. A
    drying step follows, involving conveying the ore to the dryer
    building, screening, drying, tertiary crushing, conveying ore to dry
    rock storage building and dry rock storage. The next step is the
    milling of the ore. In well-controlled mills, this is largely confined
    in the mill building, and presents low emissions because the mill air
    is collected and ducted through control devices (US EPA, 1986). In
    poorly controlled mills the emissions may be high.

    3.2.2  Manufacture of products

         Chrysotile use today mainly involves products where it is
    incorporated into matrices. The asbestos-cement industry is by far the
    largest user of asbestos fibres world-wide, accounting for some 85% of
    all use. Asbestos-cement production facilities exist in more than 100
    countries and produce 27 to 30 million tonnes annually (Pigg, 1994).
    Asbestos-cement products contain 10-15% of asbestos, mostly
    chrysotile, although limited amounts of crocidolite have been used in
    large diameter, high-pressure pipes.

         There are five major asbestos-cement products: (a) corrugated
    sheets; (b) flat sheets and building boards; (c) slates; (d) moulded
    goods, including low-pressure pipes; and (e) high-pressure water pipes
    (Pigg, 1994).

         Possible emission sources are: (a) feeding of asbestos fibres
    into the mix; (b) blending the mix; and (c) cutting or machining
    end-products. Emissions may vary according to the dust control
    measures and technology.

         Although declining in the North American and Western European
    markets, asbestos-cement product manufacturing continues to grow in
    South America, South-East Asia, the eastern Mediterranean region and
    eastern Europe (Pigg, 1994). Japan, Thailand, Malaysia, Korea and
    Taiwan imported 430 000 tonnes, well over 30% of world-wide imports in
    1989 (Industrial Minerals, 1990). It has been reported that "asbestos
    use" (the generic term used by the author) in Japan has reached
    proportions which indicate that it leads the world in consumption of
    fibres (Frank, 1995).

        Table 1. World production, of asbestos (tonnes)a (from: US Department of Interior, 1993)

    Countryb                          1988          1989           1990           1991           1992

    Argentina                         2328           225            300e           250e            50

    Bosnia & Herzegovinac               --            --             --             --           1000

    Brazil                         227 653       206 195        232 332r       233 100r       233 000

    Bulgaria                           300           300            500r           500e,r         500

    Canada                         710 357       701 227        685 627        689 000r       585 000

    Chinae                         150 000r      181 000r       221 000r       230 000        240 000

    Columbiae, d                      7600          7900           8000           8000           8000

    Cyprus                          14 585            --             --            ---             --

    Egypt                              166           312            369            450r           450

    Greece                          71 114        73 300r        65 993r          5500e,r          --

    India                           31 123        36 502         26 053r        24 094r        25 000

    Irane                             3410r,g       3300           2800r          3000r          3000

    Italy                           94 549        44 348           3862           3000e,r        1500

    Japane                            5000          5000           5000           5000           5000

    Kazakhstanf                         --            --             --             --        300 000

    Korea                             2428          2361           1534           1500e          1600

    Russia                              --            --             --             --      1 400 000

    Serbia & Montenegroc                --            --             --             --           1700

    South Africa                   145 678       156 594        145 791        148 525r       123 951g

    Swaziland                       22 804        27 291         35 938         13 888r        35 000

    Turkey                              50e           --             --             --             --

    Former-USSRe                 2 600 000     2 600 000      2 400 000      2 000 000             --

    Table 1. (continued)

    Countryb                          1988          1989           1990           1991           1992
    (sold or used by producers)     18 233        17 427              W         20 061         15 573

    Former-Yugoslavia               17 030          9111           6578           5500e            --

    Zimbabwe                       186 581       187 006r       160 861r       141 697r       140 000
    Total                        4 310 989r    4 259 399      4 002 538r     3 533 065r     3 120 524

    a  Marketable fibre production. Table includes data available until 19 April 1993
    b  In addition to the countries listed, Afghanistan, Czechoslovakia, North Korea and Romania also 
       produce asbestos, but output is not officially reported, and available general information is 
       inadequate for the formulation of reliable estimates of output levels.
    c  Formerly part of Yugoslavia; data were not reported separately until 1992.
    d  Estimated fibre production (in tonnes), based on reported crude production, was as follows: 
       1988: 152 896; 1989:-158 149; 1990: 159 600; 1991: 160 332; 1992: 160 000 (estimated).
    e  Estimated
    f  Formerly part of the USSR; data were not reported separately until 1992.
    g  Reported figure.
    r  Revised
    W  Withheld to avoid disclosing proprietary data; excluded from "total"
    Table 2.  Demand for asbestos in the USA
    (Thousand tonnes) (US Department of Interior, 1986, 1991)

                                  1977           1984           1991
    Asbestos-cement pipe          115             37            4
    Asbestos-cement sheet          27             12            2
    Coating and compounds          36             22            1
    Flooring products             150             46            -
    Friction products              57             48            10
    Installation: electrical        4              1            -
    Installation: thermal          17              2            -
    Packing and gaskets            28             13            3
    Paper products                  7              2            -
    Plastics                        8              1            -
    Roofing products               70              7            15
    Textiles                       10              2            -
    Other                         143             33            1

    Totala                        672            226            34

    a   The totals given are not the exact sums of the values for 
        individual products, owing to independent rounding.

         Other asbestos products consume smaller quantities of chrysotile
    asbestos. Friction products, gaskets and asbestos paper are among
    them. Production of shipboard and building insulation, roofing and,
    particularly, flooring felts and other flooring materials, such as
    vinyl asbestos tiles, has declined considerably, some of them having
    disappeared completely from the market place. Friable asbestos
    materials in building construction have been phased out in many
    countries due to international recommendations.

         Moulded brake linings on disc- and drum-type car brakes are among
    the chrysotile products that are still manufactured. Woven brake
    linings and clutch facings for heavy vehicle use are made from
    high-strength chrysotile yarn and fabric reinforced with wire; this
    material is dried and impregnated with resin. In the moulding process,
    the fibres are combined with the resin, which is then thermoset. Final
    treatment involves curing by baking and grinding to customer

    3.2.3  Use of products

         Many chrysotile-containing products have entered global commerce.
    The nature of the product and local work practices determine dust
    emissions. Non-friable products and appropriate technological controls
    greatly reduce fibre release. Manipulation of friable products without
    controls may release high levels of airborne dust. However, some
    conditions may produce chrysotile aerosols even with non-friable
    products, e.g., the use of high-speed power tools without controls.

         Concern about the possible exposure of inhabitants of buildings
    with asbestos-containing materials has led to extensive monitoring
    (HEI, 1991). In this respect the exposure of custodian and maintenance
    staff is still being studied (see Chapter 4).

         Manufacturing data are not available from individual countries
    concerning specific chrysotile-containing products.


         Few recent reports of occupational and environmental exposure
    levels are available, particularly those that differentiate among the
    forms of asbestos. Workplace concentrations were very high when
    monitoring first began (in the 1930s). In countries where controls
    were implemented, the levels generally reduced considerably with time
    and continue to decline. In contrast, there is less difference between
    the early results of measurements in both outdoor and indoor
    non-occupational environments (1970s) and recent data.

         Environmental Health Criteria 53 (IPCS, 1986) reported that 58.5%
    of samples had fibre concentrations of < 0.5 f/ml and 80.7% < 1.0
    f/ml in textile industries in the United Kingdom over the period 
    1972-1978. Corresponding measurements in France in 1984 were 65.3% with 
    < 0.5 f/ml and 85.4% with < 1.0 f/ml. It also reported 86.5% of 
    samples with < 0.5 f/ml and 95.0% with < 1 f/ml in asbestos-cement
    industries in the United Kingdom during the period 1972-1978.
    Corresponding measurements in France in 1984 were 93.5% with < 0.5
    f/ml and 97.4% with < 1.0 f/ml. In industries manufacturing friction
    products, 71.0% of samples had < 0.5 f/ml and 85.5% < 1.0 f/ml in
    the United Kingdom during 1972-1978, while the corresponding results
    in France in 1984 were 62.8% with < 0.5 f/ml and 85.0% with < 1.0
    f/ml. Typical concentrations (fibres > 5 µm in length) in outdoor air
    measured in various locations in Austria, Canada, Germany, South
    Africa and the USA ranged from < 0.0001 to about 0.01 f/ml,
    concentrations in most samples being less than 0.001 f/ml.
    Concentrations (fibres > 5 µm in length) measured in various
    buildings in Canada and Germany ranged from values below the limit of
    detection to 0.01 f/ml. The highest concentrations were found in
    buildings with sprayed-on friable asbestos.

    4.1  Occupational exposure

         This section focuses mainly on exposures found in industries
    where only commercial chrysotile was used. Emphasis is placed on data
    obtained directly by the membrane filter method, but, in the case of
    some older studies, data are conversions from original particle
    counts. In the latter case, fibre concentrations are subject to the
    limitations discussed in sections 2.4.1 and 2.4.2.

    4.1.1  Mining and milling

         Several sets of data have been published concerning the exposure
    levels of mine and mill workers employed in the production facilities
    of Thetford Mines and Asbestos, Quebec, Canada. A substantial body of
    exposure data was collected by using midget impingers and enumerating
    all dust particles (Gibbs & Lachance, 1972). Table 3 lists mean
    concentrations of dust in the mills in millions of particles per m3
    (mpcm) and per cubic foot (mpcf) of air during the period 1949 to
    1965. The mill with the highest dust concentrations had more than
    twice the mean values given in Table 3, and that with the lowest
    concentrations had less than one half.

        Table 3.  Mean dust concentrations in asbestos mills of Quebec, Canada 
              (from Gibbs & Lachance, 1972)


    Concentration     1949    1951    1953    1955    1957    1959    1961    1963    1965

    mpcm              2650    1940    1770    1130    1060     570     350     530     180
    mpcf                75      55      50      32      30      16      10      15       5
         Studies of the relationships between particle counts and fibre
    concentrations have shown poor correlation (Gibbs & Lachance, 1974;
    Dagbert, 1976). Gibbs & Lachance (1974) stated that no single
    conversion factor could be applied to all mines and mills. Assuming a
    conversion factor of roughly 106 f/ml for each mpcm (3 f/ml for each
    mpcf), it can be calculated that mean fibre concentrations in the
    Quebec mills before mid-1955 were well above 150 f/ml (see discussions
    in section 2.4).

         Nicholson et al. (1979) reported fibre concentrations obtained by
    the membrane filter method in five mines and mills of Thetford Mines,
    Quebec, Canada during the period October 1973 to October 1975 (Table

         In Zimbabwe, Cullen et al. (1991) reported estimates of fibre
    levels prior to 1980. After 1980, the measured concentrations were
    below 10 f/ml in all facilities. In India, the concentrations measured
    in four mills in 1989 by Mukherjee et al. (1992) are presented in
    Table 5.

         Parsons et al. (1986) reported that the concentrations in
    refining and bagging areas in a Newfoundland mill were generally less
    than 0.5 f/ml, but concentrations in the screening area ranged up to
    13.9 f/ml.

         Average concentrations of asbestos fibres (length > 5 µm) in the
    Quebec mining industry during the period 1973-1993 are presented in
    Fig. 1. The average concentrations in Quebec chrysotile mining towns
    are shown in Fig. 2.

    4.1.2  Textile production

         Nine textile plants in the USA were studied in 1964 and 1965 by
    Lynch & Ayer (1966). The results of the membrane filter analysis are
    presented in Table 6. The presence of small amounts of amosite or
    crocidolite fibres cannot be excluded due to the non-specificity of
    the assay instrument (PCOM).

        Table 4.  Asbestos fibre concentrationsa in five chrysotile mines and mills at 
    Thetford Mines, Quebec, Canada (from Nicholson et al., 1979)

    Location                                                Five mines and mills
                                                  1        2          3         4        5
    General mill air         Number of samples    14       37         5         6        7
                             mean                 35       12         15        18       9
                             range                14-57    7-27       7-27      12-29    5-12

    Bagging asbestos         Number of samples    2        6          2         2
                             mean                 16       16         9         16
                             range                12-20    10-24      4-13      14-17

    Quality control          Number of samples             2          1         1
                             mean                          22         20        9
                             range                         21-22      -         -

    Crusher                  Number of samples             4
                             mean                          26
                             range                         8-47

    Dryer                    Number of samples             2
                             mean                          36
                             range                         27-45

    Shops                    Number of samples             3
                             mean                          10
                             range                         6-15

    Non-work location        Number of samples    1        2
                             mean                 0.8      1.3
                             range                -        1-1.7

    a The concentration of fibres (> 5 µm) is given in f/ml.
    Table 5.  Average personal sample fibre concentrations in four 
    mills in India (from Mukherjee et al., 1992)

    Process                            Fibre concentration (f/ml)
                                       Average       Range
    Jaw crusher                        1.7           1.3-2.1
    Pulverizer                         8.9           2.3-15.4
    Lime mixer                         2.6           2.5-2.6
    Huller                             12.7          8.9-16.4
    Primary eccentric screen           12.9          1.8-25.8
    Decorticator                       8.8           1.3-18.4

    FIGURE 1

    FIGURE 2

        Table 6.  Mean dust concentrations (f/ml) by plant and operation in nine textile plants in the USA
    during the period 1964/1965 (from Lynch & Ayer, 1966)


    Operation           Fibresa                                    Textile plants
                                  1         2         3         4         5         6         7         8         9

    Fibre preparation   A        38.1      12.3      23.3      34.0       -         8.1       7.6      35.5      11.8
                        B        15.0      10.0      13.3      18.3       -         3.0       4.5      17.0       2.6
    Carding             A        18.1      13.6      20.6      32.9       -         6.0      17.2      28.2       8.3
                        B        10.2       9.21      3.3      15.2       -         3.5       8.1      13.4       2.0
    Spinning            A         9.6       4.1      20.2      29.8       -         5.1      24.8      20.8       7.4
                        B         6.6       3.2      18.9      15.7       -         3.5      10.8      10.5       1.8
    Twisting            A         9.3       6.9      15.8      51.4       -         4.8      25.9      16.7       3.1
                        B         6.4       5.2       7.5      22.4       -         3.3      12.9       7.2       1.1
    Winding             A        11.7       4.4       9.6      28.6       -         4.5      25.7       7.9       3.6
                        B         7.5       3.9       8.9      17.5       -         3.2      11.7       2.7       1.3
    Weaving             A         7.7       7.0       2.9      33.8       4.5       2.9       9.5       8.1       2.9
                        B         4.8       3.1       2.3      17.8       3.9       2.2       5.7       3.0       1.5

    a A = total fibres,  B = fibres longer than 5 µm
         The exposure estimates (1930-1975) in an extensively studied
    textile plant in South Carolina, USA, in which chrysotile was the
    predominant fibre used, are presented in Table 7 (Dement et al.,

    Table 7.  Exposure estimates in a chrysotile textile plant (1930-1975)
    (estimated mean exposure to fibres longer than 5 µm in f/ml)a

    Operation                Without controls         With controls

    Fibre preparation        26.2-78.0                5.8-17.2
    Carding                  10.8-22.1                4.3-9.0
    Spinning                 4.8-8.2                  4.8-6.7
    Twisting                 24.6-36.0                5.4-7.9
    Winding                  4.1-20.9                 4.1-8.4
    Weaving                  5.3-30.6                 1.4-8.2

    a From: Dement et al. (1983a)

         Application of controls in the dusty processes at the South
    Carolina plant led to significant reduction of exposure. Currently
    available control technology allows much lower levels to be attained.

         Table 8 shows a summary of exposure classifications in an English
    textile plant in the period 1951-1974 (Peto et al., 1985). The early
    particle count data in this report were based on fibre collection with
    a thermal precipitator. The conversion factor used, therefore,
    reflects only a precipitator-membrane filter relationship. Comments on
    the validity of such conversions have been discussed by Walton (1982).

         Kimura (1987) reported geometric mean concentrations of 2.6-12.8
    f/ml in the period 1970-1975 and 0.1-0.2 f/ml in the period 1984-1986
    in asbestos spinning in Japan.

    4.1.3  Asbestos-cement

         As mentioned in section 3.2.2, the principal use of chrysotile in
    the world today is in asbestos-cement products. In the production of
    asbestos-cement pipes, some crocidolite is still used with chrysotile
    in certain plants.

         Table 9 summarizes the results of the analysis of personal
    samples, collected in the late 1970s when reportedly only chrysotile
    was used, in an asbestos-cement facility in the USA (Hammad et al.,
    1979). In 80% of the samples the concentrations were less than 2 f/ml,
    and in about 60% they were less than 0.5 f/ml.

        Table 8.  Mean concentrations of airborne asbestos fibres in a textile planta


    Period         Very high                High                          Medium                       Low

    1951-1955b     unloading, stacking      roving, spinning, carding     doubling, rope spinning      other areas
                   28 f/ml                  l4 f/ml                       8 f/ml                       4.5 f/ml

    1956-1960b     unloading, stacking      carding                       roving, spinning, mixing     other areas
                   28 f/ml                  16 f/ml                       9 f/ml                       4.5 f/ml

    1961-1965      unloading, stacking      carding                       carding, roving,             other areas
                                                                          winding, beaming
                   20 f/ml                  15 f/ml                       7.5 f/ml                     2.5 f/ml

    1966-1970      unloading, stacking      carding                       carding, roving,             other areas
                                                                          rope cards
                   20 f/ml                  15 f/ml                       7.5 f/ml                     2.5 f/ml

    1971-1974      none                     none                          carding, roving              other areas
                                                                          7.5 f/ml                     2.5 f/ml

    a  Peto et al. (1985)
    b  Results of particle measurements were converted to fibre concentrations using the relationship 35 p/ml = 1 f/ml
            Table 9.  Chrysotile fibre concentrations (fibres longer than 5 µm)
    in selected dust zones of an asbestos-cement production facilitya

    Location                 Number        Fibre concentration (f/ml)
                             of samples    range           mean

    Regrinding                  4          0.44-l.2        0.86
    Mixing                      9          0.51-8.9        2.8
    Forming                    20          0.12-5.0        0.52
    Siding and shingle 
      finishing                14          0.14-4.9        0.68
    Panel finishing            11          0.33-12.0       2.8
    Flat and corrugated 
      finishing                12          0.33-8.0        2.6
    Warehouse                   5          0.13-2.5        0.63
    Maintenance                 7          0.20-2.7        0.58

    a  From: Hammad et al. (1979)
         Exposure estimates in a Canadian plant (Finkelstein, 1983) for
    the years 1949, 1969 and 1979 were 40, 20 and 0.2 f/ml, respectively,
    for willow operators, 16, 8 and 0.5 f/ml for forming machine
    operators, and 8, 4 and 0.3 f/ml for lathe operators. In Japan, Kimura
    (1987) reported geometric mean concentrations in bag opening and
    mixing of 4.5-9.5 f/ml in 1970-1975 and 0.03-1.6 f/ml in 1984-1986,
    whilst in cement cutting and grinding the mean concentrations were
    2.5-3.5 f/ml in 1970-1975 and 0.17-0.57 in 1984-1986. Albin et al.
    (1990) reported fibre concentrations, based on estimates, in a Swedish
    asbestos-cement plant of 1.5-6.3 f/ml during 1956. Later, based on
    direct measurements, values were 0.3-5.0 f/ml in 1969 and 0.9-1.7 f/ml
    in 1975. Higashi et al. (1994) reported geometric average
    concentrations of 0.05-0.45 f/ml measured in area samples and 
    0.05-0.78 f/ml in personal samples of an asbestos-cement plant.

         Few data are available in the open literature on exposures
    encountered during installation of asbestos-cement products. It would
    be expected that cutting, sanding, drilling or otherwise abrading
    asbestos-cement without efficient ventilation controls would give rise
    to high exposures (Nicholson, 1978).

         Weiner et al. (1994) reported concentrations in a South African
    workshop in which chrysotile asbestos-cement sheets were cut into
    components for insulation. The sheets were cut manually, sanded and
    subsequently assembled. Initial sampling showed personal sample mean
    concentrations of 1.9 f/ml for assembling, 5.7 f/ml for sweeping, 8.6
    f/ml for drilling and 27.5 f/ml for sanding. After improvements and
    clean-up of the work environment, the concentrations were 0.5-1.7

         Nicholson (1978) reported concentrations of 0.33-1.47 f/ml in a
    room during and after sawing and hammering of an asbestos-cement

    4.1.4  Friction products

         Skidmore & Dufficy (1983), based on simulated past conditions
    (Table 10), and McDonald et al. (1984) reported data on workplace
    exposures during friction product manufacturing.

         McDonald et al. (1984) reported that in the 1930s estimated
    average dust levels were 35-180 mpcm (1-5 mpcf) in 67% of analysed
    locations, while in the 1960s average dust levels were below 7 mpcm
    (0.2 mpcf) at 38% of locations and below 18 mpcm (0.5 mpcf) at 67% of
    locations in which measurements were obtained.

        Table 10.  Average concentrations of chrysotile fibres (f/ml) longer > 5 µm from woven 
    asbestos products during various periods

                                Pre-1931         1932-1950      1951-1969      1970-1979

    Storage/distribution        >20              2-5            2-5            0.5-1
    Preparation                 >20              0-20           2-5            1-2
    Impregnation/forming        >20              2-5            1-2            0.5-1
    Grinding                    >20              5-10           2-5            0.5-1
    Drilling, boring            >20              2-5            1-2            1-2
    Inspection                  >20              2-5            1-2            0.5-1
    Packing                     >20              1-2            0.5-1          <0.5
    Office/laboratory           10-20            <0.5           <0.5           <0.5

    * Skidmore & Dufficy (1983)
         Kimura (1987) reported geometric mean fibre concentrations of
    10.2-35.5 f/ml in 1970-1975, and 0.24-5.5 f/ml in 1984-1986 in
    spinning and grinding of friction products in Japan.

         A considerable number of reports have included airborne asbestos
    concentrations during maintenance and replacement of vehicle brakes.
    In the early period, poor or no engineering control measures were
    utilized, resulting in high total dust exposure. This was particularly
    so during grinding of brakes and compressed air blowing off dust, both
    operations of very short duration. Significantly lower levels were
    measured when engineering controls were introduced.

         An overview of air concentrations measured during maintenance and
    replacement of asbestos-containing vehicle brakes is presented in
    Table 11.

        Table 11.  Asbestos air concentrations measured during maintenance and replacement of vehicle brakes

    Mean concentration    Comment                                                     Reference

    3.8a                  grinding truck brakes                                       Lorimer et al., 1976
    15.9a                 blowing off                                                 Lorimer et al., 1976
    3.8a                  grinding                                                    Rohl et al., 1976
    16.0a                 blowing off                                                 Rohl et al., 1976
    2.5a                  dry brushing                                                Rohl et al., 1976 
    > 1a                  17 of 19 operations                                         Menichini & Marconi, 1982
    > 2a                  11 of 19 operations                                         Menichini & Marconi, 1982
    0.09b                 fibres longer than 5 µm                                     Jahn et al., 1985
    6.2a                  blowing off, grinding                                       Jahn et al., 1985
    0.03b                 fibres longer than 5 µm                                     Elliehausen, 1985
    0.06b                                                                             Ruhe & Lipscomb, 1985
    < 0.5                 TWA                                                         Cheng & O'Kelly, 1986
    0.13                  maximum                                                     Cheng & O'Kelly, 1986
    4-5a                  fibres longer than 5 µm, blowing off, grinding              Rodelsperger et al., 1986
    5-10a                 fibres longer than 5 µm, blowing off, grinding, trucks      Rodelsperger et al., 1986
    < 0.05b                                                                           Kauppinen & Korhonen, 1987
    0.01-0.2b             trucks and buses                                            Kauppinen & Korhonen, 1987
    > 1a                  blowing off                                                 Kauppinen & Korhonen, 1987
    < 0.004                                                                           Sheehy et al., 1987
    < 0.004b                                                                          Godbey et al., 1987
    0.09-0.12                                                                         Van Wagenen, 1987
    0.046b                                                                            Cooper et al., 1988
    0.03b                 TWA < 0.002 f/ml                                            Moore, 1988

    a    These results are mean personal samples obtained by PCOM; fibres > 5 µm; these represent episodic 
         releases and not time-weighted averages; operation specific.
    b    Mean personal air samples (8-h time-weighted average)
    4.1.5  Exposure of building maintenance personnel

         The subject of asbestos exposure of maintenance personnel in
    buildings has been raised recently and particularly by US OSHA (1994).

         Price et al. (1992) estimated the time-weighted averages (TWAs),
    of asbestos exposures experienced by maintenance personnel, on the
    basis of 1227 air samples. The TWAs, obtained by PCOM, were 0.009 f/ml
    for telecommunication switch work, 0.037 f/ml for above-ceiling
    maintenance work, and 0.51 f/ml for work in utility spaces. Median
    concentrations ranged from 0.01 to 0.02 f/ml.

         The Health Effects Institute (1991) evaluated an operation and
    maintenance programme in a hospital on the basis of 394 air samples
    obtained during 106 on-site activities. The mean asbestos
    concentration (PCOM) was about 0.11 f/ml for personal samples and
    about 0.012 f/ml for area samples. Eight-hour TWA concentrations
    showed that 99% of the personal samples were below 0.2 f/ml, and 95%
    were below 0.1 f/ml.

         Corn et al. (1994) evaluated exposures of building maintenance
    personnel on the basis of about 500 personal samples collected during
    maintenance work. However, the building personnel were being monitored
    during an asbestos "operations and management" programme, so that
    these values may reflect special work practices and environment
    conditions. Typical personal exposures are presented in Table 12.

    Table 12.  Personal asbestos exposures of building maintenance 
    personnel (fibres longer than 5 µm)a


    Activity                      Concentration during work    8-h TWA

    Electrical/plumbing work      0-0.035                      0.0149
    Cable running                 0.001-0.228                  0.0167
    HVAC work                     0-0.077                      0.0023

    a From:  Corn (1994)

         Published data for custodial workers, as they exist, reflect
    unusual circumstances. Sawyer (1977) studied fibre release from a
    friable chrysotile-containing surface formulation during routine
    custodial activities performed in the Yale Art and Architecture
    Building. The fibre levels, determined by PCOM, ranged from 1.6 f/ml,
    obtained during sweeping, to 15.5 f/ml, obtained during dusting of
    library books. These values were obtained as short-term episodes. Most
    other values, presented as 8-h TWAs, were about two orders of
    magnitude lower (HEI, 1991).

    4.1.6  Various industries

         Higashi et al. (1994) reported the results of their environmental
    evaluations at 510 workplaces in 1985 (roofing materials,
    asbestos-cement sheets, friction materials, construction materials)
    and 430 workplaces in 1992. The percentage of workplaces in which
    exposure concentrations were less than 0.3 f/ml was 70% in 1985 and
    98% in 1992. All concentrations in a modernized asbestos-cement plant
    were less than 0.1 f/ml.

         Rickards (1991, 1994) reported the results of the measurement of
    asbestos fibre concentrations covering exposures of over 39 900
    workers in 27 countries in 1989 and over 26 500 workers in 28
    countries in 1991 and 1992. His modified results are presented in
    Table 13. The 1993 data, by industry sector, is shown in Fig. 3 (AIA,
    1995). Kogevinas et al. (1994) summarized exposure data obtained from
    chrysotile-exposed workers in 11 countries. The exposure levels ranged
    considerably, reflecting industry and other factors.

    Table 13.  Percentages of over 26 500 workers in 28 countries exposed
    to various asbestos fibre concentrations in the workplace
    (members of Asbestos International Association)a


                                  Asbestos fibre concentration (f/ml)
                                  < 0.5    0.5-1     1-2     > 2

    Percentage of workers
    1989                          83.5     11.1      4.5     0.9
    1991                          84.4      9.4      4.2     2.1
    1992                          89.1      6.3      3.9     0.8

    a  Rickards (1991, 1994)

         Fei & Huang (1989) reported fibre concentrations in an asbestos
    paper factory utilizing chrysotile in the Sichuan Province of west
    China. The concentration of 135 fibre measurements ranged between 0.6
    f/ml and 55.1 f/ml, the latter value being the average of 6 assays in
    a pulp-reducing area.

    4.2  Non-occupational exposure

    4.2.1  Ambient air

         There are some data concerning fibre levels in the air close to
    chrysotile mines. Baloyi (1989) found fibre levels around the Shabani
    Mine (Zimbabwe) to range from below the limit of detection of the
    method (< 0.01 f/ml) to 0.02 f/ml of air, assayed by PCOM.

    FIGURE 3

         Asbestos concentrations in the outdoor air have been measured in
    many studies. Chrysotile is the predominant fibre found.
    Concentrations measured at various locations in Austria, Canada,
    Germany, South Africa and the USA were reported in Environmental
    Health Criteria 53 (IPCS, 1986; Table 14). Typical concentrations of
    fibres longer than 5 µm ranged from less than 0.0001 f/ml to about
    0.01 f/ml, most samples having concentrations less than 0.001 f/ml.
    Results of some more recent studies are presented in Table 14. Almost
    all analyses were made by TEM. A review of available data was given in
    HEI (1991).

         Corn (1994) estimated that outdoor air concentrations, expressed
    as PCOM equivalent fibres (longer than 5 µm), in remote locations in
    the USA are generally less than 0.0005 f/ml, in urban areas they are
    up to 0.002 f/ml, and in suburban locations they are considerably

    4.2.2  Indoor air

         Concentrations measured in various buildings in Canada and
    Germany were presented in Environmental Health Criteria 53 (IPCS,
    1986, Table 12). Concentration of fibres longer than 5 µm ranged from
    below the detectable level of the method to 0.01 f/ml. The highest
    concentrations were found in buildings with sprayed-on asbestos.

         The results of some more recent studies are presented in Table

         The average airborne fibre concentrations in outdoor air, 71
    schools and 49 public buildings in the USA are presented in Table 16.

         Corn (1994) estimated an average level of PCOM equivalent fibres
    (> 0.2 µm width) of 0.00017 f/ml in 71 schools in the USA. Five per
    cent of the school indoor concentrations exceeded 0.0014 f/ml, the
    highest value being 0.0023 f/ml.

         Lee et al. (1992) found that only 0.67% of chrysotile fibres in
    indoor air are longer than 5 µm.

