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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 77



    MAN-MADE MINERAL FIBRES









    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.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1988


         The International Programme on Chemical Safety (IPCS) is a
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        ISBN 92 4 154277 2 

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR MAN-MADE MINERAL FIBRES

1. SUMMARY

    1.1. Identity, terminology, physical and chemical
          properties, analytical methods
    1.2. Sources of human and environmental exposure
    1.3. Environmental transport, distribution, and transformation
    1.4. Environmental concentrations and human exposure
    1.5. Deposition, clearance, retention, durability, and translocation
    1.6. Effects on experimental animals and  in vitro test systems
    1.7. Effects on man
    1.8. Evaluation of human health risks
          1.8.1. Occupationally exposed populations
          1.8.2. General population

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1. Identity, terminology, physical and chemical properties
    2.2. Production methods
          2.2.1. General
          2.2.2. Historical
    2.3. Analytical methods
          2.3.1. Air
          2.3.2. Biological materials

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1. Production
    3.2. Uses
    3.3. Emissions into the environment

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

5. ENVIRONMENTAL CONCENTRATIONS AND HUMAN EXPOSURE

    5.1. Environmental concentrations
          5.1.1. Air
                  5.1.1.1   Occupational environment
                  5.1.1.2   Ambient air
                  5.1.1.3   Indoor air
          5.1.2. Water supplies
    5.2. Historical exposure levels
    5.3. Exposure to other substances

6. DEPOSITION, CLEARANCE, RETENTION, DURABILITY, AND TRANSLOCATION

    6.1. Studies on experimental animals
    6.2. Solubility studies

7. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    7.1. Experimental animals
          7.1.1. Inhalation
                  7.1.1.1   Fibrosis
                  7.1.1.2   Carcinogenicity
          7.1.2. Intratracheal injection
          7.1.3. Intrapleural, intrathoracic, and
                  intraperitoneal administration
    7.2.  In vitro studies
    7.3. Mechanisms of toxicity  - mode of action

8. EFFECTS ON MAN

    8.1. Occupationally exposed populations
          8.1.1. Non-malignant dermal and ocular effects
          8.1.2. Non-malignant respiratory disease
                  8.1.2.1   Cross-sectional studies
                  8.1.2.2   Historical prospective studies
          8.1.3. Carcinogenicity
                  8.1.3.1   Glass wool
                  8.1.3.2   Rock wool and slag wool
                  8.1.3.3   Glass filament
                  8.1.3.4   Mixed exposures
                  8.1.3.5   Refractory fibres
    8.2. General population

9. EVALUATION OF HUMAN HEALTH RISKS

    9.1. Occupationally exposed populations
    9.2. General population

10. RECOMMENDATIONS

    10.1. Further research needs
          10.1.1. Analytical methods
          10.1.2. Environmental exposure levels
          10.1.3. Studies on animals
          10.1.4. Studies on man
    10.2. Other recommendations
          10.2.1. Classification of MMMF products

REFERENCES

WHO  TASK GROUP ON  ENVIRONMENTAL HEALTH CRITERIA  FOR  MAN-MADE
MINERAL FIBRES

 Members

Dr B. Bellmann, Fraunhofer Institute for Toxicology and Aerosol
   Research, Hanover, Federal Republic of Germany
Dr J.M.G. Davis, Institute of Occupational Medicine, Edinburgh,
   United Kingdoma
Dr J. Dodgson, Environmental Branch, Institute of Occupational
   Medicine, Edinburgh, United Kingdom
Professor L.T. Elovskaya, Institute of Industrial Hygiene and
   Occupational Diseases, Moscow, USSR  (Vice-Chairman)
Professor M.J. Gardner, Medical Research Council, Environmental
   Epidemiology    Unit,    Southampton    General    Hospital,
   Southampton, United Kingdom  (Chairman)
Dr M. Jacobsen, Institute of Occupational Medicine, Edinburgh,
   United Kingdom
Professor M. Kido, Pulmonary Division, University of Occupa-
   tional and Environmental Health, Fukuoka, Kitakyushu, Japan
Dr M. Kuschner, School of Medicine, State University of New
   York, Stonybrook, New York, USAa
Dr K. Linnainmaa, Department of Industrial Hygiene and Toxico-
   logy, Institute of Occupational Health, Helsinki, Finland
Dr E.E. McConnell, Toxicology Research and Testing Program,
   National   Institute   of  Environmental   Health  Sciences,
   Research Triangle Park, North Carolina, USA  (Rapporteur)
Dr J.C. McDonald, Dust Disease Research Unit, School of Occupa-
   tional   Health,   McGill   University,  Montreal,   Quebec,
   Canadaa
Dr A. Marconi, Laboratory of Environmental Hygiene, High Insti-
   tute of Health, Rome - Nomentana, Italy
Mr I. Ohberg, Rockwool AB, Skvde, Sweden
Dr F. Pott, Medical Insitute for Environmental Hygiene of the
   University  of  Dusseldorf, Dusseldorf,  Federal Republic of
   Germanya
Dr T. Schneider, Department of Occupational Hygiene, Danish
   National   Institute   of  Occupational   Health,  Hellerup,
   Denmark
Dr J.C. Wagner, Medical Research Council, Llandough Hospital,
   Penarth, United Kingdoma

 Representatives from Other Organizations

Dr A. Berlin, Health and Safety Directorate, Commission of the
   European Communities, Luxembourgb
Ms E. Krug, Health and Safety Directorate, Commission of the
   European Communities, Luxembourg
Dr R. Murray (International Commission on Occupational Health),
   London School of Hygiene, London, United Kingdomb

--------------------------------------------------------------------------
a  Invited but unable to attend.
b  Present for part of the meeting only.

 Observers

Dr R. Anderson (Thermal Insulation Manufacturers Association),
   Manville Corporation, Denver, Colorado
Dr D.M. Bernstein, Geneva Facility, Research & Consulting
   Company AG, Geneva, Switzerland
Dr J.W. Hill (Joint European Medical Research Board), Pilkington
   Insulation,  Ltd.,  St  Helens,  Burton-in-Kendal,  Cumbria,
   United Kingdom
Dr O. Kamstrup (Joint European Medical Research Board), Rockwool
   A/S, Hedehusene, Denmark
Dr J.L. Konzen (Thermal Insulation Manufacturers Association),
   Medical   and   Health  Affairs,   Owens-Corning  Fiberglass
   Corporation, Toledo, Ohio, USA
Dr W.L. Pearson (Canadian Man-Made Mineral Fibre Industry),
   Fiberglas Canada Inc., Willowdale, Ontario, Canada
Dr G.H. Pigott (European Chemical Industry Ecology and Toxico-
   logy  Centre),  ICI Central  Toxicology Laboratory, Alderley
   Park, Macclesfield, Cheshire, United Kingdom

 Secretariat

Dr F. Valic, IPCS Consultant, World Health Organization, Geneva,
   Switzerland  (Secretary) a
Ms B. Goelzer, Office of Occupational Health, World Health
   Organization, Geneva, Switzerland
Dr M. Greenberg, Department of Health and Social Security,
   London, United Kingdom
Ms M.E. Meek, Bureau of Chemical Hazards, Environmental Health
   Centre, Health Protection Branch, Health and Welfare Canada,
   Tunney's   Pasture,   Ottawa,  Ontario,   Canada   (Temporary
    Adviser)
Dr L. Simonato, Unit of Analytical Epidemiology, International
   Agency for Research on Cancer, Lyons, France

-------------------------------------------------------------------------
a  Head,  Department  of  Occupational Health,  Andrija Stampar
   School of Public Health, Zagreb, Yugoslavia.


NOTE TO READERS OF THE CRITERIA DOCUMENTS

    Every  effort has been  made to present  information in  the
criteria  documents  as  accurately as  possible  without unduly
delaying their publication.  In the interest of all users of the
environmental  health  criteria  documents, readers  are  kindly
requested  to communicate any errors  that may have occurred  to
the Manager of the International Programme on  Chemical  Safety,
World  Health Organization, Geneva,  Switzerland, in order  that
they  may  be  included in  corrigenda,  which  will  appear  in
subsequent volumes.



                            *    *    *

ENVIRONMENTAL HEALTH CRITERIA FOR MAN-MADE MINERAL FIBRES


    A WHO Task Group on Environmental Health Criteria  for  Man-
made  Mineral  Fibres  met  at  the  Monitoring  and  Assessment
Research Centre, London, on 14-18 September 1987.

    Dr   B.  Bennett,  who  opened  the  meeting,  welcomed  the
participants  on behalf of the host institution. Dr M. Greenberg
greeted  the participants on  behalf the government,  and Dr  F.
Valic welcomed them on behalf of the heads of the three IPCS co-
sponsoring   organizations   (UNEP/ILO/WHO).   The   Task  Group
reviewed  and revised the  draft criteria document  and made  an
evaluation of the health risks of exposure to  man-made  mineral
fibres.

    The drafts of this document were prepared by MS M.E. MEEK of
the   Environmental  Health  Directorate,  Health   and  Welfare
Canada, Ottawa.

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



                           *   *   *



    Partial  financial  support  for  the  publication  of  this
criteria  document  was kindly  provided  by the  United  States
Department of Health and Human Services, through a contract from
the   National  Institute  of  Environmental   Health  Sciences,
Research   Triangle   Park,  North   Carolina,   USA  -   a  WHO
Collaborating Centre for Environmental Health Effects.

1.  SUMMARY

1.1.  Identity, Terminology, Physical and Chemical Properties, 
Analytical Methods

    Man-made mineral fibres (MMMF), most of which  are  referred
to as man-made vitreous fibres (MMVF), are  amorphous  silicates
manufactured from glass, rock, or other minerals, which  can  be
classified   into   four  broad   groups:  continuous  filament,
insulation  wool  (including  rock/slag wool,  and  glass wool),
refractory   (including  ceramic  fibre),  and  special  purpose
fibres.  Nominal  fibre diameters for these groups are 6 - 15 m
(continuous  filament),  2 - 9 m   (insulation wools, excluding
refractory fibre), 1.2 - 3.5 m  (refractory fibre), and  0.1  -
3 m    (special  purpose  fibres),  respectively.    Continuous
filament  and special purpose  fibres are made  exclusively from
glass,  whereas insulation wools can  also be made from  rock or
slag (rock wool or slag wool, also referred to as  mineral  wool
in the USA).  Refractory fibres are a large group  of  amorphous
or   crystalline  synthetic  mineral  fibres   that  are  highly
resistant to heat.  They are produced from kaolin clay, from the
oxides   of  aluminium,  silicon,  or  other  metals,  or,  less
commonly, from non-oxide materials, such as silicon  carbide  or
nitride.   MMMF usually contain  a binder and  mineral oil as  a
dust suppressant.

    MMMF  do not split  longitudinally into fibrils  of  smaller
diameter, but may break transversely into shorter segments.  The
chemical  composition  of  the various  MMMF  largely determines
their  chemical resistance and solubility  in various solutions,
whereas  thermal  conductivity  is  also  determined  by   fibre
diameter, finer fibres giving lower thermal conductivity.

    Analyses  for  MMMF  have  been  restricted  largely  to the
measurement  of  total  airborne mass  concentrations  or,  more
recently  (since  the  early  1970s),  to  the  determination of
airborne  fibre  levels  by phase  contrast  optical  microscopy
(PCOM).  A WHO reference method for monitoring fibre  levels  by
PCOM  has  been  used  fairly  widely  since  the  early  1980s.
Scanning  and  transmission  electron microscopy  offer improved
resolution  and  fibre  identification in  the  determination of
MMMF.  WHO has also developed reference methods to  compare  and
standardize assessments of MMMF by scanning electron microscopy,
but   the  use  of  these   techniques  needs  to  be   extended
internationally.

1.2.  Sources of Human and Environmental Exposure

    The  global production of  man-made mineral fibres  has been
estimated  to be 4.5 million tonnes in 1973 and 6 million tonnes
in 1985.  Fibrous glass accounts for approximately 80%  of  MMMF
production in the USA, 80% of which is glass wool,  mainly  used
in  acoustic or thermal insulation.   Textile grades (5 - 10% of
fibrous   glass  production)  are   used  principally  for   the
reinforcement  of resinous materials  and in textiles,  such  as

draperies.   Less than 1% of the production of glass fibre is in
the form of fine fibres used in speciality applications, such as
high  efficiency  filter  paper  and  insulation  for  aircraft.
Mineral   wool  (rock  wool/slag   wool),  which  accounts   for
approximately  10 - 15% of  MMMF production in the  USA, is used
mainly  in acoustic and  thermal insulation.  In  Europe,  glass
wool and rock wool are produced in approximately  equal  volumes
and  are  also  used  for  thermal  and   acoustic   insulation.
Refractory  fibres (1  - 2%  of all  MMMF)  are  used for  high-
temperature applications.

    There  are few quantitative data  on emissions of MMMF  from
manufacturing   facilities.   Fibre  levels  in  emissions  from
fibrous  glass plants have been  reported to be of  the order of
0.01  fibres/cm3.  Although quantitative data are not available,
it   is  likely  that  the   emission  of  MMMF  following   the
installation  or disturbance of insulation is the main source of
exposure of the general population.

1.3.  Environmental Transport, Distribution, and Transformation

    Because of the lack of data, only general conclusions on the
transport,  distribution,  and  transformation of  MMMF  in  the
general  environment can be  drawn, based  on  consideration  of
their   physical   and   chemical  properties   and  of  related
information  concerning the behaviour of  natural mineral fibres
in  ambient air and water.  MMMF in ambient air are, on average,
shorter and thinner than those in the  occupational  environment
(because  of sedimentation of  larger diameter fibres  and  also
transverse  breakage).   In general,  most  MMMF are  more water
soluble  than naturally occurring  asbestiform minerals and  are
likely  to  be  less persistent  in  water  supplies.  They  are
removed from air by mechanical forces, sedimentation, or thermal
destruction,  and from water  by dissolution and  deposition  in
sediments.

1.4.  Environmental Concentrations and Human Exposure

    As  a  general  rule, levels  of  MMMF  in the  occupational
environment  have  been  determined by  phase  contrast  optical
microscopy.    Average   concentrations   during   the   current
manufacture  of  fibrous glass  insulation  range from  0.01  to
0.05   fibres/cm3.   Levels in  continuous  fibre plants  are an
order  of magnitude lower,  and concentrations in  mineral  wool
plants,  in the USA,  range up to  an order of  magnitude higher
(0.032 - 0.72 fibres/cm3) than those in glass  wool  production.
Under  similar plant conditions,  mean levels of  ceramic fibres
are  about  4 times  higher than those  for mineral wool  fibres
(0.0082 - 7.6 fibres/cm3).  Average concentrations in speciality
fine-fibre  plants range from 1  to 2 fibres/cm3 and  levels are
highest   in   microfibre   production  facilities   (1   -   50
fibres/cm3).

    In  Europe,  exposure  in  MMMF  production  can  be divided
historical  into  early,  intermediate, and  late  technological
phases.   Whereas the order of magnitude of fibre concentrations
in  glass wool plants  in the early  phase is estimated  to have
been  similar to that of  current concentrations, concentrations
in rock wool and slag wool plants during the early technological
phase could have been one or two orders of magnitude higher than
those  in the late phase.   The presence of other  contaminants,
such as polycyclic aromatic hydrocarbons, arsenic, and asbestos,
in  the  early  slag wool  production  industry  has  also  been
reported.

    In   general,  airborne  fibre  concentrations   during  the
installation of products containing MMMF are comparable  to,  or
less   than,  levels  found   in  production  (<  1  fibre/ml).
Exceptions occur during blowing or spraying operations conducted
in confined spaces, such as during the insulation of aircraft or
attics,  when mean levels of fibrous glass and mineral wool have
ranged  up to 1.8  fibres/cm3 and 4.2  fibres/cm3, respectively.
Mean  concentrations  during  installation  of  loose  fill   in
confined spaces have ranged up to 8.2 fibres/cm3.

    Some data are available on the levels of MMMF in ambient and
indoor  air.  Concentrations ranging from 4 x 10-5 to 1.7 x 10-3
fibres/cm3,  measured by TEM,  have been found  in ambient  air.
Mean  values ranging from  5 x 10-5  to, typically, around  10-4
fibres/cm3, but occasionally over 10-3 fibres/cm3, occur  in the
air of public buildings.

1.5.  Deposition, Clearance, Retention, Durability, 
and Translocation

    Alveolar deposition of MMMF is governed principally by size.
For  fibres of constant diameter,  alveolar deposition decreases
with  increasing length.  On the basis of available data, it has
been   suggested  that  there  is   a  rapid  decrease  in   the
respirability  of fibres > 1 m  in diameter in the rat compared
with a suggested upper limit in man of ~ 3.5 m  (5 m  by mouth
breathing).

    Short  MMMF (<5 m  in  length) are efficiently cleared  by
alveolar  macrophages, whereas this form of clearance appears to
be much less effective for fibres greater than about 10  m   in
length.    At  present,  it   is  difficult  to   draw  definite
conclusions  concerning the relative durability  of man-made and
naturally-occurring  mineral fibres  in vivo.  In addition, there
are  fibres within each of these classes of MMMF that may behave
differently  from the class  as a whole.   For instance,  longer
fibres and fibres of fine diameter dissolve more rapidly in lung
tissue than shorter or coarse ones of the same type.

    The  few available data  indicate that translocation  of the
fibres   to  other  organs   and  tissues  is   limited.   Fibre
concentrations  in  the  tracheobronchial lymph  nodes  of  rats
exposed  to  glass  wool and  rock  wool  for 1  year  were low,
compared with those of glass microfibres.  Levels of  all  fibre

types  in  the  diaphragm  were  essentially  zero.   The trans-
migration of fibres appears to be influenced by fibre  size  and
durability,  short  fibres being  present  in higher  numbers in
other tissues than long ones.

1.6.  Effects on Experimental Animals and  In Vitro Test Systems

    In the majority of the inhalation studies conducted to date,
there has been little or no evidence of fibrosis of the lungs in
a  range of animal species exposed to glass fibre concentrations
of  various types of MMMF  up to 100 mg/m3,  for periods ranging
from  2 days to 24 months.  In most studies, the tissue response
was confined to accumulation of pulmonary macrophages,  many  of
which contained the fibres.  In all cases, the severity  of  the
tissue  reaction in animals exposed  to glass fibre and,  in one
study,  glass  wool, was much less than that for equal masses of
chrysotile  or crocidolite asbestos.   Moreover, in contrast  to
asbestos,  fibrosis  did  not progress  following  cessation  of
exposure.  However, the number of asbestos fibres  reaching  the
lung  may  have been  greater than those  for fibrous glass  and
glass wool.

    A statistically significant increase in lung tumours has not
been found in animals exposed to glass fibres  (including  glass
microfibres)  or rock wool  in inhalation studies  conducted  to
date.   However, in several of the relevant studies, an increase
in lung tumours that was not statistically significant was found
in  exposed animals.  In  all of the  carcinogenicity  bioassays
conducted  to  date,  similar mass  concentrations of chrysotile
asbestos  have clearly induced lung tumours, whereas crocidolite
asbestos has induced few or no tumours.  However, available data
are  insufficient  to  draw conclusions  concerning the relative
potency  of  various fibres  types,  because the  true  exposure
(number of respirable fibres) was not characterized in  most  of
these studies.

    Inhalation  or  intrapleural  injection of  aluminium  oxide
refractory  fibre  containing  about 4%  silica  caused  minimal
pulmonary  reactions  in rats  and  no pulmonary  neoplasms were
induced.   On  the other  hand,  the incidence  of  interstitial
fibrosis  and  pulmonary  neoplasms following  the inhalation of
fibrous ceramic aluminium silicate glass was similar to that for
chrysotile-exposed animals; however, half of the induced tumours
were  not  typical  of those  observed  in  animals  exposed  to
asbestos.

    There has been some evidence of fibrosis in various species,
following   intratracheal   administration   of  glass   fibres.
However, in most cases, the tissue response has been confined to
an  inflammatory  reaction.   An  increased  incidence  of  lung
tumours has been reported following intratracheal administration
of  glass microfibres to 2  species in the same  laboratory, but
these results have not been confirmed by other investigators.

    Studies  involving  intrapleural or  intraperitoneal admini-
stration  of MMMF to  animals have provided  information on  the
importance of fibre size and  in vivo durability in the induction
of fibrosis and neoplasia.  The probability of  the  development
of  mesotheliomas  following  intrapleural  and  intraperitoneal
administration of these dusts was best correlated with the  num-
ber of fibres with diameters of less than 0.25 m   and  lengths
greater  than 8 m;  however, probabilities were also relatively
high  for fibres with diameters of less than 1.5 m  and lengths
greater than 4 m.   A model in which the  carcinogenic  potency
of  fibres is considered to  be a continuous function  of length
and  diameter and also of stability has been proposed.  Asbestos
has  been  more  potent than  equal  masses  of glass  fibre  in
inducing tumours following intrapleural administration. However,
certain types of ceramic fibres were as potent as  equal  masses
of  crocidolite asbestos in inducing  mesotheliomas after intra-
peritoneal  injection.  A similar  tumour response was  observed
after  intraperitoneal  injection  of  a  comparable  number  of
actinolite asbestos fibres longer than 5 m,  basalt  wool,  and
ceramic  wool.  Again, individual fibre  characteristics are the
important criteria for studies using this route of exposure.

    In  in  vitro   assays, cytotoxicity  and cell transformation
have  also been  a function  of fibre  size  distribution,  long
(generally  > 10 m),  narrow (generally  < 1 m)   fibres being
the most toxic.  In general, "coarse" (> 5 m  diameter) fibrous
glass  (e.g., JM 110)   has been less  cytotoxic in most  assays
than  chrysotile or crocidolite asbestos.  The cytotoxicity of a
single  type  of  ceramic fibre  was  also  low.   However,  the
cytotoxicity or transforming potential of fine glass  (e.g.,  JM
100)  has approached  that of  these types  of  asbestos.   With
respect  to genotoxicity, glass  fibres have not  induced  point
mutations  in bacterial assays.  Glass fibres have been reported
to  induce delayed mitosis, numerical and structural chromosomal
alterations,  but  not  sister chromatid  exchanges in mammalian
cells  in  vitro.  Only a few  in vitro studies on MMMF other than
glass fibres are available.

    The  effects of fibre coating  on the toxicity of  MMMF have
been  examined,  to a limited extent, in inhalation and  in vitro
studies.   However,  the available  data  are both  limited  and
contradictory and no firm conclusions can be drawn at this time.
Effects of combined exposure to MMMF and other  pollutants  have
been   examined  in  inhalation  and  intraperitoneal  injection
studies.  Concomitant exposure to airborne glass fibres enhanced
the  toxic effects of styrene in mice, and the incidence of lung
cancer in rats exposed by inhalation to radon was  increased  by
concomitant   intrapleural   injection  of   glass  fibres.   In
contrast,  the  carcinogenic  potency of  glass fibres following
intraperitoneal administration was reduced by pre-treatment with
hydrochloric acid (HCl).

1.7.  Effects on Man

    Fibrous  glass and rock  wool fibres (mainly  those  greater
than 4.5 - 5 m  in diameter) cause mechanical irritation of the

skin, characterized by a fine, punctate, itching erythema, which
often disappears with continued exposure.  However, few reliable
data  are available concerning  the prevalence of  dermatitis in
workers exposed to MMMF.  In several early case reports and in a
more  recent limited cross-sectional  study, eye irritation  was
also associated with exposure to MMMF in the work-place.

    In  reports that appeared  in the early  literature, several
cases  of acute irritation  of the upper  respiratory tract  and
more   serious  pulmonary  diseases,  such   as  bronchiectasis,
pneumonia,  chronic bronchitis, and  asthma, were attributed  to
occupational  exposure  to MMMF.   However,  it is  likely  that
exposure  to MMMF was incidental  rather than causal in  most of
these  cases,  since  the  reported  conditions  have  not  been
observed consistently in more recently conducted epidemiological
studies.

    Some  cross-sectional  epidemiological studies  suggest that
there  may  be  MMMF  exposure-related  effects  on  respiratory
function;  others  do not.   In  a large,  well-conducted study,
there was an increase in the prevalence of low  profusion  small
shadowing  on the chest  radiographs of cigarette  smokers  with
increasing length of employment in MMMF manufacturing.  However,
no  consistent pattern of MMMF-related  non-malignant effects on
the  respiratory  system  has  emerged,  to  date,  from  cross-
sectional surveys.

    There has been little evidence of excess mortality from non-
malignant   respiratory  disease  (NMRD)  in   MMMF  workers  in
analytical  epidemiological studies that have  been conducted to
date,  including  the  two largest  investigations  conducted in
Europe  and the USA.   There were no  statistically  significant
increases  in NMRD mortality  in any sector  of the industry  in
comparison   with   local  rates  in  the  US  study,  though  a
statistically  significant  excess  was reported  for glass wool
workers  in  comparison with  national  rates.  In  the European
study,  there were no excesses of NMRD mortality.  The mortality
rates were not related either to time since first exposure or to
duration or intensity of exposure.

    There  has not been  any evidence, in  studies conducted  to
date,  that pleural or  peritoneal mesotheliomas are  associated
with occupational exposure to MMMF.

    An  excess of mortality due to lung cancer has been observed
in  the  large epidemiological  studies  on rock  wool/slag wool
production workers conducted in Europe and the USA, but  not  in
studies  on  glass wool  or  continuous filament  workers.   The
excess  of lung cancer  mortality and/or incidence  in the  rock
wool/slag  wool  production  industry was  apparent  when either
local  or  national  rates  were  used  for   comparison   (both
statistically  significant in the US study and not statistically
significant  in the European  study).  There was  a relationship
(not  statistically significant) with time  from first exposure,
in   the  European  study,  but   not  in  the  US   study.   No

relationships   with   duration   of  employment   or  estimated
cumulative  exposure to fibres  were observed.  In  the European
study,  a statistically significant  excess of lung  cancer  was
found  in  workers in  the  "early technological  phase", during
which airborne fibre levels were estimated to have  been  higher
than  in later production  phases.  A statistically  significant
increase  in lung  cancer mortality  in the  European study,  20
years after first exposure, appeared to be associated  with  the
use  of  slag,  but there was a large overlap between the use of
slag  and the  early technological  phase.  Neither  the use  of
bitumen  and pitch nor the presence of asbestos in some products
accounted  for the observed lung cancer excess.  In the European
study,  there  was  no excess  lung  cancer  mortality  in  rock
wool/slag   wool  production  workers  employed   in  the  "late
technological phase", when concentrations of fibres were thought
to  be lower  after the  full introduction  of dust  suppressing
agents.

    For glass wool production workers, there were no excesses of
lung  cancer mortality compared with  local rates in either  the
large  European  or US  cohorts,  but there  were  statistically
significant  increases  compared  with national  rates.  In both
investigations,  mortality  from  respiratory cancer  showed  an
increase  with time from  first exposure that  was not  statist-
ically  significant.  However, it was not related to duration of
employment  or  estimated cumulative  fibre  exposure in  the US
study,  or  to different  technological  phases in  the European
study.   The SMR for respiratory cancer, in workers who had been
exposed  in the manufacture  of small diameter  (<3 m)   glass
wool fibres in the US cohort, was elevated compared with that in
those who had never been exposed in this production sector.  The
excess in these workers was related to time from first exposure,
but  neither  the  overall increase  nor  the  time trends  were
statistically  significant.   A statistically  significant large
excess  of lung cancer, observed in a smaller Canadian cohort of
glass  wool production workers,  was not related  to time  since
first exposure or duration of employment.

    There has not been an increase in lung cancer  mortality  or
incidence  in continuous filament production  workers in studies
conducted to date.

    There  have been some suggestions  of excesses of cancer  at
sites  other than  the lung  (e.g., pharynx  and buccal  cavity,
larynx,  and  bladder) in  studies  on MMMF  production workers.
However, in most cases, excesses of cancer of these sites, which
were not observed consistently, were small, and were not related
to  the time  since first  exposure or  duration of  employment.
Moreover,  confounding factors in  the etiology of  some of  the
cancers  (e.g., alcohol consumption)  have not been  taken  into
account in studies conducted to date.