        Table 14.  Asbestos fibre concentrations in outdoor air (f/ml PCOM equivalent fibresa - TEM)


    Environment         Median        Mean          Rangef               Reference

    Japan               0.0218                      0.007-0.047          Kohyama, 1989

    Switzerland                       <0.0004b                           Litistorf et al., 1985
    USA                 0.0003c                     ND-0.008             Chesson et al., 1985
    Canada              0.0007                      0.0006-0.0009        Sebastien et al., 1986a
    USA                               0.00005c                           Tuckfield et al., 1988
    Canada              0.0001b                     ND-0.003             Nicholson, 1988
    Japan                             0.0198e       <0.004-0.111         Kohyama, 1989
    England                           0.00016b      ND-0.00016           Jaffrey, 1988
    England                           0.0004b                            Jaffrey, 1990
    Slovak Republic                   0.002d        0.001-0.02           Juck et al., 1991
    Italy                                           0.0001-0.012         Chiappino et al., 1993

    a  PCOM equivalent fibre: >5 µm long; > 0.25 µm wide; aspect ratio > 3:1
    b  total structures >5 µm
    c  PCOM analysis
    d  near to an asbestos-cement plant
    e  residential area
    f  ND - not detected

    Table 15.  Asbestos fibre concentrations (f/ml) in buildings (fibres longer than 5 µm)


    Sitea                           Meanb         Rangeb              Reference

    High-rise office                0.0034        0.0002-0.0065       Chatfield,1986
    Schools                         0.0006        ND-0.0014           Chatfield,1986

    United Kingdom
    Buildings with ACM                            ND-0.0017           Burdett & Jaffrey, 1986
    Buildings without ACM                         ND-0.0007           Burdett & Jaffrey, 1986
    Residences with ACM             0.0003        ND-0.0025           Gazzi & Crockford, 1987
    Residences without ACM          ND            ND                  Gazzi & Crockford, 1987

    Residences with ACM             0.0001        ND-0.002            CPSC, 1987
    Buildings with ACM              0.00005       ND-0.00056          Hatfield et al., 1988;
                                                                      Crump & Farrar, 1989;
                                                                      Chesson et al., 1990
    Buildings without ACM           ND            ND                  Hatfield et al., 1988;
                                                                      Crump & Farrar, 1989;
                                                                      Chesson et al., 1990
    Schools                         0.00024       ND-0.0023           Corn et al.,1991
    Schools with ACM                0.0002        ND-0.0016           McCrone, 1991

    Slovak Republic
    Buildings                       0.0045        0.00085-0.024       Juck et al.,1991

    Public buildings                              0.0045-0.0061       Minne et al.,1991

    a  ACM = asbestos-containing material
    b  ND = not detected

    Table 16.  Mean concentrations of asbestos fibres longer than 5 µma


                                                 Sample size        Mean concentration

    Outdoor air                                      48                 0.00039
    Schools                                          71                 0.00024
    Public buildings (no ACM)                         6                 0.00099
    Public buildings (with ACM in 
       good condition)                                6                 0.00059
    Public buildings (with damaged ACM)              37                 0.00073

    a  Modified from Mossman et al. (1990)


    5.1  Inhalation

    5.1.1  General principles

         Factors affecting the inhalation, deposition, clearance and
    translocation of asbestos and other fibres were discussed in
    Environmental Health Criteria monographs 53 (IPCS, 1986), 77 (IPCS,
    1988) and 151 (IPCS, 1993). The main principles are summarized in this

         It is considered that the potential respiratory health effects
    related to exposure to fibre aerosols are a function of the internal
    dose to the target tissue, which is determined by airborne
    concentrations, patterns of exposure, fibre shape, diameter and length
    (which affect lung deposition and clearance) and biopersistence. The
    potential responses to fibres, once they are deposited in the lungs,
    are a function of their individual characteristics.

         Because of the tendency of fibres to align parallel to the
    direction of airflow, the deposition of fibrous particles in the
    respiratory tract is largely a function of fibre length. In addition,
    the shape of the fibres as well as their electrostatic charge may have
    an effect on deposition (Davis et al., 1988). Fibres of various shapes
    are more likely than spherical particles to be deposited by
    interception, mainly at bifurcations.

         Since most of the data on deposition have been obtained in
    studies on rodents, it is important to consider comparative
    differences between rats and humans in this respect; these differences
    are best evaluated on the basis of the aerodynamic diameter. The ratio
    of fibre diameter to aerodynamic diameter is approximately 1:3. Thus,
    a fibre measured microscopically to have a diameter of 1 µm would have
    a corresponding aerodynamic diameter of approximately 3 µm. A
    comparative review of the regional deposition of particles in humans
    and rodents (rats and hamsters) has been presented by US EPA (1980).
    The relative distribution between the tracheobronchial and pulmonary
    regions of the lung in rodents follows a pattern similar to human
    regional deposition during nose breathing for insoluble particles with
    a mass median aerodynamic diameter of less than 3 µm. Fig. 4 and 5
    illustrate these comparative differences. As can be seen, particularly
    for pulmonary deposition of particles, the percentage deposition in
    rodents is considerably less, even within the overlapping region of
    respiratory tract deposition, than in humans. These data indicate
    that, although particles with an aerodynamic diameter of 5 µm or more
    may have significant deposition efficiencies in man, the same
    particles will have extremely small deposition efficiencies in the

    FIGURE 4

    FIGURE 5

         In the nasopharyngeal and tracheobronchial regions, fibres are
    generally cleared fairly rapidly via mucociliary clearance, whereas
    fibres deposited in the alveolar space appear to be cleared more
    slowly, primarily by phagocytosis and to a lesser extent via
    translocation and by dissolution. Translocation refers to the movement
    of the intact fibre after initial deposition at foci in the alveolar
    ducts and on the ciliated epithelium at the terminal bronchioles.
    These fibres may be translocated via ciliated mucous movement up the
    bronchial tree and removed from the lung, or may be moved through the
    epithelium with subsequent migration to interstitial storage sites or
    along lymphatic drainage pathways or transport to pleural regions.
    Fibres short enough to be fully ingested are thought to be removed
    mainly through phagocytosis by macrophages, whereas longer fibres may
    be partially cleared at a slower rate either by translocation to
    interstitial sites, breakage or by dissolution. A higher proportion of
    longer fibres is, therefore, retained in the lung.

    5.1.2  Fibre deposition

         The deposition of chrysotile asbestos in the peripheral lung
    airways of rats exposed  in vivo for 1 h to 4.3 mg respirable
    chrysotile/m3 was studied by Brody et al. (1981). In rats killed
    immediately after exposure, chrysotile fibres were rarely seen by
    scanning electron microscopy in alveolar spaces or on alveolar duct
    surfaces, except at alveolar duct bifurcations. Most were less than 10
    µm in length and 0.4 µm in diameter, indicating that longer fibres
    present in the dust cloud had been deposited in the upper airways.
    Concentrations were relatively high at bifurcations nearest the
    terminal bronchioles, and lower at the bifurcations of more distal
    ducts. In rats killed after 5 h the patterns were similar, but the
    concentrations were reduced. The relative importance of interception,
    impaction, diffusion and sedimentation on the deposition pattern of
    chrysotile fibres was considered by Brody & Roe (1983) who concluded
    that the high deposition observed at alveolar duct bifurcations of
    rats can be attributed to the high breathing frequency and small
    airway size of these rodents. They pointed out that the enhanced
    deposition at alveolar duct bifurcations observed in the rat may not
    occur in all species.

         Coin et al. (1992) examined the patterns of deposition and
    retention of chrysotile asbestos in the central and peripheral regions
    of the rat lung in the first month following a single 3-h inhalation
    exposure. They found that pulmonary deposition did not differ between
    peripheral and central regions.

         Pinkerton & Yu (1988) exposed rats to airborne chrysotile fibres
    for 7 h/day, 5 days/week for 12 months, and investigated the numbers
    and lengths of chrysotile fibres found in anatomically distinct
    regions of the lung parenchyma. The fibre concentration was greatest
    in the dorsal region and least in the costolateral and caudal regions,
    in agreement with calculations based on the deposition model for rat
    lung of Asgharian & Yu (1988). With the exception of the dorsal
    region, parenchymal changes correlated well with the fibre

    concentration. There were differences in the length distributions of
    fibres in the various regions, fibres in the dorsal region having the
    greatest proportion of fibres longer than 10 µm. The proportion of
    fibres longer than 20 µm was greatest in the cranial and lateral

    5.1.3  Fibre clearance and retention  Fibre clearance and retention in humans

         Available data obtained from lung burden studies show that
    chrysotile fibres deposited in the lung are cleared more rapidly than
    tremolite fibres, so that the tremolite/chrysotile ratio increases
    with time after exposure. It has been shown by Sebastien et al. (1989)
    and Churg et al. (1993) that on average about 75% of the fibres in the
    lungs of long-term chrysotile miners and millers from the Thetford
    Mines region of Quebec were tremolite and only about 25% chrysotile,
    despite the fact that tremolite accounted for only a few percent of
    the fibres in the chrysotile ambient dust (Sebastien et al., 1986a).
    Rowlands et al. (1982) found similar quantities of tremolite fibres,
    compared with chrysotile, in the lung samples of Quebec miners and
    millers. Limitations of retention data in lungs with respect to
    chrysotile exposure have been discussed in a review by Case et al.
    (1994).  Fibre clearance and retention in laboratory animals

         Several studies on laboratory animals, mainly rats, have
    investigated the lung clearance of chrysotile as measured by changes
    in the lung retention of fibres following acute, short-term and
    long-term inhalation or single dose via intratracheal exposure.
    Results of these studies are summarized in Table 17.

         Morgan et al. (1977) used a radiotracer technique to study the
    lung clearance of chrysotile A, chrysotile B, amosite, crocidolite and
    anthophyllite asbestos following short nose-only inhalation exposures
    (3 h). There was a rapid decline in fibre lung content followed by a
    slow phase. The initial decline was assumed to represent mucocilliary
    clearance of fibres deposited in the smaller conducting airways, and
    the slow phase to alveolar clearance. Half-times of alveolar
    clearance, measured over a period of several months following
    exposure, were in the range of 60-90 days. No significant difference
    was observed between amphibole and chrysotile asbestos.

         Middleton et al. (1979), using UICC samples, exposed rats via
    inhalation over a 6-week period to concentrations of 1, 5 and 10
    mg/m3 and then estimated the amount of asbestos in lung by infrared
    spectrophotometry after lung ashing. The fractional deposition of
    chrysotile was lower than for amosite and crocidolite, but the
    alveolar clearance rates of chrysotile and amphibole fibres were
    similar. The lower deposition rate of chrysotile was believed to be
    related to differences in airborne asbestos concentration during
    exposure and to the curly nature of chrysotile fibres.

        Table 17.  Studies of chrysotile clearance in experimental animals

    Species             Number of animals      Protocola                             Resultsa                            Reference

    Rats                (SPF Wistar)           Groups exposed to 9.7-14.7            Linear increase in lung             Wagner et al., 1974
                        total of 1013          mg/m3 of UICC amos, anthophyl,        burden of amphiboles with 
                        rats: group size       croc, chrys A & chrys B for           time. Much less chrys found 
                        of 19-58               periods of 1 day, 3,6,12 or           in lung and no clear 
                                               24 months.                            increase with dose.

    Rats                total of 56 rats:      Groups exposed nose-only              Half-time clearance about           Morgan et al., 1977
    (Albino male)       group size of 8        to neutron-activated UICC             3 months. Fibres translocated 
                                               amos, anthophyl, croc,                to subpleural sites.
                                               chrys A & chrys B for 1 h. 
                                               Deposition measured 

    Rats                not specified          Groups exposed to 1, 5 and 10         Deposition rate of chrys 25%        Middleton et al., 1979
    (SPF Wistar                                mg/m3 of UICC amos, croc and          of that of amphiboles but 
    AF/HAN strain)                             chrys A 7 h/day, 5 days/week          clearance rate independent 
                                               for 6 weeks. Asbestos in lung         of fibre type.
                                               measured by ashing and 
                                               infrared spectrophotometry.

    Rats                total of 15 rats:      Groups exposed nose-only to 4.3       Most fibres deposited at            Brody et al., 1981
    (CD-1 strain male)  group size of 3        mg/m3 chrys for 1 h. Distribution     bifurcations of alveolar ducts. 
                                               of fibres in lung measured by SEM     Fibres taken up by Type 1 
                                               and TEM at times from 1 h to 8        epithelial cells.

    Rats                unspecified            Groups instilled intratracheally      Number of chrys fibres              Bellmann et al., 1987
    (Wistar female)                            with 2 mg UICC chrys A. Rats killed   increased with time and also 
                                               at 1 day, 1, 6, 12, 18 and 24         their mean length.
                                               months after instillation. Fibre 
                                               numbers and composition determined
                                               after low-temperature ashing of 
                                               lung using TEM and ATEM.


    Table 17.  (continued)

    Species             Number of animals      Protocola                             Resultsa                            Reference

    Guinea-pigs         total of 18 animals    Animals instilled intratracheally     Chrys fibre concentration           Churg et al., 1989
    (Hartley strain                            with a mixture of UICC chrys B        declined more rapidly than 
    female)                                    and amos. Sub-groups of 6 animals     that of amos. Concentration 
                                               killed at 1 day, 1 week and 1         ratio declined from 8:1 to 
                                               month after administration. Fibre     2:1.
                                               concentration in lung tissue 
                                               determined using hypochlorite 
                                               digests of tissue with TEM and 

    Rats                total of 23 animals    Animals exposed to 10 mg/m3           Deposition similar in central       Coin et al., 1994
    (SPF                                       chrys for 3 h. Subgroups were         and peripheral regions. 
    Sprague-Dawley                             killed immediately after              Average diameter of fibres 
    male)                                      exposure and after 1, 8, 15           decreased with time and 
                                               and 29 days. Peripheral and           length increased.
                                               central regions of the left 
                                               lung digested and fibres 
                                               characterized by SEM.

    Rats                not specified          Exposures nose-only to                In lungs of chrys- and croc-        Abraham et al., 1988
    (Fischer 344                               10-15 mg/m3. Chrys: 7 h/day,          exposed rats longer and 
    male)                                      5 days/week for 6 weeks Croc:         narrower fibres than in 
                                               6 h/day, 5 days/week for 90           airborne dust. 90 days 
                                               days Animals sacrificed 90            post-exposure 95% clearance 
                                               days after exposure.                  of chrys, no clearance of 
                                                                                     croc (by fibre numbers). 

    Rats                total of 48 rats:      Groups exposed to 5 mg/m3             Progressive increase in mean        Kauffer et al., 1987
    (Sprague-Dawley     group size of 8        UICC Canadian chrys for 5 h.          length, decrease in mean 
    male)                                      Subgroups killed at the end           diameter of fibres in lungs. 
                                               of exposure and after 1, 7,           Decrease in mean length and 
                                               28 and 90 days. TEM analysis          diameter in BAL.
                                               of fibres in lung and BAL.


    Table 17.  (continued)

    Species             Number of animals      Protocola                             Resultsa                            Reference

    Hamsters            not specified          Animals instilled with one            Ratio of short chrys fibres         Kimizuka et al., 1987
    (Syrian golden,                            intratracheal dose of 1 mg UICC       30% to 13% in the lung; 2 years 
    sex not                                    Canadian chrys or amos in 0.1         after instillation increased 
    specified)                                 ml saline, killed at 4 and 56         again to 56% (diameter 
                                               weeks, and 2 years (chrys),           < 0.05 µm). Short amos fibres 
                                               2 years (amos). SEM analysis          (< 5 µm) decreased from 41% 
                                               with EDXA.                            initially to 4% after 2 years.

    Rats                not specified          Rats instilled intratracheally        Apparent increase in number         Coffin et al., 1992
    (Barrier derived                           with chrys, croc and erionite         of chrys fibres between 1 and 
    Fischer 344)                               at weekly intervals for 21 weeks.     10 days followed by gradual 
                                               Instilled dose of chrys 32 mg.        decline.
                                               Rats killed at 1 h, 1 day, 1, 4, 
                                               8, 12 and 24 months following 
                                               final instillation. Fibres 
                                               recovered from lung by 
                                               low-temperature ashing and 
                                               analysed by TEM.

    Rats                not specified          Rats exposed to 10 mg/m3              Splitting chrys fibres lead to      Jones et al., 1994
    (SPF Wistar                                UICC chrys A for 7 h/day,             increasing number of long thin 
    AF/HAN strain                              5 days/week for up to 18              fibres with time; after 150 days 
    male)                                      months. Groups removed from           of exposure lung burden no 
                                               exposure after exposures of           longer increased.
                                               1 day, 4, 13, 26, 52, 65 and 
                                               95 weeks, and subgroups 
                                               killed at 3 and 38 days after 
                                               removal. Numbers and 
                                               dimensions of fibres 
                                               recovered from lung measured 
                                               by SEM. Fibres with dia > 0.3 
                                               µm analysed by EDXA.

    a  amos = amosite; croc = crocidolite; chrys = chrysotile; anthophyl = anthophyllite.
         In contrast, Abraham et al. (1988) found that the alveolar
    clearance of chrysotile was faster than that of crocidolite. In their
    study, rats were exposed by inhalation to 10-15 mg/m3 of either
    chrysotile (6 weeks) or crocidolite (90 days). At the end of exposure,
    lung fibre concentrations and size distributions were similar for both
    types of fibres. However, during the subsequent 90 days, 95% of
    chrysotile (by fibre number) was removed, whereas there was no
    measurable clearance of crocidolite. Similar findings were reported by
    Bérubé et al. (1996). The fibre retention of chrysotile in the rat
    lung after 5 and 20 days of inhalation exposure to 8 mg/m3 was
    considerably lower than the fibre lung retention of crocidolite

         Wagner & Skidmore (1965), in a 6-week inhalation exposure study
    on rats using about 30 mg/m3, reported that, over a period of 2
    months, the rate of clearance for chrysotile was higher by a factor of
    3 than that for amosite or crocidolite. In addition, the retention of
    chrysotile, as measured a few days after the end of the 6-week
    exposure period, was only about one third that of the amphiboles.

         In a subsequent study by the same group (Wagner et al., 1974), it
    was found that, while the lung burden of amphibole fibres increased
    steadily with time, that of chrysotile appeared to reach a plateau
    after 3 months of exposure and at a much lower level compared to the
    simultaneous amphibole level. The difference was attributed to the
    enhanced clearance rate of chrysotile. This difference in the lung
    clearance of chrysotile and amphibole fibres has been confirmed by
    several studies (Davies et al., 1978, 1986a; Davis & Jones, 1988) with
    amphibole levels at the end of a one-year inhalation period in rats
    being approximately 10 times those of chrysotile administered at the
    same mass dose. In their inhalation study of the retention of UICC
    chrysotile fibres in rat lung (10 mg/m3, 7 h/day, 5 days/week, for up
    to 18 months), Jones et al. (1994) also found that the mass of
    chrysotile in the lungs increased for several months and then appeared
    to decline, although exposure continued, in agreement with the Wagner
    et al. study (1974). Oberdörster (1994), using various types of
    published data, including a 30-month exposure of baboons (Oberdörster
    & Lehnert, 1991), calculated that the chrysotile clearance half-times
    in monkeys are in the order of 90-100 days.

         Limited information exists concerning the effect of cigarette
    smoke on the lung clearance of asbestos fibre. Muhle et al. (1983)
    investigated the effect of cigarette smoke on the retention of UICC
    chrysotile A and UICC crocidolite in rats. Results showed a doubling
    of crocidolite fibres in the lungs of the groups exposed to cigarette
    smoke compared with animals not exposed to cigarette smoke. A plateau
    was found for chrysotile, as in the study of Wagner et al. (1974), but
    this was not influenced by cigarette smoke. This difference between
    the two fibre types can be explained by a higher deposition rate of
    chrysotile in the upper airways by interception compared with
    crocidolite and a decrease in deep lung clearance induced by cigarette
    smoke. Lippmann et al. (1980) showed that tracheobronchial clearance
    in humans is influenced by cigarette smoke and Cohen et al. (1979) and

    Bohning et al. (1982) showed that long-term smoking reduces long-term
    deep lung clearance.

         Several studies have shown that short fibres are generally
    cleared at faster rates than long fibres. In their inhalation
    experiment, Kauffer et al. (1987) exposed rats to UICC Canadian
    chrysotile for 5 h at 5 mg/m3. Animals were killed at different
    intervals over the subsequent 90 days and their lungs lavaged. In the
    lung tissue, the prevalence of fibres less than 5 µm in length
    decreased while that of fibres longer than 5 µm increased with
    post-exposure time. An opposite pattern of distribution was observed
    in the bronchoalveolar lavage (BAL) fluids. This indicates that fibres
    greater than 5 µm in length are cleared less efficiently from the rat
    lung than fibres less than 5 µm in length.

         Davis (1989) also found that short fibres (< 10 µm in length)
    are cleared more rapidly than long fibres (> 10 µm in length). In his
    study, rats were exposed by inhalation to chrysotile or amosite fibres
    at 10 mg/m3 for 12 months. The lung clearance percentages over a
    6-month period after exposure were 55 and 90% for long and short
    chrysotile fibres, respectively. The lung clearance percentages for
    long and short amosite fibres were 14 and 20%, respectively.

         In the study by Abraham et al. (1988), referred to previously in
    this section, the mean length of chrysotile fibres increased during
    the 90 days from 5 to 13 µm with a reduction in fibre diameter from
    0.13 to 0.09 µm due to fibre splitting. Crocidolite fibres remained
    practically unchanged (mean length 6.2 to 5.7 µm and mean diameter
    0.12 to 0.10 µm). These findings indicate that shorter chrysotile
    fibres will be preferentially cleared and that with time the
    proportion of thinner fibres increases due to fibre splitting.

         The observation that chrysotile fibres undergo longitudinal
    splitting is supported by many other studies. In a study of the number
    and dimensions of chrysotile fibres in rat lungs following short
    inhalation exposures, Roggli & Brody (1984) found that the Mg:Si ratio
    of chrysotile fibres did not differ significantly from that of the
    original material. Over a period of 1 month there was a decline both
    in the numbers of fibres in lung and in the estimated total mass of
    chrysotile remaining. The mean length of the residual fibres appeared
    to increase. The mean fibre diameter decreased, which suggests that
    chrysotile fibres were splitting longitudinally into smaller groups of

         Coin et al. (1992, 1994) found that chrysotile fibres > 16 µm in
    length were not cleared at a significant rate from the rat lung over a
    30-day period following a 3-h inhalation exposure. They found that the
    average diameter of retained fibres decreased over time, consistent
    with longitudinal splitting, and that the average length of retained
    fibres increased over time, consistent with slower clearance of longer
    fibres. The authors attributed the failure of these long fibres to be
    cleared from the lung to the inability of pulmonary macrophages to
    engulf them.

         Le Bouffant et al. (1987) exposed rats to 5 mg/m3 of chrysotile
    B for 24 months. They found that most of the fibres had undergone
    splitting by the end of the inhalation period and that chrysotile
    fibre numbers rapidly declined following inhalation.

         Kimizuka et al. (1987), who administered chrysotile and amosite
    fibres by intratracheal instillation to hamsters, found initially a
    rapid reduction in the ratio of short to long chrysotile fibres,
    indicating faster clearance of short fibres. At 2 years, however, the
    proportion of short fibres had increased again to more than 50%. This
    is most likely due to breaking up of the longer and thicker fibres in
    the lungs. This notion was supported by the decrease in diameter of
    chrysotile with time. Amosite showed progressive reduction in the
    proportion of short fibres in the lung tissue, which was not reversed
    with time.

         The numbers of chrysotile fibres remaining in the lung over a
    2-year period, following their administration by intratracheal
    instillation, were measured by Bellmann et al. (1987). Virgin UICC
    chrysotile A was used, as well as the same material from which the
    magnesium had been removed by leaching with oxalic acid  in vitro. As
    shown in Fig. 6,

    FIGURE 6

    the number of intact chrysotile fibres longer than 5 µm increased by a
    factor of about 15 over the 2-year duration of the study. A
    significant reduction in the mean diameter of fibres > 5 µm in length
    was observed, which provides evidence of fibre splitting. The
    magnesium-leached fibres were removed from the rat lung with a
    half-time of only 2 days.

         Coffin et al. (1992) administered large amounts of chrysotile
    fibres (6-32 mg) to the rat by intratracheal instillation and measured
    retention. There was an apparent increase in fibre numbers between 1
    and 10 days after instillation, which the authors attributed to the
    splitting of fibre bundles. After this initial period there was no
    significant further change in the numbers of Stanton fibres (equal to
    or greater than 8 µm in length and equal to or less than 0.25 µm in
    diameter). However, the doses administered may well have been
    sufficient to overload macrophage-mediated clearance of fibres from
    the alveolar region of the lung.

    5.1.4  Fibre translocation

         Available experimental evidence indicates that chrysotile fibres
    can be transported through the epithelium with subsequent migration to
    the interstitium. Information on the movement of chrysotile fibres
    from the lung parenchyma to either the parietal or visceral pleura is
    conflicting. While chrysotile fibres have been detected in pleural
    tissues of workers who died of asbestos-related diseases in several
    studies, other studies did not show this. Additionally, chrysotile
    fibres were not found in the rat pleura in an acute inhalation study.  Fibre translocation in humans

         In a study of asbestos fibres in the lung parenchyma and the
    parietal pleura of 29 asbestos workers, Sebastien et al. (1980) found
    that chrysotile fibres predominated in the pleura and that amphibole
    fibres could not be detected. A similar result was reported by Dodson
    et al. (1990). Kohyama & Suzuki (1991) found short chrysotile fibres
    in pleural plaques and in mesothelial tumours. In contrast, Boutin et
    al. (1993) found 0.21 × 106 fibres per g of parietal pleura and 1.96
    × 106 in samples of lung parenchyma. Fibre concentrations were higher
    in subjects with a history of asbestos exposure and most of the fibres
    were amphiboles. Churg (1994) reported detection of chrysotile fibres
    in the subpleural parenchyma in chrysotile miners and millers.
    Kobayashi et al. (1987) reported the detection of few asbestos fibres
    as asbestos bodies in the extrathoracic organs (pancreas, spleen,
    etc.) of human subjects exposed to chrysotile.  Fibre translocation in animal models

         In the inhalation study of Brody et al. (1981), the examination
    of tissues by electron microscopy revealed that chrysotile fibres
    deposited at the bifurcations of the alveolar ducts were taken up not
    only by alveolar macrophages but also by type I epithelial cells
    during the 1-h inhalation exposure. Some days after exposure, fibres
    were found in interstitial macrophages and fibroblasts. These
    observations suggest that there may be direct fibre penetration of the
    epithelial surface and that chrysotile fibrils can be transported to
    the interstitium through type I epithelial cells.

         Oghiso et al. (1984) exposed rats by intermittent inhalation to
    chrysotile fibres (95% < 6 µm in length, no fibre > 0.5 µm diameter)
    or crocidolite fibres (98.7% < 5 µm in length, 4.2% > 0.5 µm
    diameter) for 3 months and then killed them after 2-16 months.
    Electron microscopy revealed some similarities, but also distinct
    differences in the pulmonary distribution of the two types of fibre.
    Thickened alveolar duct bifurcations, associated with aggregates of
    macrophages, were seen long after exposure ceased, but crocidolite-
    exposed rats also had subpleural collections of alveolar macrophages,
    many of which contained crocidolite fibres.

         Coin et al. (1992) exposed rats to chrysotile fibres by
    inhalation for 3 h (see section 5.1.2) killing them at times up to 29
    days following exposure. The authors found no evidence of
    translocation of chrysotile fibres to the pleura. They did find,
    however, substantial numbers of inhaled fibres deposited within 1-2 mm
    of the visceral pleura of the rat.

         The fate of chrysotile (mean length 3.6 µm, mean diameter 0.05
    µm), crocidolite (mean length 2.5 µm, mean diameter 0.14 µm) and glass
    fibres, following injection into the pleural cavity of rats, was
    studied by Bignon et al. (1979). By 90 days after injection, fibres
    were found at similar concentrations in lung, liver, kidney and brain,
    while in the thoracic lymph nodes the concentrations were higher. The
    authors concluded that the majority of fibres can migrate rapidly from
    the site of administration, principally via the pulmonary lymphatics.
    In the case of chrysotile, particularly, the mean length of fibres
    found in the lung parenchyma was greater than that of the administered
    material. In view of the way the fibres were administered in this
    study, the relevance of the results to prediction of the behaviour of
    fibres following inhalation may be limited.

    5.1.5  Mechanisms of fibre clearance

         There is considerable uncertainty about the mechanisms
    responsible for the more rapid removal of chrysotile fibres from the
    lung than in the case of amphibole asbestos fibres. It is uncertain
    whether the more effective removal of chrysotile fibres is due to more
    rapid fibre dissolution or to more rapid clearance of shorter fibres
    as a result of breakage. Another explanation may be movement and
    dispersion in the watery atmosphere in the lung.

         Most of the evidence for the preferential dissolution of
    magnesium from chrysotile is derived from measurement of the
    magnesium/silicon ratio of fibres recovered from lung using analytical
    electron microscopy. A reduction in the Mg/Si ratio measured in fibres
    recovered from human lung was first reported by Langer et al. (1970).
    Subsequently, Jaurand et al. (1977) found that the extent of magnesium
    depletion varied from one fibre to another and even along the axis of
    the same fibre. Sebastien et al. (1986b) examined chrysotile fibres
    longer than 5 µm and thicker than 0.1 µm and found magnesium depletion
    as high as 50%. On the other hand, Churg & DePaoli (1988) found only
    slight magnesium depletion in fibres recovered from the lung of
    chrysotile miners many years after their last exposure.

         One possible explanation for the diversity of results is the
    impossibility of measuring Mg:Si ratios at a resolution applicable to
    individual chrysotile fibrils. In relatively thick chrysotile fibres,
    only the fibrils near the surface of a bundle will be subjected to
    leaching and those in the interior may remain intact. Another factor
    is that, once leaching occurs, the unsupported silica structure on the
    outside of a fibril may disintegrate and this may impose an upper
    limit to estimates of magnesium depletion based on Mg:Si ratios
    (Morgan, 1994). Hume & Rimstidt (1992) have proposed that the brucite
    layer of chrysotile dissolves in the lung leaving the silica layer
    exposed; this then dissolves at a slower rate and it is suggested that
    this is the rate-controlling step. These authors developed a
    "shrinking-fibre model", which predicts that a chrysotile fibre 1 µm
    in diameter will dissolve completely in 9 ± 4.5 months.

         Results of available experimental studies also gave conflicting
    evidence with regard to magnesium depletion. For example, Jones et al.
    (1994) obtained values for magnesium depletion ranging from 10 to 40%.
    Kimizuka et al. (1987) reported magnesium depletion in the lung of
    hamsters. On the other hand, Coin et al. (1994) found no significant
    leaching of magnesium over a period of 30 days following
    administration of chrysotile to rats by inhalation, and Churg et al.
    (1989) reported a similar result with guinea-pigs following
    intratracheal instillation.

         Bellman et al. (1987) showed that magnesium is removed from
    chrysotile fibres following their administration to rats by
    intratracheal instillation and that leaching rates are much greater
    during the first month than subsequently. These authors also showed
    that chrysotile fibres, from which the magnesium had been removed by
    prior treatment with oxalic acid  in vitro, were removed from the
    lung with a half-time of only a few days. This explains the
    observation that the carcinogenic potency of magnesium-leached
    chrysotile is much reduced, or eliminated completely, compared with
    that of the untreated fibre (Morgan et al., 1977; Monchaux et al.,

         Limited information is available in support of the fibre
    fragment-ation hypothesis. Churg et al. (1993) showed that short
    chrysotile fibres are present in considerably larger numbers than long
    fibres in the lungs of chrysotile miners and millers even years after
    exposure has ceased. While this finding may reflect fragmentation of
    long inhaled fibres into shorter fibres, it might also reflect
    retention of some portion of the fibre burden in a sequestration
    compartment with no change in size distribution.

         In summary, available data indicates that both fibre breakage and
    dissolution are likely mechanisms for the rapid removal of chrysotile
    fibres from the lung.

    5.2  Ingestion

         An important question in the evaluation of the possible risks
    associated with the ingestion of chrysotile asbestos is whether fibres
    can migrate from the lumen into and through the walls of the
    gastro-intestinal tract to be distributed within the body and
    subsequently cleared.

         Review of the available data has been published in Environmental
    Health Criteria 53 (IPCS, 1986). The main conclusions were: 

    (a)  It is not possible to conclude with certainty that chrysotile
         fibres do not cross the gastrointestinal wall. However, available
         evidence indicates that, if penetration does occur, it is
         extremely limited (Cook, 1983).

    (b)  There is no available information on bioaccumulation/retention of
         ingested chrysotile fibres. Simulated gastric juice has been
         shown to alter the physical and chemical properties of chrysotile
         fibres (Seshan, 1983).

    (c)  There was no difference in the level of urinary chrysotile
         between subjects drinking water with high compared to those
         drinking water with much lower natural chrysotile contamination
         (Boatman et al., 1983).

         Finn & Hallenbeck (1985) investigated the number of chrysotile
    fibres in the urine of six workers occupationally exposed to
    chrysotile. The levels of chrysotile fibres in the urine of exposed
    workers were significantly higher than in a control group.


    6.1  Introduction

         Several caveats are important in the interpretation of results of
    inhalation studies in laboratory animals and in cells  in vitro. A
    search of the literature on the effects of chrysotile in experimental
     in vivo and  in vitro models reveals few dose-response studies with
    appropriate positive and negative "control" dusts. Concentrations of
    chrysotile and other dusts used in inhalation experiments are several
    magnitudes higher than concentrations encountered in the workplace and
    environment today. Moreover, preparations of chrysotile and other
    dusts used in many experiments are poorly characterized. In the
    majority of studies before 1980, concentrations are expressed on a
    mass basis rather than on a fibre number basis. This may be misleading
    when comparing samples of chrysotile and amphibole asbestos, because
    the former may contain more than 10 times more fibres per unit weight.

         There has been a great deal of debate concerning the relevance of
    various routes of exposure in experimental animals to risk assessment
    in humans (McClellan et al., 1992; IPCS, 1993). The general consensus
    is that all routes of administration should be considered, but that
    they should be given different weightings in relation to assessment of
    potential hazard to humans.

         Positive results in an inhalation study on animals have important
    significance for the hazard evaluation of exposure to airborne fibres
    in humans. Strong arguments would need to be made against the
    relevance for humans of such a finding. However, the lack of a
    response in an inhalation study on animals does not mean that the
    material is not hazardous for humans. For instance, rats, being
    obligate nose-breathers, have a greater filtering capacity than

         As discussed by IPCS (1988), a negative result in a properly
    conducted intratracheal study would suggest that a given type of fibre
    may not be hazardous for parenchymal lung tissue. A positive result,
    however, would require further study since the normal filtering
    capacity of the respiratory tract has been bypassed. However,
    pulmonary clearance mechanisms are intact. The results of studies
    involving intrapleural injection or implantation and intraperitoneal
    injection should be viewed in a similar way to intratracheal
    instillation studies. With these methods, both filtering and clearance
    mechanisms are compromised. Such studies may be more sensitive than
    inhalation studies because a higher number of fibres can be
    introduced. Therefore, a negative result would be highly relevant, but
    a positive result should be confirmed by further investigation.

    6.2  Effects on laboratory mammals

    6.2.1  Summary of previous studies

         The results of early inhalation experiments were presented in
    Environmental Health Criteria 53 (IPCS, 1986). Fibrosis has been
    observed in many species following inhalation of chrysotile. In
    several studies there was progression of fibrosis following cessation
    of exposure (Wagner et al., 1974, 1980; Wehner et al., 1979). In the
    majority of the studies only the airborne mass concentrations were
    measured; the numbers and size distributions were not considered.
    Shorter fibres were found to be less fibrogenic (Davis et al., 1980).

         Unlike fibrosis, which has been observed in several animal
    species following inhalation of chrysotile, a consistently increased
    incidence of lung tumours or pleural mesothelioma has been observed
    only in the rat. Rats with lung tumours had significantly more
    fibrosis than those without (Wagner et al., 1974). In a study with
    exposure to approximately 10 mg/m3 of three amphibole and two
    chrysotile asbestos types, Wagner et al. (1974) found 11
    mesotheliomas, 4 of which occurred following exposure to Canadian but
    none following exposure to Rhodesian chrysotile. Davis et al. (1978)
    compared amosite, crocidolite and Rhodesian chrysotile at 10 mg/m3 as
    well as at equal fibre numbers (fibres > 5 µm in length). Both by
    mass and by fibre number, chrysotile proved the most fibrogenic and
    carcinogenic, but the authors pointed out that, while numbers of
    fibres longer than 5 µm were roughly equal, the chrysotile dust cloud
    had many more very long fibres (> 20 µm in length).

         Since it became obvious that relatively few mesotheliomas
    developed in rats following asbestos inhalation and since Wagner
    (1962) had shown that they could be induced by direct dust injection
    into body cavities, the injection technique has been frequently used.
    The results of such early experiments were summarized by IPCS (1986).
    The major finding from these studies is that, following injection,
    short fibres are less fibrogenic (Burger & Engelbrecht, 1970; Davis,
    1972) and that the most carcinogenic fibres are > 8 µm in length and
    < 0.25 µm in diameter (Stanton & Wrench, 1972; Pott & Friedrichs,
    1972; Pott et al., 1972, 1976; Stanton et al., 1977). Short fibres
    show little carcinogenicity. The numbers of mesotheliomas produced in
    these studies were high (up to 90% of animals). Several authors
    reported a clear dose-response effect (Smith et al., 1968; Stanton &
    Wrench, 1972; Wagner et al., 1973).

         The ability of asbestos to cause gastrointestinal cancer
    following ingestion has been examined in many experimental studies
    reviewed extensively by Condie (1983) and Toft et al. (1984). Early
    studies on ingested asbestos were reviewed by IPCS (1986). There was
    no conclusive evidence of either histopathological or biochemical
    effects on the gastrointestinal wall, or of carcinogenicity in the
    animal species studied.

    6.2.2  Recent long-term inhalation studies

         The results of the more recent inhalation studies in various
    animal species are presented in Table 18.

         In an inhalation study on rats (10 mg/m3 UICC chrysotile B for
    up to 12 months), Wagner et al. (1984) observed a mean fibrosis grade
    4.1 and a 25% incidence of adenomas and carcinomas. Le Bouffant et al.
    (1987), using Canadian chrysotile as a positive control in experiments
    with MMM(V)Fs in rats (5 mg/m3 chrysotile B, 5 h/day, 5 days/week for
    24 months), reported unquantified fibrosis and pulmonary tumours in
    21% of male and 17% of female rats. Muhle et al. (1987), exposing rats
    to 6 mg/m3 Calidria chrysotile 5 h/day, four times each week for 12
    months, reported the presence of pulmonary fibrosis in 42% of rats,
    but found no pulmonary tumours.

         Davis et al. (1985) examined the effects on rats of tremolite and
    brucite, two materials frequently found as contaminants of
    commercially produced chrysotile (10 mg/m3, 7 h/day, 5 days/week, for
    12 months). A sample of asbestiform tremolite from Korea was highly
    fibrogenic and carcinogenic, while brucite was less hazardous.
    However, it was demonstrated that the sample which was supposedly
    brucite was contaminated with chrysotile fibres, and it was not
    possible to determine the relative pathogenicity of these two

         The same group (Davis et al., 1986a) examined the long-term
    effects of dust from samples of wet dispersed chrysotile (WDC) in
    rats. WDC is a preparation used to produce textile yarn. Raw
    chrysotile is first separated into individual fibrils by treatment
    with detergents and then rebound with electrolytes while the slurry is
    extruded from a narrow nozzle. Handling this material liberates much
    less dust than standard chrysotile textile yarn. In the experimental
    studies, however, where respirable dust was produced by milling, both
    specimens of WDC dust and the parent chrysotile material (5 mg/m3, 7
    h/day, 5 days/week for 12 months) produced widespread fibrosis and
    pulmonary tumours in up to 50% of animals. One experimental WDC sample
    with relatively thick fibres produced as much disease at a dose level
    of only approximately 100 fibres/ml (> 5 µm in length, measured by
    PCOM) as was found in the other groups treated with WDC or standard
    chrysotile where dose levels were 500-650 fibres/ml. The authors
    concluded that WDC separates into fibrils in lung tissue more rapidly
    than standard chrysotile. The relatively few thick WDC fibres could
    generate as many long thin subunits as clouds of similar mass that
    originally contained more thin fibres.

         Platek et al. (1985) treated rats and monkeys with a specially
    prepared short fibre sample of chrysotile for 18 months (the mass dose
    level was only 1 mg/m3, of which < 1 fibre/ml was longer than 5 µm
    as measured by PCOM). After a total follow-up of 24 months the rats
    had developed neither fibrosis nor pulmonary tumours. No fibrosis was
    found in monkeys by open lung biopsies after 24 months. Davis et al.
    (1986b), exposing rats to amosite asbestos fibres (all fibres were 

    < 5 µm in length), found no pulmonary carcinomas, while numbers of
    benign tumours and levels of pulmonary fibrosis were similar to those
    in control animals. In contrast, a dust cloud generated from raw
    amosite with many very long fibres was extremely fibrogenic and
    carcinogenic. Similar studies examined the importance of fibre length
    with inhaled Canadian chrysotile (Davis & Jones, 1988). Unfortunately,
    in this case, the "short" fibre chrysotile preparation did have a
    small proportion of long fibres, and fibrosis and pulmonary tumours
    did develop. However, a comparison cloud generated from the same
    original chrysotile sample, to maximize the number of long fibres,
    produced 5 times more fibrosis and 3 times more tumours for the same
    mass dose.

         Airborne chrysotile asbestos is able to hold a high electrostatic
    charge, and there have been reports that this may effect fibre
    deposition in the lower pulmonary tract (Vincent et al., 1981; Jones
    et al., 1983). Consequently, Davis et al. (1988) treated rats with
    equal clouds of UICC Rhodesian chrysotile, either carrying the normal
    electrostatic charge or discharged by exposure to ionizing radiation
    from a thallium-204 source. Rats treated with discharged chrysotile
    had less fibrosis, tumours and retained chrysotile in their lung
    tissue, but not all these differences were statistically significant.

         Davis et al. (1991a) examined the effect on rats of inhaling
    chrysotile or amosite asbestos (10 mg/m3, 7 h/day, 5 days/week for 12
    months) simultaneously with either titanium dioxide (10 mg/m3) or
    quartz (2 mg/m3). Increased levels of pulmonary fibrosis above levels
    produced by chrysotile or amosite alone were observed in combination
    with quartz, but not with addition of titanium dioxide. Tumour
    production was also increased, but in this case a combination of
    asbestos and titanium dioxide was as carcinogenic as a combination of
    asbestos and quartz. Of particular interest in this study was the
    finding of granulomas on the visceral pleural surface that contained
    both particles and asbestos fibres in animals treated with asbestos
    and quartz. Similar granulomas have not been reported in previous
    experiments with pure asbestos where fibres accumulated beneath the
    external elastic lamina of the lung and seldom penetrated to the
    pleural surface. The increased pleural penetration of asbestos fibres
    in coexposures with quartz dust was associated with increased
    production of mesotheliomas. The recorded proportions of mesotheliomas
    were higher than those previously reported in any experiments with
    commercial varieties of asbestos. Evidence of interspecies differences
    in response to asbestos and other mineral fibres has been reported.
    Hamsters treated with respirable refractory ceramic fibre developed no
    pulmonary carcinomas but 43% developed mesotheliomas. Chrysotile
    produced neither type of tumour in this species. The mass dose levels
    were 29 mg/m3 for ceramic fibres and 11 mg/m3 for chrysotile
    (6 h/day, 5 days/week for 18 months) (Hesterberg et al., 1991).
    Twenty-one percent of rats treated with Canadian chrysotile (10
    mg/m3, 6 h/day, 5 days/week for 24 months) developed both lung
    tumours (19% of animals) and mesothelioma (one rat)( Bunn et al.,
    1993; Hesterberg et al., 1993).

        Table 18.  Long-term inhalation studies

    Species              Group size     Protocola                               Resultsa                                Reference
    Rat                  24 male,       Exposure: 10 mg/m3 UICC chrys B         Mean fibrosis grade 4.1 (Wagner         Wagner et al., 1984
                         24 female      for up to 12 months. Used as a          scale). Adenomas and carcinomas 
                                        positive control in experiments         12/48 (25%).
                                        with MMM(V)F.

    Rat                  150 male       Exposure: 1.0 mg/m3 chrys 7 h/day,      No fibrosis or tumours at 24 months.    Platek et al., 1985
    (Sprague-Dawley)                    5 days/week, for 18 months. Ball
                                        milled. Concentration of airborne
                                        fibres >5 µm in length was 0.79 

    Monkey               10             Exposure: 1.0 mg/m3 chrys 7 h/day,      No fibrosis (estimated by biopsy)       Platek et al., 1985
                                        5 days/week,for 18 months. Ball         at 28 months.
                                        milled. Concentration of airborne 
                                        fibres >5 µm in length was 0.79 

    Rat                  24 male,       Exposure: 5 mg/m3 chrys B 5 h/day,      Fibrosis reported in chrys group        Le Bouffant et al., 1987
                         23 female      5 days/week for 24 months. Used         but not quantified. Pulmonary 
                                        as a positive control in                tumours in 5/24 (21%) male rats
                                        experiments with MMM(V)F.               and in 4/23 (17%) female rats.

    Rat (Wistar)         48 male        Exposure: 10 mg/m3 tremolite or         Tremolite very fibrogenic.              Davis et al., 1985
                                        brucite 7 h/day, 5 days/week for        Pulmonary tumours and 
                                        12 months.                              mesotheliomas in 20/39 (51%) 
                                                                                rats. Brucite caused mild 
                                                                                fibrosis. Pulmonary tumours 
                                                                                in 5/38 (13%) rats.

    Rat (Wistar)         48 male        Exposure: 7 h/day, 5 days/week          All chrys samples very fibrogenic.      Davis et al., 1986a
                                        for 12 months; mean conc. of WDC        Pulmonary tumours and mesotheliomas 
                                        samples 5 mg/m3, concentration          in 16/42 (38%) for standard chrys, 
                                        of chrys yarn 4.3 mg/m3.                18/41 (44%), 18/37 (49%), 21/43 
                                                                                (49%), 21/44 (48%) for WDC 

    Table 18.  (continued)

    Species              Group size     Protocola                               Resultsa                                Reference
    Rat (Wistar)         48 male        Exposure: 10 mg/m3 of respirable        Long amos extremely fibrogenic.         Davis et al., 1986b
                                        dust 7 h/day, 5 days/week for 12        Pulmonary tumours and 
                                        months. Long fibre amos: cloud          mesotheliomas in 13/40 (33%). 
                                        generated from raw material. Short      Short amos no fibrosis. No 
                                        fibre amos: very few fibres > 5 µm      pulmonary tumours or mesotheliomas.
                                        in length.

    Rat (Wistar)         50 female      Exposure: 6 mg/m3 of Calidria           Some septal fibrosis in 21/50           Muhle et al., 1987
                                        chrys 5 h/day, 4 times each week        (42%) rats. No pulmonary tumours.
                                        for 12 months. Used as a positive 
                                        control in experiments with MMM(V)F.

    Rat (Wistar)         48 male        Exposure: 10 mg/m3 7 h/day, 5           Long fibre chrys very fibrogenic.       Davis & Jones, 1988
                                        days/week for 12 months. Long fibre     Pulmonary tumours and mesotheliomas 
                                        chrys: cloud generated from raw         in 23/40 (58%) rats.
                                        chrys. Short fibre chrys: fibres 
                                        >5 µm reduced 5 times; fibres >30 µm 
                                        reduced 80 times.

    Rat (Wistar)         48 male        Exposure: 10 mg/m3 7 h/day, 5           Interstitial fibrosis reduced by        Davis et al., 1988
                                        days/week for 12 months. Two clouds     38% in "discharged" group compared 
                                        of UICC chrys A, one of which had       to standard chrys. Pulmonary 
                                        reduced electrostatic charge by         tumours and mesotheliomas in 
                                        exposure to ionizing radiation from     11/39 (28%) rats in "discharged" 
                                        a thallium-204 source of beta           group; 14/36 (11%) rats in 
                                        particles.                              standard chrys group.

    Table 18.  (continued)

    Species              Group size     Protocola                               Resultsa                                Reference

    Rat (Wistar)         48 male        Exposure: 10 mg/m3 7 h/day, 5           Advanced fibrosis increased for         Davis et al., 1991a
                                        days/week for 12 months. Six            both asbestos types by addition 
                                        treatment groups, UICC chrys A          of quartz but not by titanium 
                                        or UICC amosite alone or mixed          dioxide. Pulmonary tumours and 
                                        with either 10 mg/m3 of titanium        mesotheliomas: chrys 13/37 (35%) 
                                        dioxide or 2 mg/m3 of quartz.           rats, chrys + TiO2 26/41 (51%) 
                                                                                rats, chrys + quartz 22/38 (58%) 
                                                                                rats; amos 14/40 (35%) rats, 
                                                                                amos + TiO2 20/40 (50%) rats, 
                                                                                amos + quartz 26/39 (67%) rats.

    Rat (Fisher 344)     63             Exposure: 10 mg/m3 chrys A 6            Mean fibrosis grade 4.0 (Wagner         Bunn et al., 1993
                                        h/day, 5 days/week for 24 months.       scale). Pulmonary tumours and 
                                        Used as a positive control in           mesotheliomas 13/63 (21%) rats.
                                        experiments with MMM(V)F.

    Hamster              100 male       Exposure: 11 mg/m3 chrys B 6            Mean fibrosis grade 4.3 (Wagner         Hesterberg et al., 1991
                                        h/day, 5 days/week for 18 months.       scale) at 3 months. No pulmonary 
                                        Used as a positive control in           tumours or mesotheliomas.
                                        experiments with MMM(V)F.

    Baboon                              Exposure: 6 h/day, 5 days/week                                                  Goldstein & Coetzee, 1990
                                        for up to 4 years
                         21             1) UICC chrysotile A, exposure          1) No mesotheliomas
                                           not specified
                         18             2) UICC amosite 1100 f/cm3,             2) 1/18 (5.6%) animals with 
                                           exposure for 4 years                    mesothelioma
                         78             3) UICC crocidolite 1130-14 000         3) 3/78 (3.8%) animals with
                                           f/cm3, exposure for 1.5-3 years         mesothelioma

    Table 18.  (continued)

    Species              Group size     Protocola                               Resultsa                                Reference

    Baboon                              Exposure: 6 h/day, 5 days/week                                                  Hiroshima et al., 1993
                         4              1) UICC chrysotile A 106,074-368,772    1) No mesothelioma
                                           f/cm3 for 8.5-24 months
                         5              2) UICC amosite 997,678 f/cm3 for       2) 2/5 animals with
                                           49 months (dose that produced           mesothelioma 
                         5              3) crocidolite (Transvaal or UICC)      3) 2/5 animals with
                                           432,291 f/cm3 for 15 months             mesothelioma
                                           769,784 f/cm3 for 35 months
                                           (dose that produced mesothelioma) 

    a chrys = chrysotile; MMM(V)F = man-made mineral (vitreous) fibres; WDC = wet dispersed chrysotile; amos = amosite.
         Studies in baboons suggest that chrysotile is less apt to cause
    mesothelioma in comparison to crocidolite and amosite asbestos. In two
    reports (Goldstein & Coetzee, 1990; Hiroshima et al., 1993), no
    mesotheliomas nor lung carcinomas were reported after exposure to
    chrysotile, although mesotheliomas were observed in amosite- and
    crocidolite-exposed baboons. However, the chrysotile exposure levels
    were lower than those of amosite or crocidolite in the latter study,
    while the level of chrysotile in the former study was not specified.
    Studies in baboons indicate that fibrosis is observed with UICC
    samples of chrysotile, amosite and crocidolite asbestos (Hiroshima et
    al., 1993). In all cases, the severity of fibrosis was directly
    related to cumulative dose.

         In experimental inhalation studies with different fibre types it
    has been an almost universal finding that fibres that are very
    fibrogenic are also carcinogenic. Davis & Cowie (1990) emphasized this
    by reporting on advanced fibrosis in 144 rats, aged 2.5 years or more,
    that had been exposed to a number of different asbestos types,
    including Rhodesian and Canadian chrysotile. The 85 animals that had
    pulmonary tumours showed almost twice the level of advanced pulmonary
    fibrosis as the 59 animals that had not developed tumours.

    6.2.3  Intratracheal and intrabronchial injection studies

         Table 19 shows the results of intratracheal injection studies
    with chrysotile documenting fibrosis in sheep, rats and mice.

         At high doses (100 mg) of chrysotile administered via
    intratracheal instillation in sheep, fibrosis appeared to be more
    marked with chrysotile than with crocidolite (Sebastien et al., 1990).
    However, the development of fibrosis exhibited evidence of an apparent
    threshold in this model, as fibrosis was not observed in sheep after
    injection of 1, 10 or 50 mg of chrysotile (Begin et al., 1987).
    Repeated instillations of 100 mg chrysotile over a 2-year period in
    sheep resulted in progression of fibrosis and lung infections (Begin
    et al., 1991).

         Use of an intratracheal injection model in rats has yielded
    additional data suggesting the decreased fibrogenicity of short-fibre
    chrysotile (Lemaire, 1985, 1991; Lemaire et al., 1985, 1989). No
    fibrogenicity was observed with injections of short chrysotile at 1, 5
    and 10 mg; however, UICC chrysotile B caused peribronchiolar fibrosis
    at all concentrations.

         Intratracheal studies in mice indicated focal collagen deposition
    in mice exposed to chrysotile, but more severe fibrosis after exposure
    to quartz (Bissonnette et al., 1989). Collagen and elastin deposition
    per unit lung weight was greater after instillation of UICC chrysotile
    in comparison to UICC crocidolite (injected rats kept for a 12-month
    period after a single 1.6 mg injection) (Hirano et al., 1988).

        Table 19.  Intratracheal injection studies (fibrogenicity)


    Species             Dose and group size            Protocol                      Results                         Reference

    Rats                UICC chrysotile B, short       Single exposure.              Severe peribronchiolar          Lemaire, 1985, 1991; 
    (Wistar, male)      chrysotile (4T30) (1, 5,       Histopathology at 1-60        fibrosis at all conc. with      Lemaire et al., 1985, 
                        10 mg) N = 5/group             days and 8 months             chrysotile B. No fibrosis       1989
                                                                                     with short chrysotile.

    Mouse               UICC chrysotile A (0.5 mg)     Single exposure.              No severe fibrosis until        Bissonnette et al., 1989
    (Balb/c, sex        number not specified           Histopathology at 0.5,        9 months.
    not specified)                                     1, 2, 3, 6 and 9 

    Sheep (male)        UICC Canadian chrysotile B     Single exposure.              Fibrosis only in 100 mg         Begin et al., 1987
                        (1, 10, 50, 100 mg) N =        Histopathology at 60 days     group.

    Sheep (male)        UICC chrysotile A,             Single exposure.              Histological score for          Sebastien et al., 1990
                        UICC crocidolite, latex        Histopathology at 8           fibrosis = 1.9 ± 0.3 
                        beads (100 mg) N = 15/group    months.                       in crocidolite and 
                                                                                     2.8 ± 1 in chrysotile 
         The rat and sheep intratracheal injection models of fibrosis have
    also been used to elucidate the time frame of appearance of bombesin
    and vasoactive intestinal peptide (Day et al., 1985, 1987),
    populations of cells in bronchoalveolar lavage (BAL) (Lemaire, 1985),
    pulmonary function and alveolitis (Begin et al., 1985, 1986), and
    cytokines or inflammatory mediators (Lemaire et al., 1986a; Keith et
    al., 1987) in relationship to the development of fibrotic disease. The
    rat intratracheal injection model has also been used to assess the
    inflammatory and fibrogenic potential of other fibre types (xonotlite,
    Fibrefrax, attapulgite) in comparison to UICC chrysotile B and short
    chrysotile 4T30 (Lemaire et al., 1989). Overall, the order of
    reactivity was xonotlite < attapulgite < short chrysotile 4T30 <
    Fibrefrax < UICC chrysotile B.

         Intratracheal and intrabronchial injection studies on
    carcinogenicity are presented in Table 20. Studies by Coffin et al.
    (1992) evaluated UICC chrysotile A in comparison to UICC crocidolite
    and erionite. Large differences in the incidence of mesothelioma in
    intratracheal injection studies were demonstrated on the basis of
    tumour-to-fibre ratios based on lung burdens of fibres averaged from 1
    day to 1 year. Erionite was 500-800 times more tumorigenic and
    crocidolite 30-60 times more tumorigenic than chrysotile on fibre
    number basis.

         Other studies have examined the co-carcinogenic effects on rats
    of chrysotile in combination with benzo (a)pyrene (BP) (Fasske, 1988)
    or the systemic carcinogen  N-nitrosoheptamethyleneimine (NHMI) and
    cadmium (Harrison & Heath, 1988). In the former study, BP appeared to
    be a weaker lung carcinogen than chrysotile. Synergistic effects of BP
    and chrysotile were not observed in comparison to chrysotile alone. In
    the latter study, the lung tumorigenic effects of chrysotile and NHMI
    appeared to be more than additive in comparison to those observed with
    NHMI or chrysotile alone.

         Kimizuka et al. (1993) explored the co-carcinogenicity of
    chrysotile and amosite asbestos with BP in hamster lungs. Although
    tumours were not observed with either type of asbestos or BP alone,
    lung carcinomas occurred with chrysotile and BP (83%) and with amosite
    and BP (67%). The incidence of lung carcinomas in rats was higher when
    chrysotile was instilled repeatedly with the carcinogen
     N-bis(hydroxypropyl)nitrosamine (DHPN) (23/38 rats) than it was with
    chrysotile alone (1/31 rats) or chrysotile in combination with smoking
    (4/29 rats) (Yoshimura & Takemoto, 1991). Mesotheliomas were not
    observed with asbestos, smoking or DHPN alone, but were found in
    combination groups.

    6.2.4  Intraperitoneal and intrapleural injection studies

         The results of the most significant intraperitoneal and
    intrapleural injection studies are presented in Table 21.

        Table 20.  Intratracheal/intrabronchial injection studies (carcinogenicity)


    Species           Dose and group sizea          Protocola                       Resultsa                          Reference

    Rat               UICC chrys A (6, 16, 32       21 weekly intratracheal         At 6, 16 and 32 mg, %             Coffin et al., 1992
    (Fischer 344,     mg)b; N = 132 for 6 and       instillations. Animals          mesothelioma were 8.3, 7.5 
    male)             16 mg, 41 for 32 mg           kept for lifespan.              and 9.8, % carcinoma were 
                                                                                    27.3, 14.3 and 2.4, 
                                                                                    respectively. No 
                                                                                    dose-response relationship.

    Rat               1) Milled UICC chrys B        Single intrabronchial           1) 17/70 (24%) lung carcinomas    Fasske, 1988
    (Wistar, both        (1 mg)                     dose. Rats kept for                and 1/70 (1.4%) mesothelioma
    sexes)            2) Benzo(a)pyrene (0.5 mg)    33 months.                      2) 7/78 (9%) lung carcinomas 
                      3) Chrys (1 mg) + BP                                             and 3/78 (4%) mesothelioma
                         (0.5 mg)  N = 70-80/group                                  3) 15/78 (19%) lung carcinomas 
                                                                                       and 1 mesothelioma.

    Rat               1) UICC chrys B (2 mg)        Single intratracheal            Lung tumours incidence:           Harrison & Heath, 1988
    (Lister hooded)   2) Chrys (2 mg) + cadmium     instillation of particular      1) Chrys alone 1/86 (1.2%)
                         (0.18 mg)                  materials. 10 weekly            2) NHMI alone 2/48 (4.2%)
                      3) Chrys (2 mg) + NHMI        subcutaneous administrations    3) Chrys + cadmium 1/94 (1.1%)
                         (1 mg x10, s.c.)           of NHMI                         4) Chrys + NHMI 8/50 (16.6%)
                      4) Chrys (2 mg) + NHMI                                        5) Chrys + NHMI + cadmium 6/44 
                         (1 mg x10, s.c.) +                                            (13.6%)
                         cadmium (0.18 mg)
                      5) NHMI (1 mg x10, s.c.)

    Table 20.  (continued)


    Species           Dose and group sizea          Protocola                       Resultsa                          Reference

    Rat               1) Chrys (15 mg), N=31        Single intratracheal dose       Yoshimura & Takemoto, 1991
    (Wistar)          2) DHPN (1 mg/kg bw)          of chrys, DHPN 3 
                         intraperitoneally, N=37    intraperitoneal doses, 
                      3) DHPN + chrys, N=38         exposure to smoke of 10 
                      4) chrys + smoke of 10        cigarettes/day, 6 days/week 
                         cigarettes, N=29           throughout lifespan.
                      5) chrys + DHPN + smoke       
                         of 10 cigarettes, N=29     Lung carcinomas:
                                                    1) 1/31 (3.2%)
                                                    2) 8/37 (21.6%)
                                                    3) 23/38 (60.5%)
                                                    4) 4/29 (13.8%)
                                                    5) 15/29 (51.7%)

                                                    1) 0
                                                    2) 0
                                                    3) 8/38 (21.1%)
                                                    4) 2/29 (6.9%)
                                                    5) 4/29 (13.8%)

    Hamster           12/group                      Weekly intratracheal            chrys, amos and BP alone:         Kimizuka et al., 1993
                      1) UICC chrys (0.2 mg)        application through 6           no tumours.
                      2) UICC amos (0.2 mg)         weeks. Tumours examined         4) 16 carcinomas in 12
                      3) BP (0.4 mg)                18 and 24 months after             (83% of animals)
                      4) Chrys + BP                 last instillation.              5) 11 carcinomas in 12
                      5) Amos + BP                                                     (68% of animals)

    a  NHMI =  N-nitrosoheptamethyleneimine, a relative systemic carcinogen; BP = benzo(a)pyrene; chrys = chrysotile; amos = amosite;
       DHPN =  N-bis(2-hydroxypropyl) nitrosamine.
    b  Accumulated instilled doses.  Equivalent to 6.5, 17.4 and 34.8 million fibres, respectively.