    No epidemiological data are available on cancer mortality or
incidence in refractory fibre workers.

    There  have  been  isolated  case  reports  of   respiratory
symptoms  and dermatitis associated with exposure to MMMF in the
home and office environments. However, available epidemiological
data are insufficient to draw conclusions in this regard.

1.8.  Evaluation of Human Health Risks

1.8.1.  Occupationally exposed populations

    Data  available  are  insufficient to  derive  an  exposure-
response  relationship  for  dermatitis and  eye  irritation  in
workers exposed to MMMF.  In addition, although there  has  been
some  evidence  of  non-neoplastic respiratory  effects in MMMF-
exposed workers, no consistent pattern has emerged and it is not
possible,  therefore, to draw conclusions  concerning the nature
and extent of the hazard in this regard.

    Although  there is no  evidence that pleural  or  peritoneal
mesotheliomas have been associated with occupational exposure in
the production of various MMMF, there have been  indications  of
increases  in  lung  cancer from  the  principal epidemiological
studies,  mainly in workers  in the rock  wool/slag wool  sector
employed  in an early production phase.  Although it is possible
that other factors may have contributed to this excess, possible
contaminants  and potential confounding factors examined to date
have  not  explained the  excess  lung cancer  rate.   Moreover,
available data are consistent with the hypothesis that it is the
airborne  fibre  concentrations  that  are  the  most  important
determinant of lung cancer risk.

    In  general, airborne MMMF  fibre concentrations present  in
work-places  with modern control  technology are low.   However,
mean elevated levels within the same order as those estimated to
have  been  present  in the  early  production  phase have  been
measured in several segments of the production  and  application
industry  (e.g.,  ceramic fibre  and  small diameter  glass wool
production  and spraying of insulation wool in confined places).
The lung cancer risk for the small number of workers employed in
these  sectors  could  potentially  be  elevated  if  protective
equipment is not used.

1.8.2.  General population

    On  the  basis  of available  data,  it  is not  possible to
estimate  quantitatively the risks  associated with exposure  of
the  general population to  MMMF in the  environment.   However,
levels  of MMMF in the  typical general and indoor  environments
measured  to date are much  lower (by some orders  of magnitude)
than  some occupational exposures  in the past  associated  with
raised lung cancer risks.  Thus, the overall  picture  indicates
that the possible risk for the general population is  very  low,
if  there is  any at  all, and  should not  be a  cause for  any
concern if current low exposures continue.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1.  Identity, Terminology, Physical and Chemical Properties

    The  man-made  mineral  fibres  (MMMF),  discussed  in  this
document, will be restricted largely to a subset known  as  man-
made  vitreous fibres (MMVF), which are fibres manufactured from
glass,  natural rock, or  other minerals.  They  are  classified
according to their source material.  Slag wool, rock  wool,  and
glass  wool or filaments are  produced from slag, natural  rock,
and  glass,  respectively  (Ottery et  al.,  1984).   Refractory
fibres,  including ceramic fibres,  which are also  discussed in
this  report, comprise a large  group of amorphous or  partially
crystalline synthetic mineral fibres that are highly refractory.
They  are produced from  kaolin clay or  the oxides of  alumina,
silicon,  or  other metals,  or,  less commonly,  from non-oxide
materials,  such as silicon  carbide, silicon nitride,  or boron
nitride.

    In North America, slag wool and rock wool are often referred
to  as  "mineral wool";  in Europe and  Asia, the term  "mineral
wool" also includes glass wool.  A "wool" is an  entangled  mass
of fibres in contrast to the more ordered fibres  in  continuous
filament (textile) glass.

    While   naturally   occurring  fibres   are  crystalline  in
structure,   most   man-made   mineral  fibres   are   amorphous
silicates.a    The amorphous networks  of MMMF are  composed  of
oxides of silica, boron, and aluminium, oxides of  the  alkaline
earth  and alkali metals, oxides of bivalent iron and manganese,
or  amphoteric  oxides  (e.g., Al2O3,  Fe2O3) (Klingholz, 1977).
The chemical compositions of various types of MMMF are presented
in Fig. 1 and Tables 1 and 2.  Common trade names are  given  in
Table  3  and  codes for  fibres  commonly  used in  studies  of
biological  effects are included  in Table 4.   The  terminology
currently  used is not  consistent or well  defined.  Categories
and  materials are named with  reference to use, structure,  raw
material,  or process.  The  distinctions are not  always clear,
and categories may overlap.

    MMMF products usually contain a binder and an oil  for  dust
suppression.   Textile  fibre may  contain  a sizing  agent  for
lubrication.   Some  special  fibres contain  a  surfactant  for
improving  dispersion.  MMMF may be produced with only an oil as
a  dust  suppressant. Special  purpose  fibres may  be  produced
without  any  additives (Hill,  1977).   Some chemicals  used in
binders are presented in Table 5.

----------------------------------------------------------------
a Most   ceramic  (aluminosilicate)  fibres  have  an  amorphous
structure  when  they  are  produced,  but  some  conversion  to
crystalline  material (cristobalite, mullite) can  occur at high
temperature  (>  1000 C) (Vine  et  al., 1983;  Gantner,  1986;
Khorami et al., 1986; Strbel et al., 1986).

FIGURE 1

Table 1.  Examples of the composition of continuous glass 
filament, glass wool, rock wool, and slag wool (% by weight)
-------------------------------------------------------------
Component  Continuous   Glass woolb  Rock woolc  Slag woolc
           glass 
           filamenta
-------------------------------------------------------------
SiO2       52 - 56      63           47 - 53     40 - 45
CaO        16 - 25      7            16 - 30     10 - 38
Al2O3      12 - 16      (+Fe2O3) 6   6 - 13      11.5 - 13.5
B2O3       8 - 13       6            -           -
MgO        0 - 6        3            -           -
Na2O       0 - 3        14           2.3 - 2.5   1.4 - 2.5
K2O        0 - 3        1            1 - 1.6     0.3 - 1.4
TiO2       0 - 0.4      -            0.5 - 1.5   0.4 - 2
Fe2O3      0.05 - 0.4   -            0.5 - 1.5   8.2
F2         -            0.7          -           -
-------------------------------------------------------------
a   From: Klingholz (1977).
b   From: Mohr & Rowe (1978).
c   From: IARC (in press).


Table 2.  Composition of some commercial ceramic fibresa (% by weight)
------------------------------------------------------------------------------------
Component   Fiber-  Fiber-  Fiber- Fiber-  Alumina   Zirconia  Fireline   NextelR
            fraxR   fraxR   maxTm  fraxR   bulk      bulk      ceramic    ceramic
            bulk    long    bulk   HSA     (SAFFILR)                      fibre 312
                    staple
------------------------------------------------------------------------------------
Al2O3       49.2    44      72     43.4    95        -         95-97.25   62
SiO2        50.5    51      27     53.9    5         < 0.3     95-97.25   24
ZrO2        -       5       0      0       0         92        -          -
Fe2O3       0.06    0       0.02   0.8     -         -         0.97-0.53  -
TiO2        0.02    0       0.001  1.6     -         -         1.27-0.70  -
K2O         0.03    -       -      0.1     -         -         -          -
Na2O        0.20    -       0.10   0.1     -         -         0.15-0.08  -
CaO         -       -       0.05   -       -         -         0.07-0.04  -
MgO         -       -       0.05   -       -         -         trace      -
Y2O3        -       -       -      -       -         8         -          -
B2O3        -       -       -      -       -         -         0.06-0.03  14
Leachable   < 10    < 10    11     < 10    -         -         -          -
chlorides   ppm     ppm     ppm    ppm
Organics    -       -       -      -       -         -         2.47-1.36  -
------------------------------------------------------------------------------------
a  From: IARC (in press).

    Unlike some natural fibres, MMMF do not split longitudinally
into   fibrils  of  smaller  diameter,  though  they  may  break
transversely   into   shorter   fragments.   Consequently,   the
diameters  of fibres to which workers may be exposed will depend
on the diameter as manufactured, but the length of  such  fibres
will vary according to the extent to which they have been broken
subsequently (HSC, 1979).

    A  particle of any  shape, density, and  size has a  defined
settling  speed in air.  The  diameter of a sphere  with density
1 g/cm3  and having the same  settling speed as the  particle in
question  will be its aerodynamic diameter (Dae).  For MMMF, the
Dae is roughly 3 times the geometric diameter, with only a small
dependence on fibre length.

2.2.  Production Methods

2.2.1.  General

    The methods of production of various MMMF are  presented  in
Fig. 2.  Man-made mineral fibres are produced from a liquid melt
of  the  starting material  (e.g.,  slag, natural  rock,  glass,
clays)  at  temperatures  of  1000  -  1500 C.    Three   basic
fiberizing  methods, which vary  from plant to  plant and  which
have  changed with technological advances,  are used: mechanical
drawing, blowing with hot gases, and centrifuging.  Combinations
of   these  methods  (e.g.,   drawing/blowing,  blowing/blowing,
centrifuging/blowing) are sometimes used (Klingholz, 1977).

    MMMF  are manufactured to nominal  diametersa and  fall into
four  broad  groups  (Fig. 2):  continuous filaments, insulation
wools,  refractory  fibres,  and special  purpose  fibres (Hill,
1977;  Ottery et al., 1984).  Continuous filaments, used in tex-
tiles  and for reinforcing plastics, are produced by the drawing
process  and individual fibre diameters (6 - 15 m)  are closely
distributed around the median value.  Few are  respirable.   The
nominal diameter of insulation wools, which are produced largely
by  centrifuging or blowing or a combination of both, is about 4
or 5 m.b     The production method gives a much wider distribu-
tion  around the  nominal diameter,  with a  high proportion  of
respirable  fibres.  For special  applications, such as  hearing
protection,  the  nominal  diameter  may  be as low as 1 - 2 m.
Special  fibres,  which  account for  only  about  1%  of  world
production,  are  used in  special  applications, such  as high-
efficiency  filter  papers  (Hill,  1977)   and  insulation  for
aircraft and space vehicles (Kilburn, 1982).  The  diameters  of
the  majority of these  fibres are less  than 1 m.   Continuous
filaments  and special purpose  submicron-range fibres are  made
exclusively  from glass, whereas  insulation wools can  also  be
manufactured from rock or slag.

----------------------------------------------------------------
a   The nominal diameter is the median length-weighted diameter.
    All  fibres in the  sample are joined  together in order  of
    increasing  diameter; the diameter  halfway along this  long
    fibre is then the nominal diameter.
b   Some glass fibre insulation wool with a nominal  fibre  dia-
    meter  of  about  2 m   is  now  being  produced  in  North
    America.

Table 3.  Synonyms and trade names of MMMF productsa
------------------------------------------------------------------------
Term/Name                 Category   Remarks
------------------------------------------------------------------------
TEL                         GW
Fibreglass insulation       GW       FiberglasR is a trade name
Boron silicate glass        GW       Most glass wools are of boro-
 fibre                                silicate type
Saint Gobain                GW       Major insulation producer
                                      (TEL process)
GF/D Whatman filter         GF       Filters made from glass fibres
GF/C microfilter            GF       Filters made from glass fibres
Rock wool                   RW       RockwoolR is a trade name
Pyrex glass fibres          GF       PyrexR is a glass with high  
                                      chemical resistance
Basalt wool                 RW
Mineral wool
Man-made mineral                     Slag or rock wool (USA)
 insulation fibres                   Glass, slag, or rock wool (Europe)
Insulation wool
Refractory fibres           CF
Fibrous ceramic aluminium   CF
 silicate glass
SaffilR                              alumina oxide (4% silica)b
FiberfraxR                  CF
Ceramic wool                CF
Owens-Corning BetaR         GF
Calcium silicate            CF
Calcium-alumino-silicate    CF
Refractory ceramic fibre    CF
Alumina and zirconia fibre  CF
Zirconia                    CF
Fireline ceramic            CF
NextelR ceramic fibre       CF
FibermakTM
------------------------------------------------------------------------
a   Only synonyms and trade names used in this document are listed.
b   Microcrystalline.

    GW = glass wool.
    GF = glass fibre other than wool.
    RW = rock wool.
    SW = slag wool.
    CF = ceramic fibre.

Table 4.  Codes for Manville glass fibres mentioned in 
this documenta
---------------------------------------------------------
           Designation   Range of nominal   Glass typeb
                         diameters (m)
---------------------------------------------------------
Code:      JM 80         .24 - .28          475
           JM 100        .28 - .38          475
           JM 102        .35 - .42          475
           JM 104        .43 - .53          475, E
           JM 106        .54 - .68          475, E
           JM 110        1.9 - 3            475
---------------------------------------------------------
a   Current data. Specifications have changed over time.
b   475: General purpose borosilicate.
    E: Electrical grade, alkali-free borosilicate.

Table 5.  Chemicals used in 
binders for MMMFa
-------------------------------
Phenol formaldehyde resin
Urea formaldehyde resin
Melamine formaldehyde resin
Polyvinyl acetate
Vinsol resin
Urea
Silicones
Dyes
Ammonium sulfate
Ammonium hydroxide
Starch
Carbon pigment
Epoxy resins
Pseudo-epoxy resins
Bitumens
-------------------------------
a From: Hill (1977) and WHO (1983a).

FIGURE 2

    Available  data on the  physical and chemical  properties of
some MMMF are presented in Table 6.  The chemical composition of
the various MMMF determines their chemical resistance  (the  sum
of  the acidic oxides divided  by the sum of  the amphoteric and
basic  oxides  measured in  molar  units).  Typical  values  are
0.50 -  0.65 for   slag wool,  0.80 -  1.10 for  rock wool,  and
1.55 - 2.50 for glass wool (Klingholz, 1977).  The solubility of
MMMF in aqueous and physiological solutions varies considerably,
according   to  their  chemical   composition  and  fibre   size
distribution.   Solubility  increases  with  increasing   alkali
content  for a  given composition  of other  elements, and  fine
fibres degrade more rapidly than coarse ones  in vitro (Spurny et
al.,  1983).  Thermal conductivity is mainly a function of fibre
diameter  and bulk  density, with  finer fibres  having a  lower
thermal conductivity.


Table 6.  Physical and chemical properties of some MMMF
--------------------------------------------------------------------------------------------------------
MMMF                  Fibre size          Fibre sur-  Melting   Density     Refractive  Physical
                      distributiona       face areab  pointb,c  (g/cm3)     indexa      stateb
                      (m)                (m2/g)      (C)
--------------------------------------------------------------------------------------------------------

Glass filament        range of fibre      -           -         2.596a      1.548        
                      diameters: 6 - 9.5

Glass wool            range of fibre      -           -         2.605a      1.549        
(coarse)              diameters: 7.5 - 15

Glass wool            range of fibre      -           -         
                      diameters:
- micro glass fibres  0.75 - 2                                  2.568a      1.537
- special purpose     0.25 - 0.75
  glass fibres

Ceramic               mean fibre dia-     0.5         1790      2.73b       -           white fibre
(FiberfraxR bulk)     meters: 2 - 3;
                      mean fibre length:
                      < 102 mm

Ceramic (Fiber-       mean fibre dia-     -           1790      2.62b       -           white fibre
fraxR long staple)    meters: 5 and 13;
                      mean fibre length:
                      < 254 mm

Ceramic               mean fibre dia-     7.65        1870      3b          -           white, mullite,
(FibermaxTM bulk)     meters: 2 - 3.5                                                   polycrystalline

Ceramic               mean fibre dia-     2.5         1790      2.7b        -           white to light
(FiberfraxR HSA)      meters: 1.2;                                                      grey
                      mean fibre length:
                      3 mm

Ceramic               mean fibre dia-     -           2040      3b          -           white
(SAFFILR - alumina    meters: 3; mean
bulk)                 fibre length:
                      3 mm

Table 6.  (contd.)
--------------------------------------------------------------------------------------------------------
MMMF                  Fibre size          Fibre sur-  Melting   Density     Refractive  Physical
                      distributiona       face areab  pointb,c  (g/cm3)     indexa      stateb
                      (m)                (m2/g)      (C)
--------------------------------------------------------------------------------------------------------

Ceramic               mean fibre dia-     -           2600      0.24-0.64b  -           white
(zirconian bulk)      meters: 3 - 6;
                      mean fibre length:
                      < 1.5 mm

Fireline ceramic      -                   -           1700      -           -           white to cream
                                                                                        colour

Ceramic               mean fibre dia-     < 1         1700       > 2.7b     -           white, smooth,
(NextelR fibre        meters: 8 - 12;                                                   transparent,
312 filament)         mean fibre length:                                                continuous poly-
                      continuous                                                        crystalline 
                                                                                        metal oxide
--------------------------------------------------------------------------------------------------------
a   From: NIOSH (1977).      
b   From: IARC (in press).
c   Vitreous fibres have no precies melting point.
2.2.2.  Historical

    Production  conditions  in  early mineral  wool  plants were
usually  very  primitive,  particularly those  operating  before
1950.  Many different raw materials were used, especially in the
slag  wool industry.  In  addition to foundry  and steel  slags,
chrome, lead, and copper slags were also used.  The  glass  wool
industry,  being based on an  already existing raw material  and
melting technology, was technologically more advanced and stable
(Ohberg, in press).

    The production environment during these early operations was
poorly controlled and could occasionally be heavily polluted.

    Some plants started in a batch operation mode  and  operated
this way for a period that varied between plants.  Subsequently,
production  methods  changed to  continuous operating procedures
(Cherrie & Dodgson, 1986; Ohberg, in press). Oil was not usually
used as a dust suppressant during these early operations.

    In  a  historical  environmental  investigation  (Cherrie  &
Dodgson,   1986),  conducted  as  part  of  the  large  European
epidemiological  study (Simonato et  al., 1986a, in  press), the
absence of oil and or the use of batch production was defined as
the  early  technological  phase.   The  introduction  of  dust-
suppressing  agents and implementation of  continuous production
procedures  constituted the late  phase.  Between the  early and
late   phases,  in  most  production  facilities,  there  was  a
transition period called the intermediate phase.

    Methods   of  product  manufacture  and   manipulation  were
principally   manual,  the  products   were  very  simple,   and
production  rates  were  low in  the  early  phase.  Later,  the
diversity  and complexity of the  products increased as well  as
the  production  rate.  The  degree  of mechanization  was  also
increased  (i.e.,  introduction  of  saws,  cutters,  conveyors,
etc.), with a corresponding gradual reduction of manual handling
(Cherrie  et al., in press; Dodgson et al., in press; Ohberg, in
press).

2.3.  Analytical Methods

2.3.1.  Air

    The  methods currently used for  the collection, quantifica-
tion, and identification of airborne fibrous particulates in the
occupational   and   general  environments   are  summarized  in
Table 7.   The detection  limits shown  in Table  7 are  optimal
values.   Rather higher detection limits are achieved in routine
practice;  namely,  0.25 m  for  PCOM,  0.05 m  for  SEM,  and
0.005 m for TEM.


Table 7.  Measurement of MMMF
--------------------------------------------------------------------------------------------------------
Measure- Sampling         Quantification    Identif-     Detect-  Comments         Reference
ment                                        ication      tion
                                                         limit
                                                         (m)
--------------------------------------------------------------------------------------------------------
Mass     glass wool or    gravimetric                             biologically     WHO (1981)
         cellulose        (analytical                             relevant             
         ester            balance)                                fraction not
         membrane                                                 determined
         filters;    
         pore size   
         0.6 - 1.5 m

Fibre    cellulose ester  phase contrast    morphology   2 x 10-1 fibres with      WHO (1981, 1985);
number   membrane         optical                                 diameter         Chatfield (1983)
         filters;         microscopy                              < 0.2 m not           
         pore size        (PCOM)                                  detected; not
         0.5 - 1.5 m                                             possible to          
                                                                  distinguish  
                                                                  MMMF from    
                                                                  other fibres 

Fibre    membrane or      scanning          morphology;  5 x 10-4 improved         Burdett & Rood
number   Nuclepore        electron          chemical              resolution       (1983); Chatfield
         polycarbonate    microscopy        composition           and fibre        (1983)
         filters          (SEM)             by EDXAa              identification

Fibre    membrane or      transmission      morphology;  2 x 10-5 best resolution  Chatfield (1983)
number   Nuclepore        electron          chemical              and fibre 
         filters          microscopy        composition           identification; 
                          (TEM)             by EDXA;              sample 
                                            crystalline           preparation     
                                            structure             not standardized
                                            by SAEDb                                                
--------------------------------------------------------------------------------------------------------
a  EDXA = Energy dispersive X-ray analysis.
b  SAED = Selected area electron diffraction.
    For  MMMF,  analyses have  been  restricted largely  to  the
measurement  of  total  airborne  mass  concentration  or,  more
recently,   to  the  determination  of   airborne  fibre  number
concentrations by phase contrast optical microscopy (PCOM).  The
method  for sampling personal exposure levels involves drawing a
measured volume of air through a filter mounted in a holder that
is  located  in  the breathing  zone  of  the  subject.   Static
sampling  methods  are  not recommended  for  measuring personal
exposures.   When measuring mass concentrations  of MMMF, either
cellulose  ester membrane or  glass fibre filters  can be  used.
The  filters are stabilized in  air and weighed against  control
filters, both before and after sampling, to permit correction of
weight changes caused by varying humidity.  Only cellulose ester
filters  are used for assessing fibre number concentrations.  In
this  case, the filter is made optically transparent with one of
several  clearing agents (e.g., triacetin,  acetone, or ethylene
glycol monomethyl ether)  and the fibres present  within  random
areas  are counted and classified using PCOM.  For this purpose,
a  fibre is defined  as a particle  having a length  to diameter
ratio  (aspect ratio) > 3  and a  length >  5 m.    Respirable
fibres  are those with diameters < 3 m.   Fibres with diameters
exceeding 3 m are termed non-respirable fibres.

    Sampling   strategies  should  be  well-designed,  based  on
careful  consideration of "how",  "where", "when", and  "for how
long"  to sample, as  well as "how  many samples" to  collect to
ensure  that  the  results are  comparable.  Sampling strategies
will   vary  depending  on   the  reason  for   sampling,  e.g.,
epidemiology,  dust  control,  etc.  Sampling  strategy has been
discussed  in  the literature  (NIOSH,  1977; Valic,  1983; WHO,
1984).

    Although  the basic methods  for the determination  of total
airborne  mass and fibre number concentrations in most countries
are similar, differences in the sampling procedure,  the  filter
size and type, the clearing agent, and the microscope used, and,
particularly,  statistical  and  subjective errors  in counting,
contribute to variations in results.  In order that results from
different  countries  should  be more  comparable,  a  reference
method for monitoring MMMF at the work-place based on  PCOM  was
proposed by WHO in 1981 and has been widely used in  a  slightly
modified  form (WHO,  1985)  since  that time.   The results  of
recent  slide  exchanges  among participating  laboratories have
shown  a  maximum systematic  counting  difference of  about 1.8
times for this method (Crawford et al., in press).

    Rendall  & Schoeman (1985) reported that the contrast of the
phase image for the counting of glass fibres was improved by the
low-temperature  ashing of the membrane filter attached to glass
slides  by acetone vapours  followed by microscopic  examination
using  simple  Khler illumination.   Automatic counting methods
are  currently being developed and may in future provide greater
consistency in results (Burdett et al., 1984).

    The  improved  resolution  of electron  microscopy  and  the
identification   capacity,   particularly   of  the   analytical
transmission   electron  microscope  (TEM  with   selected  area
electron diffraction (SAED) and energy dispersive X-ray analysis
(EDXA)), make these methods more suitable for analysis of fibres
in  the general environment,  where MMMF may  constitute only  a
small  fraction of the  airborne fibrous material.   However, to
date,  use of these  methods for the  determination of MMMF  has
been restricted largely to the characterization of  fibre  sizes
airborne in the occupational environment.

    In analysing by SEM, the fibres collected  on  polycarbonate
filters can be directly examined.  This avoids the need  to  use
transfer techniques that may affect the fibre size distribution.
WHO  has developed a  reference method for  SEM, principally  to
characterize  fibre size (WHO,  1985).  Using the  same sampling
method  as  for  the PCOM  method,  samples  are collected  on a
polycarbonate  (Nuclepore)  or  PVC-copolymer  membrane   filter
(Gelman DM 800) and observed at a magnification of  5000  times.
Fibre lengths and diameters are measured from optically enlarged
images of photomicrographs.

    In  the past,  methods of  sample preparation  for TEM  have
varied  considerably,  making  comparison of  values obtained by
different  investigators difficult.  At present, direct transfer
preparation  techniques involving carbon coating of particles on
the surface of a polycarbonate or membrane filter  and  indirect
sample  preparation methods, in which attempts have been made to
retain the fibre size distribution, are the most widely accepted
for analysis of fibres in air and water (Toft & Meek, 1986).

    The   size  distribution  of   "superfine"  MMMF  has   been
successfully  measured by a direct transfer sampling method on a
membrane  filter,  subsequent  analysis by  analytical  TEM, and
fibre  measurement by an image analysis system (Rood & Streeter,
1985).   On the basis  of their results,  the authors  concluded
that  a substantial proportion of the fibres would not have been
detected by PCOM or SEM, even fibres longer than 5 m.

2.3.2.  Biological materials

    Several  techniques have been developed for the recovery and
determination  of mineral fibres in  biological tissues.  Fibres
are commonly separated from tissue samples by  digestion  (e.g.,
by  sodium hypochlorite or potassium hydroxide)  or ashing (both
low and high temperature) and identified subsequently  by  light
or  electron  microscopy.   Methods for  sampling, analysis, and
identification  of  mineral fibres  in  lung tissues  have  been
reviewed recently by Davis et al. (1986).

    To  date, methods for the  sampling and analysis of  tissues
for  fibrous particles  have not  been standardized  and  it  is
difficult  to  compare  the results  of  various  investigators.
Moreover,  available data indicate that common methods of tissue
separation, such as tissue digestion with sodium hypochlorite or

potassium  hydroxide, cause substantial losses  of MMMF (Johnson
et  al.,  1984b).  Thus,  data on levels  of MMMF in  biological
tissues should be cautiously interpreted.

    A method for the sampling and determination of fibres in the
eyes  of workers handling MMMF has been described by Schneider &
Stokholm  (1981).  Mucous threads and dried mucous, stained with
alcian  blue,  were removed   from the eye,  placed on a  slide,
ashed   in  a  low-temperature  asher,  and  examined  for  non-
respirable  fibre  content  by optical  microscopy.  The authors
reported  a good correlation,  among 15 samples,  between  fibre
levels  in  the  eyes and  total  dust  exposure or  total  non-
respirable  fibre  exposure.   Levels were  not  correlated with
airborne respirable fibre concentrations.

3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1.  Production

    Few  recent quantitative data  are available concerning  the
global  production of  MMMF.  As  illustrated in  Table 8,  this
value was reported to be 4.5 million tonnes in 1973 (WHO, 1983a;
Jrvholm,  1984).   In 1976, the value of the production of MMMF
was  estimated to be  greater than 1  billion US dollars  (Corn,
1979).

Table 8.  Estimated world production of MMMF materials 
in 1973a
---------------------------------------------------------
Area             Insulation   Textile        Total
                 materials    materials                 
                 1000    %    1000     %     1000    %
                 tonnes       tonnes         tonnes
---------------------------------------------------------
America

  Central/South  120     3    20       2     140     3
  North America  1600    43   400      46    2000    43

Australia        30      1    -        -     -       -

Europe

  Eastern        600     16   85       10    685     15
  Western        1200    32   260      30    1460    32

Japan            200     5    100      12    300     7

  World          3750    100  865      100   4585    100
---------------------------------------------------------
a From: WHO (1983a).

    It  has been estimated that, in 1985, total world production
of  MMMF  was  between  6  and  6.5  million  tonnes,  of  which
insulation  wools accounted for  approximately 5 million  tonnes
and textile grades for 1 - 1.5 million tonnes (EURIMA, 1987)a.