    Table 21.  Intrapleural and intraperitoneal injection studies


    Species           Group size     Protocola                                 Resultsa,b                             Reference

    Rat (Wistar,      40             Single intrapleural injection of          Mesotheliomas in 14/32 (44%)           Le Bouffant et al., 1985
    20 males, 20                     20 mg chrys, 1% >5 µm in                  rats (sexes unspecified)
    females)                         length

    Rat (Wistar,      24             Single intraperitoneal injection          Mesotheliomas reported in 90%          Davis et al., 1986a
    males)                           of 25 mg of 4 samples of WDC,             of rats in all groups (actual 
                                     1 sample standard chrys                   numbers unspecified). Median 
                                                                               survival for WDC rats was 
                                                                               310-340 days, for standard 
                                                                               chrys rats was 400 days

    Rat (Wistar,      32             Single intraperitoneal injection          Mesotheliomas     Median survival      Muhle et al., 1987
    females)                         of:
                                     Calidrian chrys (0.5 mg)                  2/32   (6%)       812
                                     Canadian chrys (1.0 mg)                   27/32 (84%)       357

    Rat (Wistar,      24             Single intraperitoneal injection          Mesotheliomas Median survival          Davis et al., 1986b
    male)                            of:
                                     long amosite (20 mg)                      20/21             520
                                     long amosite (10 mg)                      21/24             535
                                     short amosite (25 mg)                     1/24              837
                                     short amosite (10 mg)                     0/24

    Rat (Wistar,      24             Single intraperitoneal injection          Mesothelioma      Mean induction
    male)                            of Canadian chrysotile:                                     period               Davis & Jones, 1988
                                     long fibre (25 mg)                        23/24 (96%)       361
                                     long fibre (2.5 mg)                       22/24 (92%)       511
                                     long fibre (0.25 mg)                      16/24 (67%)       736
                                     short fibre (25 mg)                       22/24 (92%)       504
                                     short fibre (2.5 mg)                       8/24 (33%)       675
                                     short fibre (0.25 mg)                     0/24 (0%)

    Table 21.  (continued)


    Species           Group size     Protocola                                 Resultsa,b                             Reference

    Rat (Wistar,                     Single intraperitoneal injection of:      Mesothelioma      Mean survival        Pott et al., 1987
    female)           34             UICC Rhodesian chrys (6 mg)               26/34 (76%)       497
                      34             UICC Rhodesian chrys (25 mg)              27/34 (79%)       420
                      34             UICC Rhodesian chrys (6 mg) 
                                       (HCl treated)                            0/34 (0%)
                      34             UICC Rhodesian chrys (25 mg) 
                                       (HCl treated)                            0/34 (0%)
                      39             UICC Rhodesian chrys milled (10 mg)        1/39  (2.6%)
                      32             UICC Canadian chrys (1.0 mg)              26/32 (81%)       392
                      30             UICC Canadian chrys (1.0 mg) + 
                                       separate injection of PVNO              24/30 (80%)       462
                      32             Calidrian chrys (0.5 mg)                   2/32 (6%)        742
                      36             UICC Canadian chrys (0.05 mg)              7/36 (19%)       448
                      34             UICC Canadian chrys (0.25 mg)             21/34 (62%)       406
                      36             UICC Canadian chrys (1.0 mg)              31/36 (86%)       245

    Rat (Wistar,                     Single intraperitoneal injection          Mesothelioma      (survival times      Tilkes & Beck, 1989
    female)                          of:                                                         not recorded)
                      50             UICC Rhodesian chrys (2.0 mg)             25/50 (50%)                            
                      25             UICC Rhodesian chrys
                                     (10.0 mg)                                 14/25 (54%)                            
                      50             long asbestos-cement chrys (2.0 mg)       19/50 (38%)                            
                      25             long asbestos-cement chrys (10.0 mg)       8/25 (32%)                            
                      50             short asbestos-cement chrys (2.0 mg)      20/50 (40%)                            
                      25             short asbestos-cement chrys (10.0 mg)      8/25 (32%)                            
                      50             core asbestos-cement chrys (2.0 mg)       11/50 (22%)                            
                      25             core asbestos-cement chrys (10.0mg)       12/25 (48%)                            

    Table 21.  (continued)


    Species           Group size     Protocola                                 Resultsa,b                             Reference

    Rat (Wistar)                                                                                                      Yang et al., 1990
                                                                               Mesothelioma      Mean survival        
                      53             Chinese chrys short (50 mg)               26/53 (49.1%)     630                  
                      52             Chinese chrys long (50 mg)                38/52 (73.1%)     647                  
                      51             Chinese croc short (50 mg)                23/51 (45.1%)     636                  
                      54             Chinese croc long (50 mg)                 40/54 (74.1%)     492                  
                      3              UICC chrys (50 mg)                         7/13 (53.8%)     550                  
                      13             UICC croc (50 mg)                          8/13 (61.5%)     586                  
                      14             UICC glass fibre (50 mg)                  10/14 (71.4%)     605                  
                      32             Saline control (2 x 1 ml)                  0/32   726                            

    Rat (Wistar,                     Single intraperitoneal injection of       Mesothelioma      Median survival      Davis et al., 1991b
    male)                            UICC Rhodesian chrysotile:
                      24                15.0 mg                                19/24 (79%)       476                  
                      24                10.0 mg                                20/24 (83%)       476                  
                      24                 7.5 mg                                20/24 (83%)       516                  
                      24                 5.0 mg                                19/24 (79%)       506                  
                      32                 2.5 mg                                22/32 (69%)       613                  
                      32                 0.5 mg                                26/32 (81%)       693                  
                      32                 0.05 mg                               12/32 (38%)       903                  
                      48                 0.01 mg                                2/48 (4%)        NA                   

    Rat (Wistar,      33 or 36       Single intraperitoneal injection of       Mesothelioma      Median survival      Davis et al., 1991c
    male)                            tremolite:
                                     Californian (asbestiform)                 36/36 (100%)      301                  
                                     Swansea (asbestiform)                     35/36  (97%)      365                  
                                     Korea (asbestiform)                       32/33  (97%)      428                  
                                     Italy (non-asbestiform)                   24/36  (67%)      755                  
                                     Carr Brae (non-asbestiform)                4/33  (12%)      NA                   
                                     Shinness (non-asbestiform)                 2/36   (6%)      NA                   

    Table 21.  (continued)


    Species           Group size     Protocola                                 Resultsa,b                             Reference

    Rat               40             Single intrapleural injection of:         Mesothelioma      Mean survival
    (Sprague-Dawley,                 Standard Canadian chrys                   11/40 (28%)       632                  Van der Meeren et al., 1992
    male)                            (20 mg)
                                                                               Median survival                        
                                     Phosphorylated Canadian                   11/40 (28%)       612                  
                                     chrys (20 mg) (3 samples)                 13/40 (33%)       to                   
                                                                               16/40 (40%)       642                  

    Rat (Fischer      50/dose        Single intrapleural injection of:         Mesothelioma                           Coffin et al., 1992
    344, male)
                                     UICC Rhodesian chrys                      118/142 (83%)                          
                                     UICC croc                                 65/142 (45%)                           
                                     UICC erionite                             137/144 (95%)                          

                                     [NB. Number of chrys fibres 
                                     (length > 8 µm, diameter < 0.25 
                                     µm) was over 100 times higher 
                                     than for croc or erionite]                                                       

    a chrys = chrysotile; PVNO = polyvinyl-pyridine- N-oxide; asb = asbestos; croc = crocidolite; NA = not assessed.
    b  All survival or induction periods are given in days.
         When Davis et al. (1986a) treated rats by intraperitoneal
    injection of a series of four wet dispersed chrysotile (WDC)
    preparations (see section 6.2.2) and a standard chrysotile sample,
    mesotheliomas were induced in over 90% of animals. The mean induction
    period of WDC preparations was 310-340 days, shorter than that for
    standard chrysotile. It was suggested by the authors that this was due
    to the rapid separation of WDC fibre bundles in the tissue. Muhle et
    al. (1987) included two samples of chrysotile in intraperitoneal tests
    along with man-made fibres. While Canadian chrysotile produced
    mesotheliomas in 84% of animals (dose of 1.0 mg), a sample of
    chrysotile from Calidria produced only 6% mesotheliomas (dose of 0.5
    mg). Calidrian chrysotile consists of thick and often agglomerated
    bundles which are difficult to separate and size. Tilkes & Beck (1989)
    examined the carcinogenicity of chrysotile fibres separated from
    asbestos-cement sheeting by single intraperitoneal injection in rats.
    At doses of 2.0 and 10.0 mg both weathered and unweathered chrysotile
    materials produced similar number of mesotheliomas to raw chrysotile.
    The incidences of mesothelioma were not dose-related.

         Le Bouffant et al. (1985) examined the carcinogenicity of "short"
    chrysotile fibres by intrapleural injection of 20 mg in 40 rats.
    Mesotheliomas were induced in 44% of animals, but the dust sample
    contained over 1% of fibres > 5 µm in length. Davis & Jones (1988)
    administered to six groups of 24 rats by a single intraperitoneal
    injection "long" and "short" chrysotile samples at doses of 0.25, 2.5
    and 25 mg. All animals were followed practically throughout their life
    span. At 25 mg, samples of long and short chrysotile produced similar
    numbers of mesotheliomas (> 90%). At 2.5 mg, the long chrysotile
    material produced almost the same proportion of mesotheliomas while
    the short material produced tumours in only 33% of animals. At 0.25
    mg, the long chrysotile still produced 67% of mesotheliomas while the
    short chrysotile produced none. The mean mesothelioma induction period
    was dose-dependent and significantly longer with short fibre
    preparations. In fact, it is difficult to conclude whether the zero
    mesothelioma incidence with short fibre exposure at the dose of 0.25
    mg was an exposure threshold or the consequence of an induction period
    longer than the follow-up period. While in this study samples of long
    and short chrysotile fibres produced similar number of mesotheliomas
    at the dose of 25 mg, the same group of authors (Davis et al., 1986b)
    had previously reported that the intraperitoneal injection of 25 mg of
    amosite with all fibres shorter than 5 µm produced only a single
    mesothelioma in 24 rats. The authors attributed this difference to the
    presence of a small but significant number of long fibres in the
    "short" chrysotile sample.

         Pott et al. (1987) examined the carcinogenicity of many mineral
    samples, including several chrysotile preparations, in a large
    intraperitoneal injection study on rats. It was reported that UICC
    Canadian chrysotile exhibited a clear dose-response effect over a dose
    range of 0.05 to 1.0 mg, although Rhodesian chrysotile showed no
    difference between doses of 6 and 25 mg. Milled UICC Rhodesian
    chrysotile produced only 2.6% mesotheliomas at a dose level of 10 mg,
    and treatment with hydrochloric acid eliminated the carcinogenic

    potential of Rhodesian chrysotile completely. Injecting the animals
    with polyvinyl-pyridine- N-oxide (PVNO) after an injection of UICC
    Canadian chrysotile had no effect on carcinogenicity. The results were
    confirmed in a further study by the same group of authors (Pott et
    al., 1989). These authors emphasized that the maximum carcinogenic
    potency of fibres is reached at a fibre length of > 20 µm.

         Davis et al. (1991b) reported detailed dose-response studies
    following intraperitoneal injection of UICC Rhodesian chrysotile, UICC
    crocidolite, UICC amosite and erionite in rats. Dose levels ranged
    from 0.005 to 25 mg, and a clear dose-response effect was seen for all
    four minerals. Only two mesotheliomas were recorded with the lowest
    chrysotile dose (0.01 mg), which contained 55.8 × 106 fibres of all
    lengths and 872 000 fibres > 8 µm in length. When the dose-response
    was considered by mass, erionite and chrysotile appeared significantly
    more carcinogenic than amosite or crocidolite. When considered by
    fibre number (fibres > 8 µm in length), chrysotile, amosite and
    crocidolite appeared similar, but erionite showed significantly higher
    carcinogenicity. In this study, fibres were sized by SEM.

         In a similar comparison of fibre number and carcinogenicity by
    intrapleural injection, Coffin et al. (1992) counted and sized fibres
    by TEM. A dose level of 20 mg chrysotile produced similar numbers of
    mesotheliomas in rats (83%) to erionite and twice the proportion of
    mesotheliomas produced by crocidolite (45%). However, the chrysotile
    fibre numbers ( > 8 µm in length) were reported to be 100 times
    greater than in the crocidolite preparation and 500 times greater than
    in erionite. 

         Van der Meeren et al. (1992) treated rats by intrapleural
    injection of either standard chrysotile or three samples of
    phosphorylated chrysotile at the same dose. There were no significant
    differences in mesothelioma production but the unphosphorylated
    chrysotile was reported to have at most half the number of "Stanton"
    size fibres per mg compared to the phosphorylated materials.

         Pott (1994) evaluated results from carcinogenicity studies in
    rats and lung cancer risk data in humans. He concluded that there is
    no evidence of a lower carcinogenic potency of chrysotile fibre
    compared to amphibole asbestos fibres.

         Because tremolite contamination of chrysotile is believed by some
    to enhance its pathogenicity, an injection study by Davis et al.
    (1991c) is of interest. Six tremolite samples (three of asbestiform
    type and three non-asbestiform varieties) were administered to rats by
    intraperitoneal injection. The three asbestiform preparations produced
    mesotheliomas in over 90% of animals, while the non-asbestiform
    samples produced a lower response which appeared to be related to the
    number of elongated spicules in the dust. Two preparations, with
    relatively few of these spicules, produced only a few mesotheliomas
    similar in numbers to those found in control rats.

    6.2.5  Ingestion studies

         The main chrysotile-related findings, reported in the
    Environmental Health Criteria 53 (IPCS, 1986), are as follows:

    (a)  There were no consistent pathological findings in the
         gastrointestinal tract of rats that had consumed up to 250 mg
         chrysotile per week for periods up to 25 months (Bolton et al.,
         1982), although some evidence of cellular damage was observed in
         the intestinal mucosa of rats fed 50 mg of chrysotile per day
         (Jacobs et al., 1978).

    (b)  In six identified studies on rats with chrysotile fed in diet
         (250 mg per week for up to 25 months, or 10% in diet over
         lifetime, or 1% short-range or 1% intermediate-range chrysotile
         fed to nursing mothers and over the lifetime of pups) (Donham et
         al.,1980; Bolton et al.,1982; McConnell, 1982; NTP, 1985), there
         was no significant treatment-related increase of carcinoma
         incidence. Only benign tumours of the large intestine were found
         in rats, fed with an intermediate range of chrysotile fibres, in
         the NTP study. Of special significance is the finding that no
         increase in tumour incidence was observed following
         administration of short-range chrysotile fibres, composed of size
         ranges similar to those found in drinking-water (McConnell, 1982;
         NTP, 1985).

         Since the publication of Environmental Health Criteria 53 (IPCS,
    1986), there have been only a few studies in which possible harmful
    effects of the ingestion of chrysotile asbestos have been examined in
    experimental animals. All these studies gave negative findings.
    McConnell et al. (1983) treated over 3000 hamsters (equal numbers of
    males and females) with various preparations of chrysotile and amosite
    in special food pellets containing 1% by weight of asbestos. Neither
    the male nor the female asbestos-treated groups showed a statistically
    significant increase in neoplasia in any tissue or organ compared to
    control groups. A study on Swiss albino male mice, fed orally with
    chrysotile asbestos suspended in water at a dosage of 20 mg/kg per day
    during 60 days, did not show induction of chromosomal aberrations or
    sperm abnormalities (Rita & Reddi, 1986). The most recent completed
    experimental ingestion study was reported by Truhaut & Chouroulinkov
    (1989). These authors fed groups of 70 rats with either chrysotile or
    a mixture of chrysotile and crocidolite (75:25) in palm oil at dose
    levels of 10, 60 or 360 mg per day for 2 years. No increase in tumour
    incidence in the treated animals was found compared to controls.
    Aberrant crypt foci were induced in rats given chrysotile by gavage at
    a dosage of 70 mg/kg per day (Corpet et al., 1993).

         The subject of asbestos ingestion has been reviewed by Davis
    (1993), Polissar (1993) and Valiœ & Beritiœ-Stahuljak (1993).

    6.3  Studies on cells

         Cell cultures and cells from bronchioalveolar lavage (BAL) of
    animals or humans exposed to asbestos have been used to document the
    cytotoxicity and genotoxicity of asbestos preparations as well as
    other effects on cells, i.e. proliferative alterations, production of
    cytokines, which may be predictive of disease. Other studies have
    focused on perturbations of cell organelles or cell-signalling
    pathways which are traditionally activated in other experimental
    models of inflammation, fibrosis and carcinogenesis. These assays have
    been valuable in determining mechanisms of disease and the properties
    of fibres, i.e. length and free-radical-generating properties, which
    are important in cell transformation and proliferation (Mossman &
    Begin, 1989).

         The mechanisms of fibre-induced carcinogenicity have been
    recently reviewed by IARC (1996).

    6.3.1  Genotoxicity and interactions with DNA

         Table 22 summarizes results of some key  in vitro genotoxicity

         Many studies have been performed to determine whether or not
    chrysotile and other types of asbestos interact with DNA either
    directly by physical association or indirectly via the production of
    reactive oxygen species (ROS), which may be generated primarily by
    iron-driven redox reactions on the surface of fibres. The latter
    mechanism may be particularly relevant to the enhanced biological
    activities of crocidolite and amosite, which contain approximately
    26-36% iron, in comparison to chrysotile (generally < 2% iron by
    weight), in some preparations (Lund & Aust, 1991). The importance of
    iron in these reactions is illustrated by the observations that the
    DNA breakage is also observed with ferric citrate (Toyokuni &
    Sagripanti, 1993), and that reactivity of fibres is inhibited with
    iron chelators, such as desferrioxamine (Lund & Aust, 1991). Cell-free
    assays have shown that UICC samples of Canadian chrysotile, amosite
    and crocidolite cause lipid peroxidation (Weitzman & Weitberg, 1985),
    presumably by catalysing the formation of toxic hydroxyl radicals from
    hydrogen peroxide, a reaction inhibited by desferrioxamine (Weitzman &
    Graceffa, 1984; Gulumian & Van Wyk, 1987).

         Chrysotile asbestos causes breakage of isolated DNA  in vitro 
    (Kasai & Nishimura, 1984), but this phenomenon is also observed with
    ferric citrate (Toyokuni & Sagripanti, 1993) and other chemical
    systems that generate ROS. Oxidative damage to DNA, as indicated by
    the formation of 8-hydroxydeoxyguanosine from deoxyguanosine
    (Leanderson et al., 1988), or calf thymus DNA (Adachi et al., 1992)
     in vitro is more potent with chrysotile in comparison to man-made
    fibres on an equal weight basis. However, the hydroxyl-radical-
    producing capacity attributed to this activity may be related more
    directly to the surface area of the material (Leanderson et al.,

        Table 22.   In vitro studies on genotoxicity


    Species              Type of fibres              End-point (change)              Results                            Reference
    (cell type)

    Drosophila           NIEHS samples of            Aneuploidy (+)                  Chrysotile and amosite (+)         Osgood & Sterling, 
    (female germ         chrysotile, crocidolite,                                    at high dose (25 mg/ml),           1991
    cells)               amosite, tremolite                                          only chrysotile (+) at low 
                                                                                     (5 mg/ml) dose. No effects 
                                                                                     with other types of asbestos.

    Rat (pleural         Canadian chrysotile;        Aneuploidy (+);                 Chrysotile caused more effects     Yegles et al., 1993
    mesothelial          UICC crocidolite1           chromosomal aberrations         on a weight basis, but 
    cells)                                           (+)                             crocidolite more effects on 
                                                                                     a fibre basis. NOEL in 1 of 
                                                                                     2 experiments.

    Rat (pleural         Canadian chrysotile         Aneuploidy (+)                  NOEL                               Jaurand et al., 1986

    Rat (pleural         UICC chrysotile             Morphologic transformation      Only one dose evaluated.           Paterour et al., 1985
    mesothelial                                      (+)

    Rat (lung            NIEHS intermediate          Polyploidy (+);                 Dose-dependent increases.          Li, 1986
    epithelial           chrysotile                  chromosomal aberrations 
    cells)                                           (+)

    Rat (bone            Indian chrysotile           Chromosomal aberrations         Increase in chromosomal            Fatma et al., 1992
    marrow cells)                                    (+)                             aberrations; decrease in 
                                                                                     mitotic index of bone 
                                                                                     marrow cells. Only one 
                                                                                     dose evaluated

    Table 22.  (continued)


    Species              Type of fibres              End-point (change)              Results                            Reference
    (cell type)

    Golden Syrian        UICC chrysotile; glass      Morphologic transformation      Chrysotile caused the strongest    Mikalsen et al., 1988
    hamster              fibre 100, 110; amosite;    (+)                             effects on a weight basis. No 
    (embryo cells)       crocidolite;                                                synergistic effects of BP
                         Benzo(a)pyrene (BP)

    Chinese hamster      UICC chrysotile;            Aneuploidy (+); chromosomal     NOEL, erionite > crocidolite       Palekar et al., 1987
    (lung fibroblast)    UICC crocidolite;           aberrations (+)                 > chrysotile on a fibre basis

    Chinese hamster      35 dusts, including         Chromosomal aberrations (+)     Chrysotile more active on          Koshi et al., 1991
    (lung fibroblasts)   UICC and sized UICC                                         a weight basis than other 
                         chrysotile                                                  types of asbestos. No 
                                                                                     dose-response. Shorter 
                                                                                     preparations less active 
                                                                                     than long fibres.

    Mouse Balb/3T3       UICC chrysotile;            Morphological transformation    With chrysotile, dose-response     Lu et al., 1988
    (fibroblasts)        UICC crocidolite TPAa       (+)                             increases in transformation. 
                                                                                     Chrysotile and TPA act 

    Hamster-human        UICC chrysotile             Mutations at HGPRT (-) and      Dose-response mutations at         Hei et al., 1992
    hybrid                                           S1 locus (+)                    S1 locus.

    Table 22.  (continued)


    Species              Type of fibres              End-point (change)              Results                            Reference
    (cell type)

    Human (bronchial     UICC chrysotile A;          Chromosomal aberrations (-)     No statistically significant       Kodama et al., 1993
    epithelial cells)    UICC crocidolite            binuclei and micronuclei        effect of chrysotile on 
                                                     (-,+)                           numerical or structural 
                                                                                     chromosome changes. 
                                                                                     Dose-dependent (NOEL) in 
                                                                                     micronuclei and binuclei 
                                                                                     only at 3 days.

    Human (lung          UICC chrysotile A;          Mitotic index (-)               Cytological changes with           Verschaeve et al., 
    fibroblasts)         glass fibres                                                chrysotile indicative of           1985
                                                                                     cell death (scattered 
                                                                                     chromatin observed). No 
                                                                                     effects of glass fibres.

    Human                Chrysotile (USSR);          Chromosomal aberrations (+)     Latex and clinoptilite also        Korkina et al., 1972
    (lymphocytes)        Clinoptilite;                                               + at same weight 
                         Latex                                                       concentration as chrysotile

    Human female         UICC chrysotile;            Chromosomal aberrations (+)     Only one concentration             Olofsson & Mark, 1989
    (pleural,            UICC crocidolite;                                           evaluated. Numerical and 
    mesothelial          UICC amosite                                                structural alterations 
    cells)                                                                           with all asbestos types, 
                                                                                     but no breakage nor 
                                                                                     polyploidy. Aberrations 
                                                                                     in 2/4 untreated controls.

    a TPA = 12-O-tetradecanoylphorbol-13-acetate
             Chrysotile asbestos has been shown to induce chromosomal
    aberrations (Sincock et al., 1982; Lechner et al., 1985; Jaurand et
    al., 1986), anaphase abnormalities (Palekar et al., 1987; Pelin et
    al., 1992; Jaurand et al., 1994), and sister chromatid exchange
    (Livington et al., 1980; Kaplan et al., 1980) in cultured rodent and
    human cells.

    6.3.2  Cell proliferation

         Interactions of chrysotile with the DNA of rodent cells may
    result in chromosomal or mutational events indicative of the
    initiation of carcinogenesis or genetic damage associated with
    cytolysis and cell death. However, cell proliferation, a phenomenon
    intrinsic to the long promotion and progression phases of the
    carcinogenic process, may be a more important contributing factor to
    both cancer and fibrosis. Sustained increases in incorporation of
    tritiated thymidine have been documented in human embryonic lung
    fibroblasts after exposure to UICC chrysotile at 10 µg/ml medium, but
    not at 5 µg/ml (Lemaire et al., 1986b). Moreover, effects were not
    observed with latex beads or titanium dioxide at up to 10-fold higher
    concentrations. In hamster tracheal epithelial cells, both UICC
    chrysotile and crocidolite asbestos caused increases in activity of
    ornithine decarboxylase (ODC), a rate-limiting enzyme in the
    biosynthesis of polyamines, which accompanied increases in labelling
    by tritiated thymidine in these cells (Landesman & Mossman, 1982;
    Marsh & Mossman, 1988, 1991). Elevations in ODC activity were also
    observed with Code 100 fibreglass and long chrysotile (>10 µm)
    fibres, but to a lesser extent with short chrysotile (<2 µm) (Marsh &
    Mossman, 1988).

         Both rats (Brody & Overby, 1989; McGavran et al., 1990) and mice
    (McGavran et al., 1990), following a single exposure to approximately
    10 mg/m3 air, exhibited rapid reversible proliferation of epithelial
    and interstitial cells, as measured by incorporation of tritiated
    thymidine, which was followed by increased accumulation of alveolar
    macrophages and localized interstitial fibrosis using morphometric
    techniques (Chang et al., 1988). In mice, endothelial and smooth
    muscle cells of arterioles and venules near alveolar duct
    bifurcations, the site of deposition of asbestos fibres, also
    incorporate increased levels of tritiated thymidine up to 72 h after
    initiation of a 5-h exposure to chrysotile (McGavran et al., 1990).

         Morphometric analyses of ultrastructural changes in
    chrysotile-exposed rat lungs have also been used to determine the
    responses of alveolar type II epithelial cells after inhalation of
    chrysotile asbestos over a 2-year period (Pinkerton et al., 1990).
    During this time, type II cell number and volume increased to values
    more than 4 times those seen in controls. Inhalation of chrysotile
    over a one-year period resulted in regional differences in the
    localization and lung burden of fibres, which were proportional to the
    relative degree of tissue injury at that site (Pinkerton et al.,

         The induction of protooncogenes which govern cell division has
    been compared in cultures of rat pleural mesothelial cells (RPM) and
    hamster tracheal epithelial cells (HTE) (Heintz et al., 1993). These
    studies indicated that UICC crocidolite asbestos and UICC chrysotile
    asbestos cause persistent induction of the protooncogenes c-fos and
    c-jun in RPM cells in a dosage-dependent fashion. Crocidolite was much
    more potent than chrysotile in stimulating gene expression of both
    protooncogenes on a fibre number basis. In HTE cells, only c-fos
    induction was observed, but patterns of induction by both types of
    asbestos were similar to those observed in RPM cells. No increases
    were documented with the use of polystyrene beads or riebeckite.

    6.3.3  Inflammation

         Using intratracheal injection (1, 10, 25, 50 or 100 mg of UICC
    Canadian chrysotile) into the isolated tracheal lobe of the lungs of
    sheep and following pulmonary lavage, Begin et al. (1986) examined the
    extracted fluid and cells for evidence of inflammation by differential
    cell counts and estimations of lactate dehydrogenase (LDH), alkaline
    phosphatase, œ-glucuronidase and levels of fibronectin and
    procollagen. Only the 100 mg dose produced any changes from control
    levels, a finding which the authors suggested supported the idea of a
    "tolerance threshold". Comparing UICC Canadian chrysotile to short
    Canadian chrysotile and a chrysotile coated with either phosphate or
    aluminium (intratracheal injection of 100 mg), the UICC chrysotile
    preparation and the samples of coated chrysotile all produced evidence
    of similar levels of pulmonary inflammation, but the short chrysotile
    preparation produced no changes from control values. By administering
    100 mg of chrysotile intratracheally at 10-day intervals, Begin et al.
    (1990) found that normal sheep showed much less evidence of pulmonary
    inflammation in lavage fluids than those with fibrosis, and the fibre
    retention was 2.5 times greater when fibrosis was present.

         Lemaire et al. (1985) administered, by a single intratracheal
    injection, 5 mg of either UICC Canadian chrysotile or short fibre
    preparation (all fibres < 8 µm in length) to rats. Lung morphology
    was examined at intervals of up to 60 days. The UICC chrysotile
    produced nodular lesions around the terminal bronchioles with
    accumulation of inflammatory cells followed by collagen deposition. In
    contrast, the short fibre preparation produced an accumulation of
    inflammatory cells but no fibrosis. It was found that standard
    chrysotile caused an influx of PMN during the first day, which
    persisted for 7 days. In contrast, the short chrysotile caused only a
    transient increase in PMN on day 1. Both preparations stimulated an
    influx of lavageable macrophages, which were frequently binucleate,
    and frequent mitotic figures were recorded. These studies were
    extended to include different dose levels and to include attapulgite,
    xonotlite and aluminium silicate fibres. Intratracheal dose levels
    were 1, 5 and 10 mg. One month after treatment, UICC Canadian
    chrysotile and aluminum silicate, which contained long fibres, had
    produced fibrotic lesions at all doses, while short chrysotile and

    attapulgite (a short fibre clay material) produced an accumulation of
    inflammatory cells but no fibrosis. Xonotlite produced only a minimal

         Pulmonary lavage was used to examine the inflammatory response to
    chrysotile and amosite dust in rats following short-term inhalation
    (Donaldson et al., 1988a; Davis et al., 1989). UICC Rhodesian
    chrysotile produced a rapid increase in both lavageable macrophages
    and PMN within 2 days of the start of inhalation at a dose level of 10
    mg/m3. Amosite at the same dose had little effect; the chrysotile
    response was even greater than the early response stimulated by
    amosite at 50 mg/m3. By 52 days of study, the 50 mg amosite dose had
    elicited more macrophages than 10 mg of chrysotile, and by 75 days it
    had elicited more neutrophils as well. By 75 days, the numbers of
    macrophages in lavage fluids was falling in both chrysotile and
    amosite treatments, perhaps because macrophages aggregated around
    fibre deposits were becoming less susceptible to lavage. In contrast
    to the findings with asbestos, quartz at a concentration 10 mg/m3
    produced only minimal increases in macrophages and neutrophils during
    the first 30 days of dusting, but subsequently a massive influx of
    both cell types occurred and persisted until the end of the study. In
    this report, levels of LDH and œ-glucuronidase in lavage fluids
    closely mirrored the numbers of lavage cells for all dust types.
    Donaldson et al. (1990) used the same experimental procedure to
    examine leucocyte chemotaxis. Following inhalation for up to 75 days
    of chrysotile, amosite, quartz or titanium dioxide, chemotactic
    activity towards zymosan-activated serum was found to be reduced with
    the first 3 dusts. In contrast, chemotaxis of cells lavaged from
    animals treated with titanium dioxide showed only a small impairment
    of chemotaxis. After inhalation of chrysotile (10 mg/m3) for 1 h,
    cells from BAL exhibited a diminished capacity to secrete superoxide
    anion, an active oxygen species implicated in bactericidal activity,
    when incubated with the opsonized zymosan (Petruska et al., 1990).

    6.3.4  Cell death and cytotoxicity

         Several studies have documented the short-term cytotoxic effects
    of chrysotile asbestos and other particulates on cells in culture
    (reviewed in Mossman & Begin, 1989). These studies indicate that
    geometry and size are important determinants of cytotoxicity in a
    number of cell types; longer fibres are more potent than short fibres
    in most of these bioassays (Wright et al., 1986; Mossman & Sesko,

    6.3.5  Liberation of growth factors and other response of cells of the 
           immune system

         Macrophages and other cell types of the immune system produce a
    number of cytokines or growth factors (Rom & Paakko, 1991; Schapira et
    al., 1991; Perkins et al., 1993), products of arachidonic acid and
    lipoxygenase metabolism (Kouzan et al., 1985; Dubois et al., 1989),

    proteolytic enzymes (Donaldson et al., 1988b), neuropeptides (Day et
    al., 1987), immunomodulation factors (Bozelka et al., 1986),
    chemotactic factors (Hays et al., 1990), and activated oxygen species
    (Cantin et al., 1988) after exposure to chrysotile asbestos (reviewed
    in part by Mossman & Begin, 1989). Whether these substances are
    important causally to the induction of asbestos-associated disease or
    in mitigating the disease process is unclear. For example, some of
    these factors, such as platelet-derived growth factor (PDGF), are also
    induced after exposure to iron spheres (Schapira et al., 1991) and
    other innocuous particles used as negative controls. However, such
    particles are not translocated to the interstitium, while chrysotile
    fibres are readily translocated (Brody & Overby, 1989).

         The initial inflammatory response to inhaled asbestos fibres and
    subsequent development of fibrosis, and also possible neoplasia, is
    claimed to be mediated by a number of chemical factors, most of which
    are produced by pulmonary macrophages that have phagocytosed fibres.
    Lemaire et al. (1986c) examined the production of fibroblast growth
    factor (FGF) by pulmonary macrophages from rats given a single
    intratracheal injection of either 5 or 10 mg of Canadian chrysotile.
    In control rats, pulmonary macrophages secrete FGF while monocytes
    from peripheral blood secrete fibroblast growth inhibitory factor
    (FGIF). Subsequent to asbestos treatment, secretion of FGF by
    pulmonary macrophages was significantly increased and monocyte
    production of FGIF was reduced. The stimulation of fibroblast
    proliferation by alveolar macrophages was further examined by
    co-culturing macrophages from normal rats and rats treated by a single
    intratracheal injection of 5 mg of Canadian chrysotile with long
    fibroblasts (Lemaire et al., 1986d). Macrophages from
    chrysotile-treated animals caused significantly more fibroblast
    proliferation than controls. Bonner & Brody (1991) demonstrated that,
    when rats were exposed for only 3 h to chrysotile at a dose level of
    10 mg/m3, macrophages lavaged one week later stimulated 2-5 times
    more production of PDGF than controls. However, exposure to iron (50
    mg/m3) caused a similar increase. Cantin et al. (1989) showed that
    development of asbestosis is associated with increased secretion of
    plasminogen activator by pulmonary macrophages. In sheep given 100 mg
    of Canadian chrysotile every 2 weeks by intratracheal injection, some
    animals developed fibrosis and some did not. Lavaged macrophages from
    animals developing fibrosis were found to secrete larger amounts of
    plasminogen activator than those from animals that did not developed
    fibrosis. Bonner et al. (1993) believe that the combination of
    retention and translocation, along with release of growth factors and
    other inflammatory mediators, is responsible for the fibrogenic
    effects of fibres.

         After exposing rats by inhalation to chrysotile or crocidolite
    asbestos at a dose level of approximately 10 mg/m3 for up to 91 days,
    Hartmann et al. (1984a,b) found that the expression of the Ia antigen
    on macrophages lavaged from crocidolite-treated animals was increased
    4-fold in male Fischer-344 rats while chrysotile produced no increase
    over controls. In female ACI rats, crocidolite produced similar

    effects but in these animals chrysotile also stimulated an increase in
    Ia expression at approximately half the level of crocidolite.
    Significantly greater thymocyte DNA synthesis was induced by
    supernatants from co-cultures of alveolar macrophages and splenic
    lymphocytes from asbestos-treated rats than from controls.

         An effect on splenocyte mitogenesis by chrysotile treatment was
    noted by Hannant et al. (1985). In these studies rats were given a
    10 mg intraperitoneal injection of Rhodesian chrysotile, quartz or
    titanium dioxide. After 14 days, splenocytes from animals treated with
    chrysotile or quartz showed a significant reduction in mitogenic
    response to phytohaemagglutinin and concanavalin A compared to
    controls. Titanium dioxide produced no effect. Intraperitoneal
    injection of chrysotile into mice caused impairment of subsequent
    production of antibody to the protein antigen.


         Studies reviewed are restricted to those that were considered by
    the Task Group to be of clear relevance to characterizing the risks
    associated with exposure to chrysotile. Limitations of
    particle-to-fibre count conversions on which the exposure estimates in
    the following studies are based are presented in Chapter 2.

    7.1  Occupational exposure

    7.1.1  Pneumoconiosis and other non-malignant respiratory effects

         The non-malignant lung diseases resulting from exposure to
    asbestos fibres comprise a somewhat complex mixture of clinical and
    pathological syndromes not readily definable for epidemiological
    study. Traditionally, the prime concern has been asbestosis, generally
    implying a disease associated with diffuse interstitial pulmonary
    fibrosis accompanied by varying degrees of pleural involvement. More
    recently, as severe asbestosis has become less frequent clinically,
    attention has been directed primarily to syndromes reflecting fibrosis
    of the small and large airways rather than of the lung parenchyma. As
    a cause of death, the pneumoconioses have never been reliably recorded
    on death certificates. In investigations of mortality, therefore, all
    chronic non-malignant respiratory diseases are generally considered as
    one group. Additionally, mortality studies are generally not
    sufficient to detect clinically significant morbidity. Equally, in
    studies of morbidity, the etiological or diagnostic specificity of the
    usual methods of assessment, i.e. chest radiography, physiological
    testing and symptom questionnaire, is limited.

         Early studies in both the United Kingdom and USA demonstrated an
    extremely high prevalence of asbestosis among textile workers exposed
    only to chrysotile at very high dust levels (Dreeson et al., 1938).

         Extensive morbidity surveys of chrysotile workers were initiated
    in the Quebec chrysotile mines and mills in the 1960s (McDonald et
    al., 1974). These studies included the use by six readers of the then
    newly developed UICC/Cincinnati (later ILO) radiographic
    classification of nearly 7000 films, examinations by questionnaire and
    lung function tests of over 1000 current employees, and detailed
    assessments of cumulative dust exposure for each man. In the initial
    survey, there was a fairly systematic relationship between exposure
    and these measures of response. The authors concluded that exposure to
    70-140 mpcm (2-4 mpcf) for a working life of 50 years was associated
    with a 1% risk of acquiring clinically significant disease.

         Based on additional study of radiological changes in 515 men aged
    60-69 years (average 64.6 years) who had been employed for at least 20
    years (average 42.3 years) at Thetford Mines, the dustier of the two
    Quebec mining regions, dose-response relationships for small opacities
    were essentially linear (Liddell et al., 1982). However, any increase
    in prevalence in small opacities (>1/0 or >2/1) above the level of
    the intercepts (which were high) only became apparent at an
    accumulated exposure at age 45 of 1200 f/ml-years, equivalent to an

    average concentration of about 30 f/ml (Liddell et al., 1982). In
    contrast to small opacities, pleural thickening was not related to
    cumulative exposure, although it was more common in men with long

         Becklake et al. (1979) reported a second study in Quebec of 86
    men whose last chest film was taken within 12 months of leaving
    employment in 1960-1961, and who were examined again in 1972. In 66
    men who had been employed for at least two years, there was evidence
    of an increase in small irregular parenchymal opacities in 8 men (12%)
    but in none of the 20 men with shorter employment. Increase of pleural
    thickening was seen in a further 13 (20%) of the 66 men and 4 (20%) of
    the 20 men.

         A dose-related reduction in vital capacity (p= 0.023) and
    expiratory volume (p<0.001) was observed with increasing cumulative
    exposure (i.e. > 8 f/ml-years) to chrysotile asbestos in miners and
    millers (stratified random sample of 111 men) in Zimbabwe, exposed for
    more than 10 years. The relationship between cumulative exposure and
    radiographic parenchymal category demonstrated a steep increase with
    each change in category (p<0.00001). Individual estimates of
    cumulative exposure based on company records of employment history and
    fibre concentrations (measured and estimated) ranged from 1.1 to 654
    fibres/ml-years. Controls were a subset of miners (n=66) with no prior
    respiratory illness, who were lifelong non-smokers with normal chest
    X-ray and minimal cumulative exposure to chrysotile asbestos (<8
    fibres/ml-years) (Cullen et al., 1991).

         A number of other studies of radiographic and functional changes
    have been conducted in occupational populations exposed primarily to
    chrysotile, in some cases during mining and milling operations (Rubino
    et al., 1979a; McDermott et al., 1982; Viallat et al., 1983; Cordier
    et al., 1984; Enarson et al., 1988), asbestos-cement (Weill et al.,
    1979; Jones et al., 1989) and asbestos textiles (Berry et al., 1979;
    Becklake et al., 1980). Results were generally comparable to those
    already described, the presence of small opacities increasing with
    cumulative exposure (although with some variability in the shape and
    steepness of these trends) and pleural changes primarily related to
    time since initial exposure. As demonstrated in several of these
    studies, e.g., Becklake et al., 1979; Rubino et al., 1979a; Berry et
    al., 1979; Viallat et al., 1983, and as well recognized clinically,
    X-ray changes can develop among workers after exposure ceases, in some
    cases many years later.

         Studies that correlate disease prevalence or symptoms with
    cumulative exposure can underestimate disease risk due to progression
    of disease after employment ceases. Although workers were exposed to
    both chrysotile and crocidolite (the latter being approximately 5% of
    all asbestos used), results for 379 men employed at least 10 years in
    the Rochdale asbestos textile plant are informative in this regard
    (Berry et al., 1979). Exposure estimated from work histories ranged
    from an average of 2.9 to 14.5 f/ml. Overall, small opacities (>1/0)
    were recorded in 88/379 (23%) of chest radiographs, with evidence of a

    gradient seriously confounded by date of first employment and transfer
    of subjects with suspected asbestosis to less dusty conditions. On the
    basis of data on incidence, the authors drew conclusions on exposure-
    response between cumulative exposure and prevalence or incidence of
    crepitations, possible asbestosis and certified asbestosis - all three
    depending on clinical opinion and judgement. The authors concluded
    that possible asbestosis occurs in no more than 1% of men after 40
    years of exposure to concentrations between 0.3 and 1.1 f/ml.

         Mortality studies of Quebec miners and millers by McDonald et al.
    (1994) have shown exposure-response relationships for
    pneumoconiosis-related mortality. Crude rates of 0.23 cases per 1000
    man-years were observed for those with cumulative exposures less than
    3530 mpcm-years (100 mpcf-years) and a rate of 2.7 cases per 1000
    man-years was reported for those with more than 10 590 mpcm-years 
    (> 300 mpcf-years). Dement et al. (1994) also reported mortality due 
    to non-malignant respiratory diseases among chrysotile textile 
    workers. An SMR of 1.88 was observed for those with cumulative 
    exposures less than 2.7 f/ml-years and rose rapidly to 12.78 with 
    cumulative exposures greater than 110 f/ml-years. It was noted that 
    cases of pneumoconioses recorded on death certificates are often 
    verified by pathological diagnosis.

         Chest X-ray changes among textile and friction product workers in
    China were reported by Huang (1990). A total of 824 workers employed
    for at least 3 years in a chrysotile products factory from the
    start-up of the factory in 1958 until 1980, with follow-through to
    September 1982, were studied. Chest X-ray changes compatible with
    asbestosis were assessed using the Chinese standard system for
    interpretation of X-rays. Cases were defined as Grade I asbestosis
    (approximately equivalent to ILO >1/1). Overall, 277 workers were
    diagnosed with asbestosis during the follow-up period, corresponding
    to a period prevalence of 31%. Exposure-response analysis, based on
    gravimetric data converted to fibre counts, predicted a 1% prevalence
    of Grade I asbestosis at a cumulative exposure of 22 f/ml-years.

    7.1.2  Lung cancer and mesothelioma

         It has been suggested that in the absence of pulmonary fibrosis,
    lung cancer cannot be attributed to asbestos exposure regardless of
    fibre type; however, there is also evidence to the contrary. For
    example, in a recent case-control study, there was evidence of a
    statistically significant increase in risk of lung cancer without
    radiological signs of fibrosis (Wilkinson et al., 1995). The question
    remains the subject of active controversy (Hughes & Weill, 1991;
    Henderson et al., 1997).

         Results of cohort studies of workers almost exclusively exposed
    to chrysotile asbestos and considered by the Task Group to be most
    relevant to this evaluation are summarized in Table 23 and described
    in section Studies that contribute less to our understanding
    of the effects of chrysotile, due primarily to concomitant exposure to
    amphiboles or to limitations of design and reporting, are presented in

    section Information most relevant to characterization of risk
    (i.e. exposure-response assessment) is emphasized.

         Assessment of exposure response for mesothelioma is complicated
    in epidemiological studies by factors such as the rarity of the
    disease, the lack of mortality rates in the populations used as
    reference and problems in diagnosis and reporting. In many cases,
    therefore, cruder indicators of risk have been developed, such as
    absolute numbers of cases and death and ratios of mesothelioma over
    lung cancers or total deaths. The mesothelioma/lung cancer ratio in
    particular is highly variable depending on the industry and the nature
    and intensity of asbestos exposure, in addition to a number of factors
    not related to asbestos exposure. Data on mesothelioma occurrence in
    occupational cohorts should, therefore, be cautiously interpreted.

         For the studies reviewed here, the number of mesothelioma deaths
    is reported, together with the percentage over total deaths (Table
    23). It should be noted, however, that additional cases of
    mesothelioma have been reported in workers from the factories included
    in the studies reported in Table 23 who were not included in the
    original cohort studies. However, in the absence of information on the
    numbers of workers at risk, such reports do not contribute to
    quantification of risk.  Critical occupational cohort studies - chrysotile

    a)  Mining and milling

         Mortality from lung cancer and mesothelioma has been studied
    extensively in miners and millers of Quebec and in a smaller operation
    at Balangero in northern Italy.

         In 1966, a cohort of some 11 000 men and 440 women, born between
    1891 and 1920, who had worked for one month or more in chrysotile
    production in Asbestos and Thetford Mines and 400 persons employed in
    a small mixed asbestos products factory in Asbestos, Canada, was
    identified. The cohort, which has now been followed up to 1988, was
    selected from a register compiled of all workers, nearly 30 000, ever
    known to have been employed in the industry. The factory workers were
    included because there was frequent and often unrecorded movement
    between the plant and the mine and mill. Apart from a failure to trace
    9% of the cohort, most after less than 12 months' employment before
    1930, losses have amounted to well under l%. The intensity of exposure
    was estimated for each cohort member by year, based on many thousand
    midget impinger dust particle counts and, more recently, membrane
    filter fibre counts.

        Table 23. Results of cohort studies of chrysotile-exposed workersa

    Study                  No. of      All causes        Lung cancer                        Mesothelioma    Mean exposure    Slope of 
                           subjects                                                                                          dose-responsec
                                       No. of   SMR      No. of   SMR      95% CIb          No. of deaths   f/ml   f/ml
                                       deaths            deaths                             (percentage)           -years

    Mining & Milling
    McDonald et al., 
    1980d,e,f              10 939      3291     1.09     230      1.25     [1.09 - 1.42]    8 (0.24%)       ns     90        0.0006
    McDonald et al., 
    1993d,e,f              5335        2800     1.07     315      1.39     [1.24 - 1.55]    25 (0.8%)       ns     90        ns
    Nicholson et al., 
    1979d                  544         178      1.11     28       2.52     [1.68 - 3.65]    1 (0.56%)       ns     ns        0.0017
    Piolatto et al., 
    1990                   1094        427      1.49     22       1.1      [0.7 - 1.7]      2 (0.47%)       ns     ns        ns

    Asbestos-cement Production
    Thomas et al., 
    1982                   1592        351      1.02     30       0.91     [0.61 - 1.30]    2 (0.57%)       <2     ns        ns
    Ohlson & Hogstedt, 
    1985f                  1176        220      1.03     9        1.58     0.72 - 3.00      0 (0%)          2      10-20     ns
    Gardner et al., 1986   1510        384      0.94     35       0.92     0.64 - 1.27      1 (0.26%)       <1     ns        ns
    Hughes et al., 1987 
    (plant 1)f             2565        477      0.91     48k      1.17     [0.86 - 1.54]    2 (0.42%)       11     40        0.0003
    Hughes et al., 1987 
    (plant 2)f,g           2751        ns       ns       70       1.32     [1.03 - 1.66]    1 (ns)          11     19        0.007
    Textile Manufacture                                                                                                      
    Dement et al., 
    1994h,i                3022        1258     1.28     126      1.97     [1.64 - 2.35]    2 (0.16%)       5-12   32-105    0.02-0.03
    McDonald et al., 
    1983af,h               2543        570      1.27     59k      1.99     [1.52 - 2.57]    1 (0.18%)       ns     ns        0.01

    Friction Materials Production
    Newhouse & Sullivan, 
    1989j                  8812        ns       ns       84k      0.93     [0.74 - 1.16]    3 (ns)          2-5    12        0.0006
    McDonald et al., 
    1984f                  3641        803      1.09     73k      1.49     [1.17 - 1.87]    0 (0%)          ns     ns        0.0005

    Table 23. (continued)

    Study                  No. of      All causes        Lung cancer                        Mesothelioma    Mean exposure    Slope of 
                           subjects                                                                                          dose-responsec
                                       No. of   SMR      No. of   SMR      95% CIb          No. of deaths   f/ml   f/ml
                                       deaths            deaths                             (percentage)           -years

    Mixed products
    et al., 1988           824         285      1.04     24       1.86     [1.19 - 2.77]    0 (0%)          ns     ns        ns
    Cheng & Kong, 1992     1172        151      1.16     21       3.15     [1.95 - 4.81]    ns (ns)         ns     ns        ns
    Chen et al., 1988      551         156      ns       19k      2.34     [1.41 - 3.67]    1 (0.64%)       ns     ns        ns
    Zhu & Wang, 1993       5893        496      ns       18       5.3      [2.67 - 7.1]     ns (ns)         ns     ns        ns

    a  ns = not stated
    b  values in square brackets were calculated by Task Group
    c  Increase in relative lung cancer risk for 1 f/ml-year
    d  Partially overlapping studies
    e  McDonald et al. (1993) extends the follow-up of McDonald et al. (1980)
    f  20+ years since first employment
    g  Only chrysotile-exposed workers; mean exposure refers to both chrysotile and amphibole workers
    h  Partially overlapping studies
    I  Slopes estimated based on regression of SMRs and risk ratios
    j  Only workers employed after 1950; 10+ years since first employment; dose-response from Berry & Newhouse (1983).
    k  Respiratory cancers
         The most relevant analyses of this cohort are those published by
    McDonald et al. (1980) and McDonald et al. (1993), and in a
    preliminary fashion by Liddell (1994). In the first of these reports,
    where 4463 men had died, the standardized mortality ratio (SMR) for
    men 20 or more years after first employment, assessed against
    provincial rates, was 1.09 for all causes and 1.25 for lung cancer.
    There was no excess mortality for lung cancer in men employed for less
    than 5 years, but at 5 years and above there were clear excesses.
    Based on analysis by cumulative exposure up to age 45, there was a
    linear relationship with lung cancer risk.

         In the second paper (McDonald et al., 1993), mortality up to the
    end of 1988 of the 5351 men who had survived into 1976 (of whom 16
    could not be traced and 2827 had died) was followed. In this survivor
    population, the SMRs 20 or more years after first employment were 1.07
    for all causes and 1.39 for lung cancer. The investigators subdivided
    the men into 10 groups based on cumulative exposure up to age 55. The
    highest relative risk (3.04) was in the highest exposure group 
    (> 35 000 mpcm-years; > 1000 mpcf-years), the second highest
    (1.65) was in the second highest exposure group (14 000 to 35 000
    mpcm-years; 400 to 1000 mpcf-years) and the third highest (1.50) was
    in the third highest exposure group (10 500 to 14 000 mpcm-years; 300
    to 400 mpcf-years). In the remaining 7 groups below 10 500 mpcm-years
    (300 mpcf-years), there was no indication of a trend or pattern of
    exposure-response with relative risks all being above 1 and averaging
    1.27. Similar results were obtained in a heavily exposed subset of the
    cohort with a long duration of exposure (Nicholson et al., 1979). In
    the analysis of the large Quebec cohort, the relative increase in risk
    attributable to chrysotile exposure was lower for ex-smokers than
    smokers and negligible for smokers of 20 or more cigarettes a day. The
    authors concluded that the interaction appeared to be less than

         The number of deaths attributed to mesothelioma in the Quebec
    cohort has increased with increasing age and time from first
    employment more rapidly than total mortality (McDonald et al., 1993).
    At the end of 1988, when some 75% of the cohort had died, and the
    youngest survivor was aged 73, in a total of 7312 male deaths, there
    were 33 suspected cases of mesothelioma, 15 coded to ICD 163 and 18 to
    a variety of other diagnostic codes. After review of all available
    evidence, including autopsies in 23 and biopsies in 10, the
    probability of the diagnosis being correct was assessed by the authors
    as high in 17, moderate in 11, and low in 5. All 33 cases were pleural
    but in one of low diagnostic probability, the peritoneum was also
    affected. Of the 33 cases, 20 were miners or millers from Thetford
    Mines, 8 were miners or millers from Asbestos, and the remaining five
    cases were observed among men employed in a small asbestos products
    factory in Asbestos. The median duration of employment was 36 years
    (range 2.5 to 49 years). There was no case of mesothelioma among the
    4371 members of the cohort (40% of 10 925) employed for less than 2
    years, eight cases among those 2396 (22%) employed for 2-10 years, and
    25 mesotheliomas among the other 38% of the cohort (4158 men) with at
    least 10 years of employment. Crude rates of mesothelioma by

    cumulative exposure were calculated. Rates varied from 0.15 cases per
    1000 man-years for those with exposures less than 3500 mpcm-years (100
    mpcf-years) to 0.97 cases per 1000 man-years for those with exposure
    of 10 500 mpcm-years (300 mpcf-years) or more.

         The most recent account of mortality among the chrysotile miners
    and millers of Balangero, Italy, was reported by Piolatto et al.
    (1990) for a cohort comprising 1094 men employed for at least one year
    between 1946 and 1987, with exposures estimated individually in
    fibre-years. Of the total, 36 could not be traced and 427 had died.
    The SMR for all causes based on national rates was 1.49, a high figure
    largely explained by hepatic cirrhosis and accidents. Numbers of
    deaths from all cancers (n=86) and lung cancer (n=22) were close to
    expected (76.2 and 19.9) and there was no evidence that the risk for
    either of these causes was related to duration of exposure,
    fibre-years of cumulative exposure, or time since first or last
    exposure. Little information was provided on the basis for the
    estimates of cumulative exposure. The first fibre counts were taken in
    1969. Earlier exposure levels were estimated by simulating working
    situations occurring at various periods since 1946 in the plant, and
    fibre counts were measured by PCOM (Rubino et al., 1979b).

         The cohort of chrysotile production workers employed at the
    Balangero mine and mill, studied by Piolatto et al. (1990), was almost
    exactly one tenth the size of the Quebec cohort. At the end of 1987,
    when 427 (45%) of the cohort had died, there were two deaths from
    pleural mesothelioma, both in men employed for more than 20 years,
    with cumulative exposure estimated respectively at 100-400 and > 400
    f/ml years. One diagnosis was confirmed histopathologically, and one
    was based on radiological findings and examination of pleural fluid.
    Fibrous tremolite was not detected in samples of chrysotile from this
    mine, but another fibrous silicate (balangeroite), the biological
    effects of which are not known, was identified in low proportions by
    mass (0.2-0.5%). At a comparable stage in the evolution of the Quebec
    cohort, mesothelioma accounted for 10 out of 4547 deaths, a lower but
    not dissimilar proportion.

    b)  Asbestos-cement production

         Numerous studies have been conducted on asbestos-cement workers,
    but only four, analysing five factories, were of groups exposed almost
    only to chrysotile. In general, cumulative exposures were low, as were
    the observed SMRs. In the USA, Hughes et al. (1987) studied two
    asbestos-cement plants in Louisiana. Observed and expected deaths 20
    years from onset of employment were provided according to exposure
    category. In plant 1, which dealt predominantly with chrysotile, small
    amounts of amosite were used from the early 1940s until the late 1960s
    and crocidolite for 10 years beginning in 1962. In plant 2,
    crocidolite was used continuously in the pipe department located in
    one building. Chrysotile was only used in the remaining three
    buildings, and lung cancer and mesothelioma mortality data were
    supplied for workers (63% of the total) whose only employment
    assignment was in these buildings. Cohort mortality analyses were

    conducted for both plant 1 and plant 2 workers 20 or more years after
    initial employment. There were 22 respiratory cancer deaths among 996
    plant 1 employees with more than 6 months of service, which indicated
    a small non-significant lung cancer risk. However, a corresponding
    analysis of 42 lung cancer cases among 1414 plant 2 employees with
    more than 3 months of service and no assignment in the pipe building
    indicated a substantial lung cancer risk. Two deaths attributed to
    mesothelioma were reported among cohort members at plant 1 (mean
    exposure of 40 f/ml-years), while 1 death from mesothelioma was
    reported among workers at plant 2 (mean exposure of 19 f/ml-years).

         Among 1176 Swedish asbestos-cement workers who were estimated to
    have used >99% chrysotile (Ohlson & Hogstedt, 1985), 11 cases of lung
    cancer were observed compared to 9 expected (9 observed versus 5.7
    expected for those with a 20-year latency). This non-significant
    increase occurred in a plant with relatively low exposures. In a 10%
    sample of the work force, all employed for more than 10 years, overall
    cumulative exposure was 18 f/ml-years. Among the entire cohort, no
    deaths from mesothelioma were observed. In a study conducted in the
    United Kingdom (Gardner et al., 1986), the lack of lung cancer
    increase (35 observed versus 38 expected) can be explained by low
    cumulative exposures. Since 1970, mean levels were under 1 f/ml
    throughout the factory and most were under 0.5 f/ml. Higher
    concentrations of unknown magnitude would have existed prior to 1968.
    The possibility of low level smoking in the workforce compared to the
    general population masking lung cancer risks from chrysotile is
    considered unlikely by the authors. One death from mesothelioma (0.26%
    of total deaths) was reported among cohort members in this study. A
    study by Thomas et al. (1982) also did not indicate an excess lung
    cancer risk (30 observed versus 33.0 expected). Two deaths from
    mesothelioma (0.57% of all deaths) occurred in this cohort. As with
    the studies of Ohlson & Hogstedt (1985) and Gardner et al. (1986), the
    exposures in this plant were very low, the vast majority from 1972 to
    plant closure being consistently below 1 f/ml.

         It must be noted, however, that in most of the cohort studies of
    asbestos-cement workers, there was no attempt to evaluate the most
    important confounder of lung cancer, i.e. smoking, or, alternatively,
    smoking rates were examined only for small subcohorts shortly before
    the end of follow-up.

    (c)  Textile manufacture

         The health of employees has been studied in any detail in only
    three asbestos textile plants. These comprise a factory at Rochdale,
    England, originally studied by Doll (1955) and more recently by Peto
    et al. (1985), another located in Mannheim, Pennsylvania, USA, studied
    by McDonald et al. (1983b) and a plant in Charleston, South Carolina,
    USA. Only the study in South Carolina is considered primarily relevant
    for assessment of the health effects of chrysotile. Although the SMRs
    for lung cancer in these plants were broadly equivalent, the rates of
    mesothelioma varied considerably, which may reflect the greater
    proportions of amphiboles in the Mannheim and Rochdale cohorts.

         The textile workers in the South Carolina plant have been studied
    in two separate but overlapping cohorts (Dement et al., 1983b;
    McDonald et al., 1983a; Brown et al., 1994; Dement et al., 1994). The
    only amphibole used in this plant was approximately one tonne of
    imported crocidolite from the early 1950s until 1972, plus a very
    small quantity of amosite for experimental purposes briefly in the
    late 1950s. The crocidolite yarn was processed at a single location
    only, so Charleston can be considered an almost pure chrysotile
    operation. Exposure levels for workers at this plant were estimated by
    Dementet al. (1983a) using nearly 6000 exposure measurements covering
    the period 1930-1975 and taking into account changes in plant
    processes and engineering controls (Table 7). The conversion of past
    exposures measured in mpcm (mpcf) to f/ml was based on both paired
    sample data (100 pairs) and concurrent samples (986 samples) by these
    two methods collected in plant operations during 1968-1971.

         The most recent update of the Charleston study by Dement et al.
    (1994) demonstrated an overall lung cancer SMR of 1.97 (126 observed)
    and an overall SMR for non-malignant respiratory diseases (ICD 470-478
    and 494-519) of 3.11 (69 observed). The data for white males, for
    which data were more complete, demonstrated an overall lung cancer SMR
    of 2.34 for those achieving at least 15 years of latency. The risk of
    lung cancer was found to increase rapidly in relation to cumulative
    exposure. Data for the entire cohort demonstrated an increase in the
    lung cancer risk of 2-3% for each fibre/ml-years of cumulative
    chrysotile exposure. Two mesotheliomas were observed among this cohort
    and an additional mesothelioma was identified among plant workers,
    occurred after the study follow-up period. Analyses of an overlapping
    cohort from the same factory (McDonald et al., 1983a) provided similar

         It can be seen in Table 23 that the regression line slopes for
    relative risks of lung cancer in relation to accumulated exposure in
    the Charleston plant are all some 30 times steeper than those observed
    in chrysotile mining and cement product manufacture.

    (d)  Friction materials manufacture

         There have been only two cohort studies in which the risks of
    lung cancer in the manufacture of asbestos friction materials have
    been examined. One of these was among employees of a plant in
    Stratford, Connecticut, USA, which used only chrysotile (McDonald et
    al., 1984). The other was in a large plant in the United Kingdom
    where, apart from two periods before 1944 when crocidolite was needed
    for one particular contract, only chrysotile was used (Berry &
    Newhouse, 1983; Newhouse & Sullivan, 1989).

         In the United Kingdom plant, there were no excesses in deaths due
    to all causes or to lung cancer (Newhouse & Sullivan, 1989). Berry &
    Newhouse (1983) carried out case-control studies on deaths from lung
    cancer and gastrointestinal cancer using a detailed assessment based
    on the work history for each subject and estimated levels of
    chrysotile exposure. The first fibre counts were taken in 1968.

    Earlier work practices were simulated using original machinery and
    appropriate basic materials to estimate historical fibre counts. Fibre
    counts (both personal and static sampling) were measured by PCOM
    (Skidmore & Dufficy, 1983) (Table 10). There was no evidence of any
    exposure- response relationship for either cancer site. For lung
    cancer, an estimated relative risk of 1.06 for a cumulative exposure
    of 100 f/ml-years was associated with a 95% confidence interval of 0.6
    to 2.0. A total of 13 deaths from mesothelioma (0.54% of all deaths)
    was observed among this cohort.

         The study in Stratford, Connecticut, was complicated by the fact
    that the high SMR for lung cancer, based on state death rates, was
    largely explained by mortality among men employed in the plant for
    less than one year. The exposure-response relationship for lung cancer
    was described; however, there was in fact no significant relationship
    between risk and cumulative exposure. No mesotheliomas were observed
    among the cohort members in this study.

    (e)  Mixed products manufacture

         In a study of 824 workers employed during 1946-1973 in a factory
    producing various chrysotile products in Lodz, Poland, and followed-up
    until 1985, there was a significant increase in lung cancer mortality,
    based on 24 observed and 12.9 expected deaths (SMR 1.86, 95% CI 
    1.19-2.77). When workers were grouped according to cumulative asbestos
    dust exposure, the SMR of lung cancer was 1.55 in the group with
    exposure to up to 50 mg/m3-years and 3.11 in the group with higher
    exposure (Szeszenia-Dabrowska et al., 1988). No mesotheliomas were
    observed among the cohort members in this study.

         In a cohort of 1172 workers in Tianjin, China, exposed to
    chrysotile in the manufacture of asbestos textiles, friction materials
    and asbestos-cement for at least one year, and followed from January
    1972 to December 1987, Cheng & Kong (1992) reported increased risk of
    mortality from lung cancer (21 observed/6.67 expected; SMR= 3.15;
    p<0.05) and "other" non-malignant respiratory disease (29
    observed/11.78 expected; SMR= 2.46; p<0.05). The comparison was made
    with the general population of Tianjin. Based upon employment history
    and monitoring data collected between 1964 and 1975, estimates of
    qualitative and quantitative (i.e. low, middle or high; cumulative
    exposures of <400, 400-800 or >800 mg/m3-years) exposure to
    "asbestos dust" were derived for each worker. The Task Group noted
    that these exposures were extremely high. Analysis of the relative
    risk of lung cancer according to level, duration or latency since
    first exposure indicated significant excess risk of mortality at all
    levels of cumulative exposure (SMRs ranged from 2.71 to 4.85; 
    p <0.01), with "middle" or "high" levels of exposure (p <0.01), with
    duration of exposure > 15 years (SMRs ranged from 3.02 to 6.67; 
    p <0.01), and with > 20 years latency (SMRs ranged from 2.97 to
    3.11; p <0.05). Information on the distribution of workers across
    industries or movement of workers from one industry to another was not

         Chen et al. (1988) reported mortality for 1551 workers in
    Shanghai, China, producing asbestos textiles, rubber, brake linings,
    seal material and thermal insulation products between 1958 and 1985.
    Compared to the population of Shanghai, lung cancer was increased (SMR
    = 2.28, 14 observed for males; SMR = 2.17, 5 observed for females).