    Estimated annual production of fibrous glass in the  USA  in
the  late  1970s  was 370 000  tonnes  for  textile  fibres  and
1 200 000 tonnes for glass wool.  Total annual production in the
USA  has been estimated  to be 200 000  tonnes for mineral  wool
(slag and rock wool) and 21 000 tonnes for ceramic  fibre  (NRC,
1984).  In the United Kingdom, production of wool materials rose
from 3500 tonnes in 1937 to 130 000 tonnes in 1977 (WHO, 1983a).

--------------------------------------------------------------------------
a   Information provided by the European Insulation Manufacturers 
    Association, Luxembourg.

3.2.  Uses

    The  main  uses of  MMMF are presented  in Fig. 3.   Fibrous
glass accounts for approximately 80% of MMMF production  in  the
USA, with 80% of this being wool fibres used mainly  in  thermal
or  acoustic  insulation (Kirk-Othmer,  1980).  Insulation wools
are   usually  compressed  into  "bats",  "boards",  "blankets",
"sheets"  etc.  or bagged as  loose wool for blowing  or pouring
into structural spaces.  Some products are sewn or glued  on  to
asphalt  paper,  aluminium  foil, etc.   Textile  grades,  which
account  for 5 - 10% (or greater) of all fibrous glass, are used
extensively  in reinforcing resinous materials (e.g., automobile
bodies or boat hulls), paper and rubber products,  in  textiles,
such  as draperies, and  in electrical insulation  and  cording.
Less  than 1% of the production of glass fibre is in the form of
fine  fibres  (fibre  diameters  < 1 m),   which  are  used  in
specialty applications such as high efficiency filter papers and
insulation for aircraft and space vehicles.

FIGURE 3

    Rock  wool and slag  wool, which account  for  approximately
10 -  15% of  MMMF production  in the  USA, are  used mainly  as
acoustic  or  thermal  insulation for  industrial  buildings  or
processes.   In Europe, where  the production volumes  of  glass
wool and rock wool are similar, rock wool and slag wool are also
used extensively for domestic insulation.

    Ceramic  fibres  (1 -  2% of all  MMMF) are used  mainly for
high-temperature   insulation,   e.g.,   thermal  blankets   for
industrial  furnaces.  Smaller quantities are used for expansion
joint filling.

3.3.  Emissions into the Environment

    Data  on emissions of MMMF from manufacturing facilities are
limited.   Fibre  levels in  emissions  from fibrous  glass  and
mineral   wool  plants  in  the  Federal  Republic  of  Germany,
determined  by  SEM,  were  of  the  order  of  10-2  fibres/cm3
(Tiesler, 1982).  On the basis of these data, it  was  estimated
that the total fibrous dust emissions from MMMF plants  in  this
country  were  about  1.8 tonnes/year.   Emissions of respirable
fibres  (defined  by the  investigators  as fibres  with lengths
exceeding   10 m   and  diameters  of  less  than  1 m)   were
estimated to be 80 kg/year.

    It  seems likely that the  main source of emissions  of MMMF
(mainly  glass fibres)  in indoor  air is  insulation in  public
buildings   or  homes.   Although  quantitative   data  are  not
available,   emissions   are  probably   highest  shortly  after
installation  or following disturbance  of the insulation  (NRC,
1984).

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    The  transport, distribution, and transformation of MMMF  in
the  general  environment  have not  been  specifically studied.
However,  some general conclusions can be drawn, on the basis of
the  physical and chemical  properties of MMMF  and  information
concerning  the  behaviour  of  natural  mineral  fibres  in the
ambient air and water.

    Mineral  fibres  with small  diameters  are most  likely  to
remain airborne for long periods.  Marconi et al. (in press) and
Riediger  (1984) reported that, during  operations involving the
use  of mineral  wool products,  there is  a general  trend  for
airborne  fibres to become  shorter and thinner  with increasing
distance   from   working   areas.   For   example,  during  the
installation  of rock wool blankets,  Marconi et al. (in  press)
reported  that the respirable fraction of airborne fibres in the
working areas accounts for about 67% of total  airborne  fibres.
At a distance of about 5 m from the working area, the respirable
fraction is about 90% of the total fibres.  This is attributable
to the sedimentation of larger diameter fibres.

    The  solubility of MMMF  in water varies  considerably as  a
function   of   their   chemical  composition   and  fibre  size
distribution  (section 2).  Solubility increases with increasing
alkali  content for a given  composition of other elements,  and
fibres with fine diameters degrade more rapidly than coarse ones
(Spurny et al., 1983).  However, in general, MMMF are more water
soluble than naturally occurring asbestiform minerals and, thus,
most are likely to be less persistent in water supplies.

    MMMF  can be removed from  the environment by breakage  into
successively   smaller   fragments,  thus   losing  their  fibre
characteristics,  by  sedimentation  and  subsequent  burial  in
soil,  or by thermal  destruction (e.g., during  incineration of
MMMF-containing   waste).    Dissolution   and  deposition   and
subsequent burial in sediments are the most likely mechanisms of
removal from water.

5.  ENVIRONMENTAL CONCENTRATIONS AND HUMAN EXPOSURE

5.1.  Environmental Concentrations

5.1.1.  Air

5.1.1.1.  Occupational environment

    (a)  Production

    Available  data on levels  of MMMF in  production industries
are  presented in  Tables 9  and 10.   Although in  most of  the
surveys   conducted  to  date,   both  mass  concentrations   of
particulate  matter  and  respirable  fibre  levels  have   been
determined,  this  discussion  will  be  restricted  largely  to
information  on  fibre concentrations  that  appear to  be  most
relevant for the evaluation of potential health effects.

    Comparison  of data from  various surveys is  complicated by
lack  of consistency in the classification of various operations
and job categories and by differences in sampling  strategy  and
fibre  counting criteria.  For  example, a reference  method for
the   determination  of  airborne   MMMF  in  the   occupational
environment  has been introduced only  relatively recently (WHO,
1981, 1985); reassessment using the WHO PCOM reference method of
levels determined previously by interference microscopy resulted
in an increase in reported airborne concentrations  in  European
insulation  plants  of  approximately two-fold  (Cherrie et al.,
1986).  However, in spite of the difficulties in comparing data,
some  general  conclusions  concerning airborne  fibre  size and
concentrations in occupational environments can be drawn.  Fibre
levels in plants manufacturing MMMF are substantially lower than
those  measured in factories  using asbestos.  In  addition,  in
general,  the  measured median  diameter  of airborne  fibres is
consistently and substantially smaller than the nominal diameter
of  the fibres in the  product.  The median airborne  fibre dia-
meters were 4 m,  1.5 m,  and 0.2 m  for a product of nominal
fibre diameters of 14 m,  6 m,  and 1 m,  respectively (Esmen
et al., 1979a).  Esmen et al. (1979a) have shown that there is a
negative  correlation (r =  -0.96) between the  overall  process
average exposure levels (fibres/cm3) and the size of the nominal
diameter  produced.   A similar  pattern  has been  observed  by
Cherrie & Dodgson (1986).


Table 9. Airborne concentrations of MMMF in production industries
--------------------------------------------------------------------------------------------------------
Sampling               Analysis                                  Results                       Reference
                                      Occupational group mean fibre        Fibre size
                                      concentrations in fibres/cm3         distribution
--------------------------------------------------------------------------------------------------------
After 1970:            Phase                                               % fibres with dia-  Konzen 
650 samples in 6       contrast                                            meter < 3.5 m:     (1976)
wool insulation, 5     optical        Glass wool plants, 0.11 - 0.16       68.9 - 87.1
continuous textile,    microscopy;    Continuous textile, 0.07 - 0.37      76.9 - 98.0
and 4 fibre            length:        Non-corrosive product, 0.12          72.3
glass-reinforced       diameter       Flame attenuated                         
plastic products       > 3:1          fibre production, 0.38               89.3
plants          

1975-78:               Phase          Estimate of exposure for various     Concentration of    Corn &        
> 1500 personal        contrast       operations:                          fibres with dia-    Sansone 
8-h samples in         optical                                             meter < 1.5 m      (1974); 
16 production          microscopy;                                         and length > 8 m:  Corn et    
facilities (loose,     length:        Continuous, < 0.003                  0                   al. (1976);
continous, and         diameter       Coarse, 0.001 - 0.005                10-5 - 10-4         Esmen      
mixed) including 5     > 3:1;         Fibre glass insulation, 0.01 - 0.05  10-3 - 10-2         et al.     
mineral wool plants    length         Mineral wool, 0.2 - 2                5 x 10-2 -          (1978,     
in the USA             > 5 m;                                             5 x 10-1            1979a);    
                       transmission   Specialty-fine, 1 - 2                0.5 - 1             Corn    
                       electron       Microfibre, 1 - 50                   0.5 - 20            (1979);
                       microscopy                                                              Esmen  
                                                                                               (1984) 

> 950 breathing        phase          Continous filament glass fibres:     % with diameter     HSC (1979); 
zone and static        contrast       mean < 0.02; insulation wools-       < 1 m: glass wool  Head             
general atmospheric    optical        fibre production: 0.12 - 0.89;       insulation - 16%;   & Wagg
> 4-h samples at 25    microscopy;    production of basic fibrous          mineral wool insul- (1980)
manufacturing plants   length:        materials (slab, board, etc):        ation - 18%; glass
and construction       diameter       0.02 - 0.37; conversion of basic     microfibres - 60%;
sites in the           > 3:1;         materials to finished products       ceramic fibre - 18%
United Kingdom         length         (e.g., pipe sections): 0.02 - 0.35;
                       > 5 m;        special purpose fibres: 0.8 -
                       diameter       3.70; ceramic fibre-manufacture
                       < 3 m; 10%    and conversion: 1.09 - 1.27
                       re-examined 
                       by interference  
                       microscopy for
                       fibre size    
                       distribution  

Table 9. (contd.)
--------------------------------------------------------------------------------------------------------
Sampling               Analysis                                  Results                       Reference
                                      Occupational group mean fibre        Fibre size
                                      concentrations in fibres/cm3         distribution
--------------------------------------------------------------------------------------------------------
                                     
After 1980:            phase          In order of decreasing concentra-    Tendency for fibre  Hammad & 
> 200 personal         contrast       tions:                               diameters to be     Esmen
8-h samples in         optical        Very fine glass fibre plant:         smaller than in     (1984)
7 plants (2 mineral    microscopy;    0.048 - 6.77                         the first survey
wool, 2 ordinary       length:        Mineral wool plants:
glass fibre, 2         diameter       0.032 - 0.72
ordinary and fine      > 3:1;         Ordinary and fine glass fibre plants:
glass fibre, and       length         0.014 - 2.22
1 very fine glass      > 5 m;        Ordinary glass fibre plants:             
fibre) in the USA      transmission   0.017 - 0.062
                       electron    
                       microscopy  
                                   
                                   
                                   

> 300 personal and    phase                                                % with diameter     Dement 
stationary samples in  contrast                                            < 1 m:             (1975)
11 plants (4 large     optical        Large diameter glass insulation      2 - 46%
diameter insulation,   microscopy:    plants, 0.04 - 0.20
6 manufacturing or     all visible    Small diameter glass fibre           62 - 96%
using small diameter   fibres;        plants, 0.8 - 21.9                   
fibres, and 1 making   electron       Fibrous glass reinforced plastics    < 1%
fibrous glass          microscopy     plant, 0.03 - 0.07
reinforced products)   for a       
in the USA             proportion
                       of samples
--------------------------------------------------------------------------------------------------------

Table 9. (contd.)
--------------------------------------------------------------------------------------------------------
Sampling               Analysis                                  Results                       Reference
                                      Occupational group mean fibre        Fibre size
                                      concentrations in fibres/cm3         distribution
--------------------------------------------------------------------------------------------------------
1981: unspecified      phase          Centrifuging/blowing: < 0.1 - 0.44   Less than 1%        Riediger 
number of samples      contrast       Centrifuging rock and slag wool:     of fibres with      (1984)
at 75 locations        optical        < 0.1 - 0.4                          length > 20 m and
in plants in           microscopy:    Blowing rock wool: < 0.1 - 0.5       diameter < 0.25 m
the Federal Republic   length:        Cutting glass fibre filters:
of Germany             diameter       0.1 - 0.2
                       > 3:1;         Glass fibre reinforced plastics
                       length         (grinding and cuffing): < 0.1 - 0.4
                       > 5 m;        
                       diameter      
                       < 3 m;   
                       scanning   
                       electron   
                       microscopy 
                       for a      
                       proportion 
                       of samples 
                       (40 out of 
                       75)        
                                  

Unspecified number     phase                                               % of fibres         Indulski 
of static samples      contrast                                            with diameter       et al.
in 3 rock wool         optical                                             < 1.5 m:           (1984)
and 1 continuous       microscopy:    Rock wool: 0.10 - 0.65               17 - 53.5
filament plant         length:        Glass fibre (continuous filament):   27
                       diameter       0.10 - 0.46
                       > 3:1;         
                       length          
                       > 5 m;        
                       diameter        
                       < 3 m

Table 9. (contd.)
--------------------------------------------------------------------------------------------------------
Sampling               Analysis                                  Results                       Reference
                                      Occupational group mean fibre        Fibre size
                                      concentrations in fibres/cm3         distribution
--------------------------------------------------------------------------------------------------------

430 personal 8-h       phase          Mean concentrations ranged from      Geometric mean dia- Esmen 
samples in 3 ceramic   contrast       0.0082 (fibre cleaning) to 7.6       meter, 0.7 + 0.2    et al.
fibre production       optical        (process helper); individual range,  m; ~90% < 3 m     (1979b)
and product            microscopy;    0.0012 - 56                          in diameter; dia-
manufacturing          length:                                             meters of airborne
plants                 diameter                                            fibres from manu-
                       > 3:1;                                              facturing operations
                       length                                              greater than those
                       > 5 m;                                             from production
                       transmission                                        zones
                       electron 
                       microscopy

10 samples each        phase          Revised fibre concentrations         Median fibre        Cherrie 
from 10 rock and       contrast       approximately twice the original     lengths: rock       et al.
glass wool plants      optical        levels; mean levels in insula-       wool plants, 10 -   (1986)
in Europe examined     microscopy;    tion wool plants < 0.1 and in        20 m; glass wool
by Ottery et al.       length:        continuous filament plants < 0.01    plants, 8 - 15 m;
(1984) plus 20         diameter                                            median diameters:
"high" and "low"       > 3:1;                                              rock wool, 1.2 -
density samples        length                                              2 m; glass wool,
reassessed using       > 5 m;                                             0.7 - 1 m; 20 -
WHO PCOMa              diameter                                            50% of fibres with
reference method       < 3 m;                                              lengths > 8 m and
                       scanning                                            diameters < 1.5 m
                       electron                                            (% higher in glass
                       microscopy                                          wool than in rock
                                                                           wool plants)
--------------------------------------------------------------------------------------------------------
a   PCOM = Phase contrast optical microscopy.

Table 10.  Airborne gravimetric concentrations of MMMF in production industries
--------------------------------------------------------------------------------------------------------
Sampling        Analysis                                Results                       Reference
                                Short-term samples                  Time-weighted
                                (mg/m3)                             average concen-
                                                                    tration (mg/m3)
--------------------------------------------------------------------------------------------------------
1972;           Total airborne                                      0.1 - 0.75        Roschin & Azova
unspecified     dust in                                                               (1975)
number          breathing     
of samples      zone
in glass    
fibres plant
            

Mullitosilica   Gravimetry,     2.6 - 10.5 (loading in equipment,   2 - 3             Skomarokhin
fibres          chemistry, and  cutting, and packing glass fibres)                    (1985)
                microscopy
                                SiO2:Al2O3 ~1.0
                                SiO2 ~45.2%
                                Al2O3 ~53.1%
                                Fe2O3 - 0.09%
                                CaO - 0.19%
                                MgO - 0.34
                                K2O - 0.11
                                Na2O - 0.19
                                length: 1 - 3 m < 2.3%
                                        4 - 6 m - 4.3 - 7.6%
                                        7 - 11 m - 7 - 11.3%
                                        12 - 17 m - 10.5 - 13%
                                        18 - 25 m - 17.3 - 20.3%
                                        > 25 m - 38 - 48.7%
                                diameter: 1 - 3 m
--------------------------------------------------------------------------------------------------------
    The average concentrations measured by PCOM during the manu-
facture  of  fibrous  glass  insulation  are  of  the  order  of
0.03 fibres/cm3.   Average  concentrations  in continuous  fibre
plants are about one order of magnitude lower and concentrations
in  mineral  wool  (rock and slag) plants in the USA range up to
one  order of magnitude higher.  Corresponding concentrations in
European  rock wool plants are  of the order of  0.1 fibres/cm3.
Under  similar  plant conditions,  airborne fibre concentrations
are  about 4 times higher in ceramic fibre production than in US
mineral wool (rock and slag) plants, and average  ceramic  fibre
concentrations  have been reported to  range from 0.0082 to  7.6
fibres/cm3  (Esmen et al., 1979b).   Average airborne concentra-
tions   in   speciality  fine  fibre  plants  range  from  1  to
2 fibres/cm3   and  concentrations  are  highest  in  microfibre
production facilities (1 - 50 fibres/cm3).  However,  it  should
be  noted  that  individual exposure  varies  considerably;  for
individuals in the same job classification, concentrations range
over 2 orders of magnitude (Corn, 1979).

    Total  dust  concentrations are  typically  of the  order of
1 mg/m3,  irrespective of the fibre type manufactured (excluding
ceramic).  Overall averages were 4 - 5 mg/m3 for one  rock  wool
and  one glass wool plant where manufacturing was reported to be
heavy  or very heavy (Esmen et al., 1979a).  The situation in 13
European  plants was similar  (Cherrie et al.,  1986).  Averages
for  3  US  ceramic fibre  production  plants  were 6,  1.6, and
0.85 mg/m3,  respectively.   Results  from a  USSR ceramic fibre
plant are comparable (Skomarokhin, 1985).

    With  respect  to the  relationship  between fibre  and mass
concentrations,  Ottery et al. (1984)  summarized their observa-
tions as follows:

    "Where  fibre  and mass  concentrations  were compared  on a
plant-average  basis  a  broad  correlation  was  observed   (in
general, those plants which are "dusty" are also the  ones  with
higher  airborne fibre concentrations).  However,  this relation
was  not consistent between  different occupational groups,  nor
was  there  any  detectable  correlation  when  mass  and  fibre
concentrations were considered on an individual basis."

This  is  generally consistent  with  the observations  of other
investigators (Esmen et al., 1978; Head & Wagg, 1980).


Table 11. Airborne concentrations of MMMF in application industries
--------------------------------------------------------------------------------------------------------
Application                  Number of      Analysis                  Concentration         Reference
                             samples                                  (fibres/cm3)
                                                                      Mean (range)
--------------------------------------------------------------------------------------------------------
Denmark
Attic insulation, existing   total of 200   phase contrast optical    0.89 (0.04 - 3.5)     Schneider  
 buildings                   samples at     microscopy; length:                             (1979, 1984)
                             24 sites       diameter > 3:1; length
Insulation, new buildings                   > 5 m; diameter <        0.10 (0.04 - 0.17)
                                            3 m; scanning elec-
Technical insulation                        tron microscopy           0.35 (0.03 - 1.6)

Italy
Ship insulation (rock wool
 blankets)
- inside room                8              phase contrast optical    0.19 (0.05 - 0.65)    Marconi         
- outside room               9              microscopy; length:       0.021 (0.002 - 0.05)  et al.    
- installers                 14             diameter > 3:1; length    0.13 (0.009 - 0.41)   (1986)
- "finishing" workers        14             > 5 m; diameter          0.12 (0.03 - 0.31)
                                            < 3 m
Sweden
Attic insulation, existing   total of 58    phase contrast optical    1.1 (0.1 - 1.9)       Hallin         
 buildings                   samples at     microscopy; length:                             (1981);   
                             14 sites       diameter > 3:1; length                         Schneider
Insulation, new buildings                   > 5 m; diameter <        0.57 (0.007 - 1.8)    (1984)   
                                            3 m
Technical insulation                                                  0.37 (0.01 - 1.39)
 (boilers, cisterns)

Acoustic insulation                                                   0.15 (0.11 - 0.18)
- spraying                                                            0.51 (0.13 - 1.1)
- hanging fabric                                                      0.60 (0.30 - 0.76)
--------------------------------------------------------------------------------------------------------

Table 11. (contd.)
--------------------------------------------------------------------------------------------------------
Application                  Number         Analysis                  Concentration         Reference
                             of                                       (fibres/cm3)
                             samples                                  Mean (range)
--------------------------------------------------------------------------------------------------------
United Kingdom
Domestic loft insulation                    phase contrast optical                          Head & Wagg 
- glass fibre blanket        12             microscopy; length:       0.70 (0.24 - 1.8)     (1980)
- loose fill-mineral wool    16             diameter > 3:1; length    8.2 (0.54 - 21)
                                            > 5 m; diameter < 3 m

Fire protection-structural steel   
- sprayed mineral wool       22                                       0.77 (0.16 - 2.6)

Application in industrial products
- industrial engine exhaust
  insulation (mineral wool)  15                                       0.085 (0.02 - 0.36)

USA
Fibrous glass duct wrapping  5              phase contrast optical    0.02 - 0.09           Fowler et 
Wall and plenum insulation   5              microscopy; size cri-     0.01 - 0.47           al. (1971)
Pipe insulation              6              teria not described       0.02 - 0.09
Housing insulation           1                                        0.20

Acoustic ceiling installer   12             phase contrast optical    0.0028 (0 - 0.0006)   Esmen et 
                                            microscopy; length:                             al. (1982)
Duct installation                           diameter > 3:1; length
- pipe covering              31             > 5 m; diameter < 3      0.06 (0.0074 - 0.38)
- blanket insulation         8              m; transmission          0.05 (0.025 - 0.14)
- wrap around                11             electron microscopy       0.06 (0.030 - 0.15)

Attic insulation (fibrous glass)
- roofer                     6                                        0.31 (0.073 - 0.93)
- blower                     16                                       1.8 (0.67 - 4.8)
- feeder                     18                                       0.70 (0.06 - 1.5)

Attic insulation (mineral wool)
- roofer                     9                                        0.53 (0.041 - 2.03)
- blower                     23                                       4.2 (0.50 - 15)
- feeder                     9                                        1.4 (0.26 - 4.4)
                             
Installer of building        31                                       0.13 (0.013 - 0.41)
insulation
--------------------------------------------------------------------------------------------------------
    (b)  User industries

    Available  data on airborne fibre  concentrations associated
with  the installation of products containing MMMF are presented
in Table 11.  Airborne concentrations during the installation of
insulation  vary  considerably,  depending  on  the  method   of
application and the extent of confinement within the work-space.
Concentrations  during installation are comparable  to, or lower
than,  levels found in  the production of  the fibrous  material
(Esmen  et al., 1982), with the exception of blowing or spraying
operations  conducted  in confined  spaces,  such as  during the
insulation  of aircraft or attics  (Head & Wagg, 1980;  Esmen et
al.,  1982).   In  various surveys,  mean  concentrations during
the  installation  of fibrous  glass  insulation in  attics have
ranged  up  to 1.8  fibres/cm3;  mean concentrations  during the
application   of   mineral   wool   insulation   under   similar
circumstances have been as high as 8.2 fibres/cm3.   During  the
installation  of rock wool blankets  in very confined spaces  on
board  ships, concentrations have been less than 0.65 fibres/cm3
(Marconi et al., in press).  It should be noted that  the  time-
weighted  average  exposure  of insulation  workers  is probably
considerably   less   than  these   mean  concentrations  during
application, as insulators work with MMMF materials from < 10 to
100% of their time, depending on their employment and  the  type
of  construction site (Fowler  et al., 1971).   The majority  of
joiners  and carpenters may use from 0.5 to 15% of their working
hours on MMMF work (Schneider, 1984).  On the basis of estimates
made by Esmen et al. (1982), time-weighted average exposures may
exceed  1  fibres/cm3 only  for  workers insulating  attics with
mineral wool (TWA = 2 fibres/cm3; range, 0.29 - 6.3 fibres/cm3).
Time-weighted  average exposures for workers using fibrous glass
in attics or employed in building insulation were  estimated  to
be  0.7  fibres/cm3  (range, 0.42  -  1.2  fibres/cm3) and  0.11
fibres/cm3 (range, 0.08 - 0.2 fibres/cm3), respectively.

    Air  at construction sites  and in certain  other industrial
and  domestic  environments  may contain  substantial amounts of
non-fibrous  dust.  The gravimetric  concentration of fibres  in
total dust samples has been determined by optical microscopy for
a  range of user industries (Schneider, 1979).  The ratio weight
of all fibres of all sizes in total dust samples/weight of total
dust  had a geometric  mean of 0.14,  with 90% between  0.06 and
0.33.

    Howie et al. (1986) recently investigated fibre release from
filtering  facepiece  respirators containing   "superfine" MMMF.
These respirators are often used for the protection  of  workers
in  dusty  occupational  environments.   Following  the  use  of
several  different types of these  respirators for either 15  or
40 min,  downstream respirable fibre concentrations  ranged from
not detectable (<0.1 fibres/cm3) to 200 fibres/cm3,  using  the
WHO reference PCOM method of monitoring.

5.1.1.2.  Ambient air

    Few  data  are  available concerning  concentrations of MMMF
present in the general environment.  The fibrous  glass  content
of several samples of outdoor air was determined in a  study  by
Balzer   et  al.  (1971),  which  was  designed  principally  to
investigate the possible erosion of fibres from air transmission
systems  lined  by fibrous  glass.   Mean concentrations  on the
rooftops  of  3  buildings  on  the  University  of California's
Berkeley Campus, determined by PCOM and petrographic microscopy,
were about 2.7 x 10-4 fibres/cm3 (range, < 5 x 10-5 - 1.2 x 10-3
fibres/cm3).    Levels  at  other  sites  averaged  4.5  x  10-3
fibres/cm3, the lowest levels being 4 x 10-4 fibres/cm3.  Fibres
other than MMMF may have been included in the results  of  these
analyses.

    Balzer  (1976) reported the  results of a  further study  in
which   MMMF  levels  were  determined  by  light  and  electron
microscopy in 36 samples of ambient air from  various  locations
in  California  (Berkeley,  San  Jose,  Sacramento,  the  Sierra
Mountains,  and Los Angeles).   Fibre counts were  determined by
combining   the  light  microscopic  count   of  fibres  greater
than 2.5 m  in diameter and the electron microscopic  count  of
fibres less than, or equal to, 2.5 m  in diameter.   Levels  of
glass  fibres averaged 2.6 x  10-3 fibres/cm3 and accounted  for
approximately  1/3 of the total fibrous material in the samples.
However, the significance of these results is  uncertain,  since
the  methods of sampling and  analysis and the results  were not
well described in the published account of this study.

    Mean  airborne glass fibre concentrations measured by analy-
tical TEM ranged from 4 x 10-5 fibres/cm3 at 1 rural location to
1.7  x  10-3  fibres/cm3 in  1 out  of 3  cities in  the Federal
Republic  of Germany (1981-82; 9 - 21 samples at each location).
These levels were 3 - 40% of the asbestos concentrations; median
diameters  of the glass fibres  ranged from 0.25 m  to  0.89 m
and median lengths from 2.54 to 3.64 m (Hhr, 1985).

5.1.1.3.  Indoor air

    On  the basis of analysis  using PCOM (Balzer et  al., 1971;
Esmen  et al., 1980) and  calculation of the "glass"  content of
collected particulate (Cholak & Schafer, 1971), it has generally
been  concluded that the contribution of fibrous-glass-lined air
transmission  systems to  the fibre  content of  indoor  air  is
insignificant.   Using  very conservative  assumptions, Esmen et
al.  (1980)  estimated  that the  level of  fibres  in  occupied
spaces  is of the order of 0.001 fibres/cm3 during the first day
of  operation  of air  transmission  systems with  medium  grade
fibrous glass filters and essentially the same as ambient levels
during the remaining filter life.