         Zhu & Wang (1993) reported significantly increased relative risk
    (RR= 5.3; 95% CI= 2.6-7.1) and attributable risk (AR= 63.6%; p<0.01)
    of mortality due to lung cancer between 1972 and 1991 in a cohort of
    5893 asbestos workers from eight factories in China (45 974
    person-years for men and 39 445 person-years for women) exposed to
    chrysotile compared to a control group of unexposed workers (number
    not reported; 122 021 person-years). Quantitative data concerning the
    level of exposure to chrysotile (or other compounds) were not

    (f)  Gas mask manufacture

         In a study of a group of women who assembled civilian masks using
    only chrysotile and a group of women who assembled military masks
    where crocidolite was used, Acheson et al. (1982) reported one death
    from mesothelioma among 177 deaths in the former group (0.6%) compared
    with 5 deaths from mesothelioma among 219 deaths (2.3%) in the latter.
    The experience of the chrysotile group was thus comparable with
    frequencies observed both in chrysotile mining and milling and in the
    manufacture of chrysotile-containing products. The authors noted that
    the case of mesothelioma occurred in a woman who had transferred to
    the factory that manufactured crocidolite gas masks.  Comparisons of lung cancer exposure-response - critical

         The slopes of the relationship between cumulative exposure to
    chrysotile and the relative risk of lung cancer are summarized in
    Table 23 for those studies that reported this information. These
    studies all expressed this relationship using the following linear
    relative risk (RR) model:

                             RR = 1 + B × E

    where B is the slope and E is the cumulative exposure to chrysotile
    asbestos expressed in f/ml-years.

         The slopes from the studies of the mining and milling industries
    (0.0006 to 0.0017), the latter having been estimated on a subset of
    the cohort on which the former was based, and the friction production
    industries (0.0005 to 0.0006) are reasonably similar. Hughes et al.
    (1987) in a study of cement workers (section reported a
    similar slope (0.0003) in one plant (plant 1) that only used
    chrysotile, and a nearly 20-fold higher slope (0.007) among workers
    only exposed to chrysotile in another plant (plant 2).

         The slopes of 0.01 and 0.03 reported for the two studies of the
    chrysotile-exposed textile workers conducted on overlapping
    populations, as well as the slope of 0.007 from one of the two plants
    (plant 2) of cement workers in the study of Hughes et al. (1987), were
    an order of magnitude greater than those reported for the other
    cohorts. It should be noted that the two textile cohorts were
    identified from the same textile facility, but were based on different
    cohort definitions. Hence, it is not surprising that the slopes from
    these two studies were similar. The slopes in the studies of
    chrysotile-exposed textile workers are also remarkably similar to
    those reported in other studies of textile workers with mixed fibre
    exposures (Peto, 1980; McDonald et al., 1983b; Peto et al., 1985).
    This similarity in findings provides some support for the validity of
    the slopes reported in the chrysotile-exposed textile cohorts.

         The reason for the much higher slopes observed in studies of
    textile workers is unknown, although several possible explanations
    have been suggested. The first is that these differences might be
    attributed to errors in the classification of exposures in these
    studies. Particular concern has been raised about errors in the
    exposure assessment related to conversions from mpcm (mpcf) to
    fibres/ml that were performed, particularly in the mining and milling
    studies (Peto, 1989). Sebastien et al. (1989) conducted a lung burden
    study specifically designed to examine whether the differences in lung
    cancer slopes observed in the Charleston chrysotile textile cohort and
    the Quebec mining industries could be explained by differences in
    errors in exposure estimates. Lung fibre concentrations were measured
    in: (a) 32 paired subjects that were matched on duration of exposure
    and time since last exposure; and (b) 136 subjects stratified on the
    same time variables. Both analyses indicated that the
    Quebec/Charleston ratios of chrysotile fibres in the lungs were even
    higher than the corresponding ratios of estimated exposures. This
    finding was interpreted by the author as being clearly inconsistent
    with the hypothesis that exposure misclassification could explain the
    large discrepancy in the lung exposure-response relationships observed
    in the two cohorts.

         Sebastien et al. (1989) offered a second possible explanation for
    the differences, which was that observations in the Charleston textile
    cohort may have been confounded by exposure to mineral oils. Dement et
    al. (Dement, 1991; Dement et al., 1994) have conducted two nested
    case-control studies designed to evaluate the potential for
    confounding by exposure to mineral oils in the Charleston textile
    cohort. Cases and controls were assigned to a qualitative mineral
    exposure category as well as asbestos exposure. The relationship
    between chrysotile exposure and lung cancer risk was observed to be
    virtually unaffected by control for exposure to mineral oils in these
    analyses. The authors concluded that confounding by machining fluids
    was unlikely. It should also be noted that studies of other cohorts of
    workers exposed to machining fluids (including mineral oils) have
    failed to detect an increase in lung cancer risk (Tolbert et al.,

         Finally, it has been suggested that the higher lung cancer risk
    observed among textile workers might be explained by differences in
    fibre size distributions (Dement, 1991; McDonald et al., 1993; Dement
    et al., 1994). Textile operations have been shown to produce fibres
    that are longer in length than in mining and other operations using
    chrysotile asbestos (Dement & Wallingford, 1990). The study of
    Sebastien et al. (1989) also examined the hypothesis that differences
    in fibre size distribution could explain the discrepancy in lung
    cancer exposure-response relationships between the Quebec mining and
    Charleston textile cohorts. Although the authors concluded that
    differences in fibre size distributions were an unlikely explanation,
    it was noted that there was a slightly higher percentage of long
    chrysotile fibres (> 20.5 µm) in the lungs of workers from the
    Charleston textile facility than in the Quebec miners.  Other relevant studies

    (a)  Mining and milling

         Kogan (1982) reported on the morbidity and mortality of
    chrysotile miners and millers in the former USSR. Dust exposure levels
    were reported to be extremely high in the 1950s (over 100 mg/m3) and
    were substantially reduced to 3 to 6 mg/m3 in the 1960s and 1970s.
    The occurrence of asbestosis was substantially reduced by 1979; SMRs
    of lung cancer in male miners based on reference rates from a
    neighbouring city were 3.9 during 1948 to 1967 and 2.9 during 1968-
    1979. In male millers the corresponding values were 4.3 and 5.8.
    Corresponding figures for women were: miners, 3.9 and 9.4; millers,
    2.9 and 9.7 (observed deaths not reported).

         Zou et al. (1990) conducted a retrospective cohort mortality
    study of 1227 men employed at a chrysotile mine in Laiyuen, Hebei
    province of China, prior to 1972. Mortality in this cohort was
    compared with that from 2754 local residents of Laiyuen who had never
    been exposed to asbestos. Based on follow-up of this cohort from 1972
    to 1981, 67 deaths were identified (of which 6 were from lung cancer
    and 3 from mesothelioma) in the asbestos cohort and 247 deaths in the
    referent population. The lung cancer rate in the exposed cohort was
    reported to be significantly greater (p<0.001) than the rate in the
    referent group. The interpretation of this study is limited by the
    poor description of the methodology used for standardization and
    statistical testing.

         Cullen & Baloyi (1991) reviewed the X-rays, demographic data, and
    medical and occupational histories for 51 workers with
    asbestos-related diseases that had been submitted for compensation to
    a medical board in Zimbabwe since its independence in 1980. One
    pathologically confirmed case of mesothelioma and one case that
    radiologically resembled mesothelioma were identified. These cases
    were associated with occupational exposures to chrysotile asbestos in
    the Zimbabwe mines and/or mills.

    (b)  Asbestos-cement production

         In other studies of asbestos-cement workers, there has been
    greater exposure to commercial amphiboles. A study by Neuberger &
    Kundi (1990, 1993) showed an increased lung cancer risk (SMR = 1.72),
    which became a small, non-significant  one (SMR = 1.04) after
    adjustment for individual smoking histories. Two studies,
    (Finkelstein., 1984; Magnani et al., 1987) showed high lung cancer
    risks (SMRs = 4.8 and 2.68, respectively), suggesting very heavy
    exposures. All other asbestos-cement worker studies (Clemmensen &
    Hjalgrim-Jenson, 1981; Alies-Patin & Valleron., 1985; Raffn et al.,
    1989; Albin et al., 1990) showed positive results, with SMRs up to
    1.8; however, smoking was not controlled for in these studies.

    (c)  Mixed products manufacture

         In several reported studies, workers have been exposed to
    unspecified forms of asbestos in production of either unspecified or
    mixed products (see, for example, Berry et al., 1985; Enterline et
    al., 1987).

         Epidemiological data for asbestos-exposed workers in Germany who
    died between 1977 and 1988 were reported in a proportional mortality
    study by Rösler et al. (1993), although diagnostic criteria were not
    clearly specified nor was it possible to clearly separate exposure to
    chrysotile alone from that to mixed fibre types. Among those exposed
    mainly to chrysotile (464 deaths), the lung cancer proportional
    mortality ratio (PMR) was 1.54 (95% CI = 1.16-2.01); 24 deaths (5.2%)
    were due to pleural mesothelioma and 5 (1.1%) to peritoneal
    mesothelioma. Mortality for those exposed to both chrysotile and
    crocidolite (115 deaths) was similar, and there was a higher
    proportion of deaths (3.5%) due to peritoneal mesothelioma. The PMR
    for pleural mesothelioma was highest in textile manufacture, followed
    by insulation, paper, cement and polymers, and was lowest in friction
    product manufacture. Peritoneal mesotheliomas were reported in
    textile, insulation and cement manufacture.

         A series of 843 mesothelioma cases identified during 1960 to 1990
    in the state of Saxony-Anholt, which was formerly part of the German
    Democratic Republic, was reported by Sturm et al. (1994). According to
    the authors, asbestos products were primarily made from chrysotile
    asbestos from the Ural mountains of Russia. Only small amounts of
    chrysotile from Canada and even smaller quantities of amphiboles from
    Mozambique or Italy were used in manufacturing. The authors indicated
    that, out of 812 cases with complete data, 67 were exposed only to
    chrysotile, 331 were exposed to chrysotile and possibly amphiboles,
    279 were exposed to both chrysotile and amphiboles, and 135 were
    exposed only to amphiboles.

    (d)  Application and use of products

         Cohort studies of populations of workers using only or
    predominantly chrysotile-containing products in applications such as
    construction have not been identified. Some relevant information is
    available, however, from population-based analyses of primarily
    mesothelioma in application workers exposed generally to mixed fibre

         Although the odds ratio for lung cancer associated with exposure
    to "asbestos" has been estimated in many case-control studies, the
    studies have not been in general able to distinguish between
    chrysotile and amphibole exposure, and are therefore less informative
    for the present evaluation (see, for example, Kjuus et al., 1986). In
    a multisite case-control study from Montreal, Canada, however,
    exposures to chrysotile and to amphiboles were separated, although
    exposure to amphiboles was not controlled for in the analysis on
    exposure to chrysotile (Siemiatycki, 1991). In this study, the
    occupational history of male cases (aged 35-70) of cancer at 20 sites
    and of 533 population controls was evaluated by a team of industrial
    hygienists and chemists to assess exposure to 293 agents. Overall, the
    lifetime prevalence of exposure to chrysotile was 17%, and that of
    exposure to amphiboles, 6%. The main occupations involving exposure to
    chrysotile that were considered were motor vehicle mechanics, welders
    and flame cutters, and stationary engineers. When lung cancer cases
    (N=857) were compared with cases of all other types of cancers, the
    odds ratio (OR) of any exposure to chrysotile was 1.2 (90% CI=1.0-1.5;
    175 exposed cases), and that of 10 or more years of exposure with at
    least 5 years of latency ("substantial exposure") was 1.9 (90% CI 
    1.1-3.2; 30 exposed cases). Corresponding ORs of exposure to 
    amphiboles were 1.0 and 0.9. The OR of exposure to chrysotile was 
    higher for oat cell carcinoma than for other types of lung cancer. 
    Twelve cases of mesothelioma were included in this study. The OR of 
    any exposure to chrysotile was 4.4 (90% CI=1.6-11.9; 5 exposed cases) 
    and that of substantial exposure was 14.6 (90% CI=3.5-60.5; 2 cases).
    Corresponding ORs of exposure to amphiboles were 7.2 (90% CI=2.6-19.9;
    4 cases) and 51.6 (90% CI=12.3-99.9; 2 cases).

         Based on analyses of mortality of workers with mixed exposures to
    chrysotile and amphiboles in the United Kingdom, by far the greatest
    proportion of mesotheliomas occurs in users of asbestos-containing
    products, rather than those involved in their production. In the
    United Kingdom, all death certificates that mention mesothelioma have
    been recorded since 1968, and 57 000 workers subject to the 1969
    Asbestos Regulation or the 1984 Asbestos (Licensing) Regulations have
    been followed-up. Analyses of these data have led to the following

    1.   Asbestos exposure caused approximately equal numbers of excess
         deaths from lung cancer (749 observed, 549 expected) and
         mesotheliomas (183 deaths) within the occupations covered by the
         1969 and 1984 regulations (OPCS/HSE, 1995).

    2.   Only a few (5%) of British mesothelioma deaths were among workers
         in regulated occupations (Peto et al., 1995). The majority of
         deaths occurred in unregulated occupations in which
         asbestos-containing products are used, particularly in the
         construction industry. The risk was particularly high among
         electricians, plumbers and carpenters as well as among building

         Extensive case-control studies of 668 cases of mesothelioma as
    ascertained through pathologists were conducted by McDonald & McDonald
    (1980) throughout Canada (1960-1975) and the USA (in 1972). Relative
    risks were as follows: insulation work, 46.0; asbestos production and
    manufacture, 6.1; heating trades (other than insulation), 4.4. Four
    subjects were men who had been employed in Quebec chrysotile mines and
    three were children of employees; no other subjects had lived in the
    mining area. In some 12 listed occupations, there was no excess of
    cases over controls, e.g., garage work, carpentry, building

         Begin et al. (1992) analysed 120 successful claims for pleural
    mesothelioma submitted to the Quebec Workman's Compensation Board
    during 1967-1990. Of these, 49 cases occurred among workers in the
    mining and milling industry, 50 in the manufacturing and industrial
    application sector and 21 in other types of industry. The miners and
    millers were thought to be primarily exposed to chrysotile, while the
    rest were believed to be exposed to mixtures of amphiboles and
    chrysotile. The numbers of cases ascertained by Begin et al. via the
    compensation system were consistent with the numbers of incident
    mesotheliomas observed in miners and millers but grossly
    underestimated the recorded frequency of mesothelioma in the other
    industrial sectors (McDonald & McDonald, 1993).

         In other large population-based case-control studies of
    mesothelioma (see, for example, Bignon & Brochard, 1995), it was not
    possible to separate the effect of chrysotile from that of amphiboles.

         Attempts have been made by three groups of investigators to
    assess the contribution of chrysotile to mesothelioma risk by
    considering the duration of its use compared with other fibres. These
    analyses were based, in part, on models for the risk of mesothelioma
    associated with exposure to various forms of asbestos, which have been
    widely used by regulatory agencies in the USA, such as the Consumer
    Product Safety Commission (1987), the Environmental Protection Agency
    (1986) and the Occupational Safety and Health Administration (1986).
    Formulae for these models are similar (see, for example, the HEI
    report) and will not be described here in detail. The analyses include
    studies of insulation workers (Nicholson & Landrigan, 1994) and
    railroad machinists in the USA (Mancuso, 1988), and cement workers in

    Denmark (Raffn et al., 1989). Although the authors of these studies
    suggest the occurrence of mesothelioma prior to the widespread
    introduction of amphiboles into industries, there is unresolved
    controversy about the reliability of the data on which these
    conclusions are based.

         Motor mechanics who repair asbestos-containing brakes and
    clutches can be exposed to chrysotile, as this is by far the
    predominant fibre used in this application. Exposures can occur during
    removal of wear debris from brake and clutch assemblies and during
    grinding of new linings (Rohl et al., 1976; Rodelsperger et al.,
    1986). Cases of mesothelioma have been reported among brake mechanics
    (Langer & McCaughey, 1982; Woitowitz & Rodelsperger, 1991; Woitowitz &
    Rodelsperger, 1992).

         In two case-control studies of mesotheliomas, there was no excess
    risk among garage workers or mechanics (Teta et al., 1983; Woitowitz &
    Rodelsperger, 1994). In the latter study, there were two control
    groups; one was based on hospital cases undergoing lung resection, in
    most instances because of lung cancer, and the other was from the
    general population. The authors noted that confounding due to asbestos
    exposure in other occupations limited their ability to detect
    mesothelioma risks among car mechanics.

         The proportional mortality for mesothelioma among British motor
    mechanics was reported to be lower than the national average (PMR =
    0.40) (OPCS/HSE, 1995). The extent to which all motor mechanics were
    exposed to friction products was not defined.

    7.1.3  Other malignant diseases

         Results of cohort studies of workers almost exclusively exposed
    to chrysotile asbestos and considered by the Task Group to be most
    relevant to this evaluation are summarised in Table 23 and described
    in section Studies that contribute less to our understanding
    of the effects of chrysotile, due primarily to concomitant exposure to
    amphiboles or to limitations of design and reporting, are presented in
    section  Critical occupational cohort studies involving chrysotile

         There has been considerable unresolved controversy regarding the
    possible carcinogenic effect of asbestos on the larynx, kidney and
    gastrointestinal tract. Moreover, there is little evidence that
    permits an assessment of chrysotile, in particular, as a risk factor
    for these cancers. In four of the cohorts exposed almost exclusively
    to chrysotile, data were presented on SMRs for laryngeal cancer
    (Hughes et al., 1987; Piolatto et al., 1990; McDonald et al., 1993;
    Dement et al., 1994). Non-significant excesses were observed in some
    of the studies. It is not possible to draw conclusions about the
    association with laryngeal cancer because the data are too sparse and
    because confounding may play an important role in creating
    associations. Where examined, laryngeal cancer was strongly associated

    with cigarette smoking (McDonald et al., 1993) and alcohol consumption
    (Piolatto et al., 1990).

         Owing to the rarity of kidney cancer, cohort studies have limited
    statistical power to detect even moderate increases of kidney cancer.
    There was no overall excess of kidney cancer in the cohort of miners
    and millers followed by McDonald et al. (1993), although some
    increases occurred in subgroups stratified by mine and exposure;
    however, the number of cases precludes meaningful interpretation. In
    the study in asbestos-cement production workers, in which the SMR for
    kidney cancer in plant 1 (chrysotile) was 2.25, based on only four
    cases, the SMR for lung cancer was 1.17 (Hughes et al., 1987). No
    other data on kidney cancer risks were presented for the other cohorts
    of chrysotile workers.

         In predominantly "chrysotile"-exposed cohorts, there is no
    consistent evidence of excess mortality from stomach or colorectal
    cancer. In the analysis of mortality in the Quebec cohort up to 1989
    (McDonald et al., 1993), the SMR for gastric cancer was elevated in
    the highest exposure category (SMR = 1.39); the corresponding SMR for
    lung cancer was 1.85. Overall, there was no systematic relationship
    with exposure.  Other relevant studies

         Most case-control studies have investigated the association
    between exposure to unspecified or several forms of "asbestos" and
    various cancers (see, for example, Bravo et al., 1988; Parnes, 1990;
    Jakobsson et al., 1994). In the multisite case-control study conducted
    in Montreal (see section, 177 cases of kidney cancer were
    included (Siemiatycki, 1991). The OR of any exposure to chrysotile was
    1.2 (90% CI=0.9-1.7; 31 exposed cases), and that of substantial
    exposure was 1.8 (90% CI=0.9-3.7; 6 cases). Corresponding ORs of
    exposure to amphiboles were 0.7 (8 cases) and 0.8 (1 case).

         In this study, a total of 251 stomach, 497 colon and 257 rectal
    cancer cases were included (Siemiatycki, 1991). The ORs for any and
    substantial exposure to chrysotile were 1.3 and 0.7 for stomach
    cancer, 1.0 and 1.6 (90% CI=1.0-2.5) for colon cancer, and 0.7 and 0.5
    for rectal cancer. Exposure to amphiboles was not associated with a
    significant increase in risk of any of these cancers.

    7.2  Non-occupational exposure

         Data available on incidence or mortality in populations exposed
    in the vicinity of sources of chrysotile since Environmental Health
    Criteria 53 was published have not been identified. In studies
    reviewed at that time, increases in lung cancer were not observed in
    four limited ecological epidemiological studies of populations in the
    vicinity of natural or anthropogenic sources of chrysotile (including
    the chrysotile mines and mills in Quebec) (IPCS, 1986).

         Data available on incidence or mortality in household contacts of
    asbestos workers were reviewed in Environmental Health Criteria 53. In
    several case-control studies reviewed therein, there were more
    mesothelioma cases with household exposure than in controls, after
    exclusion of occupation. However for most of these investigations, it
    is not possible to distinguish the form of asbestos to which household
    contacts were exposed on the basis of information included in the
    published reports.

         Available data on effects of exposure to chrysotile asbestos
    (specifically) in the general environment are restricted to those in
    populations exposed to relatively high concentrations of chrysotile
    asbestos in drinking-water, particularly from serpentine deposits or
    asbestos-cement pipe. These include ecological studies of populations
    in Connecticut, Florida, California, Utah and Quebec, and a 
    case-control study in Puget Sound, Washington, USA, reviewed in
    Environmental Health Criteria 53. On the basis of these studies, it
    was concluded that there was little convincing evidence of an
    association between asbestos in public water supplies and cancer
    induction. More recent identified studies do not contribute
    additionally to our understanding of health risks associated with
    exposure to chrysotile in drinking-water.


    8.1  Environmental transport and distribution

         Soils developed on chrysotile-bearing serpentinitic rocks exist
    in some areas of the world. Brooks (1987) and Roberts & Proctor (1993)
    have shown that this rock type forms very poor soils and gives rise to
    unique plant communities. Natural distribution of chrysotile has only
    become an issue in the last 25 years or so.

         Because of their small size, chrysotile fibres may be transported
    from their place of origin by wind and water. Wind is the primary
    medium of transport, and, in areas where chrysotile is abundant, large
    concentrations have been observed in rain and snow run-off (Hallenbeck
    et al., 1977; Hesse et al., 1977; Bacon et al., 1986). There is
    contradictory evidence concerning an increase in global
    concentrations. Cossette et al. (1986) suggested that the global
    distribution, estimated by chrysotile content in ice core deposits,
    has been relatively constant. This is in contrast to findings by Bowes
    et al. (1977), which suggested increases in asbestos deposits in the
    Greenland ice core samples from the mid-1750s to the present. The
    mobility of fibres from sites of asbestos-bearing strata is often due
    to sparse vegetation cover because of adverse physical and chemical
    conditions not conducive to plant growth.

         The management of sediments deposited during flooding by streams
    draining asbestos-bearing materials appears to be one of the great
    concerns in relation to environmental exposure. The large water supply
    system in the California aqueduct is contaminated by run-off
    containing chrysotile (Hayward, 1984; Jones & McGuire, 1987).

    8.1.1  Chrysotile fibres in water

         Lake and stream data have been reviewed by Schreier (1989), and
    chrysotile concentrations are highly variable, depending on proximity
    to source areas and river flow regime. Concentrations of 1 × 106 to 1
    × 108 f/litre are typical in most rivers draining serpentinitic rocks
    but concentrations of up to 1 × 1013 f/litre have been reported by
    Schreier (1987) in a stream draining asbestos-bearing bedrock. There
    are significant seasonal fluctuations in concentrations in most
    streams and the fibres may remain in suspension for long periods of

         Chrysotile is very stable in alkaline water but magnesium
    leaching occurs from the fibre structure under acidic conditions. Many
    rivers have acidic conditions and chrysotile's surface charge changes
    from positive in alkaline conditions to negative under acidic
    conditions (due to the loss of Mg2+ from surface brucite layers). In
    addition, suspended chrysotile fibres may adsorb organic materials,
    which eventually cover the entire fibre surface (Bales & Morgan,

    8.1.2  Chrysotile fibres in soils

         In the absence of organic material, which when present forms
    organic acids, chrysotile fibres are fairly resistant to alteration.
    However, in acid soil environments magnesium and trace metals are
    released and their concentrations locally increased, whereupon they
    are selectively taken up by plants or soil biota, e.g., by earthworms
    (Schreier & Timmenga, 1986). Fibres exposed to surface processes will
    be affected by acid rain and are likely to be transformed. Most
    attention has been given to the release of trace metals under acidic
    weathering conditions (Schreier et al., 1987a; Gasser et al., 1995).
    However, most studies have focussed primarily on the non-fibrous
    serpentine minerals. While there is evidence of deficiencies and
    adverse effects on plants and biota, little research has been
    conducted on the fibre constituents. 

    8.2  Effects on biota

         While the fibre size and geometry appear to be the main issues
    for human health, the bulk and trace metal chemistry have been
    identified as factors and agents detrimental to plant growth (Brooks,
    1987; Roberts & Proctor, 1993). The chemical impact (little calcium,
    excess magnesium, chromium, nickel, cobalt) has been studied in many
    places under the rubric term serpentinitic rock or soil materials, but
    rarely has chrysotile been identified as the key component mineral.

    8.2.1  Impact on plants

         The plants most frequently found in serpentinitic environments
    have been characterized by Brooks (1987) as belonging to insula
    (neoendemism) and depleted taxa (paleoendemism). Almost all plants on
    chrysotile-enriched soils show stress symptoms, such as reduced
    growth, lower frequency, low diversity and slight discoloration. Many
    serpentine-endemic species have been identified, and coniferous trees
    appear to be more tolerant to such soils than broadleaf species.

         There is great internal variability within sites but moisture,
    magnesium, low calcium:magnesium ratios, excessive nickel and cobalt,
    and deficiencies in molybdenum, calcium, phosphorus and nitrogen have
    all been cited as key factors responsible for poor plant growth. Since
    many of these factors interact, it is impossible to single out any one
    of them as the prime factor in limiting vegetation growth.
    Morphological responses to these adverse conditions are: xeromorphic
    foliage with different coloration; reduction in size leading to
    shrubby, stunted plagiotropic appearance; and the development of an
    extensive root system. Chemical responses are exclusion or restriction
    of some cations, excess metal uptake and metal storage in different
    compartments of the plants. There is no universal response by plants
    to these adverse conditions (Brooks, 1987).

         Physical stress results because most of the soils on
    serpentinitic bedrock are shallow and stoney, leading to poor
    water-holding capacity. All dark coloured serpentinites exhibit
    elevated diurnal temperature fluctuations. The moisture stress might
    be responsible for greater root development, and often such soils are
    prone to instability. No investigation has thus far been made to
    determine if the physical properties of fibres are relevant to hazards
    to plant roots and whether these fibres penetrate into the plant cell
    walls. In addition, no evidence has so far been provided to suggest
    that roots are injured when expanding into fibre-rich soils.

         The chemical stress is either exerted by excessive concentrations
    of some elements or serious deficiencies of metals or nutrients.
    Calcium deficiencies have often been cited as one of the key
    indicators of stress, but excess metals are likely to be more
    significant. Most chrysotile-rich soils have neutral to alkaline pH,
    which reduces metal solubility. Metal accumulation by plants is a
    topic of interest, and Brooks (1987) proposed the term
    "hyper-accumulators" for plants that grow on asbestos-rich soils and
    are enriched in nickel to levels far beyond those found in the soil
    (Wither & Brooks, 1977; Brooks, 1987).

         The use of seeds and plants native to serpentinitic sites is
    desirable for reclaiming chrysotile-contaminated sites. In addition,
    native plants on serpentinites do not grow vigorously and do not
    always respond to amendments (Brooks, 1987; Roberts & Proctor, 1993).
    Tree seedlings invariably have the greatest difficulties surviving the
    first year after planting. Almost all plants show stress symptoms and
    fertilizer amendments are necessary to maintain continuous vegetation

    8.2.2  Impact on terrestrial life-forms

         Few studies have examined the effect of chrysotile on soil
    animals. There is a general reduction in soil animals in all such
    soils, which is not surprising given the low organic matter content
    and adverse plant growing conditions.

         Earthworms are known to tolerate and accumulate trace metals but,
    in the presence of chrysotile fibres,  Lumbricus rebellus showed
    reduced survival (Schreier & Timmenga, 1986) after introduction into
    chrysotile-rich floodplain sediments. Mortality was attributed to the
    combined effect of exposure to elevated levels of nickel and magnesium
    (body burdens were 2-10 times higher in exposed animals relative to
    controls), as well as the abrasive nature of the fibres.

         Termites move large quantities of materials from great depths
    and, in studies of Zimbabwean serpentinites, Wild (1975) and Brooks
    (1987) showed increases in pH and levels of nickel, calcium and
    magnesium in the mounds. The increase in pH might be responsible for
    reducing the metal toxicity, but the termite soldiers, which consume
    more mineral materials, were found to have higher nickel and chromium
    accumulation than termites of higher social orders, which consume

    different food sources provided to them by the soldiers. The termite
    mounds were found to be fireproof.

         Information on microorganisms is also very limited. There are
    fewer nitrogen fixers in chrysotile-enriched soils (White, 1967;
    Proctor & Woodall, 1975) and fewer microorganisms (Ritter-Studnicka,
    1970). Fungal populations and heterotrophic bacteria are significantly
    reduced (Bordeleau et al., 1977). At the same time, populations of
    facultative heterotrophic and autotrophic bacteria are increased. It
    is unclear what the causes are for these differences. The lack of
    organic matter, moisture deficiencies, nutrient imbalances and metal
    toxicities have all been claimed to be responsible for the lack of
    soil microorganisms. Trace metals, such as nickel, have been found to
    inhibit the growth of eubacteria, actinomycetes, cyanobacteria,
    yeasts, filamentous fungi, protozoa and algae (Babich & Stotzky,
    1983). In contrast, Deom (1989) showed that mycorrhizal fungi were not
    adversely affected and were fully functioning in chrysotile-rich soils
    in central British Columbia, Canada.

         Ingested soil plays a significant part in grazing animals. As
    shown by Thornton (1981), up to 15% of the dry matter intake in sheep
    and 10% in grazing cattle can be soil. He also suggested that there is
    a good relationship between metal levels in the soil and those found
    in the blood of the grazing animals. This was confirmed in cattle
    grazing in fields affected by chrysotile from flooding events
    (Schreier et al., 1986). Significant increases in nickel and magnesium
    were observed in the blood of the animals at the time they were
    grazing on such fields. Unfortunately the animal population was too
    small and genetically too diverse to be used for a long-term study.

    8.2.3  Impact on aquatic biota

         The effect of asbestos fibres on aquatic biota has not been
    investigated in any detail.

         Belanger et al. (1986a, 1987) showed that siphoning activity was
    significantly reduced, and that growth and reproduction were altered
    in juvenile  Corbicula fluminea (Asiatic clam) when exposed to
    chrysotile fibres. Siphoning activity was reduced by about 20% in
    juvenile clams exposed to 102 to 108 f/litre for 30 days; shell
    growth was significantly reduced at concentrations in the range of
    104 to 108 f/litre (Belanger et al., 1986b). Clams were reported by
    Belanger et al. (1987) to accumulate chrysotile to a greater degree
    than any previously tested aquatic organism. Whole-body burdens of
    clams exposed to 108 f/litre for 30 days were nearly 103 f/mg (dry
    weight), while field-collected clams, exposed throughout their
    lifetime (2-3 years) to about 109 chrysotile f/litre accumulated as
    much as 6.5 × 108 f/mg (dry weight). Graney et al. (1983) reported
    that these clams also accumulated trace metals.

         Lauth & Schurr (1983, 1984) suggested that positively charged
    chrysotile fibres will attach to planktonic cells, inhibiting their
    swimming capacity and thus removing a potentially important food
    source from the water column.

         Several studies have been conducted on the effect of chrysotile
    on fish. Behavioural and histopathological aberrations (a few tumour
    swellings) were reported in larvae of coho salmon  (Oncorhynchus
     kisutch) when larvae were reared in chrysotile-rich water at
    concentrations of 3 × 106 f/litre for up to 86 days (Belanger et al.,
    1986c). Growth of larvae of juvenile Japanese medaka  (Oryzias
     latipes) was significantly reduced at concentrations of 106 to 108
    f/litre in a 13-week exposure study, and 100% mortality occurred at
    1010 f/litre after 56 days of exposure. Spawning frequency was 33%
    higher in control populations of medaka compared with those exposed to
    104 to 108 chrysotile f/litre. After exposure for 3 months to 108
    f/litre, chrysotile was observed to accumulate in the fish tissue at a
    concentration of nearly 500 f/mg dry weight (Belanger et al., 1990).
    Mesothelioma has been reported in fish but no reference was made to
    asbestos exposure (Herman, 1985).