    Generally,  concentrations of MMMF in  indoor air are 100  -
1000  times  less than  those  in the  occupational environment.
Several  studies in which  airborne fibre levels  in indoor  air
were  measured  by PCOM  with  polarization equipment  have been
carried out in Denmark (Table 12).  Although fibres  other  than
MMMF  may  have been  included  in these  analyses, birefringent
fibres   (mostly  organic)  were  counted  separately.   Typical
levels,  as well as total dust concentrations measured in one of
the studies (Nielsen, 1987), are shown in Table 13.
Table 12.  Respirable MMMF fibre concentrations in the indoor environment (static samples)
------------------------------------------------------------------------------------------
Site                  Number      Respirable fibre    Comments                  Reference
                      of          levels (x 10-6             
                      buildings   fibres/cm3)a
                                  -------------------
                                  Arithmetic mean 
                                  and range of 
                                  individual samples
------------------------------------------------------------------------------------------
Random sample of      11          60 (0 - 240)                                  Schneider 
mechanically venti-                                                             (1986)
lated schools

Random sample of      5           110 (60 - 160)b     MMMF ceiling boards with  Rindel 
kindergardens (sites                                  water-soluble binder      et al.
with reported indoor                                                            (1987)
air problems were     3           100 (43 - 150)b     Resin binder
excluded)
                      4           40 (10 - 70)b       No MMMF ceiling boards

140 rooms (day-care               260 (0 - 1330)      Water-soluble binder,     Nielsen 
centres, schools,                                     untreated surface         (1987)
offices) selected                 75 (0 - 425)        Water-soluble binder,  
at random, but with                                   untreated surface, 
MMMF ceiling boards                                   varnished                      
                                  70 (0 - 180)        Water-soluble binder, 
                                                      untreated surface     
                                  30 (0 - 250)        Resin binder          
                                  40 (0 - 85)         Resin binder          
                                  250 (0 - 1070)      Resin binder          
                                  140 (0 - 820)       Resin binder          
                                  25 (0 - 80)         Resin binder          
                                  40 (0 - 480)        No MMMF
                                                                     
Sites with reported   6           range, 230 - 2900   One observation           Schneider 
indoor climate                                        (0.084 fibres/m3)         (1986)
problems
------------------------------------------------------------------------------------------
a  Phase contrast optical microscopy with polarization. Length > 5 m; 
   diameter < 3 m; aspect ratio > 3:1.
b  95% confidence interval.
Table 13.  Average concentrations of total dust and 
fibres other than MMMF in indoor environments 
(static samples)a
------------------------------------------------------
Site       Number of   Total dust   Organic and other 
           measure-    (mg/m3)      bire-fringent 
           ments                    fibres
                                    (fibres/cm3)
------------------------------------------------------
Day-care   49          0.26         0.25
centres

Schools    11          0.16         0.064

Offices    39          0.13         0.025
------------------------------------------------------
a   From: Nielsen (1987).

5.1.2.  Water supplies

    Data  on  the  MMMF  content  of  water  supplies  are   not
available.   However,  glass  fibres  have  been  identified  by
optical microscopy  in samples of sewage sludge from 5 cities in
the USA (Bishop et al., 1985).

5.2.  Historical Exposure Levels

    In an analysis of the data from the large European epidemio-
logical  study referred to previously, the production history of
each  factory  was  classified  into  the  following  2 distinct
technological  phases: (a) an early  phase during which a  batch
production  system  was  in  use  and/or  no  oil  added  during
production;  and (b) a late phase during which modern production
techniques were used and oil was added.  A third  phase,  inter-
mediate between the early and late phases, was  also  identified
at some plants where a mixture of production types or techniques
operated.

    The airborne fibre levels in the early  technological  phase
in  the slag wool/rock wool industry were probably substantially
higher than in the late phase, the corresponding levels  in  the
intermediate  phase being between  these two levels  (Cherrie  &
Dodgson, 1986).  However, the pattern in the glass  wool  plants
was somewhat different.

    The  basis of these differences rests primarily with changes
over  time in  the nominal  fibre diameters  of the  MMMF  being
produced, and the addition of oil.  In the early period  in  the
slag  wool/rock  wool industry,  the lack of  oil and fibres  of
relatively  fine  nominal diameter  (3  - 6 m)   contributed to
higher airborne fibre levels.  On the other hand, in  the  glass
wool  production industry, it  is likely that  there was  little
change  in airborne  fibre levels  between the  early  and  late
phases. In the early phase, oil was not added during production,
and the nominal diameter of the fibres produced  was  relatively

large  (10 - 25 m).   In  the late phase, oil  was added during
production,  and the nominal diameter of the fibres produced was
smaller  (5 - 7 m).   The  effects of changes in  other factors
including  ventilation and production  rates were judged  to  be
less.

    Combined  experimental  and  modelling procedures  have been
used  to estimate  past exposure  levels in  the  European  MMMF
plants  (Dodgson et al.,  in press).  The  model is still  being
developed and should be considered to be preliminary (Cherrie et
al.,  in  press).   It  indicates  that  mean   airborne   fibre
concentrations  for rock wool plants  could have been about  1 -
2 fibres/cm3,  during the early technological phase, with levels
of  about 10 fibres/cm3 for the dustiest work.  Current exposure
levels are at least one order of magnitude lower.  Corresponding
estimates indicate that the mean airborne fibre levels  for  the
glass  wool  plants during  the  early technological  phase were
little   different   from  current   concentrations  (about  0.1
fibres/cm3 or less).

    The  validity  of  the model  has  been  investigated in  an
experimental  simulation of rock  wool production in  the  early
phase (Cherrie et al., in press).  The effects of added  oil  on
the  airborne fibre levels  during experimental production  were
assessed together with the effects of workers  handling  batches
of  material.   Addition  of oil  resulted  in  a 3-  to  9-fold
reduction  in the airborne fibre levels in different situations.
The  time-weighted  average  concentrations were  1.5 fibres/cm3
with oil added and about 5 fibres/cm3 without oil.  These values
agreed  reasonably  well with  the  predictions from  the model.
There  was  no  substantial difference  in  fibre concentrations
between batch and continuous operation.  However, it is possible
that the batch handling was not well simulated.

5.3.  Exposure to Other Substances

    Polyaromatic   hydrocarbons  (PAHs)  and   other  combustion
products  were present in the  working environment, particularly
in  the early  technological phase  of the  slag wool/rock  wool
industry in Europe, where cupolas were used extensively.  In one
plant,  the use of  an olivin, potentially  contaminated with  a
natural  mineral fibre with  a composition similar  to tremolite
was  reported (Cherry &  Dodgson, 1986).  The  probable  average
exposure  in the  pre-production area  was estimated  to be  0.1
fibres/cm3.   The European slag  wool plants used  copper slags,
possibly   liberating   arsenic   compounds  into   the  working
environment.

    In  MMMF plants in the USA, other airborne contaminants have
been  measured  in  areas  not  necessarily  representative   of
occupational  exposure or in  breathing zones (IARC,  in press).
The results, obtained periodically over the years  1962-87,  are
shown  in Table 14.  It  was emphasized that these  measurements
only verify the presence of other contaminants in the plants and
cannot be used to estimate the degree of exposure.

Table 14.  Exposure to other airborne contaminants in 
MMMF plants in the USAa
------------------------------------------------------
Contaminant                  Range of concentrations
------------------------------------------------------
Asbestos                     0.02 - 7.5 fibres/cm3
Arsenic                      0.02 - 0.48 g/m3
Chromium (insoluble)         0.0006 - 0.036 mg/m3
Benzene-soluble organics     0.012 - 0.052 mg/m3
Formaldehyde                 0.06 - 20.4 mg/m3
Silica (respirable)          0.004 - 0.71 mg/m3
Cristobalite (respirable)    0.1 - 0.25 mg/m3
------------------------------------------------------
a   From: IARC (in press).


6.  DEPOSITION, CLEARANCE, RETENTION, DURABILITYa, AND TRANSLOCATION

6.1.  Studies on Experimental Animals

    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  diameter,
length and aspect ratio being of secondary importance.

    Since  most of the data  on deposition of various  MMMF have
been obtained in studies on rodents, it is important to consider
differences  between rats and  man in this  regard.  Comparative
differences  between rat and man can best be evaluated using the
aerodynamic  equivalent of fibres.   The ratio of  the  absolute
diameter  to aerodynamic diameter is approximately 1:3.  Thus, a
fibre measured microscopically to have a diameter of 1 m  would
have  a  corresponding  aerodynamic  diameter  of  approximately
3 m.    In addition, any curvature  of the fibres may  have the
effect of increasing the effective aerodynamic diameter.

    A comparative review of the regional deposition of particles
in  man and rodents (rats and hamsters) has been presented by US
EPA  (1980).   The  relative distribution  between  the tracheo-
bronchial, and pulmonary regions of the lung in rodents followed
a  pattern  similar to  human  regional deposition  during  nose
breathing for insoluble particles of less than 3 m  mass median
aerodynamic  diameter  (approximately  1 m  diameter  or less).
Fig. 4 and 5 illustrate these comparative differences.   As  can
be  seen,  particularly  for pulmonary  deposition,  the percent
deposition  of particles is considerably less in the rodent than
in  man.  These  data indicate  that, while  particles  of  5 m
aerodynamic  diameter or greater may have significant deposition
efficiencies  in  man, the  same  particles will  have extremely
small deposition efficiencies in the rodent.  More  recent  work
by  Snipes et al.  (1984) indicates that,  with particles  above
3 m   aerodynamic  diameter,  the probability  of  reaching the
pulmonary  region falls  off rapidly, and that particles of 9 m
aerodynamic  diameter  have  an extremely  small  probability of
reaching the pulmonary region in rats and guinea-pigs.

    Because  of their length, fibres are more likely than spher-
ical particles to be deposited by interception, mainly at bifur-
cations.   Available data also indicate  that pulmonary penetra-
tion of curly chrysotile fibres is less than that  for  straight
solid amphibole fibres.  However, in studies on rats,  in  which
the  deposition  of  curly  versus  straight  glass  fibres  was
examined,  the  difference  was less  apparent (Timbrell, 1976).
Clearance from the peripheral respiratory tract is principally a
function  of fibre  length, with fibres  shorter than 15 - 20 m
in length being cleared more efficiently than longer ones.


-------------------------------------------------------------------------------
a   Durability  of  MMMF  in tissues  is  a  function  of  their
    physical and chemical characteristics.

FIGURE 4

FIGURE 5

    The  results of available studies concerning the deposition,
clearance,  retention, durability, and translocation  of MMMF in
animal  species are presented in  Table 15.  As for  all fibrous
particles,  deposition  of  MMMF  in  the  respiratory  tract is
determined  principally by fibre diameter.  In studies conducted

by  Morgan et al. (1980), alveolar deposition of glass fibres in
rats was much less than that for asbestiform  minerals,  because
of  the  larger aerodynamic  diameter  of MMMF.   Deposition  of
asbestiform and glass fibres, the aerodynamic diameters of which
ranged  from  1  to 6 m),   was  greatest  for fibres  with  an
aerodynamic diameter of 2 m  (Morgan et al.,  1980).   However,
there  was some deposition of glass fibres with aerodynamic dia-
meters of between 3 and 6 m.   For fibres of constant diameter,
alveolar  deposition  decreased  with increasing  fibre  length.
Morgan  & Holmes (1984b), comparing  their results in rats  with
those  concerning fibre deposition  in other species,  suggested
that  glass  fibres  with diameters  greater than 3.5 m  (aero-
dynamic diameter ~10 m)  are unlikely to be respirable  in  man
by nose breathing (Timbrell, 1965; Morgan et al.,  1980;  Hammad
et  al., 1982; Hammad, 1984).  Fibre deposition in various lobes
of the lungs of rats varied over a narrow range (5.34  -  8.38%)
following inhalation of ceramic fibres. Fibre size distributions
in  the  various  lobes, based  on  analysis  by phase  contrast
optical  microscopy, were not significantly different (Rowhani &
Hammad,  1984).  These results are similar to those observed for
glass  wool, rock wool, and  glass microfibre by Le  Bouffant et
al. (in press).

    According  to Griffis et al. (1981), there is a fairly rapid
decline  in  the  lung  content  of  glass  fibres,  immediately
following   deposition,   presumably   because  of   mucociliary
clearance  (t in  rats ~1  day).  This  is followed  by a  much
slower  phase  assumed to  represent alveolar clearance  (t  in
rats ~44.3 days) (Friedberg & Ullmer, 1984).  Short  fibres  are
efficiently  cleared  by  alveolar macrophages  (Morgan  et al.,
1982a; Morgan & Holmes, 1984b; Bernstein et al., 1984); in rats,
more  than 80% of glass fibres of less than 5 m  in length were
cleared by one year (t ~60 days).  However, macrophage-mediated
clearance  appeared to be ineffective for fibres with lengths of
30 and 60 m (Morgan & Holmes, 1984b).


Table 15.  Deposition, durability, clearance, retention, and translocation of MMMF in experimental animals
--------------------------------------------------------------------------------------------------------
Species         Study protocola                        Results                              Reference
--------------------------------------------------------------------------------------------------------

Alderley Park   Inhalation for 2 - 3 h of samples      Decrease in alveolar deposition      Morgan 
(strain 1)      of glass fibres and asbestiform        with increasing fibre length;        et al.
SPF rats        materials at concentrations of         maximum deposition for fibres        (1980); 
                0.40 - 1.63 g/litre; aerodynamic       with aerodynamic diameter of         Morgan &
                diameter of fibres ranged from         2 m; small but significant          Holmes 
                1 to 6 m; animals killed              deposition of fibres with aero-      (1984b)
                immediately or 2 days following        dynamic diameters of 3 - 6 m
                exposure

Fischer 344     Inhalation of 31 - 52 mg glass         41 - 48% of lung burden cleared      Griffis 
SPF male        fibres/m3 (2/3 respirable; CMD,        between daily exposures (i.e.,       et al.
rats            0.11 m; CML, 8.3 m), 6 h/day,        half-time for early clearance,       (1981)
                for 1, 2, 4, or 5 days                 1 day)

Beagle dogs     Inhalation for 1 h of unspecified      77% of body burden excreted in       Griffis 
                concentration of glass fibres (CMD,    4 days, mainly (> 96%) in faeces     et al.
                0.15 m; CML, 5.4 m); animals         (half-time 2 days); 5 - 17% deposi-  (1983)
                killed 4 days after exposure           ted in deep lung; respiratory tract
                                                       deposition, 45 - 64%

Male albino     Inhalation of ~300 fibres/cc (CMD,     Increased alveolar retention of      Hammad 
rats            1.1 - 1.3 m; CML, 8 - 20 m);         fibres with decreasing diameter      et al.
                animals killed 5 days after exposure   and decreasing length (maximum       (1982)
                                                       7.6% for fibres < 0.5 m in dia-
                                                       meter and 21 m in length)

Table 15.  (contd.)
--------------------------------------------------------------------------------------------------------
Species         Study protocola                        Results                              Reference
--------------------------------------------------------------------------------------------------------
Syrian          Intratracheal instillation of 0.2 mg   Preferential clearance of shorter    Holmes 
golden          sized glass fibres (3 m in dia-       fibres; ferruginous bodies around    et al.
hamsters        meter; length, 10 - 100 m); animals   fibres > 10 m in length only;      (1983); 
                killed serially up to 8 months after   time of onset of body formation      Morgan &
                administration                         decreased with increasing fibre      Holmes 
                                                       length; proportion of coated         (1984b)
                                                       fibres increased over a period of
                                                       about 3 - 4 months and then declined
                                                       after 5 months; coating did not
                                                       prevent dissolution of fibres;
                                                       longer fibres dissolved more
                                                       rapidly than shorter ones; fibres
                                                       dissolved more rapidly in trachea
                                                       than in rat lung

Alderley Park   Intratracheal instillation in rats     Rock wool fibres dissolved more      Morgan & 
(strain 1)      (0.5 mg) or hamsters (0.4 mg)          slowly in the lung than glass        Holmes
SPF rats        of rock wool (CMD, 1.1 m; CML,        fibres; diameter essentially         (1984a,b)
and Syrian      28 m); animals killed serially        unchanged after 18 months; in
golden          up to 18 months after administra-      hamsters, coating of fibres
hamsters        tion                                   < 2 m in diameter after 2 months
        
Alderley Park   Intratracheal instillation of          Fibres with diameter < 3 m and      Morgan 
(strain 1)      0.5 ml of 6 samples of glass           lengths < 10 m efficiently cleared  et al.
SPF rats        fibres (1.5 or 3 m in diameter;       (presumably by macrophage-mediated   (1982); 
                length, 5 - 60 m); animals            processes); fibres 30 and 60 m in   Morgan &
                killed serially up to 18               length not cleared to a significant  Holmes 
                months after administration            extent over 1 year; longer fibres    (1984b)
                                                       dissolved more rapidly in a non-
                                                       uniform manner leading to fragment-
                                                       ation; shorter fibres dissolved
                                                       more slowly and uniformly

Guinea-pigs     Intrapleural injection of 25 mg        Fine structure of coated glass       Davis 
                commercial glass fibre (diameter,      fibres in lung identical to that of  et al.
                0.05 - 0.99 m); animals killed        asbestos bodies                      (1970)
                6 weeks after administration

Table 15.  (contd.)
--------------------------------------------------------------------------------------------------------
Species         Study protocola                        Results                              Reference
--------------------------------------------------------------------------------------------------------
Sprague         Inhalation for 10 or 30 h of "TEL"     Mean half-time for elimination 44.3  Friedberg & 
Dawley rats     glass fibres at 86 mg/m3; animals      days (assuming first order)          Ullmer
                killed 16 - 18 h, 7, 14, 30(33),                                            (1984)
                60, or 90 days after exposure

Fischer 344     Inhalation of 10 mg/m3 rock wool,      Glass microfibres more susceptible   Johnson 
SPF rats        glass wool (with and without resin),   to etching in lung tissue than       et al.
                and glass microfibre for 7 h/day,      glass or rock wool                   (1984a)
                5 days/week, for 1 year; animals
                killed immediately or at unspecified
                periods after exposure

Male rats       Inhalation of mineral wool (CMD,       Ceramic fibres more persistent       Hammad 
                1.2 m; CML, 13 m) or ceramic         than mineral wool in lung tissue     (1984)
                fibres (CMD, 0.7 m; CML, 9 m)
                (~300 fibres/cc), 6 h/day, for
                5 or 6 days; animals killed 5, 30,
                90, 180, or 270 days after exposure

Wistar IOPS     Inhalation for 1 or 2 years of         Fibre concentrations in the air      Le Bouffant 
AF/Han rats     resin-free glass wool or rock          and lung much greater for micro-     et al.
                wool (Saint Gobain), or micro-         fibre (JM 100) than for glass and    (1984,   
                fibres (JM 100) (~5 mg/m3);            rock wool; retention and trans-      in press)
                animals killed immediately or          location less for rock and glass              
                serially for periods up to 16          wool fibres than for microfibres;
                months after exposure                  lengths of glass and rock wool
                                                       fibres retained in the lungs
                                                       shorter than those of airborne
                                                       fibres, whereas glass microfibre
                                                       sizes in lung and air similar;
                                                       generally, fibres in the lymph
                                                       nodes shorter than those in the
                                                       lungs

Table 15.  (contd.)
--------------------------------------------------------------------------------------------------------
Species         Study protocola                        Results                              Reference
--------------------------------------------------------------------------------------------------------
Male Fischer    Intratracheal instillation of 2        Short fibres cleared efficiently     Bernstein 
344 SPF rats    or 20 mg glass fibres (1.5 m          by macrophages with fewer than       et al.
                in diameter; length, 5 or 60 m);      10% remaining after 500 days;        (1980, 1984)
                animals killed serially up to 2        longer fibres dissolved more rap-
                years after administration; intra-     idly (over 50% in 18 months),
                tracheal instillation of 0.5 mg        possibly due to partial phago-
                glass fibres (1.5 m in dia-           cytosis
                meter; length, 5 or 60 m) or
                tracheal inhalation once per week,
                for 10 weeks

Pathogen-free   Inhalation of ceramic fibre (CMD,      Deposition of fibres varied over     Rowhani & 
adult albino    0.53 m; CML, 3.7 m) (~709            a narrow range (5.43% for the        Hammad
male rat        fibres/cm3), 6 h/day, for 5 days;      right diaphragmatic lobe to          (1984)
                animals killed 5 days after expo-      8.38% for the right apical lobe);
                sure; analysis by PCOMb                fibre burden for all lobes weight
                                                       dependent; no significant differ-
                                                       ence in fibre size distributions
                                                       in various lobes

Female Wistar   Intratracheal instillation of 2 mg     Half lives for fibres > 5 m in      Bellmann 
rats            microfibre (JM 104-E glass: 90% of     length: JM 104/475, 3500 days        et al.
                fibre diameters < 0.28 m, 90%        (similar to crocidolite; change      (in press)
                of fibre lengths < 5.8 m; JM 104/     in size not detected); JM 104-E glass,
                475: 90% of fibre diameters < 0.4      55 days (increase in mean length
                m, 90% of fibre lengths < 8.4 m;     and diameter in first 6 months);
                acid-treated microfibre (JM 104-E      acid-treated JM 104-1974, 14 days;
                glass: 90% of fibre diameters          rock wool, 283 days; ceramic wool,
                < 0.46 m, 90% of fibre lengths        780 days
                < 6.3 m); rock wool (90% of
                fibre diameters < 5.6 m, 90% of
                fibre lengths < 67 m); ceramic wool
                (90% of fibre diameters < 4.2 m,
                90% of fibre lengths < 177 m) with
                animals killed serially up to 2
                years after administration

--------------------------------------------------------------------------------------------------------
a   CMD = Count median diameter.
    CML = Count median length.
b   PCOM = Phase contrast optical microscopy.
    The degradation of MMMF in lung tissue consists of reduction
of  diameter with time, together with pitting and erosion of the
surface  visible on TEM  (Morgan & Holmes,  1986).  Observations
for  up to  2 years  after intratracheal  instillation  in  rats
showed  a wide range in the durability of various MMMF (Bellmann
et al., in press).  Morgan & Holmes (1986) noted that relatively
thick MMMF become thinner on dissolution and may  assume  dimen-
sions that resemble those of the fibrous  amphiboles.   However,
the  in vivo studies in this report, together with  the  in vitro
observations   of Klingholz & Steinkopf (1984), suggest that the
leaching  of  alkaline  ions that  accompanies fibre dissolution
results  in rapid changes  in the nature  of the surface  of the
fibre, and loss of substance, so that the  cell/fibre  interface
may  be altered.  In studies on rats, long glass fibres degraded
more  rapidly than short  ones (Morgan et  al., 1982; Holmes  et
al., 1983; Bernstein et al.  1984; Hammad, 1984).  It  has  been
postulated that this may be because the small (short) fibres are
completely  engulfed  by  macrophages and  therefore "protected"
from  the extracellular environment, which  contains more fluids
and enzymes that might facilitate degradation.

    Although ferruginous bodies are not observed in rats exposed
to asbestos or glass fibres, in an early study  on  guinea-pigs,
it  was demonstrated that  glass fibres could  be coated in  the
lung to form bodies with a fine structure identical to  that  of
asbestos  bodies  (Davis et  al.,  1970).  In  hamsters, various
proportions  of the fibres in lung tissue greater than 10 m  in
length  became coated to  form ferruginous bodies;  the time  of
onset  of  formation  decreased  with  increasing  fibre  length
(Holmes  et al., 1983).   In studies involving  exposure for  90
days  (0.4  mg  glass  fibres/litre),  by  Lee  et  al.  (1981),
ferruginous  bodies were first detected  in hamsters by the  6th
month following exposure and in guinea-pigs by the  12th  month.
The  coating of ferruginous  bodies appears to  be discontinuous
and  does not  prevent the  leaching and  fragmentation of  long
glass fibres (Morgan & Holmes, 1984b).

    Available  data also  indicate that  rock wool  may be  more
persistent  in lung tissue than  fibrous glass (Johnson et  al.,
1984a;  Morgan  &  Holmes,  1984a,b).   Following  intratracheal
instillation  in rats, the diameter  of rock wool fibres  in the
lung  was essentially unchanged  after 18 months;  however,  the
ends  of the fibres were perceptibly thinner.  The results of an
additional study on rats indicated that ceramic fibres were more
persistent in lung tissue than rock wool, even though  the  mean
diameter of the mineral wool fibres was greater than that of the
ceramic  fibres.  After 270  days, about 25%  of ceramic  fibres
were  still present in lung  tissue compared with 6%  of mineral
wool fibres (Hammad, 1984).

    Lee  et al. (1981) reported that dust particles were present
in  the tracheobronchial lymph nodes  after 50 days exposure  to
0.4 mg glass fibre/litre.  Following inhalation of  glass  wool,
rock  wool,  or glass  microfibre at 5  mg/m3 for 1  year, fibre

concentrations in the tracheobronchial glands of rats  were  low
(range  of  means  in males  and  females,  0.1 -  0.8  g/kg dry
tissue),  except for microfibres (JM 100), for which mean levels
were   4.8  and  3  g/kg  dry  tissue,  in  males  and  females,
respectively  (Le Bouffant et  al., 1984) (For  comparison, mean
concentrations of glass and rock wool in lung tissue ranged from
0.4 to 2.8 g/kg dry weight; mean levels of microfibre were 5.8 -
12.7 g/kg dry lung tissue).  Levels of the various  fibre  types
in  the diaphragm  were essentially  zero (Le  Bouffant et  al.,
1984).   Generally,  levels  of fibres  in  the  lymph nodes  of
animals  exposed for 2 years were higher than those after 1 year
of  exposure (Le Bouffant et  al., in press).  Bernstein  et al.
(1984)  reported  that, following  intratracheal instillation of
size-selected glass fibres of diameters of 1.5 m   and  lengths
of  either 5 m   (short) or  60 m  (long),  short fibres  were
quickly  cleared to the regional  lymph nodes, whereas the  long
fibres were not.  Even 18 months after exposure, there  were  no
significant  quantities of  fibres in  the lymph  nodes  of  the
groups  exposed to long  fibres, whereas there  were many  still
present in the animals exposed to short fibres.  Spurny  et  al.
(1983)  reported the presence of glass fibres in the  spleen  of
rats,  2 years after  intratracheal implantation.  However,  few
experimental details were provided.  Recovery of fibres from all
organs  examined 90 days after intrapleural injection of fibrous
glass (20 mg JM 104) was reported by Monchaux et al. (1982).

6.2.  Solubilitya Studies

    The  results of studies on the solubility of MMMF in physio-
logical  fluids  in vitro are presented in Table 16.  Since it is
impossible  to reproduce  in vitro the  various conditions of  pH
and  concentrations  of  complexing  agents  in  the  intra- and
extracellular  environment of the  lung, the results  of  disso-
lution  studies should be interpreted with caution.  However, on
the basis of these investigations, it appears  that  dissolution
is  a function not  only of the  fibre characteristics, such  as
chemical  composition and size,  but also of  the nature of  the
leaching  solution.  In one  of these investigations,  MMMF were
more  soluble than the amphiboles and chrysotile (Spurny, 1983).
However,  there is a wide range in the solubility of the various
MMMF,  e.g., 30- to 40-fold  in the study of  Leineweber (1984).
For example, Leineweber (1984)  reported that the  stability  of
various MMMF in physiological saline was as follows: glass fibre
(1  type)  > refractory  fibre > mineral  wool > glass  fibre (3
types). However, in distilled water, the order was significantly
different:  refractory fibre > glass  fibre (2 types) >  mineral
wool > glass fibre (2 types).

-----------------------------------------------------------------------
a   Solubility of MMMF is their behaviour in various fluids.  In
    general,  the term is  restricted to observations  in  vitro,
    since   the persistence of  fibres  in vivo is a  function of
    several factors including solubility.


Table 16.  The solubility of MMMF
---------------------------------------------------------------------------------------------------
Study protocol                           Results                                    Reference
---------------------------------------------------------------------------------------------------
Analysis by scanning electron            Surface porosity was altered and           Spurny (1983);
microscopy, microprobe analysis,         alkali elements were increased; in         Spurny et al.
X-ray diffraction, X-ray fluores-        general, order of stability:               (1983)
cence spectroscopy and mass              amphiboles > glass fibres > other
spectroscopy of UICC chrysotile          MMMF > chrysotile; in some cases,
or crocidolite glass fibres and          succession amphiboles > chrysotile
mineral wool in 5 solutions (2N          > MMMF; fine diameter fibres degrade
HCl, 2N H2SO4, 2N NaOH, water, and       more rapidly than coarse fibres
blood-serum)

Analysis by atomic absorption spec-      MMMF softened in physiological solu-       Forster (1984)
trometry, scanning electron micro-       tions and gel forms that is removed
scopy and energy dispersive X-ray        in layers; rate of dissolution in
analysis of asbestos, rock wool,         Gamble's solution: 10 ng/cm2 per h
slag wool, basalt wool, and glass        (i.e., fibres with average diameter of
wool (without binders) in deionized      3 m completely dissolved in < 5 years;
distilled water, KOH (48%), H2SO4        those  with diameter < 1 m dissolved
(48%), Ringer's solution, and Gamble's   in < 1 year); asbestos stable in
solution                                 physiological solutions

Analysis by atomic absorption spec-      Gel formation on the surfaces of all       Klingholz &
trometry, electron probe, scanning       MMMF within a few weeks, partic-           Steinkopf (1984)
electron microscopy, and energy          ularly for those with higher alkaline      
dispersive X-ray analysis of mineral     content; beneath the gel layer,
wool, glass wool, rock wool, and         areas of local corrosion ("pitting")
basalt wool (without binders) in         lead to loss of structural integrity
Gamble's solution                        and breakage into shorter lengths

Analysis by BET gas absorption,          40-fold range of durability in             Leineweber
scanning electron microscopy, and        saline; order of durability: 1 sample      (1984)
energy dispersive X-ray                  of glass fibre > refractory fibre >
spectrometry of 4 samples of             mineral wool > 3 samples of glass
fibrous glass, mineral wool, and         fibre; order in distilled water
refractory fibre in physiological        varied; correlation between the solu-
saline and distilled water               bility and total weight percentage
                                         alkalis; surface deposits observed

Table 16.  (contd.)
---------------------------------------------------------------------------------------------------
Study protocol                           Results                                    Reference
---------------------------------------------------------------------------------------------------

Determination of mass and sodium         Greater mass dissolved in serum            Griffis et al.
content by flame atomic absorption       stimulant than in buffered saline;         (1981)
spectroscopy of glass fibres in          some sodium preferentially dissolved
tris buffered saline or serum            in both solvents
stimulant

Analysis (inductive coupled plasma       MMMF much more soluble (dissolution        Scholze & 
method) for silicon, boron, and          time for glass or slag wool < 2 years,     Conradt          
potassium; weight determination and      for E glass wool (JM 104) and refrac-      (in press)
examination by scanning electron         tory fibre, 5 - 6.5 years) than nat-
microscopy                               ural mineral fibres (dissolution
                                         time > 100 years)
---------------------------------------------------------------------------------------------------
    On the basis of available data, it appears that there  is  a
correlation between solubility in physiological solution and the
alkaline   content  of  MMMF   (Klingholz  &  Steinkopf,   1984;
Leineweber,  1984) and that fibres of fine diameter degrade more
rapidly than coarse ones (Spurny et al., 1983; Forster, 1984).

7.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    There  are several factors  that should be  considered  when
evaluating  experimental data on the biological effects of MMMF.
Most  importantly, MMMF  should not  be considered  as a  single
entity,  except in a  very general way.   There are  substantial
differences in the physical and chemical properties (e.g., fibre
lengths  and chemical composition)  of the fibres,  even  within
each  of  the  broad  classes  of  MMMF  (continuous  filaments,
insulation   wools,  refractory  fibres,  and   special  purpose
fibres),  and it is  expected that these  would be reflected  in
their  biological  responses.   Finally,  the  fibres  used  for
specific research protocols may be altered to fit the  needs  of
the  study, and the  results may not  necessarily represent  the
true  biological potential of  the parent material.   Therefore,
the  potential  "toxicity"  of  each  fibrous  material  must be
evaluated individually.

    Notwithstanding   the  above  comments,  there  are  certain
characteristics  of MMMF (and  other fibres) that  are important
determinants  of  effects  on  biological  systems.   The   most
important  of these appear to  be fibre size (length,  diameter,
aspect ratio),  in vivo persistencea and  durabilitya,   chemical
composition,  surface chemistry, and  number or mass  of  fibres
(dose). In addition, it is imperative to understand that each of
the above characteristics cannot be viewed in isolation from the
others.   For example, it is  clear that two types  of fibres of
identical  dimensions could react differently within the host if
they  differ in one of  the other characteristics.  Some  of the
apparently inconsistent experimental results of studies reported
in this section may be a function of these factors.

    Other   considerations   relate  to   the  extrapolation  of
experimental  findings for hazard assessment in man.  It appears
that  if a given fibre comes into contact with a given tissue in
animals  producing  a  response, a  similar  biological response
(qualitative) might be expected in human beings under  the  same
conditions of exposure. There is no evidence that the biological
reaction of animals and human beings differ.  However, there may
be  quantitative  differences  between species,  some being more
"sensitive" than others.
-----------------------------------------------------------------------------
a   The  term persistence refers  to the ability  of a fibre  to 
    stay in the biological environment, where it was introduced. 
    The  term is  of particular  use in  inhalation  and  intra-
    tracheal instillation studies, because a large percentage of 
    the  fibres  that reach  the lung are  removed by the  muco-
    ciliary apparatus and relatively few are retained (persist). 
    The length of time that MMMF persist in the tissue is also a 
    function of their durability, which is directly  related  to 
    their  chemical  composition  and physical  characteristics. 
    The  term solubility, as used here, relates to the behaviour 
    of  MMMF in various fluids.  In general, the term solubility 
    is  more  appropriate for  use  in  in vitro than  in  in vivo 
    studies,  because, in tissue, the degradation of fibres is a 
    function of phenomena more than just their solubility. 
    
    There  has  been  a great  deal  of  debate  concerning  the
"relevance" of various routes of exposure in experimental animal
studies  to  hazard  assessment  in  man.   The  advantages  and
disadvantages  of each  of these  routes are  discussed  in  the
following sections.  It was the consensus of the Task Group that
administration  by each  route has  its place  in the  study  of
fibre toxicity, but that it is inappropriate to draw conclusions
on the basis of the results by one route of administration only.
This does not mean that all routes are required for the study of
the toxicity of a given fibre.

    Each  route cannot  be discussed  in detail  here, but  some
general observations can be made.  First, positive results of an
inhalation  study  on  animals have  important  implications for
hazard assessment in man.  Strong scientifically based arguments
would need to be made to dissuade one from the relevance of such
a  finding to man.  Conversely, a negative inhalation study does
not  necessarily mean  that the  material is  not hazardous  for
human  beings, unless it is clear that the number of fibres that
actually  reached the target tissue (in this case the lung)  was
comparable to the positive control.  Rats, being  obligate  nose
breathers,  have a greater filtering capacity than human beings.
However,  if it were demonstrated  that the "target tissue"  was
adequately  exposed and that  a biologically important  response
was not noted, then such a result would be of value  for  hazard
assessment in human beings.

    In  contrast to inhalation studies,  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, in  such  a  case, would  require
further  study before assessing  the hazard for  man, since  the
normal  filtering  capacity of  the  respiratory tract  has been
bypassed,  and there is often  a non-random distribution in  the
lung,  i.e., "bolus" effect.   In other words,  in intratracheal
instillation studies, the lung can be exposed to  material  with
which  it  normally would  never  come into  contact.   However,
pulmonary  clearance mechanisms are  still intact, though  their
efficiency may be compromised.

    The  results of studies involving  intrapleural instillation
(injection   or  implantation)  and   intraperitoneal  injection
should  be viewed in  a similar way  to those of  investigations
involving   intratracheal  instillation  studies.    With  these
methods, both filtering and clearances mechanisms are compromised.
However,  such studies may  be more "sensitive"  than inhalation
studies,  because a higher number  of fibres (> 1.0 m   in dia-
meter)  can be introduced than can be in conventional inhalation
studies.  Therefore, a negative result in such a case  would  be
highly relevant in terms of hazard assessment.  In  contrast,  a
positive  result  should  be confirmed  by further investigation
involving other routes of exposure before indicting  the  parti-
cular  type of fibre as  a human hazard in  terms of the  tissue
involved  (mesothelioma).  It should be noted that both of these

routes  are primarily  relevant to  the mesothelium  and do  not
necessarily  predict what happens in the pulmonary parenchyma or
airways.

     In  vitro  short-term  studies,  e.g.,  cytotoxicity,  cyto-
genicity, and cell transformation studies, have been,  and  are,
important in understanding the mechanisms of action  of  fibres.
The  results of such studies are of value in the overall assess-
ment of fibre toxicity but should not be used alone  for  hazard
assessment.

    Solubilitya studies   play an important  part in the  under-
standing  of the behaviour  of fibres behave  in various  media.
However,  several of the  mechanisms that determine  the persis-
tence  of  fibres  in biological  tissues  are  not  taken  into
account.  Therefore, while an important adjunct in  the  overall
study  of  fibres,  they  are  of  less  importance  in   hazard
identification.

    While it is not the purpose of this publication to outline a
specific  set  of  protocols for  the  study  of the  biological
effects  of newly developed MMMF,  it may provide some  guidance
concerning  those aspects that  should be addressed  in  experi-
mental studies to investigate the potential toxicity of fibres.

7.1.  Experimental Animals

7.1.1.  Inhalation

    Exposure  conditions  in  inhalation studies  approach  most
closely  the  circumstances  of  human  exposure  and  are  most
relevant  for the assessment of  risks for man.  Information  on
the  design and results of studies in which animals were exposed
to  MMMF  by  inhalation  is  summarized  in  Table  17.    Such
investigations  have been conducted on several species including
the rat, mouse, hamster, guinea-pig, and baboon.

----------------------------------------------------------------
a  The  term solubility, as used here, relates to the behaviour 
   of  MMMF in various fluids.  In general, the term solubility
   is  more  appropriate for  use  in  in vitro than  in  in vivo 
   studies,  because, in tissue, the degradation of fibres is a 
   function of phenomena more than just their solubility. 
 


Table 17.   Inhalation studies
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
Male A-strain   12 animals each  300 mg crushed "fibreglass      Neoplastic, hyperplastic,     Morrison            
mouse           in 3 treatment   insulation" (80% of fibres      and metaplastic lesions in    et al.
                groups; 12       were 2.5 m wide and 6 - 11     the bronchi and near the      (1981)
                vehicle- and     m long), in bedding, every     bronchiole-alveolar junc-                                 
                12 unexposed     3 days, for 30 days; 3 days     tions in the lung; admini-                                
                control animals  later, ip administration of     stration of either or both                                
                                 either retinyl palmitate (50    vitamins resulted in signi-                               
                                 mg/kg body weight), ascorbic    ficantly fewer neoplastic                                 
                                 acid (400 mg/kg body weight),   and hyperplastic lesions;                                 
                                 or both; animals sacrificed     slightly higher number of                                 
                                 90 days after first expo-       metaplastic nodules in group                              
                                 sure to fibrous glass           exposed to retinyl palmitate;                             
                                                                 control animals had 5 times                               
                                                                 as many particles in the lung                             
                                                                 as the vitamin-exposed groups;                            
                                                                 limited number of animals; no                             
                                                                 control group exposed to air                              
                                                                 only; incidence not reported;                             
                                                                 administered material not                                 
                                                                 well characterized                                        
                                                                                                                                                                                                   
Male albino     20 animals each  Exposure to glass fibres at     No lung damage in animals     Moriset
mouse of        in 3 treatment   1070 fibres/cc (87% of fibres   exposed to fibrous glass      et al.
the Cobs        groups; 20       < 8 m in length and 100% <     alone; change in the cell-    (1979)
strain          control          3 m in diameter); styrene      ularity of the bronchiolar                                
(Charles        animals          (300 ppm), fibrous glass        lining where apocrine cells                               
River,                           (1070 fibres/cc) plus sty-      became predominant in animals                             
CDR-1)                           rene (300 ppm), or filtered     exposed to glass fibres and                               
                                 air (controls), 5 h/day, 5      styrene; this type of change                              
                                 days/week, for 6 weeks          found in 10% of styrene-                                  
                                                                 exposed mice while most of                                
                                                                 the animals (90%) had thick-                              
                                                                 ened bronchiolar walls                                    
                                                                 because of stratification of                              
                                                                 the bronchiolar epithelium;                               
                                                                 authors concluded that the                                
                                                                 glass fibres were biologi-                                
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   

                                                                                                                                                                                                   
Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
                                                                 cally inert (possibly because                             
                                                                 they were in non-pathogenic                               
                                                                 size range), but that the                                 
                                                                 presence of such biologically                             
                                                                 inert respirable fibres                                   
                                                                 enhances the toxic effects of                             
                                                                 styrene (possibly because of                              
                                                                 absorption of styrene on the                              
                                                                 fibre surfaces); limited num-                             
                                                                 ber of animals and short                                  
                                                                 exposure period                                           

Male Charles    rats (46),       Exposure to 0.7 x 106           Unlike the other fibrous      Lee et          
River/Sprague   guinea-pigs      fibres/litre (> 5 m) glass     dusts administered (asbestos, al. (1981)                            
Dawley rat,     (32),            fibres (0.4 mg/litre), 6 h/     Fybex, and PKT), fibrous                                  
albino male     hamsters (34)    day, 5 days/week, for 90        glass was not fibrogenic;                                 
guinea-pig,                      days; animals sacrificed at     some alveolar proteinosis,                                
and hamster                      20, 50, or 90 days of expo-     which had cleared after 2                                 
                                 sure and at 6, 12, 18, or       years; authors concluded that                             
                                 24 months after exposure        fibrous glass satisfies                                   
                                                                 criteria for a "biologically                              
                                                                 inert" dust; 18 months and                                
                                                                 2 years after exposure, 2/19                              
                                                                 exposed rats had bronch-                                  
                                                                 iolar adenomas compared with                              
                                                                 0/19 control animals; how-                                
                                                                 ever, numbers were too small                              
                                                                 to draw meaningful conclu-                                
                                                                 sions concerning carcino-                                 
                                                                 genicity; study not well                                  
                                                                 described; limited number of                              
                                                                 animals and short exposure                                
                                                                 and observation periods                                   

Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   
SPF Fischer     2 exposed        Exposure to glass fibre         All fibres produced variable  Johnson &           
rat             animals;         (JM 100), rock wool, resin-     degrees of focal fibrosis,    Wagner                    
                2 control        coated glass wool, uncoated     type II alveolar cell pro-    (1980)                            
                animals          glass wool, or air, at 10       liferation, accumulation of                               
                                 mg/m3 for 7 h/day, 5 days/      cellular debris and lipid                                 
                                 week, over 50 weeks; animals    material and hyperplasia of                               
                                 sacrificed 4 months after       both alveolar cells and cells                             
                                 inhalation; lung tissue         lining the terminal airways;                              
                                 examined by electron micro-     fibrosis less marked than for                             
                                 scopy                           UICC chrysotile B; uncoated                               
                                                                 glass wool more reactive than                             
                                                                 coated variety; very small                                
                                                                 number of exposed and control                             
                                                                 animals                                                   
                                                                                                                                                                                                   
Rat and         30 in each of    Exposure to fibrous glass       No discernable differences    Gross               
hamster         the treatment    (uncoated, coated with          in tissue reactions for       et al.                    
(strains        groups; 20       phenol-formaldehyde resin,      the 3 different types of fib- (1970)                            
unspecified)    controls for     or starch binder) (average      rous glass; pulmonary res-                                
                each species     diameter, 0.5 m; average       ponse characterized by rel-                               
                                 length, 10 m), at ~100 mg/m3   atively small accumulation                                
                                 6 h/day, 5 days/week, over      of macrophages without signi-                             
                                 24 months; animals sacri-       ficant stromal change; authors                            
                                 ficed at 6, 12, and 24          conclude that fibrous glass                               
                                 months; intratracheal           "biologically inert"                                      
                                 injection of 1 - 10 doses of                                                              
                                 3.5 mg of the same dusts in                                                               
                                 150 rats and 60 hamsters                                                                  
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   

                                                                                                                                                                                                   
Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
Guinea-pig      100 guinea-      Exposure to 5.05 - 5.16         Little evidence of dust       Schepers           
and rat         pigs; 50 rats;   mg/cm3 (1.4 x 106 - 2.2         reaction and no fibrosis      (1955);                          
                no control       x 106 ppcf; mean diameter,                                    Schepers &          
                group            6 m) for 20 months; guinea-                                  Delahunt                          
                                 pigs exposed for additional                                   (1955)                      
                                 20 months to 1.06 - 2.48                                                                  
                                 mg/cm3 (mean diameter, 3 m);                                                             
                                 animals sacrificed at periods                                                             
                                 of up to 40 months                                                                        
                                                                                                                                                                                                   
Charles River   Not reported     Exposure to 0.42 mg/litre       At 90 days, macrophage reac-  Lee et          
CD Sprague                       (0.73 x 106 fibres/litre >      tion with alveolar protein-   al. (1979)                            
Dawley                           5 and < 10 m; average dia-     osis, which had disappeared 1                             
derived male                     meter, 1.2 m) glass fibre,     year after exposure; ferrug-                              
rat, albino                      6 h/day, 5 days/week, for 90    inous bodies in hamsters and                              
male                             days; animals sacrificed at     guinea-pigs; study not well                               
guinea-pig,                      periods of up to 2 years        described; short exposure and                             
and Syrian                       after exposure                  observation periods                                       
male                                                                                                                                                                                               
hamster                                                                                                                                                                                            
                                                                                                                                                                                                   
                                                                                                                                                                                                   
                                                                                                                                                                                                   
                                                                                                                                                                                                   
Inbred male     Unspecified      Repeated pulmonary lavage in    Profound effects on alveo-    Miller              
BD-IX rat       number in        animals exposed to 1340         lar macrophages (similar      (1980)                            
                treatment        fibres/cm3 JM reference C102    to those observed for croci-                              
                and control      glass fibres (diameter, 0.1 -   dolite); however, temporal                                
                groups           0.6 m; length, 5 - 100 m),    variation in the effects ob-                              
                                 7 h/day, 5 days/week, for       served following pulmonary                                
                                 6 months                        lavage (Sykes et al., 1983).                              

Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   
Male baboon     10 animals in    Exposure to 7.54 mg/m3 (1122    Fibrosis was slightly more    Goldstein           
 (Papio          total; number    fibres/cc > 5 m) of JM C102     marked after 18 and 30       et al.                
 ursinus)        in treated or    and C104 fibrous glass 7 h/     months exposure; also pre-    (1983,                             
                control groups   day, ~5 days/week, for up       sent in post-exposure biop-   1984)                            
                unspecified      to 35 months; lung biopsy       sies; changes similar to those                            
                                 at intervals (material avail-   observed for UICC crocidolite                             
                                 able for study at 8, 18,        (15.83 mg/m3 - 1128 fibres/cc                             
                                 and 30 months and 6, 8, and     > 5 m) but less severe; no                              
                                 12 months after exposure)       evidence of malignancy;                                   
                                                                 authors suggested that con-                               
                                                                 trary results of others might                             
                                                                 be due to the diameter of the                             
                                                                 fibre and species of the ex-                              
                                                                 erimental animal; small num-                              
                                                                 ber of animals and incidence                              
                                                                 in control group not reported;                            
                                                                 short exposure period in rela-                            
                                                                 tion to life span of the                                  
                                                                 animal                                                    

Albino rat      50 animals in    Exposure to 2.18 mg/m3 (mean    Pulmonary reaction to both    Pigott              
of the          each of the      respirable dust) Saffil alu-    forms of Saffil was minimal   et al.                    
Alderley        treatment        mina fibres (aluminum oxide     (generally confined to the    (1981)                            
Park (Wistar    groups;          refractory fibre containing     presence of groups of pig-                                
derived         50 controls      about 4% silica), 2.45 mg/m3    mented alveolar macrophages);                             
strain)                          thermally aged Saffil or air    no pulmonary neoplasms;                                   
                                 (median diameter, ~3 m;        authors concluded that Saffil                             
                                 median length, 10.5 - 62 m)    may be regarded as a nuisance                             
                                 for 6 h/day, 5 days/week,       type dust, but acknowledged                               
                                 for 86 weeks; animals sac-      that the levels of respirable                             
                                 rificed at 14, 27, or 53        dust in the atmosphere were                               
                                 weeks and at 85% mortality      low                                                       

--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   

                                                                                                                                                                                                   
Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
SPF Fischer     56 animals in    Exposure to rock wool with-     Evidence of reaction to the   Wagner              
rats            each of the      out resin (227 fibres/cc;       dust in all exposed groups    et al.                    
                treatment        diameter < 3 m; length,        but less for MMMF than for    (1984)                            
                groups;          > 5 m), glass wool with-       chrysotile; greater reaction                              
                56 controls      out resin (323 fibres/cc;       with chrysotile at 12 months                              
                                 diameter < 3 m; length >      than at 3 months, but little                              
                                 5 m), glass wool with resin    change for MMMF; in chryso-                               
                                 (240 fibres/cc; diameter <      tile exposed group, 12 lung                               
                                 3 m; length > 5 m), glass    neoplasms (11 adenocarcinomas                             
                                 microfibres (1436 fibres/cc;    and 1 adenoma) and broncho-                               
                                 diameter < 3 m; length >      alveolar hyperplasia (BAH) in                             
                                 5 m), UICC Canadian chryso-    5 animals (No. = 48); glass                               
                                 tile (3832 fibres/cc; dia-      microfibre - 1 pulmonary                                  
                                 meter < 3 m; length > 5 m)    adenocarcinoma, BAH in 3 rats                             
                                 at ~10 mg/m3, or to air, for    (No. = 48); rock wool - 2                                 
                                 7 h/day, 5 days/week for 12     adenomas, BAH in 1 rat (No. =                             
                                 months; animals sacrificed      48); glass wool with resin -                              
                                 at 3, 12, or 24 months          1 pulmonary adenocarcinoma,                               
                                                                 BAH in 3 rats (No. = 48);                                 
                                                                 glass wool without resin - 1                              
                                                                 adenoma, BAH in 1 rat (No. =                              
                                                                 47); controls - 0 neoplasms                               
                                                                 and BAH in 1 rat (No. = 48);                              
                                                                 incidence not specified                                   

Fischer         Group sizes at   Exposure to Canadian chryso-    At 3 months, minimal to mild  McConnell           
344 rat         final sacrifice: tile or glass microfibres       cellular changes in both      et al.                    
                47 - 55 in each  (JM 100), at ~10 mg/m3 for      glass microfibres (gm)- and   (1984)                            
                of the treatment 7 h/day, 5 days/week, for       chrysotile (chrys)-exposed                                
                groups; 48 - 53  12 months; life-time ob-        rats, which progressed                                    
                controls         servation with interim sac-     througout the 12-month expo-                              
                                 rifices at 3, 12, and 24        sure period - changes less                                
                                 months; studies conducted in    severe for gm- than for chrys;                            
                                 2 laboratories (NIEHS and       progression of changes in                                 
                                 MRC)                            chrys-exposed rats but not                                
                                                                 in gm-exposed animals follow-                             
                                                                 ing cessation of exposure;                                
                                                                 increased incidence of pul-                               
                                                                 monary neoplasia found only                               
                                                                 in rats exposed to chrysotile                             
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                  

                                                                                                                                                                                                   
Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   
Male Syrian     Group sizes at   exposure to 300 fibres/cc       Life span of hamsters ex-     Smith               
hamster,        final sacrifice: (~0.3 mg/m3), or 3000           posed to glass fibres sig-    et al.                 
female          47 - 60 hamsters fibres/cc (~3 mg/m3) 0.45-      nificantly longer than that   (1984,                               
Osborne-        in the treatment m mean diameter glass          of controls (with the excep-  in press)                   
Mendel rat      groups and 58 -  fibres (no binder), 100         tion of those exposed to 3.1-                             
                112 controls;    fibres/cc (~10 mg/m3)           m mean diameter fibres);                                 
                52 - 61 rats     -m mean diameter glass         foci of fibre-containing                                     
                in each of       fibres (silicone lubricant),    macrophages for both species                              
                the treatment    10 fibres/cc (~1.2 mg/m3),      exposed to glass fibres, but                          
                groups and       or 100 fibres/cc (~12           "little fibrosis" (peri-                                  
                59 - 125         mg/m3) 5.4-m mean dia-         bronchiolar when observed);                               
                controls         meter glass fibres (binder-     no tumours in MMMF-exposed                                
                                 coated), 25 fibres/cc (~9       animals with the exception                                
                                 mg/m3) 6.1-m mean dia-         of a mesothelioma in 1 ham-                               
                                 meter glass fibres (binder-     ster exposed to 1.8-m mean                               
                                 coated), 200 fibres/cc          diameter refractory ceramic                               
                                 (~12 mg/m3) 1.8-m mean         fibre; asbestosis in crocido-                             
                                 diameter refractory ceramic     lite-exposed hamsters and                                 
                                 fibre (no binder), 200          rats; no pulmonary tumours in                             
                                 fibres/cc (~10 mg/m3)           crocidolite-exposed hamsters                              
                                 2.7 m mean diameter mineral    (0/58), but 3/57 (5%) croci-                              
                                 wool (no binder), 3000          dolite-exposed rats developed                             
                                 fibres/cc (~7 mg/m3) UICC       lung neoplasms (compared with                             
                                 crocidolite asbestos or air     0 in controls) (negative res-                             
                                 (sham and unmanipulated con-    ults in positive controls)                                
                                 trols), nose-only, for 6 h/                                                               
                                 day, 5 days/week, for 24                                                                  
                                 months; life-time observa-                                                                
                                 tion                                                                                      
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   

                                                                                                                                                                                                   
Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
SPF Wistar      48 exposed       Exposure to fibrous ceramic     Survival of treated and con-  Davis                     
rats of         animals and      aluminum silicate glass at      trol groups similar; inter-   et al.                    
AF/HAN          40 controls      ~10 mg/m3 (95 fibres/cc;        stitial fibrosis in animals   (1984)                      
strain                           diameter < 3 m; length >       exposed to ceramic fibres                                 
                                 5 m), for 7 h/day, 5           occurred to a lesser, but not                             
                                 days/week, for 12 months;       significantly different, ex-                              
                                 animals sacrificed at 12,       tent than that for chryso-                                
                                 18, or 32 months                tile exposed animals; how-                                
                                                                 ever, little peribronchiolar                              
                                                                 fibrosis in ceramic fibre-                                
                                                                 exposed rats; relatively                                  
                                                                 large numbers of pulmonary                                
                                                                 neoplasms in rats exposed to                              
                                                                 ceramic fibre (tumours in 8                               
                                                                 animals - 1 benign adenoma, 3                             
                                                                 carcinomas, and 4 malignant                               
                                                                 histiocytomas) - no tumours                               
                                                                 in control animals; pattern                               
                                                                 of tumour development differ-                             
                                                                 ent from that for asbestos;                               
                                                                 large non-fibrous component                               
                                                                 of exposure aerosol                                       
                                                                                                                                                                                                   
SPF Fischer     32 exposed       Exposure to glass micro-        No significant gross or his-  Pickrell                  
344 rat         animals and      fibres at 50 000 fibres/cm3,    topathological changes        et al.                    
                32 controls      for 5 - 6 h/day, for 2 or 5                                   (1983)                      
                                 days; animals sacrificed at                                                               
                                 1, 4, 5, 8, and 12 months                                                                 
                                 after exposure                                                                            

Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   
Wistar IOPS     24 animals of    Exposure to (respirable         Simple alveolar macrophagic   Le Bouffant            
AF/HAN rat      each sex in      dust fraction) glass wool       reaction with slight septal   et al.                       
                each treatment   (Saint Gobain) at 5 mg/m3       fibrosis (rock and glass      (1984, in                 
                group; 24        (73% < 20 m in length; 69%     wool); for glass microfibre,  press)                      
                males and 24     < 1 m in diameter), rock       septal fibrosis slightly                                  
                females in       wool (Saint Gobain) (40%        more marked; 1 pulmonary                                  
                control group    < 10 m in length, 49% < 2      tumour (undifferentiated                                  
                                 m in diameter), or glass       epidermoid carcinoma) in                                  
                                 microfibre (JM 100) (94%        glass wool-exposed male (0                                
                                 < 5 m in length, 43% < 0.1     in controls) compared with                                
                                 m in diameter), or Canadian    9 in chrysotile-exposed                                   
                                 chrysotile, for 5 h/day, 5      group; digestive tract                                    
                                 days/week, over 12 or 24        tumours (unspecified) in 4                                
                                 months; animals sacrificed      glass wool-exposed animals                                
                                 at 0, 7, 12, and 16 months      (0 in controls); small num-                               
                                 after 1-year exposure and       ber of exposed animals and                                
                                 0 and 4 months after 2-year     incidence not specified                                   
                                 exposure                                                                                  

Female          120 animals      Exposure to 3 mg/m3 (252        Life span of rats exposed     Mhle et              
Wistar          in glass fibre   fibres/ml > 5 m) glass         to SO2 alone reduced; no      al. (in                       
rat             (with or without fibres (JM 104/Tempstran        significant increases in      press)                      
                SO2)-exposed     475), 2.2 mg/m3 (162 fibres/    lung tumour incidence -                                   
                groups; 50       ml > 5 m) crocidolite, 6       1 adenocarcinoma (croci-                                  
                animals in       mg/m3 (131 fibres/ml > 5 m)    dolite-exposed group), 1                                  
                crocidolite-,    Calidria chrysotile, glass      squamous cell tumour                                      
                chrysotile-,     fibres, and SO2 (100 ppm)       (glass fibre-exposed                                      
                or SO2-exposed   or SO2 alone, nose-only,        group), 1 adenoma (glass                                  
                groups; 50       for 5 h/day, 4 days/week,       fibre-and SO2-exposed                                     
                sham and 50      for 1 year                      group); bronchioalveolar                                  
                untreated                                        hyperplasia in crocido-                                   
                controls                                         lite- and combined glass                                  
                (5 - 12                                          fibre, SO2-exposed groups                                 
                animals per                                      and squamous metaplasia                                   
                group examined                                   in 1 animal in each of the                                
                for fibre                                        crocidolite- and glass                                    
                retention)                                       fibre-exposed groups;                                     
                                                                 negative results in posi-                                 
                                                                 tive control                                              
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                   

                                                                                                                                                                                                   
Table 17.   (contd.)                                                                                                                                                                               
--------------------------------------------------------------------------------------------------------
Species         Number           Protocol                        Results and comments          Reference                 
--------------------------------------------------------------------------------------------------------
F-344 rat;      4 fibre-exposed  Exposure for 7 h/day, 5         Pulmonary macrophage aggre-   Mitchell            
Male            groups and 1     days/week; monkeys, 18          gates and granulomas con-     et al.                    
cynomolgus      air control      months; rats, 21 months;        taining glass fibres in       (1986)                            
monkey          with 100 rats    Group 1: 4 - 6 m diameter      both species; pleural                                     
                and 15 monkeys   glass fibre > 20 m long        plaques in rats but not                                   
                each             with red binder (15 mg/m3);     in monkeys; no evidence of                                
                                 Group 2: 0.5 - 3.5 m diam-     pulmonary or mesothelial                                  
                                 eter glass fibre > 10 m        tumours or fibrosis in                                    
                                 long with yellow binder (15     either species                                            
                                 mg/m3); Group 3: < 3.5 m                                                                 
                                 diameter glass fibre > 10 m                                                              
                                 long (5 mg/m3); Group 4:                                                                  
                                 < 3.5 m diameter glass fibre                                                             
                                 < 10 m long (5 mg/m3)                                                                    
--------------------------------------------------------------------------------------------------------
ppcf = particles per cubic foot.        
MRC = Medical Research Council (United Kingdom).
NIEHS = National Institute for Environmental Health Sciences (USA). 
SPF = Specific pathogen free.
7.1.1.1.  Fibrosis

    No  evidence of fibrosis of the lung was observed in most of
the  inhalation studies  conducted to  date on  the mouse,  rat,
guinea-pig,  and  hamster,  exposed to  concentrations  of glass
fibres  of up to 100 mg/m3 for periods ranging from 2 days to 24
months  (Schepers & Delahunt, 1955;  Gross et al., 1970;  Lee et
al.,  1979; Morriset et al., 1979; Lee et al., 1981; Pickrell et
al., 1983; Smith et al., 1984).  In general, the tissue response
in these studies was confined to the accumulation  of  pulmonary
macrophages.   However,  reversible  alveolar  proteinosis   was
reported in 2 rather limited studies by the  same  investigators
in which several species were exposed to relatively high concen-
trations  of glass  fibres (0.4  mg/litre) (Lee  et  al.,  1979,
1981).  In the more extensive investigations of McConnell et al.
(1984) and Wagner et al. (1984), in which rats were  exposed  to
glass  microfibres at 10  mg/m3 for 12  months, "minimal  inter-
stitial  cellular reactions with  no evidence of  fibrosis" were
reported.

    However,  in contrast, Johnson & Wagner (1980) reported that
electron  microscopic examination of the  lung tissue of 2  rats
exposed to glass fibre, rock wool, resin-coated glass  wool,  or
uncoated  glass wool at  10 mg/m3 for  50 weeks, revealed  focal
fibrosis.   In a limited  study, Le Bouffant  et al. (in  press)
reported slight septal fibrosis that was a little more marked in
rats exposed to glass microfibre than in those exposed  to  rock
and glass wool.  Fibrosis was also observed in  baboons  exposed
to  7.54  mg/m3 glass  fibres for 35  months (Goldstein et  al.,
1983).  However, the incidence and severity in  control  animals
were not reported.  Moreover, the fibrotic lesions  observed  in
this study were similar to those caused by lung  mites   (Pneumo-
 nyssus sp.),  commonly present in baboons from this geographical
area  (McConnell et al., 1974).  In a more recent study in which
cynomolgus  monkeys were exposed  for 18 months  to up to  15 mg
glass fibres/m3 with mean diameters of 0.5 - 6 m,   the  tissue
response  was confined to accumulation  of pulmonary macrophages
and granulomas (Mitchell et al., 1986).

    In  all cases, the  tissue reactions in  animals exposed  to
fibrous  glass or glass  wool were much  less severe than  those
produced   by  exposure  to   equal  masses  of   chrysotile  or
crocidolite (Johnson & Wagner, 1980; Lee et al., 1981; Goldstein
et al., 1983; McConnell et al., 1984; Smith et al., 1984; Wagner
et  al.,  1984).   Moreover,  in  contrast  to  fibrotic changes
resulting  from exposure to  asbestos, tissue responses  did not
progress   following  cessation  of   exposure  to  these   MMMF
(McConnell et al., 1984; Wagner et al., 1984).

    Results  concerning  the effects  of  fibre coating  on  the
potential  of fibrous glass or  glass wool to cause  lung-tissue
damage  are  limited and  contradictory.   Whereas Gross  et al.
(1970) concluded that there were no discernible  differences  in
the  tissue reactions for  uncoated fibrous glass  compared with

those for fibrous glass coated with phenol-formaldehyde resin or
starch binder, Johnson & Wagner (1980) concluded  that  uncoated
glass wool was more reactive than resin-coated varieties.

    Pigott  et  al.  (1981) reported  minimal pulmonary reaction
(generally  confined  to the  presence  of groups  of  pigmented
alveolar macrophages) in rats exposed for 86 weeks to relatively
low concentrations of normal or thermally aged  aluminium  oxide
refractory  fibres containing about  4% silica (mean  respirable
dust concentrations of 2.18 and 2.45 mg/m3, respectively; median
fibre  diameter, 3.3 m).   However, it should be noted that the
median  fibre  diameter of  the  material is  relatively  large.
Davis et al. (1984) reported that interstitial fibrosis occurred
to  a lesser extent  in rats, exposed  for 12 months  to fibrous
ceramic  aluminium silicate  glass at  10 mg/m3  (with a  rather
large non-fibrous component in the aerosol), than in chrysotile-
exposed animals.  In contrast, Smith et al. (1984, in press) did
not find any fibrosis in hamsters and rats exposed to  12  mg/m3
refractory ceramic fibres (with about twice the  airborne  fibre
concentration) for a period of 2 years.

    With  respect to the fibrogenic effects of combined exposure
to  MMMF and other airborne  pollutants, Morriset et al.  (1979)
concluded  that, though glass fibres appeared to be biologically
inert   in   their  study  (possibly  because  they  were  in  a
nonpathogenic size range), the presence of these fibres enhanced
the  toxic effects of styrene  in mice (possibly because  of the
absorption of styrene on the fibre surface).

    The discrepancies in the results of different investigations
concerning  the severity of tissue response following inhalation
of  glass and ceramic fibres  may be the result  of variation in
fibre size distribution.  For example, Johnson &  Wagner  (1980)
suggested  that  the fibrotic  changes  observed in  their study
might have been due to the fact that their samples  contained  a
greater  proportion of fibres  longer than 5 m  than  those  of
other investigators.  However, it is difficult to  draw  general
conclusions  in this regard  because of inconsistencies  in  the
characterization of the airborne fibre size distributions and in
doses administered in different studies.

7.1.1.2.  Carcinogenicity

    In  none of  the inhalation  studies conducted  to date  has
there been a statistically significant excess of lung tumours in
animals exposed to glass fibres (including glass microfibres) or
rock wool.  However, there have only been a few relevant studies
(Gross et al., 1970, 1976; Lee et al., 1981; McConnell  et  al.,
1984; Wagner et al., 1984; Le Bouffant et al., in  press;  Mhle
et  al.,  in  press; Smith et al., in press), and group sizes at
termination  in several of  these investigations were  small  by
current standards.  However, in several of the relevant studies,
there  were small, but not  statistically significant, increases
in  tumour  incidence in  exposed  animals.  For  example,  2/19

(10.5%)  Sprague Dawley rats exposed for only 90 days to fibrous
glass  at 0.4 mg/litre  had bronchiolar adenomas  2 years  after
exposure, compared with none in the control group (Lee  et  al.,
1981).   Similarly, there were 1  - 2 neoplasms (2.1  - 4.2%) in
each group of Fischer rats exposed to rock wool (with or without
resin),  glass wool,  or glass  microfibre at  10 mg/m3  for  12
months,  compared with  none in  the controls  (Wagner  et  al.,
1984).  No mesotheliomas have been observed in  animals  exposed
to glass fibres or rock wool by inhalation; moreover, in most of
the  carcinogenicity bioassays conducted  to date, similar  mass
concentrations  of chrysotile asbestos have been far more potent
in  inducing  lung tumours  than these MMMF  (Lee et al.,  1981;
McConnell  et al.,  1984; Wagner  et al.,  1984; Smith  et  al.,
in press).  However, data are not sufficient to draw conclusions
concerning  the relative potency of various fibre types, because
the  concentration of respirable fibres was not reported in many
of these studies.

    Morrison  et al. (1981) reported  "neoplastic, hyperplastic,
and  metaplastic lesions in the  bronchi and near the  bronchio-
alveolar  junctions of the lung"  in 12 A strain mice sacrificed
90 days after exposure to 300 mg "crushed fiberglass insulation"
(80%  of fibres 2.5 m  wide)  in bedding, every  3 days for  30
days.   However, it is difficult  to assess the results  of this
study, since there was no control group exposed to air only.  In
addition,  only the  total number  of lesions,  rather than  the
incidence, was specified and the administered material  was  not
well    characterized.    Furthermore,   these    results   seem
inconsistent  with those of other investigators, particularly in
view  of the  relatively short  exposure period  and  the  small
number of exposed animals.

    Pigott  et  al. (1981)  reported  the absence  of  pulmonary
neoplasms in 50 Wistar-derived Alderley Park rats exposed for 86
weeks to relatively low mean respirable dust  concentrations  of
normal  or  thermally  aged  aluminium  oxide  refractory  fibre
containing about 4% silica at 2.18 and 2.45 mg/m3, respectively.
Davis  et  al.  (1984)  reported  "relatively  large  numbers of
pulmonary  neoplasms" in Wistar rats  of the Han strain  exposed
for  12 months to  fibrous ceramic aluminium  silicate glass  at
10 mg/m3.   Pulmonary  neoplasms  (3 carcinomas  and  1 adenoma)
developed in 8/48 exposed animals (16.6%).  However, in 4 of the
animals,   the  tumours  were  malignant   histiocytomas;  these
neoplasms  have  not  generally been  associated  with  asbestos
exposure.  There was also one peritoneal mesothelioma in another
animal  in the  exposed group  (the non-fibrous  content of  the
exposure aerosol in this study was relatively large).

    In  Syrian golden hamsters  exposed to approximately  12  mg
"refractory  ceramic  fibres"/m3  (200 fibres/cc)  for  2 years,
there  was a single  malignant mesothelioma.  However,  no other
primary lung tumours were observed in 51 animals  surviving  the
exposure  period, and no primary  lung tumours were observed  in
similarly  exposed  Osborne-Mendel  rats.  It  should  be noted,

though, that only 3 of the 57 rats and none of the  58  hamsters
that  survived  the  exposure  period  following  inhalation  of
3000 fibres/cm3  of  crocidolite  for  2  years  developed  lung
tumours in this study (Smith et al., in press).

7.1.2.  Intratracheal injection

    Administration  by the intratracheal route does not simulate
the  exposure  of  man,  since  an  uneven  dose  of  fibres  is
artificially  deposited in the respiratory  tract.  For example,
the  production of fibrous granulomas  in such studies may  be a
function  of  "bolus"  events  and  might  not  be  observed  in
inhalation  studies  where  fibre deposition  is  more  diffuse.
Although this limitation must be borne in mind  in  interpreting
the  results of intratracheal studies,  such investigations have
confirmed  the effects of MMMF observed following inhalation and
have  provided additional information on the importance of fibre
size in the pathogenesis of disease.  The results  of  available
studies  involving  intratracheal  administration  of  MMMF  are
presented  in  Table  18.  For  example, following intratracheal
administration  of uncoated or coated glass fibres (1 - 10 doses
of  3.5  mg) to  rats, Gross et  al. (1970) observed  reversible
polyploid  proliferative lesions, but no alveolar fibrosis.  For
hamsters,  the tissue reaction  was similar with  the  exception
that  diffuse, bland, acellular collagenous pleural fibrosis was
also observed.  Pickrell et al. (1983) observed proliferation of
bronchioalveolar  epithelial cells, chronic inflammation  of the
terminal  bronchioles and alveolar  ducts, and slight  pulmonary
fibrosis   following   intratracheal  administration   of  glass
microfibres to Syrian hamsters (total dose, 2 mg;  count  median
diameter, 0.2 m).     Fibrosis  was  not  observed  in  animals
exposed  in a similar  manner to 2  instillations of 3  types of
glass  fibre  "household insulation"  (total  dose, 17  - 21 mg;
count  median diameters, 2.3  - 4.1 m).   A dose-related  trend
was reported by Renne et al. (1985) in the incidence of alveolar
septal fibrosis in hamsters exposed by the  intratracheal  route
to 15 weekly doses (0.05 - 10 mg) of fibrous glass with a median
fibre  diameter and length  of 0.75 and  4.30 m,  respectively.
The authors reported that the pulmonary response to quartz alone
and  to quartz in combination with ferric oxide was considerably
more  severe than that to fibrous glass.  Drew et al. (in press)
reported  a granulomatous foreign body response following intra-
tracheal  instillation  of  a single  dose  of  20 mg  of "long"
(nominal  diameter  and length,  1.5 m   x 60 m)   and "short"
(1.5 m  x 5 m)  glass fibres in rats, which they attributed to
the  administration  technique.   However, following  10  weekly
instillations   of  0.5  mg,  only  a  macrophage  response  was
elicited.   In contrast, a  much more severe  pulmonary response
accompanied by fibrosis resulted from exposure to crocidolite.


Table 18.  Intratracheal injection studies
--------------------------------------------------------------------------------------------------------
Species      Number in groups   Protocol                      Results and comments          Reference
--------------------------------------------------------------------------------------------------------
Rat,         12 - 30 animals    Injection (1 - 10 doses) of   Rats: reversible polyploid    Gross et al.
hamster      per test group;    3.5 mg uncoated or coated     proliferative lesions but     (1970)
             20 controls        (phenol-formaldehyde resin    but no alveolar fibrosis;
             of each species    or starch binder) "glass      hamsters: tissue reaction
                                fibres" (length < 50 m)      similar to that observed in
                                                              rats, except that diffuse,
                                                              bland acellular collagenous
                                                              pleural fibrosis also seen;
                                                              observation period not re-
                                                              ported; controls not held
                                                              under same conditions as
                                                              test group

Male Syrian  20 animals per     Instillation of (2 doses) of  Glass microfibres produced    Pickrell 
hamster      test group;        2 - 21 mg of one of 2 types   proliferation of bronchio-    et al.
(Charles     30 controls        of "bare glass" or 3 types    alveolar epithelial cells,    (1983)
River                           of "household insulation";    chronic inflammation of the
Sch:(SYR))                      count median diameters        terminal bronchioles and
                                ranged from 0.1 to 4.1 m;    alveolar ducts, and slight
                                animals sacrificed at 1,      pulmonary fibrosis; no
                                3.5, and 11 months            fibrosis after instillation
                                                              of the "household insulation"

Male Syrian  25 animals each    Instillation (15 weekly       Dose-related trend in the     Renne 
golden       in test, saline,   doses of 0.05 - 10 mg         incidence of alveolar sep-    et al.
hamster      and cage control   fibrous glass with mean       tal fibrosis; the pulmonary   (1985)
Lak:LVG      groups             diameter and length of        response to quartz and ferric
                                0.75 and 4.30 m, respec-     oxide was considerably more
                                tively; animals maintained    severe
                                until 28% survival in each
                                group or until 24.5 months
                                of age

--------------------------------------------------------------------------------------------------------

Table 18.  (contd.)
--------------------------------------------------------------------------------------------------------
Species      Number in groups   Protocol                      Results and comments          Reference
--------------------------------------------------------------------------------------------------------
SPF Fischer  50 animals per     Instillation of 20 mg of      A single instillation of      Drew       
344 male     test and           short (nominal diameter       short or long fibres pro-     et al.
rat          control groups     and length, 1.5 x 5 m)       duced a granulomatous for-    (in press)
                                and long (1.5 x 60 m)        eign body response, whereas
                                glass fibres or 10 weekly     weekly instillations eli-
                                instillations of 0.5 mg       cited only a macrophage res-
                                glass fibres                  ponse; severe pulmonary res-
                                                              ponse with fibrosis after
                                                              exposure to crocidolite

Guinea-pig   5 - 8 animals per  Instillation of 0.5 cc of     Severity of the tissue        Schepers & 
             test and control   0.5% (1 group) of 5% (2       reaction (no fibrosis)        Delahunt
             groups             mean diameters of 6, 3,       inversely proportional        (1955)
                                and 1 m                      to the fibre diameter

Guinea-pig   30 animals per     Instillation (2 - 8 doses)    Tissue reaction varied with   Kuschner & 
             test and control   of "short" (< 5 m) and       fibre length, with fibrosis   Wright        
             groups             "long" (> 10 m) glass        resulting only following      (1976); 
                                fibres; total doses of 12     instillation of "1 mg"        Wright & 
                                and 25 mg, respectively                                     Kuschner
                                                                                            (1977)  

Male Syrian  136 or 138         8 weekly instillations of     Incidence of lung carcinomas  Mohr 
golden       animals per        1 mg JM 104 (wet milled)      was slightly less than that   et al.
hamster      test group         glass fibre, 50% with         of animals exposed to UICC    (1984)
                                diameters < 3 m; animals     crocidolite; however, the 
                                observed up to week 130       incidence of sarcomas      
                                                              (thorax) and mesotheliomas 
                                                              was greater in glass fibre-
                                                              exposed animals; not con-  
                                                              firmed in investigations in
                                                              other laboratories         
--------------------------------------------------------------------------------------------------------

Table 18.  (contd.)
--------------------------------------------------------------------------------------------------------
Species      Number in groups   Protocol                      Results and comments          Reference
--------------------------------------------------------------------------------------------------------
Female       34 animals per     Instillation of 0.05 mg       Lung tumours in 5/34 animals  Pott 
Wistar       test and control   (20 doses of JM 104/          (1 adenoma), 2 adenocarcin-   et al.
rat          groups             Tempstran 475 glass fibres    omas, and 2 squamous cell     (1987)
(Wistar-                        (50% with lengths and         carcinomas); 9 lung carcin- 
Wll/                            diameters < 3.2 m and        omas and 8 mesotheliomas in
KiBlegg)                        0.18 m, respectively)        142 animals with similar    
                                                              exposure to crocidolite     
                                                              (length < 2.1 m; diameter 
                                                              < 0.2 m for 50% of fibres)


Syrian       35 animals of      Instillation of 1 mg, every   "Glass fibre granulomas",     Reuzel 
golden       each sex per       2 weeks, for 52 weeks, of     but no tumours and no indi-   et al.
hamster      test and control   1 glass fibres (88% with      cation that the glass         (1983); 
             groups             diameters < 1 m; 58% with    fibres enhanced respiratory   Feron 
                                lengths < 5 m); animals      tract tumours induced by      et al. 
                                observed for up to week 85    benzo( a )pyrene (26 doses     (1985)      
                                                              of 1 mg glass fibres and
                                                              1 mg benzo( a  )pyrene); no
                                                              tumours observed in posi-
                                                              tive (crocidolite-exposed)
                                                              control group

Osborne-     22 - 25 animals    Instillation of 2 mg of       For refractory ceramic        Smith et al.
Mendel       in test groups     either glass fibre (mean      fibre, significant reduc-     (in press)
rat          at final           diameter, 0.45 m) or         tion in the life span of
and Syrian   autopsy; 24 -      1.8-m mean diameter re-      hamsters (479 days compared
golden       25 saline          fractory ceramic fibre,       with 567 days in vehicle
hamster      controls and       once a week, for 5 weeks;     controls) and a chronic
             112 - 125 cage     life-time observation         inflammatory response in
             controls at                                      the lungs of rats (probably
             final autopsy                                    due to deposition of large
                                                              quantities of foreign mat-
                                                              erials); fibrosis in rats
                                                              exposed to 0.45-m mean
                                                              diameter glass fibres; no
                                                              pulmonary tumours in hamsters
                                                              or rats exposed to either
                                                              fibre; pulmonary tumours in
                                                              8% (rats) and 7.4% (hamsters)
                                                              exposed to crocidolite
-----------------------------------------------------------------------------------------------------------------------------
    In  a study conducted as early as 1955, it was reported that
the  severity  of the  tissue  reaction (no  fibrosis) following
intratracheal administration of 3 samples of glass fibres (three
0.5-cc doses of 0.5% (1 group) or 5% (2 groups)  solutions)  was
inversely  proportional  to  fibre  diameter (mean values, 6 m,
3 m,    and  1 m)  (Schepers  &  Delahunt, 1955).   Kuschner &
Wright  (1976)  observed that  the severity of  tissue  reaction
following  intratracheal administration of  glass fibres (2  - 8
instillations  of 12 - 25  mg) to guinea-pigs varied  with fibre
length,  with fibrosis resulting  only from exposure  to samples
containing  fibres mainly longer than 10 m  (Wright & Kuschner,
1977).

    Mohr  et  al.  (1984)  found  that  the  incidence  of  lung
carcinomas  in Syrian golden hamsters following a rather unusual
intratracheal  administration technique involving weekly instil-
lations  of relatively low  doses of fibres  (8 weekly doses  of
1 mg  each of wet-milled JM 104 glass fibres, 50% with diameters
< 0.3 m)   was slightly less than  that for animals exposed  to
intratracheal  administration technique involving weekly instil-
lations  of relatively low  doses of fibres  (8 weekly doses  of
1 mg  each of wet-milled JM 104 glass fibres, 50% with diameters
< 0.3 m)   was slightly less than  that for animals exposed  to
UICC  crocidolite.   Surprisingly,  the  incidence  of  sarcomas
(thorax)   and  mesotheliomas was  greater  in the  glass fibre-
exposed animals. It has been suggested by the authors that these
results  might  be attributable  to  the relatively  short fibre
lengths  of the UICC crocidolite (Pott et al., 1987).  In a more
recent but similar study in the same laboratory, lung tumours (1
adenoma,  2  adenocarcinomas,  2 squamous  cell carcinomas) were
observed in 5 out of 34 female Wistar rats receiving  20  weekly
applications  of 0.05  mg each  of JM  104/Tempstran  475  glass
fibres (50% of fibre lengths < 3.2 m;  50% of  fibre  diameters
< 0.18 m)   (Pott et al.,  1987).  In rats  exposed to  similar
doses  of crocidolite on the same schedule (50% of fibre lengths
< 2.1 m;  50% of fibre diameters < 0.20 m),   lung  carcinomas
were  observed in 9 and mesotheliomas in 8 out of a total of 142
animals examined.

    These  results  concerning  the  carcinogenicity  of  intra-
tracheally  administered glass fibres have not been confirmed in
other laboratories.  For example, Reuzel et al. (1983) and Feron
et al. (1985) reported "glass fibre granulomas", but no tumours,
in  hamsters receiving intratracheal instillations of 1 mg glass
fibres  (88% of fibre diameters < 1 m  and 42% > 5 m  length),
once every 2 weeks, for 1 year; moreover, there was  no  indica-
tion that glass fibres enhanced the development  of  respiratory
tract  tumours induced by benzo( a )pyrene (26 doses of 1 mg glass
fibres  and 1 mg benzo( a )pyrene).   However, it should be  noted
that  no tumours were observed  in the positive controls  (i.e.,
the crocidolite-exposed group).  The strain of animals  and  the
form of glass fibre administered in this study were  similar  to
those used by Mohr et al. (1984).  Feron et al. (1985) suggested
that the discrepancies between the results of the  2  investiga-
tions  might be attributable to the differences in the length of
the observation periods (85 weeks compared with 113 weeks in the

Mohr  et  al.  (1984) study)  or  to  the effects  of  prolonged
repeated  dosing (i.e., disturbance of fibres by acute pulmonary
reaction  after each  of the  26 doses).   Kuschner  (in  press)
suggested   that  the  difference  might  be  due  to  different
instillation techniques.

    In  an additional study by Smith et al. (in press), the mean
life span of 25 hamsters receiving 2 mg of 1.8-m  mean diameter
refractory  ceramic fibre, intratracheally,  once a week,  for 5
weeks,  was significantly reduced  (479 days compared  with  567
days in vehicle controls).  However, no pulmonary  tumours  were
observed  in  the  hamsters  or in rats receiving either 0.45-m
mean  diameter glass fibres or 1.8-m   mean diameter refractory
ceramic fibre, on a similar schedule.  Two out of 25  rats  (8%)
and 20 out of 27 hamsters (74%) similarly exposed to crocidolite
developed  pulmonary tumours.  Pulmonary response to the various
types  of MMMF in this investigation was restricted to a chronic
inflammatory  reaction  in rats  exposed  to the  ceramic  fibre
(believed to be due to deposition of large quantities of foreign
materials in the lung)  and fibrosis in the same species exposed
to glass fibres with a mean diameter of 0.45 m.

7.1.3.  Intrapleural, intrathoracic, and intraperitoneal
administration

    Although  introduction of mineral fibres into the pleura and
peritoneum  of  animal species  does not simulate  the route  of
exposure of man, such studies have made it possible to clarify a
number of questions that could not feasibly have  been  investi-
gated using the inhalation model. Studies involving intrapleural
or  intraperitoneal  injection  also serve  as  useful screening
tests  to  develop  priorities for  further investigation.  Both
have  been  used to  assess the potential  for fibres to  induce
mesothelioma, when placed in contact with a target  tissue.   In
addition,  the fibrogenic potential of both particles and fibres
has been examined in studies involving intraperitoneal injection
and  short  observation  periods.  However,  factors that affect
fibre  deposition and translocation, and defence mechanisms that
determine retention of fibres within the lung are not taken into
consideration in this experimental model and these disadvantages
must  always be borne  in mind in  interpreting the  results  of
such studies.