         Trace metal uptake in native fish, exposed to very high
    chrysotile concentrations in a stream, were reported by Schreier et
    al. (1987b). These fish did not show any evidence of unusual growth
    but recorded significant levels of nickel in the epiaxial muscle
    tissue. In contrast, rainbow trout introduced into a serpentinitic
    lake with chrysotile concentrations of 2 to 100 × 106 f/litre did not
    show any adverse effect 5 years after introduction (H. Schreier, 1995,
    personal communication to the IPCS).

         Belanger et al. (1987) have suggested that a specific species of
    clam,  Corbicula, may be useful as a biomonitor for chrysotile
    asbestos in public water supplies.

         The impact of chrysotile/serpentine presence and degradation on
    the environment is difficult to gauge. Observed perturbations are many
    but their long-term impact is virtually unknown.


    9.1  Introduction

         A previous evaluation by an IPCS Task Group (IPCS, 1986)
    addressed all types of asbestos, including chrysotile. At that time,
    it was concluded that: "The risk of mesothelioma in chrysotile-exposed
    workers is less than that in workers exposed to crocidolite or

         In this monograph (EHC 203), the evaluation is focussed, to the
    extent possible, on data relevant to assessment of the health risks of
    exposure to chrysotile, although it should be noted that commercial
    chrysotile may contain a small proportion of amphiboles, some of which
    may be fibrous. This was considered appropriate in view of the fact
    that since the publication in 1986 of the Environmental Health
    Criteria 53, the use of crocidolite and more recently, amosite, has
    been largely discontinued. Moreover, the pattern of use of chrysotile
    asbestos in many countries has changed somewhat, with the 
    asbestos-cement industry being by far the largest user worldwide, 
    accounting for some 85% of all use. Although declining in the North 
    American and Western European markets, asbestos-cement product 
    manufacturing continues to grow in areas including South America, 
    South-East Asia, the eastern Mediterranean region and eastern Europe.

         Other chrysotile products include friction products, gaskets and
    asbestos paper. Production of shipboard and building insulation,
    roofing and, particularly, flooring felts, and other flooring
    materials, such as vinyl asbestos tiles, has declined considerably,
    with some of them disappearing from the market place. Friable
    chrysotile- and/or amphibole-containing materials in building
    construction have been phased out in many countries. It should be
    noted, however, that there are large quantities of these materials
    still in place in buildings, which will continue to give rise to
    exposure to both chrysotile and the amphiboles during maintenance,
    removal or demolition. Chrysotile has been used in hundreds (or even
    thousands) of products that have entered global commerce. These
    existing products may also give rise to exposure.

         This evaluation is based on studies which the Task Group
    considered contribute to our understanding of the health risks
    associated with exposure to chrysotile.

         Past uncontrolled mixed exposure to chrysotile and amphiboles has
    caused considerable disease and mortality in Europe and North America.
    Moreover, historical experience to mixed fibre types in European
    countries has clearly indicated that a larger proportion of
    mesotheliomas occurs in the construction trades than in production.
    Far larger quantities of chrysotile than of other types of asbestos
    were used in most construction applications. Epidemiological studies
    that contribute to our understanding of the health effects of
    chrysotile conducted to date and reviewed in this monograph have been
    on populations mainly in the mining or manufacturing sectors and not

    in construction or other user industries. This should be borne in mind
    when considering potential risks associated with exposure to

    9.2  Exposure

         Fibre concentrations reported below are for fibres longer than
    5 µm.

    9.2.1  Occupational exposure  Production

         Exposure is dependent upon such factors as the extent of control,
    the nature of the material being manipulated and work practices. Based
    on data available to the Task Group, mainly from North America, Europe
    and Japan, workplace exposure in the early 1930s was very high in most
    sectors of the industry for which data are available. Levels dropped
    considerably between the 1930s and the late 1970s and have continued
    declining substantially to the present day, owing to the introduction
    of controls. In the mining and milling industries in Quebec, Canada,
    the average concentration of fibres in air often exceeded 20 fibres/ml
    (f/ml) in the 1970s and is now less than 1 f/ml. In the production of
    asbestos-cement, mean concentrations in the 1970s were typically below
    about 1 f/ml. Mean concentrations of 0.05 to 0.45 f/ml were reported
    in Japan in 1992. In asbestos textile manufacture, mean concentrations
    between 2.6 and 12.8 f/ml in the period between 1970 and 1975 and 0.1
    to 0.2 f/ml in the period 1984-1986 were reported in Japan. Trends
    have been similar in the production of friction materials. Based on
    data available from Japan, mean concentrations of 10 to 35 f/ml were
    reported in production during 1970 to 1975, while levels in 1984 to
    1986 were 0.2 to 5.5 f/ml. In a plant in the United Kingdom at which a
    large mortality study was conducted, concentrations were above 20 f/ml
    before 1931 and generally below 1 f/ml during 1970-1979.

         Only limited data on concentrations of chrysotile in occupational
    environments in countries other than the USA, Europe and Japan were
    available to the Task Group. The data above on historical levels in
    uncontrolled conditions and additional information on gravimetric
    concentrations to which workers are exposed in product manufacture in
    China indicate that concentrations may be very high (up to 100 f/ml)
    in production facilities without adequate dust control. In a recent
    survey of chrysotile mills in India, average concentrations of 2 to 13
    f/ml were reported.  Use

         Few data on concentrations of fibres associated with the
    installation and use of chrysotile-containing products were available
    to the Task Group, although this is easily the most likely place for
    workers to be exposed. During maintenance of vehicles, peak
    concentrations of 16 fibres/ml were reported in the 1970s in the USA.
    Practically all measured levels after 1987 were less than 0.2 f/ml,

    due to introduction of controls. Time-weighted average exposure during
    passenger vehicle repair reported in the 1980s was less than 0.05
    f/ml. However, with no controls, blowing off debris from drums results
    in short-term high concentrations of dust.

         Data on concentrations of airborne fibres associated with
    manipulation of asbestos-cement products available to the Task Group
    were sparse. In a South African workshop where asbestos-cement sheets
    were cut into components for insulation, mean concentrations were 1.9
    f/ml for assembling, 5.7 f/ml for sweeping, 8.6 f/ml for drilling and
    27 f/ml for sanding. Following clean-up and introduction of controls,
    levels were 0.5 to 1.7 f/ml.

         There is potential for widespread exposure of maintenance
    personnel to mixed asbestos fibre types due to the large quantities of
    friable asbestos materials still in place. In buildings where there
    are control plans, personal exposure of building maintenance personnel
    in the USA, expressed as 8-h time-weighted averages, was between 0.002
    and 0.02 f/ml. These values are the same order of magnitude as
    exposures reported during telecommunication switch work (0.009 f/ml)
    and above-ceiling work (0.037 f/ml), although higher concentrations
    have been reported in utility space work (0.5 f/ml). Concentrations
    may be considerably higher where control plans have not been
    introduced. For example, in one case, short-term episodic
    concentrations ranged from 1.6 f/ml during sweeping to 15.5 f/ml
    during cleaning (dusting off) of library books in a building with a
    very friable chrysotile-containing surface formulation. Most other
    values, presented as 8-h time-weighted averages, are about two orders
    of magnitude less.

         Although few data on exposures among users of asbestos-containing
    products in industries such as construction were identified, available
    data clearly demonstrate the need for appropriate engineering controls
    and work practices for minimizing exposures to chrysotile both in
    production and use. It should be noted that construction and
    demolition operations present special control problems.

    9.2.2  General population exposure

         Sources of chrysotile in ambient air are both natural and
    anthropogenic. Most airborne fibres in the general environment are
    short (< 5 µm).

         Few recent data on concentrations of chrysotile in air in the
    vicinity of point sources have been identified. Concentrations around
    the Shibani chrysotile mine in Zimbabwe ranged from below the limit of
    detection of the method (<0.01 f/ml) to 0.02 f/ml (fibres longer than
    5 µm).

         Based on surveys conducted before 1986, concentrations (fibres 
    > 5 µm in length) in outdoor air measured in five countries (Austria,
    Canada, Germany, South Africa and USA) ranged between 0.0001 and about
    0.01 f/ml, with levels in most samples being less than 0.001 f/ml.

    Means or medians were between 0.00005 and 0.02 f/ml, based on more
    recent determinations in seven countries (Canada, Italy, Japan, Slovak
    Republic, Switzerland, United Kingdom and USA).

         Fibre concentrations in public buildings during normal use where
    there is no extensive repair or renovation are within the range of
    those measured in ambient air, even where friable asbestos-containing
    materials were extensively used. Concentrations (fibres > 5 µm in
    length) in buildings in Germany and Canada reported before 1986 were
    generally less than 0.002 f/ml. In more recent surveys in five
    countries (Belgium, Canada, Slovak Republic, United Kingdom and USA)
    mean values were between 0.00005 and 0.0045 f/ml. Only 0.67% of
    chrysotile fibres were longer than 5 µm.

    9.3  Health effects 

    9.3.1  Occupational exposure

         Adverse health effects associated with occupational exposure to
    chrysotile are fibrosis (asbestosis), lung cancer and mesothelioma.
    These effects have also been observed in animals exposed to chrysotile
    by inhalation and other routes of administration. Based on available
    data in miners and millers, there is an interaction between tobacco
    smoke and chrysotile in the induction of lung cancer which appears to
    be less than multiplicative. Epidemiological evidence that chrysotile
    asbestos is associated with an increased risk of cancer at other sites
    is inconclusive.

         Emphasis in this evaluation is on those studies that contribute
    to our understanding of the health risks associated with exposure to
    chrysotile, especially those that characterize at least to some
    extent, the exposure-response relationship. It should be noted,
    however, that exposure-response relationships have relied upon
    reconstruction of historical exposures. This is often problematic, due
    to lack of historical exposure measurements, and changes in
    measurement methods that have required use of conversion factors which
    are highly variable. Moreover, there are wide variations in exposure
    characteristics, including fibre size distributions, which are not
    well characterized in traditional measures of exposure.

         The Task Group noted that there is an exposure-response
    relationship for all chrysotile-related diseases. Reduction of
    exposure through introduction of control measures should significantly
    reduce risks. Construction and demolition operations may present
    special control problems.  Fibrosis

         The non-malignant lung diseases associated with exposure to
    chrysotile comprise a somewhat complex mixture of clinical and
    pathological syndromes not readily definable for epidemiological
    study. The prime concern has been asbestosis, generally implying a
    disease associated with diffuse interstitial pulmonary fibrosis
    accompanied by varying degrees of pleural involvement.

         Studies of workers exposed to chrysotile asbestos in different
    sectors have broadly demonstrated exposure-response relationships for
    chrysotile-induced asbestosis, in so far as increasing levels of
    exposure have produced increases in the incidence and severity of
    disease. However, there are difficulties in defining this
    relationship, due to factors such as uncertainties in diagnosis, and
    the possibility of disease progression on cessation of exposure.

         Furthermore, some variations in risk estimates are evident among
    the available studies. The reason for the variations is not entirely
    clear, but may relate to uncertainties in exposure estimates, airborne
    fibre size distributions in the various industry sectors and
    statistical models. Asbestotic changes are common following prolonged
    exposures of 5 to 20 f/ml. The risk at lower exposure levels is not
    known but the Task Group found no reason to doubt that, although there
    may be subclinical changes induced by chrysotile at levels of
    occupational exposure under well-controlled conditions, even if
    fibrotic changes in the lungs occur, they are unlikely to progress to
    the point of clinical manifestation.  Lung cancer

         Exposure-response relationships for lung cancer have been
    estimated for chrysotile mining and milling operations and for
    production of chrysotile asbestos textiles, asbestos-cement products
    and asbestos friction products. Risks increased with increasing
    exposure. The slopes of the linear dose-response relationships
    (expressed as the increase in the lung cancer relative risk per unit
    of cumulative exposure (fibre/ml-years)) were all positive (although
    some not signficantly) but varied widely. Textiles produce the highest
    risk (slopes 0.01 to 0.03). Risks for production of cement products
    (slopes 0.0003-0.007), friction materials (slopes 0.0005-0.0006) and
    chrysotile mining (0.0006-0.0017) are lower.

         The relative risks of lung cancer in the textile manufacturing
    sector in relation to estimated cumulative exposure are, therefore,
    some 10 to 30 times greater than those observed in chrysotile mining.
    The reasons for this variation in risk are not clear.  Mesothelioma

         Estimation of the risk of mesothelioma is complicated in
    epidemiological studies by factors such as the rarity of the disease,
    the lack of mortality rates in the populations used as reference, and
    problems in diagnosis and reporting. In many cases, therefore, risks
    have not been calculated, and cruder indicators have been used, such
    as absolute numbers of cases and death and ratios of mesothelioma over
    lung cancers or total deaths.

         Based on data reviewed in this monograph, the largest number of
    mesotheliomas has occurred in the chrysotile mining and milling
    sector. All of the observed 38 cases were pleural with the exception
    of one of low diagnostic probability, which was pleuro-peritoneal.

    None occurred in workers exposed for less than 2 years. There was a
    clear dose-response relationship, with crude rates of mesotheliomas
    (cases/1000 person-years) ranging from 0.15 for those with cumulative
    exposure less than 3500 mpcm (< 100 mpcf-years) to 0.97 for those
    with exposures of 10 500 mpcm (300 mpcf-years).

         Proportions of deaths attributable to mesotheliomas in cohort
    studies in the various mining and production sectors range from 0 to
    0.8%. Caution should be exercised in interpreting these proportions,
    as studies do not provide comparable data stratifying deaths by
    exposure intensity, duration of exposure or time since first exposure.

         There is evidence that fibrous tremolite causes mesothelioma in
    humans. Since commercial chrysotile may contain fibrous tremolite, it
    has been hypothesized that the latter may contribute to the induction
    of mesotheliomas in some populations exposed primarily to chrysotile.
    The extent to which the observed excesses of mesothelioma might be
    attributed to the fibrous tremolite content has not been resolved.

         Epidemiological studies of populations of workers using
    chrysotile-containing products in applications such as construction
    have not been identified, although for workers with mixed exposures to
    chrysotile and the amphiboles, by far the greatest proportion of
    mesotheliomas occurs in users of asbestos-containing products rather
    than in those involved in their production.

    9.3.2  General environment

         Data on incidence or mortality of disease in household contacts
    of chrysotile workers or in populations exposed to airborne chrysotile
    in the vicinity of point sources reported since EHC 53 was published
    in 1986 have not been identified. More recent studies of populations
    exposed to chrysotile in drinking-water have likewise not been

    9.4  Effects on the environment

         The impact of chrysotile/serpentine presence and degradation on
    the environment and lower life forms is difficult to gauge. Observed
    perturbations are many but their long-term impact is virtually


    a)   Exposure to chrysotile asbestos poses increased risks for
         asbestosis, lung cancer and mesothelioma in a dose-dependent
         manner. No threshold has been identified for carcinogenic risks.

    b)   Where safer substitute materials for chrysotile are available,
         they should be considered for use.

    c)   Some asbestos-containing products pose particular concern and
         chrysotile use in these circumstances is not recommended. These
         uses include friable products with high exposure potential.
         Construction materials are of particular concern for several
         reasons. The construction industry workforce is large and
         measures to control asbestos are difficult to institute. In-place
         building materials may also pose risk to those carrying out
         alterations, maintenance and demolition. Minerals in place have
         the potential to deteriorate and create exposures.

    d)   Control measures, including engineering controls and work
         practices, should be used in circumstances where occupational
         exposure to chrysotile can occur. Data from industries where
         control technologies have been applied have demonstrated the
         feasibility of controlling exposure to levels generally below 0.5
         fibres/ml. Personal protective equipment can further reduce
         individual exposure where engineering controls and work practices
         prove insufficient.

    e)   Asbestos exposure and cigarette smoking have been shown to
         interact to increase greatly the risk of lung cancer. Those who
         have been exposed to asbestos can substantially reduce their lung
         cancer risk by avoiding smoking.


    (a)  Research and guidance are needed concerning the economic and
         practical feasibility of substitution for chrysotile asbestos, as
         well as the use of engineering controls and work practices in
         developing countries for controlling asbestos exposure.

    (b)  Further research is needed to understand more fully the molecular
         and cellular mechanisms by which asbestos causes fibrosis and
         cancer. The significance of physical and chemical properties
         (e.g., fibre dimension, surface properties) of fibres and their
         biopersistence in the lung to their biological and pathogenic
         effects needs further elucidation. Dose-response information from
         animal studies for various asbestos fibre types is needed to
         evaluate the differential risk of exposure to chrysotile and

    (c)  Epidemiological studies of populations exposed to pure chrysotile
         (i.e. without appreciable amphiboles) are needed.

    (d)  The combined effects of chrysotile and other insoluble respirable
         particles needs further study.

    (e)  More epidemiological data are needed concerning cancer risks for
         populations exposed to fibre levels below 1 fibre/ml, as well as
         continued surveillance of asbestos-exposed populations.


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    1.  RÉSUMÉ

    1.1  Identité, propriétés physiques et chimiques, échantillonnage et 

         Le chrysotile est un silicate de magnésium hydraté de structure
    fibreuse utilisé dans un grand nombre de produits du commerce. Il est
    très répandu aujourd'hui dans le commerce mondial. Les propriétés
    physiques et chimiques de ce minéral varient selon les différents
    gisements en exploitation. De nombreux minéraux accompagnent la fibre
    dans le minerai et parmi ceux-ci figurent sans doute certaines
    variétés d'amphibole fibreuse. On pense que la trémolite est
    particulièrement importante à cet égard; sa forme et sa concentration
    varient dans d'importantes proportions.

         Du point de vue analytique, la recherche du chrysotile sur les
    lieux de travail oblige à recourir à la microscopie optique ou
    électronique. On a utilisé jusqu'ici divers instruments et dispositifs
    pour surveiller l'environnement en procédant à la recherche et au
    dosage des poussières et des fibres totales. Aujourd'hui, on utilise
    couramment la filtration sur membrane et le microscope à contraste de
    phase pour les mesures sur les lieux de travail (exprimées en nombre
    de fibres par ml d'air); on utilise aussi la microscopie électronique
    par transmission. Cette dernière technique est également employée pour
    l'analyse des prélèvements environnementaux. On a cherché à déterminer
    la charge tissulaire afin d'obtenir davantage de données sur
    l'exposition. En fonction du degré de détail que ces études on permis
    d'appréhender, on a pu en tirer des conclusions sur les mécanismes et
    les étiologies en cause.

         On utilisait auparavant des techniques gravimétriques, la
    précipitation thermique ou la collecte sur mini-impacteur pour les
    contrôles sur les lieux de travail et ces mesures de poussières (et
    non pas de fibres) sont les seuls indices dont on dispose pour
    apprécier les relations exposition-réponse. Il y a eu de nombreuses
    tentatives en vue de convertir ces valeurs en nombres de fibre par
    volume d'air, mais elles n'ont rencontré qu'un succès très limité. On
    s'est rendu compte que les facteurs de conversion dépendaient du type
    d'industrie et même du type d'opération industrielle; les facteurs de
    conversion universels sont d'une grande variabilité.

    1.2  Sources d'exposition professionnelle et environnementale

         On trouve de faibles concentrations de chrysotile dans tout
    l'environnement de l'écorce terrestre (air, calottes glaciaires et
    sol). Les phénomènes naturels et les activités humaines contribuent à
    la production d'aérosols de fibres et à leur dissémination dans
    l'environnement. Parmi les sources d'origine humaine, on peut citer
    diverses activités professionnelles génératrices de poussières qui
    vont de l'extraction et du traitement du minerai jusqu'à la
    fabrication, aux applications, à l'utilisation et finalement, au rejet
    sous forme de déchets.

         Il y a 25 pays producteurs, parmi lesquels sept gros producteurs.
    La production mondiale annuelle d'amiante a culminé vers le milieu des
    années 70 avec plus de 5 millions de tonnes, mais depuis lors elle a
    reculé à environ 3 millions de tonnes. Plus de 100 pays fabriquent des
    produits à base de chrysotile et le Japon en est le principal
    consommateur. Les grands types d'activités qui sont actuellement
    susceptibles de provoquer une exposition au chrysotile sont
    a) l'extraction minière et l'élaboration du matériau (broyage,
    battage, cardage et filage); b) la fabrication de produits à base de
    chrysotile (matériaux résistants à la friction, tuyaux et plaques ou
    feuilles de fibro-ciment, joints, papier, textiles; c) le BTP
    (construction, réparation et démolition); d) le transport et
    l'élimination. L'industrie du fibro-ciment ou amiante-ciment est de
    loin le plus gros utilisateur de fibres de chrysotile puisqu'elle
    consomme environ 85% de la production.

         Lors de la fabrication, de la pose et de l'élimination des
    produits contenant de l'amiante, de même parfois qu'à l'occasion de
    l'usure normale de ces produits, il y a libération de fibres. La
    manipulation de produits friables peut également être une source
    importante de fibres de chrysotile.

    1.3  Concentration sur les lieux de travail et dans l'environnement

         D'après des données provenant essentiellement d'Amérique du Nord,
    d'Europe et du Japon, l'exposition était très importante sur les lieux
    de travail de la plupart des secteurs de production au cours des
    années 30.Elle a beaucoup reculé à la fin des années 70 pour descendre
    finalement aux valeurs actuelles. Au Québec, la concentration
    atmosphérique moyenne en fibres dans les industries d'extraction et de
    production a souvent dépassé 20 fibres /ml (f/ml) au cours des années
    70, alors qu'elle se situe maintenant en général bien au-dessous de
    1 f/ml. Vers la même époque, la concentration moyenne dans l'industrie
    japonaise du fibro-ciment se caractérisait par des valeurs de l'ordre
    de 2,5 à 9,5 f/ml, valeurs qui sont tombées à 0,05-0,45 en moyenne en
    1992. Dans l'industrie des textiles d'amiante au Japon, la
    concentration moyenne a été de 2,6 à 12,8 f/ml entre 1970 et 1975,
    pour reculer à 0,1-0,2 f/ml entre 1984 et 1986.On a observé des
    tendances analogues dans l'industrie des matériaux antifriction: selon
    les données provenant de ce même pays, la concentration moyenne a été
    de 10-35 f/ml entre 1970 et 1975, et de 0,2-5,5 f/ml entre 1984 et
    1986. Dans une usine du Royaume-Uni où une vaste étude de mortalité a
    été effectuée, on mesuré des concentrations généralement supérieures à
    20 f/ml avant 1931 et des valeurs généralement inférieures à 1 f/ml
    pendant la période 1970-1979.

         On possède peu de données concernant la concentration en fibres
    sur les lieux où l'on installe et utilise des produits contenant du
    chrysotile, bien que ce soit là que les travailleurs ont le plus de
    chances d'être exposés. Dans des ateliers d'entretien de véhicules, on
    a enregistré dans les années 70 des pics de concentration atteignant
    16 f/ml, alors que depuis 1987, on n'a pratiquement plus jamais mesuré

    que des valeurs inférieures à 0,2 f/ml. Au cours des années 80,
    l'exposition moyenne pondérée par rapport au temps lors de la
    réparation de voitures automobiles a été en général inférieure à 0,05
    f/ml. Cependant, faute de contrôle, les débris, en s'envolant des
    fûts, on fini par donner naissance en peu de temps à de fortes
    concentrations de poussières.

         Le personnel chargé de l'entretien court un risque d'exposition à
    divers types de fibres d'amiante, du fait de la présence de grandes
    quantités de matériaux asbestiques friables. Dans les bâtiments où une
    surveillance a été instituée, comme par exemple aux Etats-Unis,
    l'exposition du personnel d'entretien, exprimée en moyenne pondérée
    par rapport au temps sur 8 h, se situe entre 0,002 et 0,02 f/ml. Ces
    valeurs sont du même ordre de grandeur que celles relevées lors de
    travaux effectués dans des installations de commutation (0, 009 f/ml)
    ou dans les combles (0,037 f/ml),mais des valeurs plus élevées ont été
    enregistrées lors de travaux effectués par les services publics (0,5
    f/ml). En l'absence de surveillance, la concentration peut être
    beaucoup plus élevée. Ainsi, dans un cas on a relevé une valeur de 1,6
    f/ml lors du balayage d'une pièce et de 15,5 f/ml lors de
    l'époussetage des livres d'une bibliothèque dans un bâtiment dont les
    surfaces étaient recouvertes d'un matériau très friable à base de
    chrysotile. La plupart des autres moyennes pondérées sur 8 h sont
    d'environ deux ordres de grandeur plus faibles.

         Des enquêtes menées avant 1986 ont montré que la teneur en fibres
    (fibres de plus de 5 µm de longueur) dans l'air extérieur, mesurée en
    Afrique du Sud, en Allemagne, en Autriche, au Canada et aux Etats-
    Unis, allait de 0,0001 à 0,001 f/ml environ, la plupart des
    échantillons contenant moins de 0,01 f/ml. La moyenne ou la médiane
    s'est située entre 0,00005 et 0,02 f/ml lors de mesures effectuées
    plus récemment au Canada, aux Etats-Unis, en Italie, au Japon, au
    Royaume-Uni, en Slovaquie et en Suisse.,

         Dans les bâtiments publics, même ceux qui contiennent des
    matériaux friables à base d'amiante, la concentration des fibres reste
    dans les limites de celles que l'on mesure dans l'air ambiant. En
    Allemagne et au Canada, la concentration en fibres (fibres de plus de
    5 µm de longueur) relevée avant 1986 dans les immeubles, était
    généralement inférieure à 0,002 f/ml. Lors d'enquêtes menées plus
    récemment en Belgique, au Canada, aux Etats-Unis, au Royaume-Uni et en
    Slovaquie, on a obtenu des valeurs moyennes comprises entre 0,00005 et
    0, 0045 f/ml. Seulement 0,67% des fibres de chrysotile avaient plus de
    5 µm de longueur).

    1.4  Absorption, élimination, rétention et translocation

         Après avoir été inhalées, les fibres de chrysotile vont se
    déposer selon divers paramètres: diamètre aérodynamique, longueur et
    morphologie. On considère que la plupart des fibres de chrysotile sont
    respirables du fait que leur diamètre est inférieur à 3 µm, ce qui
    correspond à un diamètre aérodynamique de 10 µm environ. Chez le rat

    de laboratoire, les fibres de chrysotile se déposent principalement au
    niveau de la bifurcation des canaux alvéolaires.

         Dans le rhinopharynx et la région trachéobronchique,
    l'élimination des fibres de chrysotile est assurée par l'ascenseur
    mucociliaire. Au niveau de la bifurcation des canaux alvéolaires, les
    fibres sont captées par les cellules épithéliales. L'élimination
    alvéolaire est conditionnée en grande partie par la longueur des
    fibres. On est largement fondé à penser, d'après les études sur
    l'animal, que les fibres courtes (moins de 5 µm de longueur) sont plus
    rapidement éliminées que les fibres longues (plus de 5 µm de
    longueur). On ne s'explique pas encore totalement pourquoi les fibres
    de chrysotile sont éliminées plus rapidement que celles d'amphibole.
    On a avancé l'hypothèse que les fibres courtes de chrysotile sont
    phagocytées par les macrophages alvéolaires, les fibres longues étant
    principalement éliminées par rupture, dissolution ou les deux à la
    fois. On ne sait pas encore très bien dans quelle proportion les
    fibres de chrysotile subissent une translocation vers le tissu
    interstitiel, pleural ou d'autres tissus extrathoraciques.

         L'analyse des tissus pulmonaires d'ouvriers exposés à du
    chrysotile montre que dans le cas de la trémolite, une variété
    d'amphibole communément présente en petite quantité dans le chrysotile
    du commerce, la rétention est beaucoup plus importante. L'hypothèse
    d'une élimination plus rapide du chrysotile est corroborée par
    l'expérimentation animale, qui montre que cette variété d'amiante est
    plus vite éliminée des poumons que les amphiboles et notamment la
    crocidolite et l'amosite.

         Les données fournies par les études sur l'homme et l'animal sont
    insuffisantes pour que l'on puisse déterminer si, et selon quelles
    modalités, les fibres de chrysotile ingérées sont susceptibles de se
    fixer, de se répartir dans l'organisme et d'être excrétées. Autant
    qu'on sache, s'il y a pénétration des fibres de chrysotile à travers
    la paroi intestinale, elle doit être extrêmement limitée. Selon une
    étude, il y aurait augmentation du nombre de fibres de chrysotile dans
    les urines des ouvriers professionnellement exposés à cette variété

    1.5  Effets sur les animaux et sur les cellules

         De nombreuses études au cours desquelles on a fait inhaler
    pendant de longues périodes divers échantillons de chrysotile à des
    rats, ont montré que ces fibres avaient des effets fibrogènes et
    cancérogènes. Il s'agissait notamment de fibrose interstitielle et de
    cancers du poumon et de la plèvre. Dans la plupart des cas, on a
    constaté l'existence d'une association entre la fibrose et les tumeurs
    pulmonaires chez le rat. Des effets fibrogènes et cancérogènes ont été
    également mis en évidence lors d'études à long terme sur l'animal
    (principalement des rats) au cours desquelles on a utilisé d'autres
    modes d'administration (instillation intratrachéenne et injection
    intrapleurale ou intrapéritonéale).

         Au cours de ces expériences d'inhalation, on n'a pas étudié de
    manière satisfaisante les relations exposition/dose-réponse dans le
    cas des fibroses, des cancers pulmonaires et des mésothéliomes induits
    par le chrysotile. Les études effectuées jusqu'ici, qui ont porté dans
    la plupart des cas sur une seule concentration, mettent en évidence
    des effets fibrogènes et cancérogènes à des concentrations en fibres
    aéroportées allant de 100 à quelques milliers de fibres par ml.

         Lorsqu'on regroupe les résultats des différentes études, on voit
    apparaître une relation entre la concentration atmosphérique des
    fibres et l'incidence du cancer du poumon. Toutefois, ce genre
    d'analyse n'est peut-être pas valable sur le plan scientifique, car
    les conditions expérimentales n'étaient pas identiques dans toutes les

         Les études qui n'utilisaient pas la voie respiratoire (injection
    intrapleurale ou intrapéritonéale) ont mis en évidence des relations
    dose-réponse entre la présence de fibres de chrysotile et l'apparition
    de mésothéliomes. Cependant, il n'est pas certain que les données
    obtenues soient utilisable pour évaluer le risque encouru par l'homme
    en cas d'exposition aux fibres de chrysotile.

         La trémolite, qui est un constituant mineur du chrysotile du
    commerce, s'est également révélée cancérogène et fibrogène chez le rat
    lors d'une étude comportant une seule inhalation et lors d'une autre
    étude utilisant la voie intrapéritonéale. On ne dispose pas des
    données exposition/ dose-réponse qui auraient permis une comparaison
    directe du pouvoir cancérogène de la trémolite et du chrysotile.

         L'aptitude des fibres de chrysotile à provoquer des effets
    cancérogènes et fibrogènes est fonction de leurs caractéristiques
    individuelles, notamment les dimensions et la durabilité (c'est-à-dire
    la biopersistance de la fibre dans les tissus cibles), qui, elle,
    dépend pour une part des propriétés physico-chimiques de la fibre.
    L'expérience a amplement montré que les fibres courtes (moins de 5 µm)
    sont moins actives sur le plan biologique que les longues fibres (plus
    de 5 µm). Toutefois on ignore encore si les fibres courtes ont la
    moindre activité biologique. En outre, on ne sait pas combien de temps
    une fibre doit séjourner dans les poumons pour induire des effets
    précancéreux, étant donné que l'apparition des cancers liés à
    l'amiante se produit généralement assez tard dans la vie de l'animal.