    Both  fibrosis and malignant tumours have resulted following
the  implantation of  various types  of MMMF  into the  pleural,
thoracic, or peritoneal cavities of various species; the results
of  the relevant  studies are  summarized in  Table  19.   These
investigations have been most important in focusing attention on
the  role of fibre size  and shape in the  induction of disease.
For  example, in  studies  by Davis (1972,  1976),  intrapleural
injection  of  long-fibred  samples of  fibrous  glass  produced
massive  fibrosis,  while  short-fibred  samples  produced  only
discrete  granulomas  with minimal  fibrosis.   In 1972,  on the
basis of their study involving intrapleural implantation  of  17
fibrous materials (including 6 types  of fibrous glass) in rats,

Stanton  & Wrench (1972)  first hypothesized that  "the simplest
incriminating feature for both carcinogenicity and fibrogenicity
seems to be a durable fibrous shape, perhaps in a  narrow  range
of  size".  In subsequent studies by the same authors, involving
intrapleural  implantation  of numerous  dusts including fibrous
glass,  it was  found that  the probability  of  development  of
pleural sarcomas was best correlated with the number  of  fibres
with  diameters of less  than 0.25 m  and lengths  greater than
8 m    (Stanton et al.,  1977, 1981; Stanton  & Layard,  1978).  
However,  probabilities were also  "relatively" high for  fibres
with diameters < 1.5 m  and lengths > 4 m.   On the  basis  of
an   extensive  series  of  studies   involving  intraperitoneal
administration  to  rats of  asbestos,  fine glass  fibres,  and
nemalite, Pott (1978) hypothesized a model in which the carcino-
genic potency of fibres is a continuous function of  length  and
diameter.   Based  on  the  results  of  further  studies, which
indicated  that  tumour  incidence for  long,  thin,  nondurable
fibres  was less than that  for durable fibres in  the same size
range,  Pott et al.  (1984)  concluded that  carcinogenicity  is
also a function of the durability of fibres in the body.

    In  general,  chrysotile has  been  more potent  than  equal
masses  of  glass fibres  in  inducing tumours  following intra-
pleural  injection (Monchaux et al., 1981; Wagner et al., 1984).
However,  the  potency  of glass  fibres  varies  markedly as  a
function of fibre size distribution; intraperitoneal administra-
tion of continuous glass filament with mean diameters of  3,  5,
and 7 m  did not increase tumour incidence (Pott et al., 1987).
On  the  basis of  studies  involving intrapleural  injection of
rock-,  slag-,  or  glass wool  or  glass  microfibres, it  also
appears  that tumour incidence  is roughly proportional  to  the
number  of fibres injected (Wagner  et al., 1984).  In  a recent
study,  in which  actinolite and  a basalt  wool that  contained
equal  numbers of fibres (length  > 5 m)  were administered  to
rats,  tumour  incidence  was  similar,  though  the   diameters
differed by an order of magnitude (0.1 m  versus 1.1 m)  (Pott
et al., in press).  However, it should be noted that  the  fibre
length  distributions  were  substantially different  as was the
mass injected.


Table 19.  Intrapleural, intrathoracic, and intraperitoneal administration
--------------------------------------------------------------------------------------------------------
Species        Number in groups   Protocol                      Results and comments           Reference
--------------------------------------------------------------------------------------------------------
SPF Sprague    8 groups of 48     Intrapleural injection of     Mesotheliomas in 6 (12.5%)     Wagner 
Dawley rat     animals each;      20 mg respirable samples      of chrysotile-exposed rats,    et al.
               24 controls        of uncoated and resin-        4 (8.3%) exposed to glass      (1984)
                                  coated Swedish rock wool,     fibres, 3 (6.25%) exposed to
                                  German slag wool, and Eng-    rock wool with resin, 2 (4.2%)
                                  lish glass wool, American     exposed to rock wool without
                                  glass microfibres (JM 100),   resin, 1 (2.1%) exposed to
                                  and chrysotile; number of     glass wool, and none exposed
                                  fibres > 5 m ranged from     to slag wool; tumour incidence
                                  1.2 x 108 to 4.2 x 108;       roughly proportional to number
                                  value for chrysotile,         of fibres injected
                                  196 x 108

Wistar and     ~50 animals;       Intraperitoneal administra-   Tumour incidence varied        Pott 
Sprague        50 controls        tion of 2 - 10 mg different   from none (rock wool) to       et al.
Dawley rat                        preparations of glass micro-  73% (JM 104, 1-h ball          (1984)
                                  fibres (JM 100, 104), bas-    milling); carcinogenicity 
                                  alt wool, rock wool, and      reduced by HCl and NaOH
                                  slag wool, and chemically
                                  treated (HCl or NaOH) glass
                                  microfibres (JM 104)

SPF Wistar     32 animals in      Intraperitoneal injection of  Tumours in 3 (9.3%) animals    Davis 
rat of the     exposed group      25 mg fibrous ceramic alum-   (compared with 90% in chrys-   et al.
AF/HAN                            inium silicate glass          otile-exposed animals);        (1984)
strain                                                          first tumour occurred ~850 days
                                                                after injection compared with
                                                                200 days for chrysotile (con-
                                                                trasts with the results of
                                                                inhalation study); no concur-
                                                                rent control group

--------------------------------------------------------------------------------------------------------

Table 19.  (contd.)
--------------------------------------------------------------------------------------------------------
Species        Number in groups   Protocol                      Results and comments           Reference
--------------------------------------------------------------------------------------------------------

Sprague        10 groups of 10    Exposure to 3000 WL radon/    Proportion of lung cancer      Bignon 
Dawley rat     animals inhaling   day, for 10 h/day, 4 days/    in radon only exposed rats     et al.
               radon and          week, over 10 weeks; 2 weeks  was 28% compared with 68% in   (1983)
               receiving          later, intrapleural injec-    group with combined exposure
               intrapleural       tion of 2 mg of one of 10     to radon and intrapleural
               injection of       mineral dusts (including      injection of mineral dust
               various mineral    JM 104 glass fibres); life-   (tumour type also varied); in
               dusts; 60          span observation              glass fibre-exposed group, no
               controls exposed                                 mesotheliomas but tumours in
               to radon only                                    6 (60%) animals; number in
                                                                each group too small to allow
                                                                comparison of effect by fibre
                                                                type

Balb/C         18 - 25 animals    Intrapleural injection of     Long-fibred samples            Davis 
mouse and      in exposed group   10 mg of 4 samples of boron   produced massive fibrosis,     (1976)    
rat (strain                       silicate glass fibre (long-   while short fibred samples     
unspecified)                      or short-fibred samples       produced only discrete         
                                  with mean diameters of 0.05   granulomas with minimal  
                                  or 3.5 m); animals killed    fibrosis; in first study, 
                                  2 weeks - 18 months after     no tumours in 37 mice sacri-   
                                  injection; intraperitoneal    ficed at 18 months; in second  
                                  injection of 10 mg long-      study, 3 tumours in 18 rats and
                                  fibred, 0.05-m diameter      and 3 tumours in 25 mice; no   
                                  sample in both mice and rats; control group and observation  
                                  life-span observation         period in first study short    

SPF Male       45 exposed;        Intrapleural injection of     Survival times for animals     Lafuma 
Sprague        32 controls        20 mg glass fibre (JM 104;    injected with glass fibres     et al.        
Dawley rat                        mean length, 5.89 m; mean    longer than for controls;      (1980); 
                                  diameter, 0.229 m); life-    tumours in 13% of animals      Monchaux
                                  span observation              (similar to that for leached   et al.  
                                                                (44 - 64% Mg removed)          (1981)  
                                                                chrysotile

Table 19.  (contd.)
--------------------------------------------------------------------------------------------------------
Species        Number in groups   Protocol                      Results and comments           Reference
--------------------------------------------------------------------------------------------------------

Wistar rat     40 rats in test    Intraperitoneal administra-   Tumours in 57.5% of animals;   Pott 
               groups; 80         tion of 4 doses of 25 mg      time to first tumour, 197      et al.
               controls           weekly of uncoated glass      days; authors mention that,    (1974)
                                  fibres (72.6% < 5 m long;    in current studies, lowest
                                  mean diameter, 0.5 m);       effective dose of glass
                                  life-time observation         fibres was 2 mg

SPF Wistar     24 (12 males, 12   Intraperitoneal injection of  Mild chronic inflammatory      Pigott & 
rat            females) in test   20 mg of 2 commercial grades  response with a mild amount    Ishmael
(Alderley      and control        of the refractory alumina     of collagen compared with      (1981)
Park           groups             fibre SAFFIL; animals sac-    peritoneal asbestosis in rats
strain)                           rificed up to 1 year after    receiving UICC Rhodesian
                                  injection                     chrysotile

Wistar (2      50 females of      Intraperitoneal injection of  Tumours in ~51% (Wistar-       Pott 
sources),      each strain in     10 mg glass fibres (JM 104)   Ivanovas) - 79.6% (Wistar-     et al.
SIV and        test groups                                      Hagemann) of animals           (1980)
Sprague 
Dawley rat           

European       20 hamsters in     Intraperitoneal injection of  Tumours in 3 animals (15%) -   Pott 
hamster        each test group    50 mg glass fibres (JM 106)   based on results for UICC      et al.
                                                                crocidolite and glass          (1980)
                                                                fibres; authors concluded
                                                                "rats more sensitive for
                                                                testing carcinogenicity of
                                                                fibres than European
                                                                hamsters"
--------------------------------------------------------------------------------------------------------

Table 19.  (contd.)
--------------------------------------------------------------------------------------------------------
Species        Number in groups   Protocol                      Results and comments           Reference
--------------------------------------------------------------------------------------------------------
Syrian         60 males in each   Intrapleural injection of     Tumours in 15% for sample      Smith 
golden         exposed group;     25 mg of 6 samples of glass   with mean diameter 0.1 m      et al.
hamster        60 controls        fibres                        and 82% longer than 20 m;     (1980)
                                                                3.3% incidence for sample
                                                                with 0.33 m mean diameter
                                                                and 46% longer than 20 m;
                                                                similar incidence for sample
                                                                with 1.23 m mean diameter
                                                                and 34% longer than 20 m; no
                                                                tumours in hamsters treated
                                                                with fibres with mean dia-
                                                                meters of 0.09, 0.41, or
                                                                0.49 m, but with only 0 -
                                                                2% of fibres longer than
                                                                10 m

Balb/C         25 in each         Intrapleural injection of     Long-fibred dust specimens     Davis 
mouse          exposed group      10 mg of several fibrous      produced widespread cellular   (1972)
                                  dusts including 2 samples     granulomata, which formed
                                  of boron silicate glass       firm adhesions, gradually re-
                                  fibre (mean diameters,        placed by fibrous tissue;
                                  0.05 - 1 m and 2.5 - 4 m;   short-fibred dust specimens
                                  length < 10 m) and three     produced smaller granulomata
                                  "man-made insulation fibres"  without adhesions; non-
                                  (alumino-silicate: mean dia-  fibrous mineral rocks, when
                                  meter, 4 m; calcium-sili-    finely ground, also produced
                                  cate: mean diameter, 10 m;   small non-adherent granulo-
                                  calcium-alumino-silicate:     mata; final degree of fibro-
                                  mean diameter, 4 m); ani-    sis correlated with initial
                                  mals killed 2 weeks - 18      cellularity of lesions; no
                                  months after exposure         mention of control group

--------------------------------------------------------------------------------------------------------

Table 19.  (contd.)
--------------------------------------------------------------------------------------------------------
Species        Number in groups   Protocol                      Results and comments           Reference
--------------------------------------------------------------------------------------------------------

Female Wistar  10 in each group   Intraperitoneal injection of  Initial foreign body reac-     Engle-
albino rat                        50 mg of several fibrous      tion followed by fibroblast    brecht &
                                  dusts including "long" (mean  infiltration, fibrosis, and    Burger 
                                  length, 12.9 m) and "short"  a few areas of reactive        (1975)
                                  (mean length, 2.4 m) fibrous mesothelium, but no malignant
                                  glass; animals killed at      transformation; tissue res-
                                  periods of up to 330 days     ponse of long and short
                                  after exposure                fibres similar; authors con-
                                                                cluded that "mechanical irri-
                                                                tation does not contribute to
                                                                the induction of mesotheliomas"
								
SPF Wistar     up to 36 in each   Intrapleural injections of    Occasional mesotheliomas for   Wagner 
rat            of exposed groups  20 mg ceramic fibres, fibre-  ceramic fibre (3) and glass    et al.
                                  glass, glass powder, alum-    powder (1); none for glass     (1973)
                                  inium oxide, and 2 samples    fibres compared with (23) and
                                  of SFA chrysotile; life-      (21) for the SFA chrysotile;
                                  time observation              estimated carcinogenicity
                                                                factors (x 109) were: for
                                                                ceramic fibres, 0.16; for
                                                                glass powder, 0.04; for SFA
                                                                chrysotile, 2.28 - 2.85;
                                                                authors concluded that results
                                                                were consistent with the hypo-
                                                                thesis that finer fibres are
                                                                more carcinogenic
								
Female SPF     30 - 50 rats in    Intrathoracic implantation    Probability of pleural sarc-   Stanton & 
Osborne-       test and control   on a fibrous glass vehicle    oma best correlated with the   Wrench
Mendel rat     groups             of 40 mg of 72 samples of 12  number of fibres with a dia-   (1972);
                                  different fibrous materials   meter < 0.25 m and length     Stanton 
                                  (including 22 samples of      >8 m, but relatively high     et al.
                                  fibrous glass); 2-year        correlations also noted for    (1977,
                                  observation period            fibres with a diameter up to   1981); 
                                                                1.5 m and length > 4 m;      Stanton &    
                                                                morphological observations     Layard 
                                                                indicated that short fibres    (1978)   

Table 19.  (contd.)
--------------------------------------------------------------------------------------------------------
Species        Number in groups   Protocol                      Results and comments           Reference
--------------------------------------------------------------------------------------------------------

                                                                and large diameter fibres
                                                                were inactivated by phago-
                                                                cytosis and that negligible
                                                                phagocytosis of long, thin
                                                                fibres occurred; authors con-
                                                                cluded that "the simplest
                                                                incriminating feature for
                                                                both carcinogenicity and
                                                                fibrogenicity seems to be
                                                                a durable fibrous shape, per-
                                                                haps in a narrow range of size"

SPF albino     40 animals in      Intraperitoneal injection of  Nodular deposits of connec-    Styles & 
Wistar rat     exposed and        0.2 ml of a 10% suspension    tive tissue; no fibrosis       Wilson
(Alderley      control groups     of Saffil alumina (median                                    (1976)
Park strain)                      diameter, 3.6 m; median
                                  length, 17 m) or Saffil
                                  zirconia (median diameter,
                                  2.5 m; median length, 11
                                  m); animals killed 6 months
                                  after dosing

Female Wistar  30 - 32 animals    Intraperitoneal injection of  Significant increases in       Mhle 
rat            in exposed and     0.5 mg glass fibre (JM 104;   tumour incidence for glass     et al.
               control groups     90% of fibre lengths < 8.2    fibre (17%), crocidolite      (in press)
                                  m, 90% of fibre diameters    (55%), and Canadian chryso-
                                  < 0.42 m), 0.5 mg crocido-   tile (84%); incidence in
                                  lite (90% of fibre lengths    Calidria chrysotile-
                                  < 7.7 m, 90% of fibre dia-   exposed group similar to
                                  meters < 0.36 m), 0.5 mg     controls (6%)
                                  Calidria chrysotile, 1 mg
                                  UICC Canadian chrysotile B
                                  (90% of fibre lengths < 3.6
                                  m, 90% of fibre diameters
                                  < 0.18 m)

--------------------------------------------------------------------------------------------------------

Table 19.  (contd.)
--------------------------------------------------------------------------------------------------------
Species        Number in groups   Protocol                      Results and comments           Reference
--------------------------------------------------------------------------------------------------------
Male Syrian    ~25 animals per    Intraperitoneal injection of  Abdominal mesotheliomas in     Smith 
hamster and    test and control   25 mg of 0.45-m mean dia-    32% of rats exposed to glass   et al.
female         groups at          meter fibrous glass, 1.8-     fibre, 83% in rats exposed     (in press)
Osborne-       necropsy           m mean diameter refractory   to refractory ceramic fibre,
Mendel rat                        ceramic fibre or crocidolite  80% in rats exposed to croc-
                                  (fibre size distributions     dolite (0 in controls); ab-
                                  similar to those presented    dominal mesotheliomas in 13
                                  in Table 17); life-span       and 24% of hamsters exposed
                                  observation                   to refractory ceramic fibre,
                                                                40% in hamsters exposed to
                                                                crocidolite (0 in controls)

Female         number examined    Intraperitoneal administra-   Potency to induce tumours      Pott 
Sprague        in each group      tion (single or up to 5       related principally to size    et al.
Dawley and     ranged from        repeated doses); total ad-    distribution of the fibres     (1987)
Wistar rat     30 to 99           ministered material of        and to durability; tumour
                                  treated or untreated samples  incidence for MMMF varied
                                  of JM 100 (2 - 10 mg) or      from 2.1 to 87% (the latter
                                  JM 104 (5 - 10 mg) glass      incidence occurred in the
                                  microfibres, JM 106 (10 mg),  study using 5 mg NaOH-
                                  slag wool (Rheinstahl;        treated JM 104 glass micro-
                                  Zimmerman) (40 mg), Swedish   fibres); no increase in
                                  rock wool (75 mg), ES5 (10 -  tumour incidence with glass
                                  40 mg) and ES7 (40 mg) glass  filaments with diameters of
                                  filaments, and basalt wool    3, 5, and 7 m
                                  (Grnzweig & Hartman) (75 mg);
                                  intraperitoneal administra-
                                  tion of ES3 (50 - 250 mg) or
                                  ES5 (250 mg) glass filaments
                                  by laparotomy
--------------------------------------------------------------------------------------------------------

Table 19.  (contd.)
--------------------------------------------------------------------------------------------------------
Species        Number in groups   Protocol                      Results and comments           Reference
--------------------------------------------------------------------------------------------------------
Female Wistar  35 - 50 per group; Intraperitoneal administra-   Fibre number (length > 5       Pott 
rat            100 controls       tion (single or 5 repeated    m; diameter < 3 m) in-       et al.
                                  doses) of 0.01 - 0.25 mg      jected versus tumour rate      (in press)
                                  actinolite, 0.05 - 1 mg       reported: actinolite, 100x106
                                  chrysotile, 5 mg glass fibre  fibres (56% tumours); chry-
                                  JM 104/475, 75 mg basalt      sotile, 200x106 fibres
                                  wool, 45 mg ceramic wool      (68% tumours); JM 104/475,       
                                  (Fibrefrax), 75 mg ceramic    680x106 fibres (64% tumours);
                                  wool (Manville)               basalt wool, 60x106 fibres
                                                                (57% tumours); ceramic wool
                                                                (Fiberfrax), 150x106 fibres
                                                                (70% tumours); ceramic wool
                                                                (Manville), 21x106 fibres
                                                                (22% tumours)

Rat            125 (63 males, 62  Intrapleural 3-fold injec-    Mesotheliomas in 54.5%         Pylev 
               females)           tion of 20 mg artificial                                     et al.
                                  Na, Mg-hydroxyamphibole                                      (1975)
                                  (90% < 5 m in length)
--------------------------------------------------------------------------------------------------------
WL = Working levels.
UICC = Union Internationale Contre le Cancer.
SPF = Specific pathogen free.
JM = Johns Manville.
    The  carcinogenic potency of glass fibres (JM 104) following
intraperitoneal  administration was reduced when the fibres were
pre-treated  with  hydrochloric acid  (Pott  et al.,  1984); the
authors  suggested that this was  a function of the  lower dura-
bility of the acid-treated fibres (Bellmann et al.,  in  press).
In  a study by Bignon et al. (1983), the proportion of lung can-
cer  was greater in rats exposed by inhalation to radon and then
administered intrapleural injections of one of 10 mineral  dusts
(including glass fibre)  than in rats exposed only to radon.

    Pigott  &  Ishmael  (1981)  observed  only  a  "mild chronic
inflammatory  response"  12  months  following   intraperitoneal
injections  of 20  mg of  two commercial  grades  of  refractory
alumina fibre.  Styles & Wilson (1976) observed nodular deposits
of connective tissue, but no fibrosis, following intraperitoneal
injection of alumina and zirconia fibre (0.2 ml 10% suspension).
On the basis of the results of a study in which 20 mg of various
fibrous  dusts were injected  intrapleurally in rats,  Wagner et
al.  (1973) estimated the   carcinogenicity factor (x  109)  for
"ceramic  fibre" to be  0.16 compared with  2.28 - 2.85  for SFA
chrysotile.   Following intraperitoneal administration of  25 mg
of  fibrous ceramic aluminium silicate  glass to rats, Davis  et
al.  (1984) observed  tumours in  9.3% of  the  exposed  animals
compared with 90% in similar studies with chrysotile.  Moreover,
time  to first tumour was  850 days for ceramic  fibres compared
with  200 days  for chrysotile.   However, in  a  recent  study,
abdominal mesotheliomas were observed in 83% (19 out of  23)  of
Osborne-Mendel rats receiving a single intraperitoneal injection
of  25 mg of 1.8-m   (mean diameter) refractory  ceramic fibres
(Smith et al., in press).

    The  need for caution in the extrapolation of the results of
studies  involving injection or implantation in body cavities to
predict  the potency of various fibre samples, even with respect
to the induction of mesotheliomas cannot be overemphasized.  The
relevance  of these types of  studies to other types  of cancer,
such as lung cancer, has not been established.

7.2.   In Vitro Studies

    Several  important factors that influence  the pathogenicity
of  fibrous  dusts  in  vivo (e.g.,  deposition,  clearance,  and
immunological   function)    are  absent   in  in  vitro systems.
Moreover,   the  results  of  such   assays  vary  considerably,
depending  on the test  system used.  However,  on the basis  of
available  results for all fibres, it appears that a combination
of  in  vitro tests may be useful in predicting the fibrogenicity
of fibres  in vivo.  The predictive value of  in  vitro tests  for
the carcinogenicity of fibrous dusts is, at present,  less  well
established,  but there has  been some consistency  between  the
results of specific  in vitro assays and the induction  of  meso-
theliomas in  in vivo studies  involving intrapleural administra-
tion.   In general, therefore,  in vitro assays are considered to

be useful for the investigation of mechanisms of disease induced
by fibre dusts and possibly as preliminary screening  tests  for
pathogenic fibres.

    The results of  in vitro studies on various types of MMMF are
presented  in Table 20.  To date, the effects of glass fibres of
various size distributions have been examined in a wide range of
systems  including bacteria, cultured  erythrocytes, fibroblasts
and  macrophages  from  several animal  species, macrophage-like
cell lines and cultured human fibroblasts, erythrocytes, lympho-
cytes, and bronchial epithelial cells.  In most of  the  assays,
cytotoxicity  or  cytogenetic effects  have  been a  function of
fibre size distribution, with longer (generally > 10 m),  thin-
ner  (generally < 1 m)  fibres being  the most toxic (Brown  et
al.,  1979b; Lipkin, 1980; Tilkes & Beck, 1980, 1983a,b; Hester-
berg  & Barrett, 1984; Forget  et al., 1986; Hesterberg  et al.,
1986).   In  general,  "coarse"  fibrous  glass (with relatively
large fibre diameters, e.g., JM 110)  has been less cytotoxic in
most assays than chrysotile or crocidolite (Richards  &  Jacoby,
1976; Haugen et al., 1982; Nadeau et al., 1983; Pickrell et al.,
1983).   However, the cytotoxicity or  transforming potential of
"fine"  glass (e.g., JM 100) has approached that of the asbestos
varieties (Pickrell et al., 1983; Hesterberg & Barrett, 1984).

    Results  concerning the effects of fibre coating on toxicity
in  in vitro assays have been contradictory. Brown et al. (1979a)
reported  that "clean"  samples  of rock, glass,  and slag  wool
(i.e.,  resin removed by pyrolysis) were slightly more cytotoxic
for V79-4 and A549 cells than were resin-coated samples  of  the
same materials.  In contrast, Davies (1980) found  that  removal
of the binder from rock and slag wools and resin from glass wool
had  no  effect  on  their  cytotoxicity  for  mouse  peritoneal
macrophages.

    With  respect to genotoxicity, glass fibres (JM 100 and 110)
did  not  induce  point mutations  in  E.  coli or  S. typhimurium
(Chamberlain   & Tarmy, 1977).  Casey (1983) did not observe any
effects  of fine (JM  100) or coarse  (JM 110) fibrous  glass on
sister chromatid exchange in CHO-K1 cells, human fibroblasts, or
lymphoblastoid  cells.  However, a variety  of fibrous materials
delayed mitosis in human fibroblasts and CHO-K1 cells. The order
of  potency in CHO-K1 cells was chrysotile > fine glass (JM 100)
>   crocidolite  > coarse  glass (JM 110).  JM 100 glass  fibres
induced  chromosomal  breaks, rearrangements,  and polyploidy in
CHO-K1  cells, while JM 110 glass fibres did not have any effect
(Sincock  et al., 1982).  Oshimura  et al. (1984) reported  that
glass  microfibres  (JM  100) induced  cell  transformation  and
cytogenetic  abnormalities in Syrian hamster embryo (SHE) cells.
The  cytotoxicity,  transforming  frequency,  and   micronucleus
induction  frequency of glass microfibres (JM 100)  in SHE cells
was reduced by milling (i.e., decreasing the length) (Hesterberg
et al., 1986).