         Les mécanismes par lesquels le chrysotile et autres matériaux
    fibreux produisent des effets fibrogènes et cancérogènes ne sont pas
    totalement élucidés. Dans le cas des effets fibrogènes, il y a peut-
    être un processus inflammatoire chronique dû à la production de
    facteurs de croissance (par ex. le TNF-alpha) et d'espèces oxygénées
    réactives. Dans celui des effets cancérogènes, plusieurs hypothèses
    ont été avancées. Par exemple: lésion de l'ADN par des espèces
    oxygénées réactives suscitées par les fibres; lésion directe de l'ADN
    par suite d'interactions physiques entre les fibres et les cellules
    cibles; stimulation de la prolifération cellulaire par les fibres;
    réactions inflammatoires chroniques provoquées par les fibres et

    conduisant à la libération prolongée d'enzymes lysosomiennes,
    d'espèces oxygénées réactives, de cytokines et de facteurs de
    croissance; enfin, action des fibres en tant que co-cancérogènes ou
    vecteurs de cancérogènes chimiques vers les tissus cibles. En fait, il
    est probable que tous ces mécanismes interviennent à des degrés divers
    dans l'activité cancérogène des fibres de chrysotile, car ils ont
    effectivement été observés  in vitro dans des systèmes cellulaires
    humains et mammaliens.

         Au total, les données toxicologiques disponibles montrent
    clairement que les fibres de chrysotile présentent un risque pour
    l'homme du fait de leur activité fibrogène et cancérogène. Elles ne
    sont toutefois pas suffisantes pour que l'on puisse en tirer une
    évaluation quantitative de ce risque. Cela tient au fait que les
    études utilisant la voie respiratoire n'ont pas fourni de données
    exposition-réponse suffisantes et aussi aux incertitudes quant à la
    sensibilité des études sur l'animal pour la prévision du risque chez

         Plusieurs études de cancérogénicité utilisant la voie buccale ont
    été consacrées aux fibres de chrysotile. Celles dont on possède les
    résultats n'ont pas mis en évidence d'effets cancérogènes.

    1.6  Effets sur l'homme

         Selon de nombreuses études épidémiologiques effectuées sur des
    travailleurs exposés, l'exposition au chrysotile du commerce accroît
    le risque de pneumoconiose, de cancer du poumon et de mésothéliome.

         Au nombre des affections non malignes attribuables à une
    exposition au chrysotile, figure tout un ensemble complexe de
    syndromes cliniques et pathologiques qui ne sont pas suffisamment
    définis pour que l'on puisse en faire l'étude épidémiologique. On peut
    citer en premier lieu l'asbestose qui consiste généralement en une
    fibrose pulmonaire interstitielle diffuse avec une atteinte pleurale
    plus ou moins importante.

         Les études portant sur des travailleurs exposés au chrysotile
    dans diverses circonstances ont, d'une façon générale, mis en évidence
    l'existence de relations exposition-réponse et exposition-effet dans
    le cas de l'asbestose provoquée par le chrysotile, dans la mesure où
    elles ont permis de constater qu'à un accroissement de l'exposition
    correspondait une augmentation de l'incidence et de la gravité de la
    maladie. Il reste toutefois difficile de définir ces relations, en
    raison de facteurs tels que les incertitudes du diagnostic et la
    possibilité d'une progression de la maladie après cessation de

         En outre, on constate à l'évidence des variations dans
    l'estimation du risque selon les différentes études. Les raisons de
    ses variations ne sont pas parfaitement claires, mais il est possible
    qu'elles tiennent à des incertitudes quant à l'évaluation de
    l'exposition, à la distribution par taille des fibres atmosphériques

    selon les diverses industries et aux modèles statistiques utilisés. Il
    est fréquent d'observer des effets de type asbestosique après une
    exposition prolongée à des teneurs en fibres de 5 à 20 f/ml.

         Les études consacrées aux travailleurs de l'industrie du
    fibro-ciment ne font généralement pas état d'un risque relatif élevé
    de cancer du poumon, ni globalement, ni dans certaines cohortes de
    travailleurs. La relation exposition-réponse entre le chrysotile et le
    cancer du poumon correspond à une corrélation 10 à 30 fois plus forte
    chez les ouvriers du textile que chez ceux des industries d'extraction
    et de transformation. Le risque relatif de cancer du poumon dans le
    cas d'expositions cumulées est donc 10 à 30 fois plus élevé chez les
    ouvriers du textile que chez les mineurs de chrysotile. Les raisons de
    ces différences demeurent obscures et plusieurs hypothèses ont été
    avancées pour tenter de les expliquer, notamment des variations dans
    la distribution de la taille des fibres.

         Les études épidémiologiques qui s'efforcent d'évaluer le risque
    de mésothéliome se heurtent à des difficultés qui tiennent à la rareté
    de la maladie, à l'absence de statistiques de mortalité pour les
    populations utilisées comme référence et à un certain nombre de
    problèmes de diagnostic et de notification. C'est pourquoi, bien
    souvent, le risque n'est pas calculé et on se contente d'indicateurs
    plus grossiers, par exemple le nombre absolu de cas et de décès et le
    rapport du nombre de mésothéliomes au nombre de cancers du poumon ou
    au nombre total de décès.

         Si l'on se base sur les données examinées dans la présente
    monographie, c'est dans les industries d'extraction et de
    transformation du chrysotile que le nombre de mésothéliomes est le
    plus élevé. Chez la totalité des 38 cas observés, il y avait atteinte
    pleurale, à l'exception d'un seul, entaché d'incertitude, où
    l'atteinte était pleuro-péritonéale. Aucun mésothéliome n'a été
    observé chez les travailleurs exposés moins de 2 ans. On a pu dégager
    une nette relation dose-réponse, avec des taux bruts de mésothéliomes
    (nombre de cas pour 1000 années-travailleurs)allant de 0,15 pour ceux
    dont l'exposition cumulée était inférieure à 3530 millions de
    particules par m3-années, à 0,97 pour ceux dont l'exposition était
    supérieure à 10 590 millions de particules par m3-années.

         La proportion de décès attribuables à des mésothéliomes que l'on
    peut tirer des études de cohortes portant sur les industries
    d'extraction et de transformation varie de 0 à 0,8%. Il convient
    d'interpréter ces chiffres avec prudence car les études en question ne
    fournissent pas des données comparables, avec stratification des décès
    en fonction de l'intensité et de la durée de l'exposition ainsi que du
    temps écoulé depuis la première exposition.

         On possède un certain nombre d'indices qui donnent à penser que
    les fibres de trémolite sont à l'origine de mésothéliomes chez
    l'homme. Comme le chrysotile du commerce est susceptible de contenir
    de la trémolite fibreuse, on suppose que c'est ce minéral qui provoque

    l'apparition de mésothéliomes dans certaines populations exposées au
    chrysotile. On ignore cependant quelle est la relation entre l'excès
    de mésothéliomes observé et la teneur du chrysotile en trémolite

         Les données épidémiologiques ne permettent pas de conclure qu'il
    y ait une association entre l'exposition au chrysotile et un
    accroissement du risque de cancers d'autres localisations que la
    poumon ou la plèvre. Sur ce point, on ne dispose que peu de données au
    sujet du chrysotile en tant que tel, même si l'on possède quelques
    indices disparates d'une association entre l'exposition à l'amiante
    (sous toutes ses formes) et des cancers du larynx, du rein et des
    voies digestives. Une étude effectuée au Québec sur des mineurs de
    chrysotile et des ouvriers travaillant à sa transformation, a permis
    d'observer un excès statistiquement significatif de cancers de
    l'estomac, mais il est vrai que l'on n'a pas pris en compte la
    possibilité d'une confusion due au régime alimentaire, aux maladies
    infectieuses et à d'autres facteurs de risque.

         Il faut admettre que, si les études épidémiologiques relatives
    aux travailleurs exposés au chrysotile se sont cantonnées, pour
    l'essentiel, aux industries d'extraction et de transformation, il y a
    lieu de croire, d'après l'histoire naturelle de la maladie et son
    association à divers types de fibres dans les pays occidentaux, que le
    risque est probablement plus élevé chez les ouvriers du bâtiment que
    chez les travailleurs des autres industries.

    1.7  Destinée dans l'environnement et effets sur les biotes

         Il y a des affleurements de serpentine partout dans le monde. Le
    travail de l'écorce terrestre provoque l'érosion de ses constituants
    minéraux et du chrysotile en particulier. Ceux-ci sont transportés à
    distance et entrent dans le cycle de l'eau, le processus de
    sédimentation et le profil pédologique. On a trouvé du chrysotile dans
    l'eau, l'air et dans constituants de l'écorce terrestre et on en a
    mesuré la teneur.

         Le chrysotile et les autres constituants de la serpentine qui lui
    sont associés subissent une décomposition chimique en surface. Il
    s'ensuit une modification profonde du pH du sol et l'apparition de
    traces métalliques dans l'environnement. Toutes ces transformations
    exercent des effets mesurables sur la croissance des végétaux et des
    organismes terricoles (notamment les microbes et les insectes), des
    poissons et des invertébrés. D'après certaines données, des herbivores
    comme les ovins et les bovins qui ingèrent des graminées poussant sur
    des sols où affleure la serpentine présentent des modifications de
    leurs constantes hémochimiques.

    1.  RESUMEN

    1.1  Identidad, propiedades físicas y químicas, muestreo y análisis

         El crisotilo es un mineral de silicato de magnesio hidratado
    fibroso que se ha utilizado en numerosos productos comerciales. En la
    actualidad se usa ampliamente en el comercio mundial. Se ha observado
    que sus propiedades físicas y químicas como mineral varían entre los
    depósitos geológicos explotados. Los minerales que acompañan a las
    fibras en las menas son muchos y entre ellos puede haber algunas
    variedades de anfíbol fibroso. Se considera que la tremolita es
    particularmente importante a este respecto; su forma y concentración
    presentan grandes variaciones.

         En el análisis del crisotilo en los lugares de trabajo se
    requiere ahora el uso de microscopios ópticos y electrónicos. Antes se
    habían utilizado diversos instrumentos y dispositivos para vigilar la
    presencia y concentración tanto de polvo total como de fibras en los
    diversos medios. En la actualidad se suelen utilizar la técnica del
    filtro de membrana y la microscopía óptica de contraste de fases para
    la valoración en el lugar de trabajo (expresada como fibras por ml de
    aire), y también se emplea la microscopia electrónica de transmisión.
    Para las valoraciones en el medio ambiente se requiere el uso de la
    microscopia electrónica de transmisión. Se ha recurrido a estudios de
    concentración en tejidos para mejorar la información relativa a la
    exposición. En función del grado de atención al detalle en estos
    estudios se ha llegado a distintas conclusiones acerca de los
    mecanismos y la etiología.

         Antes se utilizaban las técnicas del precipitador gravimétrico y
    térmico y el sacudidor de muestreo de polvo para la caracterización en
    el lugar de trabajo, siendo los valores del polvo (no de la fibra) los
    únicos índices de exposición inicial para calibrar las relaciones
    exposición/respuesta. Se ha intentado muchas veces convertir estos
    valores en los correspondientes a fibras por volumen de aire, pero
    tales conversiones han tenido un éxito muy limitado. Se ha comprobado
    que los factores de conversión son específicos de cada industria, e
    incluso de cada operación; en los factores de conversión universal se
    han registrado grandes variaciones.

    1.2  Fuentes de exposición profesional y ambiental

         En todo el medio ambiente de la corteza terrestre (aire, agua,
    casquetes polares y suelo) se encuentran concentraciones bajas de
    crisotilo. Las actividades tanto naturales como humanas contribuyen a
    la aerosolización y la distribución de las fibras. Entre las fuentes
    de origen humano está el polvo procedente de actividades
    profesionales, que comprenden la recuperación y elaboración de
    minerales, la fabricación, la aplicación, la utilización y en último
    término la eliminación.

         Hay producción en 25 países y son siete los principales
    productores. La producción anual de amianto alcanzó un máximo de más
    de cinco millones de toneladas a mediados de los años setenta, pero
    luego ha disminuido hasta el nivel actual de unos tres millones de
    toneladas. Se fabrican productos de crisotilo en más de 100 países,
    siendo el Japón el principal consumidor. Las principales actividades
    actuales de las que se deriva una exposición potencial al crisotilo
    son las siguientes: a) extracción y trituración; b) transformación en
    productos (materiales de fricción, tuberías y placas de cemento,
    juntas y cierres, papel y textiles); c) construcción, reparación y
    demolición; d) transporte y eliminación. La industria del amianto-
    cemento es con diferencia la principal usuaria de fibras de crisotilo,
    absorbiendo alrededor del 85% del total.

         Se desprenden fibras durante la elaboración, la instalación y la
    eliminación de productos con amianto, así como por el desgaste de los
    productos en algunos casos. La manipulación de productos friables
    puede ser una fuente importante de emisión de crisotilo.

    1.3  Niveles de exposición profesional y ambiental

         De acuerdo con datos procedentes sobre todo de América del Norte,
    de Europa y del Japón, la exposición en los lugares de trabajo a
    comienzos de los años treinta era muy alta en la mayoría de los
    sectores de la producción. Los niveles descendieron considerablemente
    a finales de los años setenta y se ha reducido enormemente hasta los
    valores actuales. En la industria de la extracción y la trituración de
    Quebec, las concentraciones medias de fibras en el aire superaban a
    menudo las 20 fibras/ml (f/ml) en los setenta, mientras que ahora
    suelen estar muy por debajo de 1 f/ml. En la producción de
    fibrocemento en el Japón, las concentraciones medias habituales eran
    de 2,5-9,5 f/ml en los setenta, mientras que en 1992 se notificaron
    unas concentraciones medias de 0,05-0,45 f/ml. En la fabricación de
    textiles de amianto en el Japón, las concentraciones medias eran de
    2,6 a 12,8 f/ml en el período comprendido entre 1970 y 1975, y de 0,1
    a 0,2 f/ml en el período comprendido entre 1984 y 1986. Las tendencias
    han sido análogas en la producción de materiales de fricción: según
    los datos disponibles del mismo país, en el período comprendido entre
    1970 y 1975 se midieron concentraciones medias de 10-35 f/ml, mientras
    que entre 1984 y 1986 se notificaron mediciones de 0,2-5,5 f/ml. En
    una instalación del Reino Unido en la que se realizó un estudio amplio
    de la mortalidad, las concentraciones eran en general superiores a
    20 f/ml en el período anterior a 1931 y normalmente inferiores a
    1 f/ml durante 1970-79.

         Se dispone de pocos datos sobre las concentraciones de fibras
    asociadas a la instalación y utilización de productos con crisotilo,
    aunque fácilmente éste es el lugar de trabajo más probable de
    exposición de los trabajadores. En el mantenimiento de los vehículos
    se notificaban en los años setenta concentraciones máximas de hasta
    16 f/ml, mientras que prácticamente todos los niveles medidos después
    de 1987 fueron de menos de 0,2 f/ml. Las exposiciones medias 

    ponderadas por el tiempo durante la reparación de vehículos de
    pasajeros en los años ochenta eran por lo general inferiores a
    0,05 f/ml. Sin embargo, en ausencia de controles la descarga de
    residuos de los cilindros daba lugar a concentraciones elevadas de
    polvo de corta duración.

         Existe la posibilidad de exposición de personal de mantenimiento
    a diversos tipos de fibras de amianto debido a la elevada cantidad de
    amianto friable en su lugar de trabajo. En edificios con planes de
    control de los Estados Unidos, la exposición del personal de
    mantenimiento de edificios expresada como promedio ponderado por el
    tiempo durante ocho horas fue de 0,002 a 0,02 f/ml. Estos valores son
    del mismo orden de magnitud que las exposiciones normales durante el
    trabajo de los operadores de telecomunicaciones (0,009 f/ml) y al aire
    libre (0,037 f/ml), aunque se notificaron concentraciones mayores en
    lugares de trabajo de espacios cerrados (0,5 f/ml). Las
    concentraciones pueden ser considerablemente más elevadas cuando no se
    han introducido planes de control. En un caso se detectaron
    concentraciones episódicas de corta duración de 1,6 f/ml al barrer y
    de 15,5 f/ml mientras se limpiaba el polvo de los libros de una
    biblioteca en un edificio con un tipo de superficie que contenía
    crisotilo muy friable. La mayoría de los demás promedios ponderados
    por el tiempo durante ocho horas son alrededor de dos órdenes de
    magnitud menores.

         De acuerdo con los estudios realizados antes de 1986, las
    concentraciones de fibras (fibras > 5 µ de longitud) en el aire
    exterior, medidas en Alemania, Austria, el Canadá, los Estados Unidos
    y Sudáfrica, oscilaban entre 0,0001 y alrededor de 0,01 f/ml, siendo
    los niveles de la mayoría de las muestras menores de 0,001 f/ml. Las
    medias o las medianas eran de 0,00005 a 0,02 f/ml, tomando como base
    determinaciones más recientes en el Canadá, los Estados Unidos,
    Italia, el Japón, el Reino Unido, la República Eslovaca y Suiza.

         Las concentraciones de fibras en edificios públicos, incluso los
    que tienen materiales con amianto friable, son del orden de las
    medidas en el aire exterior. Las concentraciones (fibras > 5 µ de
    longitud) en edificios de Alemania y el Canadá notificadas antes de
    1986 eran en general menores de 0,002 f/ml. En estudios más recientes
    realizados en Bélgica, el Canadá, los Estados Unidos, el Reino Unido y
    la República Eslovaca se obtuvieron valores medios de 0,00005 a
    0,0045 f/ml. Sólo un 0,67% de las fibras de crisotilo eran más largas
    de 5 µ.

    1.4  Absorción, eliminación, retención y desplazamiento

         La deposición del crisotilo inhalado depende del diámetro
    aerodinámico, la longitud y la morfología de la fibra. La mayoría de
    las fibras de crisotilo transportadas por el viento se consideran
    respirables debido a que su diámetro es de menos de 3 µ, igual a un
    diámetro aerodinámico de 10 µ. En ratas de laboratorio, las fibras de
    crisotilo se depositan principalmente en las bifurcaciones de los
    conductos alveolares.

         En las regiones nasofaríngea y traqueobronquial, las fibras de
    crisotilo se eliminan por medio de la acción mucociliar. Las células
    epiteliales absorben las fibras en las bifurcaciones de los conductos
    alveolares. La longitud de las fibras es un factor determinante
    importante para la eliminación alveolar de las fibras de crisotilo.
    Hay pruebas convincentes obtenidas en estudios con animales de que las
    fibras cortas (de menos de 5 µ de longitud) se eliminan con mayor
    rapidez que las largas (de más de 5 µ). No se conocen completamente
    los mecanismos que hacen que las fibras de crisotilo se eliminen de
    manera relativamente más rápida que las de anfíboles. Se ha planteado
    la hipótesis de que las fibras cortas de crisotilo pueden eliminarse
    sobre todo por fagocitosis de los macrófagos alveolares, mientras que
    las largas lo harían principalmente por rotura y/o disolución. No se
    conoce del todo en qué medida se desplazan las fibras de crisotilo a
    los intersticios, al tejido pleural y a otros tejidos extratorácicos.

         Los análisis de los pulmones de trabajadores expuestos al
    crisotilo ponen de manifiesto una retención de tremolita, amianto
    anfíbol que suele estar asociado con el crisotilo comercial en
    pequeñas proporciones, mucho mayor que la de crisotilo. La eliminación
    más rápida de las fibras de crisotilo de los pulmones humanos se ha
    confirmado en los resultados de estudios con animales, que mostraban
    que el crisotilo se elimina de los pulmones con mayor rapidez que los
    anfíboles, incluidas la crocidolita y la amosita.

         Los datos obtenidos en estudios con personas y con animales son
    insuficientes para evaluar la posible absorción, distribución y
    excreción de fibras de crisotilo a partir de la ingestión. Las pruebas
    disponibles indican que, en el caso de que se produzca penetración de
    fibras de crisotilo a través de las paredes del intestino, es
    extraordinariamente limitada. En un estudio se observó una
    concentración mayor de fibras de crisotilo en la orina de trabajadores
    expuestos profesionalmente al crisotilo.

    1.5  Efectos en animales y en células

         En numerosos estudios de inhalación de larga duración se ha
    comprobado que diversas muestras experimentales de fibras de crisotilo
    provocan efectos fibrogénicos y carcinogénicos en ratas de
    laboratorio. Entre esos efectos figuran la fibrosis intersticial y el
    cáncer de pulmón y de pleura. En la mayoría de los casos parece haber
    una asociación entre fibrosis y tumores en el pulmón de rata. También
    se han detectado efectos fibrogénicos y carcinogénicos en estudios de
    larga duración con animales (principalmente ratas) utilizando otras
    vías de administración (por ejemplo, instilación intratraqueal e
    inyección intrapleural o intraperitoneal).

         No se han investigado debidamente en estudios de inhalación de
    larga duración en animales las relaciones exposición/dosis-respuesta
    para la fibrosis pulmonar, el cáncer de pulmón y el mesotelioma
    inducidos por el crisotilo. Los estudios de inhalación realizados
    hasta la fecha, utilizando sobre todo una concentración de exposición

    única, muestran respuestas fibrogénicas y carcinogénicas a
    concentraciones de fibras en el aire que van de 100 a algunos miles de
    fibras/ml. Al combinar los datos de varios estudios, parece que hay
    una relación entre las concentraciones de fibras en el aire y la
    incidencia de cáncer de pulmón. Sin embargo, este tipo de análisis tal
    vez no sea válido desde el punto de vista científico, debido a que las
    condiciones experimentales en los estudios disponibles eran distintas.

         En los experimentos sin inhalación (estudios de inyección
    intrapleural e intraperitoneal), se ha demostrado una relación dosis-
    respuesta para el mesotelioma con las fibras de crisotilo. Sin
    embargo, es posible que los datos de estos estudios no sean adecuados
    para evaluar el riesgo humano derivado de la exposición a fibras por

         El amianto tremolita, mineral que es un componente secundario del
    crisotilo comercial, también mostró efectos carcinogénicos y
    fibrogénicos en un experimento de inhalación única y en un estudio de
    inyección intraperitoneal en ratas. No se dispone de datos sobre la
    exposición/dosis respuesta para poder establecer una comparación
    directa de la actividad carcinogénica de la tremolita y el crisotilo.

         La capacidad de las fibras para inducir efectos fibrogénicos y
    carcinogénicos parece depender de sus características individuales,
    incluidas la dimensión y la durabilidad de las fibras (es decir, la
    biopersistencia en los tejidos a los que llegan), que están
    determinadas en parte por las propiedades fisicoquímicas. Está bien
    documentado en estudios experimentales el hecho de que las fibras
    cortas (de menos de 5 µ) tienen una actividad biológica menor que las
    largas (de más de 5 µ). Sin embargo, sigue habiendo dudas acerca de si
    las fibras cortas tienen una actividad biológica significativa.
    Además, no se sabe cuánto tiempo tiene que permanecer una fibra en el
    pulmón para inducir efectos preneoplásicos, puesto que el cáncer
    relacionado con el amianto suele aparecer en una etapa posterior de la
    vida del animal.

         No se conocen completamente los mecanismos mediante los cuales el
    crisotilo y otras fibras provocan efectos fibrogénicos y
    carcinogénicos. Entre los posible mecanismos de los efectos
    fibrogénicos de las fibras cabe mencionar el proceso de inflamación
    crónica debido a la producción de factores del crecimiento (por
    ejemplo, el TNF-alfa) y especies de oxígeno reactivo. Con respecto a
    la carcinogenicidad inducida por las fibras, se han propuesto varias
    hipótesis. Son las siguientes: daños en el ADN provocados por especies
    de oxígeno reactivo inducido por las fibras; daños directos en el ADN
    por las interacciones físicas entre las fibras y las células a las que
    llegan; intensificación de la proliferación celular debida a las
    fibras; reacciones inflamatorias crónicas provocadas por las fibras,
    que da lugar a una liberación prolongada de lisozimas, especies
    reactivas de oxígeno, citoquinas y factores del crecimiento; y
    actuación de las fibras como agentes cocarcinógenos o portadores de
    productos químicos carcinógenos hasta los tejidos a los que llegan. Es

    probable, sin embargo, que todos estos mecanismos contribuyan a la
    carcinogenicidad de las fibras de crisotilo, puesto que se han
    observado tales efectos en diversos sistemas  in vitro de células
    humanas y de mamíferos.

         En conjunto, los datos toxicológicos disponibles demuestran
    claramente que las fibras de crisotilo pueden crear peligros
    fibrogénicos y carcinogénicos para el ser humano. Sin embargo, los
    datos no son suficientes para obtener estimaciones cuantitativas del
    riesgo para las personas. Esto se debe a que son insuficientes los
    procedentes de estudios de inhalación relativos a la
    exposición-respuesta y a que hay dudas cerca de la sensibilidad de los
    estudios con animales para predecir el riesgo humano.

         Se han realizado pruebas con fibras de crisotilo en varios
    estudios de carcinogenicidad por vía oral. En los estudios disponibles
    no se han notificado efectos carcinogénicos.

    1.6  Efectos en el ser humano

         Las calidades comerciales de crisotilo se han asociado con un
    aumento del riesgo de neumoconiosis, cáncer de pulmón y mesotelioma en
    numerosos estudios epidemiológicos de trabajadores expuestos.

         Las enfermedades no malignas asociadas con la exposición al
    crisotilo forman una mezcla algo compleja de síndromes clínicos y
    patológicos imposibles de definir para un estudio epidemiológico. La
    preocupación se ha concentrado primordialmente en la asbestosis, que
    generalmente consiste en una enfermedad asociada con una fibrosis
    pulmonar intersticial difusa acompañada de diversos grados de afección

         Los estudios realizados en trabajadores expuestos al crisotilo en
    distintos sectores han demostrado en general una relación
    exposición-respuesta o exposición-efecto para la asbestosis inducida
    por crisotilo, puesto que el aumento de los niveles de exposición ha
    producido un incremento de la incidencia y la gravedad de la
    enfermedad. Sin embargo, hay dificultades para definir esta relación,
    debido a factores como la incertidumbre del diagnóstico y la
    posibilidad de progresión de la enfermedad después de cesar la

         Por otra parte, entre los estudios disponibles son evidentes
    algunas variaciones en las estimaciones del riesgo. Los motivos de
    estas variaciones no son totalmente claros, pero pueden estar
    relacionados con la incertidumbre en las estimaciones de la
    exposición, la distribución por tamaños de las fibras del aire en los
    diversos sectores industriales y los modelos estadísticos. Son
    habituales los cambios en la asbestosis tras exposiciones prolongadas
    a concentraciones de 5 a 20 f/ml.

         Los riesgos relativos totales de cáncer de pulmón no son por lo
    general elevados en los estudios realizados con trabajadores de la
    producción de fibrocemento y en algunas de las cohortes de
    trabajadores de fábricas de fibrocemento. La relación
    exposición-respuesta entre el crisotilo y el riesgo de cáncer de
    pulmón parece ser en los estudios de trabajadores textiles 10-30 veces
    mayor que en los estudios de trabajadores de las industrias de la
    extracción y la trituración. No están claros los motivos de esta
    variación del riesgo, por lo que se han propuesto varias hipótesis,
    incluidas las variaciones de la distribución de las fibras por

         La estimación del riesgo de mesotelioma se complica en los
    estudios epidemiológicos debido a factores como la rareza de la
    enfermedad, la falta de tasas de mortalidad en las poblaciones
    utilizadas como referencia y los problemas de diagnóstico y
    notificación. Por consiguiente, en muchos casos no se han calculado
    los riesgos y se han utilizado indicadores más aproximativos, como el
    número absoluto de casos y de muertes y la razón mesotelioma/cáncer de
    pulmón o número total de muertes.

         Tomando como base los datos reseñados en esta monografía, el
    mayor número de mesoteliomas se ha registrado en el sector de la
    extracción y la trituración del crisotilo. Los 38 casos fueron
    pleurales con la excepción de uno de probabilidad baja de diagnóstico,
    que fue pleuroperitoneal. No se produjo ningún caso en trabajadores
    expuestos durante menos de dos años. Se observó una relación
    dosis-respuesta clara, con tasas brutas de mesoteliomas
    (casos/1000 años-persona) comprendidas entre 0,15 para los casos de
    una exposición acumulativa a menos de 3530 millones de
    partículas/m3-año (< 1000 millones de partículas por pie cúbico-año)
    y 0,97 para los de una exposición a más de 10 590 millones de
    partículas/m3-año (> 300 millones de partículas/pie cúbico-año).

         Las proporciones de muertes atribuibles a mesoteliomas en
    estudios de cohortes en los diversos sectores de la extracción y la
    producción oscilan entre el 0% y el 0,8%. Estas proporciones se han de
    interpretar con cautela, puesto que los estudios no suministran datos
    comparables con una estratificación de las muertes por intensidades de
    exposición, duración de ésta o tiempo transcurrido desde la primera.

         Hay pruebas de que la tremolita fibrosa provoca la aparición de
    mesoteliomas en el ser humano. Debido a que el crisotilo comercial
    puede contener tremolita fibrosa, se ha planteado la hipótesis de que
    ésta puede contribuir a la inducción de mesoteliomas en algunas
    poblaciones expuestas primordialmente al crisotilo. No se ha
    determinado en qué medida podría atribuirse el aumento observado de
    mesoteliomas al contenido de tremolita fibrosa.

         No se han obtenido pruebas epidemiológicas concluyentes de que la
    exposición al crisotilo esté asociada con un mayor riesgo de tipos de
    cáncer distintos del de pulmón o el de pleura. Hay información 

    limitada acerca de este tema para el crisotilo en sí, pero no son
    convincentes las pruebas aducidas para demostrar una asociación entre
    la exposición al amianto (todas las formas) y el cáncer de laringe, el
    de riñón y el gastrointestinal. Se ha observado un aumento
    significativo de cáncer de estómago en un estudio de mineros y
    trituradores de crisotilo de Quebec, pero no se ha examinado la
    posible confusión con la alimentación, con la presencia de infecciones
    y con otros factores de riesgo.

         Hay que reconocer que, aunque los estudios epidemiológicos de
    trabajadores expuestos al crisotilo se han limitado fundamentalmente a
    la extracción y la trituración, así como al sector de la fabricación,
    existen pruebas, basadas en la evolución histórica de las enfermedades
    asociadas con la exposición a mezclas de diversos tipos de fibras en
    los países occidentales, de que probablemente los riesgos sean mayores
    entre los trabajadores de la construcción y posiblemente entre los de
    otras industrias que utilizan el producto.

    1.7  Destino en el medio ambiente y efectos en la biota

         En todo el mundo hay afloramientos de serpentina. Los componentes
    minerales, entre ellos el crisotilo, se erosionan como consecuencia de
    los procesos de la corteza terrestre y se transportan hasta
    convertirse en un componente del ciclo hídrico, los sedimentos y el
    perfil del suelo. Se ha medido la presencia y las concentraciones de
    crisotilo en el agua, el aire y otras unidades de la corteza.

         El crisotilo y los minerales de serpentina asociados con él se
    degradan químicamente en la superficie. Esto da lugar a cambios
    profundos del pH del suelo e introduce una serie de metales traza en
    el medio ambiente. Esto ha producido a su vez efectos mensurables en
    el crecimiento de las plantas, la biota del suelo (incluidos
    microorganismos e insectos), los peces y los invertebrados. Algunos
    datos indican que los animales de pastoreo (ovinos y vacunos) sufren
    cambios de la química sanguínea tras la ingestión de gramíneas que han
    crecido en afloramientos de serpentina.

    See Also:
       Toxicological Abbreviations