Table 20.   In vitro studies
--------------------------------------------------------------------------------------------------------
Fibre type     Fibre size distribution   Results                                       Reference                     
--------------------------------------------------------------------------------------------------------
Fibrogenic effects                                                                                      
                                                                                                        
Glass fibres   JM 100: mean length,      Increase in total protein at 48 h and in      Aalto & Hepple-               
               2.7 m; mean              total protein and collagen synthesis at       ston (1984)                   
               diameter, 0.12 m;        96 h in rat fibroblasts; short fibres                                       
               JM 110: mean length,      more fibrogenic than long ones at 96 h                                      
               26 m; mean diameter,                                                                    
               1.9 m                                                                                   
                                                                                                        
Glass fibre    Not reported              Initial slight fibrogenic response with       Richards & Morris             
dust;                                    glass fibre compared with pronounced          (1973)                        
chrysotile                               effect of chrysotile asbestos on                                            
asbestos                                 rabbit lung fibroblasts                                                     
                                                                                                        
Alumina and    Saffil alumina: median    Low cytotoxicity for rat peritoneal macro-    Styles & Wilson               
zirconia       length, 17 m; median     phages; non-fibrogenic in intraperitoneal     (1976)                        
fibres         diameter, 3.6 m;         injection studies                                                           
               Saffil zirconia: median                                                                               
               length, 11 m; median                                                                    
               diameter, 2.5 m                                                                         
                                                                                                        
Cytotoxicity                                                                                            
                                                                                                        
Glass fibres   % of fibres < 0.6 m      Fibres < 10 m in length not cytotoxic for   Brown et al.                 
               in diameter and > 5 m    V79-4 cells, A549 cells, or mouse peri-      (1979b)                       
               in length: JM 100T,       toneal macrophages                                                          
               36%; JM 110T, 27.4%;                                                                     
               JM 100R, 36.7%; JM 110R,                                                                 
               34.6%                                                                                    
                                                                                                        
Glass fibres   Homogenized GF/D          Mildly cytotoxic for cultured human           Haugen et al.                 
               Whatman filters           bronchial epithelial cells; chrysotile          (1982)                      
               washed in HCl;            1000 times more cytotoxic than glass fibre                                  
               fibre size distribution                                                                  
               not reported                                                                             

Table 20.  (contd.)
--------------------------------------------------------------------------------------------------------
Fibre type     Fibre size distribution   Results                                       Reference                     
--------------------------------------------------------------------------------------------------------
                                                                                                        
Glass fibres   Not reported              Not toxic for human peripheral blood          Nakatani (1983)               
                                         lymphocytes; "large" glass fibre as                                         
                                         cytotoxic for mouse peritoneal macro-                                       
                                         phages as chrysotile; "small" glass                                         
                                         fibre not cytotoxic in this assay                                           
                                                                                                        
Glass fibres   "Respirable";             Morphological changes and alterations         Richards & Jacoby             
               not reported              in reticular deposition in rabbit             (1976)                        
                                         lung fibroblasts less severe for                                            
                                         chrysotile                                                     
                                                                                                        
Glass fibres   JM 100: mean diameter,    Toxicity in phagocytic ascites tumour         Tilkes & Beck                 
               0.23 m (99.8% < 10       cells from Wistar rats correlated with        (1980)          
               m long); JM 104: mean     fibre lengths and diameter                                    
               diameter, 0.32 m                                                                        
               (99.1% < 10 m long);                                                                   
               GFF:   mean diameter,                                                                    
               0.43 m (99.1% < 20                                                                     
               m long); GFF: mean                                                                      
               diameter, 0.19 m                                                                        
               (99% < 3 m long)                                                                       

Table 20.  (contd.)
--------------------------------------------------------------------------------------------------------
Fibre type     Fibre size distribution   Results                                       Reference                     
--------------------------------------------------------------------------------------------------------
Glass fibres   1. 83.8% < 1 m long;     Long narrow glass fibres as toxic for phago-  Tilkes & Beck                
                  100% < 0.3 m wide     cytic ascites tumour cells from Wistar        (1983a)                      
               2. 75% > 5 m long;       rats as chrysotile; fibres with diameters                                  
                  99.7% < 0.3 m wide    3 m, non-toxic; toxicity increased with                                   
               3. 15.5% > 5 m long;     increasing fibre length                                                    
                  22.3% < 0.3 m wide                                                                  
               4. 99.3% > 5 m long;                                                                   
                  82.9% < 0.3 m wide                                                                  
               5. 44.1% > 5 m long;                                                                   
                  3.4% < 0.6 m wide                                                                   
               6. 90.1% > 5 m long;                                                                   
                  4.1% < 0.6 m wide                                                                   
                                                                                                        
Glass fibres   Owens Corning beta-       Significant increase in squamous cell         Woodworth et al.             
               fibre: 99% > 10 m        metaplasia and labelling index in organ       (1983)                      
               long; 3% < 3 m wide;     cultures of hamster trachea (similar to                                    
               JM 100: 46% > 10 m       crocidolite)                                                                
               long; 50% < 0.2 m                                                                      
               wide                                                                                     
                                                                                                        
Glass fibres,  Not reported; glass       Some binding of carcinogens (benzo( a )-        Harvey et al.                 
glass wool     fibres from "GF/C         pyrene, nitrosonornicotine,  N -acetyl-2-      (1984)                        
               microfilter"              aminofluorene) by fibrous glass and                                         
                                         glass wool, but less than that for most                                     
                                         other mineral fibres examined, such as                                      
                                         chrysotile and attapulgite; negligible                                      
                                         haemolysis in sheep erythrocytes or                                         
                                         cytotoxicity in P388 D1 cells                                               
Table 20.  (contd.)
--------------------------------------------------------------------------------------------------------
Fibre type     Fibre size distribution   Results                                       Reference                     
--------------------------------------------------------------------------------------------------------
Three types    Microfibre insulation:    Cytotoxicity of microfibre insulation in      Pickrell et al.               
of glass       CMD, 0.1 - 0.2 m;        pulmonary alveolar macrophages from           (1983)                        
fibre-         household insulation,     beagle dogs similar to that of crocido-                                     
containing     CMD, 2 - 4 m             lite; household insulation fibres non-toxic                                 
household                                                                                               
insulation;                                                                                             
microfibre                                                                                              
insulation                                                                                              
material                                                                                                
                                                                                                        
Glass fibres;  JM 100, JM 110, and       "Fine" glass fibres (JM 100) more cytotoxic   Davies (1980)                 
rock, slag,    JM 100 (respirable);      for mouse peritoneal macrophages than UICC                                  
and glass      size distribution         crocidolite, but "coarse" glass fibre had                                   
wool           not reported              little activity; removal of binder from                                     
                                         rock and slag wools and resin from glass                                    
                                         wool had no effect                                                          
                                                                                                        
Glass fibres   JM 104; 90% < 15          Induced a small release of beta-galacto-      Jaurand et al.               
               m in length and          sidase, but was not cytotoxic for rabbit      (1980)                        
               0.5 m in diameter        alveolar macrophages                                                        
                                                                                                        
Glass fibres   Not reported              "Long" fibres produced a protracted patho-    Bruch (1974)                  
                                         genic but not cytotoxic effect in guinea-                                   
                                         pig alveolar macrophages; for short fibres,                                 
                                         morphological pattern similar to that for                                   
                                         inert dusts                                                                 
                                                                                                        
Glass fibres   JM 100-milled to alter    Glass fibres induced dose-dependent release   Forget et al.                 
               fibre lengths             of prostaglandins and beta-d-glucuronidase    (1986)                        
               (size distribution        from perfused rat alveolar macrophages,                                     
               not reported)             cell aggregation and mortality; long fibres                                 
                                         more active than short ones                                                 

Table 20.  (contd.)
--------------------------------------------------------------------------------------------------------
Fibre type     Fibre size distribution   Results                                       Reference                     
--------------------------------------------------------------------------------------------------------
Glass fibres   "Pyrex glass fibres";     In contrast to chrysotile, glass fibres       Ottolenghi et al.
               size distribution         did not promote fusion of human erythro-      (1983)           
               not reported              cyte membranes or haemolysis and fusion                        
                                         of fowl erythrocytes                                           
                                                                                                        
Glass fibres   Fibre size                Cytotoxicity in guinea-pig- and rat-lung      Tilkes & Beck    
               distribution as for       macrophages related mainly to fibre size      (1983b)          
               Tilkes & Beck             distribution; depression of phagocytosis                       
               (1983a)                                                                                  
                                                               
Glass fibres,  Not reported              Glass fibre (GF/C filters) less cytotoxic     Dumas & Page
glass wool                               for 3T3 fibroblasts than several forms of     (1986)                        
                                         chrysotile and attapulgite but more cyto-                                   
                                         toxic than UICC crocidolite; minimal cyto-                                  
                                         toxicity of Pyrex (glass wool)                                              
                                                                                                   
Glass fibres   JM 100 - mean length,     Cytotoxic in primary cultures and perm-       Ririe et al.                  
               15 m; mean diameter,     anent cell line of rat tracheal epithelial    (1985)                        
               0.2 m; JM 100            cells; toxicity reduced with milling of                                     
               (milled) - mean           the fibres                                                                  
               length, 2 m; mean                                                                  
               diameter,  0.2 m                                                                   
                                                                                                   
Glass fibres,  Glass fibres: lengths     Glass fibres increased cell permeability      Beck et al.                   
glass powder   ranged from 1 to 20 m    of guinea-pig alveolar and peritoneal         (1972); Beck                  
               and diameters from        macrophages; glass powder had little          & Bruch (1974);               
               0.25 to 1 m; glass        effect                                        Beck (1976a,b)               
               powder particle size                                                                   
               < 3 m                                                                                

Table 20.  (contd.)
--------------------------------------------------------------------------------------------------------
Fibre type     Fibre size distribution   Results                                       Reference                     
--------------------------------------------------------------------------------------------------------
                                                                                                      
Glass fibres,  JM 100 glass fibres       Glass fibres induced ornithine decarboxy-     Marsh et al.                  
glass          and particles; size       lase activity (ODC) in hamster tracheal       (1985)                        
particles      distribution not          epithelial cell cultures, while glass                                       
               reported                  particles did not                                                           
                                                                                                      
Borosilicate   Fibre size                Cytotoxicity in P388 D1 macrophage-like       Lipkin (1980)                 
glass fibres   distribution as for       cells correlated well with potency in                                       
               sample used by            tumour induction reported by Stanton &                                      
               Stanton & Layard          Layard (1978) in intrapleural implanta-                                     
               (1978)                    tion studies                                                                
                                                                                                      
Rock wool,     Not reported              Cytotoxic for V79-4 and A549 cells; "clean"   Brown et al.                  
slag wool,                               (resin removed by pyrolysis) samples          (1979a)                       
and glass                                slightly more active than resin-                                            
wool                                     coated variety                                                              
                                                                                                      
"Ceramic       Elutriated sample; 89%    Ceramic fibre less cytotoxic for P388 D1      Wright et al.                 
fibre"         of fibre lengths < 5      cells than chrysotile samples and most        (1986)                       
               m; fibre diameters       of the amphibole samples                                                   
               < 3 m; 7.4 fibres/                                                                   
               10-10 g (small number                                                                  
               compared with                                                                          
               different types of                                                                     
               chrysotile)                                                                            
                                                                                                      
Ceramic        Not reported              Ceramic fibres were inert in the V79/4        Brown et al.                  
                                         cell colony inhibition assay, but in-         (1986)                        
                                         creased the diameter of the A549 cells                                      
                                                                                                      
Table 20.  (contd.)
--------------------------------------------------------------------------------------------------------
Fibre type     Fibre size distribution   Results                                       Reference                     
--------------------------------------------------------------------------------------------------------

Xonotlite      Diameter, < 0.1 m;       Fibres phagocytosed by primary rat            Denizeau et al.              
(synthetic)    length, < 2 m            hepatocytes in culture, based on ultra-       (1985)                        
               (100%)                    structural analysis                                                         
                                                                                                       
Mineral wool,  Mineral wool:             Mineral wool not cytotoxic for rat alveo-     Nadeau et al.    
glass fibre    Df = 3.3 m, Lf =         lar macrophages, nor haemolytic for rat       (1983)                        
               221.4 m; glass           erythrocytes, but increased oxidant pro-                                    
               fibre: Df = 0.2 m,       duction in rat macrophages; glass micro-                                    
               Lf = 11.4 m              fibres induced haemolysis, but to a lesser                                  
                                         extent than chrysotile                                                      
                                                                                                        
Genetic and related effects                                                                             
                                                                                                        
Glass fibres   JM 100 (fine) and         No effects on sister chromatid exchange in    Casey (1983)                  
               JM 110 (coarse);          CHO-K1 cells, human fibroblasts, or lympho-                                 
               size distribution         blastoid cells; mitotic delay in CHO-K1                                     
               not reported              cells and human fibroblasts; order of                                       
                                         induced delay in CHO-K1 cells: chrysotile >                                
                                         fine glass > crocidolite > coarse glass                                   
                                                                                                        
Glass fibres   JM 100: mean length,      JM 100 glass fibres as active as chryso-      Hesterberg &                  
               9.5 m; mean diameter,    tile in transforming Syrian hamster           Barrett (1984)                
               0.13 m; shorter fibre    embryo cells; thick glass fibres (JM 110)                                   
               samples of similar        20 times less potent than thin (JM 110)                                     
               diameter produced by      ones; 10-fold decrease in transformation                                    
               milling; JM 100: mean     with reduction of fibre length from 9.5                                     
               diameter, 0.8 m          to 1.7 m (JM 100); no transformation                                       
                                         for fibre length of 0.95 m                                                 
                                                                                                        
Glass fibres   "AAA" glass fibre         Sizes of glass fibres that promote growth     Maroudas et al.               
               of different              in BHK 21 or 3T3 fibroblasts (> 20 m         (1973)                       
               size distributions        in length) similar to sizes that induce                                     
                                         mesotheliomas following intrapleural                                        
                                         implantation                                                                


Table 20.  (contd.)
--------------------------------------------------------------------------------------------------------
Fibre type     Fibre size distribution   Results                                       Reference                     
--------------------------------------------------------------------------------------------------------
Glass fibres   JM 100-milled (average    Glass fibres phagocytosed by Syrian ham-      Hesterberg et al.             
               length, 2.2 m) and       ster embryo cells and accumulated in peri-    (1986)                        
               unmilled (average          nuclear region of the cytoplasm; milling                                   
               length, 15.5 m) (95 -    of glass fibres (resulting in a 7-fold                                      
               98% of fibre diameters    decrease in length) reduced percentage of                                   
               < 0.5 m)                 phagocytosis, cytotoxicity, transformation                                  
                                         frequency, and micronucleus induction                                       
                                         frequency                                                                   
                                                                                                        
Glass fibres   JM 100 (mean length,      No mutagenic activity in bacterial            Chamberlain &                 
               2.7 m, mean diameter,    strains of  Escherichia coli or  Salmo-         Tarmy (1977)                  
               0.12 m); JM 110 (mean     nella typhimurium at levels of up to                                        
               length, 26 m; mean       1000 g/plate                                                               
               diameter, 1.9 m)                                                                        
                                                                                                        
Glass fibres   JM 100 (mean diameter,    JM 100 fibres induced cell transformation     Oshimura et al.               
               0.1 - 0.2 m; mean        and cytogenetic abnormalities in Syrian       (1984)                        
               length varied by          hamster embryo cells; JM 110 fibres and                                     
               milling); JM  110         milled JM 100 fibres much less potent for                                   
               (mean diameter, 0.8       both end-points                                                             
               m)                                                                                      
                                                                                                        
Glass fibres,  1.5 - 2.5 m diameter;    Exposure of CHO-K1 cells to one concen-       Sincock & Sea-                
glass powder   fibre size                tration of glass fibre did not increase       bright (1975)                 
               distribution described    the frequency of chromosomal aberrations                                    
               by Wagner et al.          or polyploid cells                                                          
               (1973)                                                                                   
                                                                                                        
JM 100 glass   Mean particle lengths     JM 100 fibres caused chromosomal breaks,      Sincock et al.                
fibres,        between 2.7 and 26 m;    rearrangements, and polyploidy in CHO-K1      (1982)                        
JM 110 glass   mean particle             cells; no effects with JM 110 fibres                                        
fibres         diameters between 0.12                                                                   
               and 1.9 m                                                                               
                                                                                                        
JM glass       Not reported              Dose-dependent interference with develop-     Krowke et al.                 
fibres                                   ment of limb buds in 11-day-old mouse         (1985)                        
                                         embryos in culture                                                          
--------------------------------------------------------------------------------------------------------
JM = Johns Manville.
CMD = Count median diameter.
CHO = Chinese hamster ovary.
    Few  data are available on  the toxicity of MMMF  other than
glass  fibres  in  in  vitro assays.  However,  Styles  &  Wilson
(1976)  reported  that the  cytotoxicity  of Saffil  alumina and
Saffil  zirconia fibres (size  range unspecified) in  rat  peri-
toneal  macrophages was low; this  agreed well with the  lack of
fibrogenicity observed in intraperitoneal injection studies with
the same materials.  Wright et al. (1986) reported that "ceramic
fibre"  (type  and source  unspecified)  was less  cytotoxic for
P388 D1 cells than chrysotile and the amphiboles.

7.3.  Mechanisms of Toxicity - Mode of Action

    The  results of toxicological studies  have demonstrated the
importance  of fibre dimension,  persistence, and durability  in
the  pathogenesis  of  fibrous dust-related  diseases.   Surface
charge and chemical composition may also play an important role.
However,  the mechanisms by  which respirable fibrous  materials
cause fibrosis and cancer are not well understood.  The sequence
of cellular events leading to fibrosis has been  hypothesized on
the  basis of observations in animals after inhalation or intra-
tracheal instillation of asbestos (Davis, 1981).  It  is  likely
that  the  sequence of  events in the  induction of fibrosis  by
other  fibres of similar  dimensions and durability  is similar.
Short  fibres deposited on the alveolar surface are phagocytosed
by macrophages and removed by the mucociliary escalator.  Fibres
longer  than 10 m   are often  surrounded  by groups  of macro-
phages, which may fuse to form multinucleated giant cells.  Some
of  the dust-containing macrophages become incorporated into the
lung  parenchyma and die, and  the fibres are rephagocytosed  by
new populations of macrophages.  The presence of these fibres in
distal  airways  stimulates  excess deposition  of  collagen and
reticulin fibres.

    The  deposition of  fibres in  the pulmonary  region of  the
respiratory  tract is thought to be important only if the fibres
can  penetrate into the  interstitium where interstitial  macro-
phages  can phagocytose them.  In the process, the macrophage is
impaired;  this may "trigger" adjacent fibroblasts in the inter-
stitium  to start producing more collagen, leading eventually to
fibrosis.

    Several  mechanisms  by  which asbestos  and  possibly other
fibrous materials  cause cancer have been suggested.  Because of
the lack of activity of most of these materials in gene mutation
assays,  it has been suggested  that they may act  by epigenetic
mechanisms  (NRC, 1984).  For example, it has been proposed that
asbestos  acts primarily as a  promoter or cocarcinogen or  that
cancer  occurs secondarily to  the induction of  inflammation or
fibrosis.  However, results of  in vitro studies in which chromo-
somal aberrations have been induced by glass fibres (Oshimura et
al.,  1984), suggest  that the  fibres can  directly affect  the
genetic material.

    Generation   of  reactive  oxygen  metabolites   by  fibrous
materials in  in vitro assays has also been observed and has been
postulated  to play a  role in cytotoxicity  (Goodglick &  Kane,
1986).   It may also be that fibrogenesis and carcinogenesis may
be a result of several of these mechanisms.

8.  EFFECTS ON MAN

8.1.  Occupationally Exposed Populations

8.1.1.  Non-malignant dermal and ocular effects

    The  effects of MMMF on the skin were recognized as early as
the turn of the century (HMSO, 1899, 1911).  Fibrous  glass  and
rock  wool fibres (mainly those greater than 4.5 - 5 m  in dia-
meter)  cause mechanical irritation of the skin characterized by
a  fine, punctate, itching erythema, which often disappears with
continued  exposure (Hill, 1978;  Bjrnberg, 1985).  Possick  et
al. (1970) described the effects of short glass  fibres  tempor-
arily  piercing the epidermis producing  sensations varying from
itching  and burning to pain.  They suggested that skin penetra-
tion was directly proportional to fibre diameter  and  inversely
proportional to fibre length.  The primary lesion is a papule or
papulo-vesicle,  and the authors  quote histological reports  of
oedema   of  the  upper  dermis  with  round  cell  infiltrates.
Secondary lesions include bacterial infections, which develop as
a  result of scratching, and  lichenification.  Urticaria occurs
in dermatographic subjects.

    Data concerning the incidence or prevalence of dermatitis in
workers  exposed to MMMF  are sparse.  Sixty-one  percent of  62
glass  wool workers in  a Swedish plant  had cutaneous signs  or
symptoms  at the end  of a working  day; 45% had  visible dermal
lesions  (Bjrnberg, 1985).  Twenty-five percent of 315 subjects
exhibited skin reactions at 72 h when patch tested for 48 h with
rock  wool (Bjrnberg & Lwhagen,  1977) and, in a  study on 135
Italian  fibrous  glass  production workers,  the  prevalence of
dermatitis  was  reported  to be  19%  (Arbosti  et al.,  1980).
However,  according  to  Gross  &  Braun  (1984),   much   lower
prevalences were reported in investigations previously conducted
in the USA.  In a study on 467 glass wool workers,  Maggioni  et
al.  (1980) reported that 14%  had skin disease, mainly  primary
irritative dermatitis.

    There are also few reliable data concerning the tolerance of
workers  to  MMMF-induced  dermatitis.  Bjrnberg  et al. (1979)
described a group of 60 workers at a glass wool  factory;  after
counselling,  38  were able  to continue work  but 22 had  to be
transferred to work with less potential for fibre exposure; 6 of
these workers eventually had to leave their jobs because of this
irritation.

    The irritant dermatitis induced by MMMF may  be  complicated
by an urticarial and eczematous reaction that  sometimes  mimics
an  allergic response, both  clinically and histologically.   In
addition, allergic reactions to resins used in  MMMF  production
occasionally   occur  (Fisher,  1982).   For  example,  allergic
dermatitis  in  54%  of  160  workers  engaged  in  glass  fibre
manufacture was attributed to exposure to epoxy  resin  (Cuypers
et al., 1975); however, coating with phenol-formaldehyde did not
have  any  effects  on  skin  reactions  induced  by  rock  wool
(Bjrnberg  &  Lwhagen,  1977).  Conde-Salazar  et  al. (1985),

in  their case  report of  severe dermatitis  in a  glass  fibre
spinner  sensitized  to  epoxy oligomer,  commented  that  glass
fibres per se produced only an irritant dermatitis.

    Until  recently,  reports  of eye  irritation in populations
exposed occupationally to MMMF were restricted to a few isolated
cases in the early literature (Gross & Braun,  1984).   However,
in  a  recent  Danish  study,  the  frequency  of  eye  symptoms
significantly   increased  and  the  number  of  microepithelial
defects on the medial bulbar conjunctiva and, in some cases, the
neutrophil  count of the conjunctival fluid were increased after
4  days of exposure in  15 rock wool workers  (employed for >  6
months) compared with controls matched for age, sex, and smoking
habits.    While  there  were  no  ophthalmological  differences
between  exposed  workers and  controls  on Monday  morning,  an
excess of mucous was found in exposed workers,  suggesting  that
the  effect  was  not  completely  reversible  over  the weekend
(Stokholm et al., 1982).

8.1.2.  Non-malignant respiratory disease

    In  reports that appeared  in the early  literature, several
cases  of acute irritation  of the upper  respiratory tract  and
more   serious  pulmonary  diseases,  such  as  bronchiecstasis,
pneumonia,  chronic  bronchitis,  and asthma  were attributed to
occupational exposure to various MMMF.  On the basis  of  recent
reviews  of these isolated reports, several authors (Hill, 1978;
Upton  & Fink, 1979; Saracci, 1980; Gross & Braun, 1984; Wright,
1984)   have  concluded  that  exposure  to  MMMF  was  probably
incidental  rather than causal in most of these cases, since the
reported conditions have not been observed in most of  the  more
recently  conducted epidemiological studies.  These case reports
are not considered further here.

    The  epidemiological  studies  of non-malignant  respiratory
disease in populations exposed occupationally to MMMF are mainly
of  two types: cross-sectional investigations  of the prevalence
of  signs  and symptoms  of  respiratory disease  and historical
prospective  (cohort) studies of mortality  due to non-malignant
respiratory disease.

8.1.2.1.  Cross-sectional studies

    The  design  and  results of  the  available cross-sectional
studies  of respiratory effects  in MMMF production  workers are
summarized in Table 21.  Most of these studies have involved one
or  a combination of  the following elements:  determination  of
respiratory  symptoms through administration  of questionnaires,
pulmonary  function testing, and radiological examination of the
lung.  Limitations that should be borne in mind in reviewing the
results   of  cross-sectional  studies  include  the  following:
persons  who have  left employment  because of  ill  health  are
selectively  excluded and health  effects are monitored  at only
one particular time (i.e., prevalence rather than  incidence  is
determined).   Nevertheless,  such  investigations  do   provide
useful preliminary data.


Table 21.  Cross-sectional studies of respiratory effects in MMMF-exposed workersa
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
Examination of chest    No unusual pattern of radio-       Ad hoc radiological assessments     Wright                     
radiographs of 1389     logical densities; frequency      by one reader difficult to inter-   (1968)                                 
employees in a glass    no higher in those with           pret epidemiologically                                              
wool manufacturing      greatest exposure than in                                                                              
plant (> 10 years       those with the least                                                                                   
exposure to dust                                                                                                                                                                                      
concentrations from                                                                                                                                                                                   
0.93 to 13.3 mg/m3)                                                                                                                                                                                   
                                                                                                                                                                                                      
Examination of chest    Radiographic abnormalities        Not possible to interpret           Nasr                       
radiographs of 2028     in 16% of workers; strength       relationship between response       et al.                           
male workers in the     of correlation between pre-       and duration of employment, be-     (1971)                                 
fibrous glass plant     valence and mean duration of      cause of confounding with age in                                    
studied by Wright       employment and between pre-       grouped data; within-group anal-                                     
(1968) (two-thirds      valence and mean age similar;     yses or logistic regression anal-                                    
employed for > 10       no difference in prevalence       yses of data could be useful                                         
years)                  between office and production                                                                          
                        workers                                                                                                
                                                                                                                                                                                                      
Examination of          No significant difference         Numerical data to support con-      Utidjian &                  
respiratory symptoms    in the prevalence of chronic      clusions not provided               Cooper                           
(determined by          respiratory illness between                                           (1976)                                 
questionnaire),         highest and lowest exposure                                                                            
radio-graphic           category                                                                                               
changes, and                                                                                                                                                                                          
pulmonary function                                                                                                                                                                                    
(VC, FEV1, and                                                                                                                                                                                        
VC/FEV1) in 232                                                                                                                                                                                       
employees in the                                                                                                                                                                                      
fibrous glass plant                                                                                                                                                                                   
studied by Wright                                                                                                                                                                                     
(1968) and Nasr et                                                                                                                                                                                    
al. (1971); for sub-                                                                                                                                                                                  
sample of 30,                                                                                                                                                                                         

Table 21.  (contd.)
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
comprehensive                                                                                                                                                                                         
physical                                                                                                                                                                                              
examination, chest                                                                                                                                                                                   
fluoroscopy,                                                                                                                                                                                          
electrocardiogram,                                                                                                                                                                                    
VC, FVC1, FVC2,                                                                                                                                                                                       
FVC3, mid-expiratory                                                                                                                                                                                  
flow rate, maximal                                                                                                                                                                                    
voluntary                                                                                                                                                                                             
ventilation,                                                                                                                                                                                          
residual volume, and                                                                                                                                                                                  
pulmonary diffusing                                                                                                                                                                                   
capacity                                                                                                                                                                                              
                                                                                                                                                                                                      
Comparison of           No evidence of pulmonary          Well-controlled study of a          Hill                       
respiratory symptoms    effects due to exposure           "survivor population" of            et al.                           
(determined by MRC      to fibrous glass, but             current employees                   (1973)                                 
questionnaire),         45% of exposed population                                                                              
radiographic            had suffered for a short                                                                               
changes, and            period from "new starter's                                                                             
pulmonary  function     glass-fibre rash"                                                                                      
(peak expiratory                                                                                                                                                                                      
flow, FEV1, and FVC)                                                                                                                                                                                  
in 70 fibrous glass                                                                                                                                                                                   
wool workers                                                                                                                                                                                          
(exposed for a mean                                                                                                                                                                                   
period of 19.85                                                                                                                                                                                       
years; mean level,                                                                                                                                                                                    
0.9 respirable                                                                                                                                                                                        
fibres/cm3) and                                                                                                                                                                                       
controls  matched                                                                                                                                                                                     
for age, sex,                                                                                                                                                                                         
height, and weight,                                                                                                                                                                                   
and living in the                                                                                                                                                                                     
same geographical                                                                                                                                                                                     
area                                                                                                                                                                                                  

Table 21.  (contd.)
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                      
Examination of          Some indication of chronic        Only study that includes            Hill                       
respiratory symptoms    non-specific lung disease         ex-employees; absence of re-        et al.                           
(determined by MRC      related to level but not          lationship with indices of dura-    (1984)                                 
questionnaire),         to length of exposure to          tion of exposure suggests pos-                                       
radiographic            fibres; prevalence of             sible confounding with exposure                                     
changes, and            small opacities related to        to other dusts                                                       
pulmonary function      environmental pollution                                                                                
(VC, FEV) in 340        (never having lived in a                                                                               
workers  (> 10          smoke-free zone), and to                                                                               
years exposure) from    previous employment in                                                                                 
a glass wool            dusty occupations, but no                                                                              
manufacturing plant     significant relationship                                                                               
                        with either length or                                                                                  
                        level of exposure to MMMF                                                                              
                                                                                                                                                                                                      
Examination of          No relationship between res-      Results suggest that fibres with    Weill                      
respiratory symptoms    piratory symptoms or adverse      small diameters have an effect      et al.                      
(determined by ATS      effects on pulmonary func-        on the lung parenchyma; sound,      (1983,                                 
questionnaire),         tion and exposure; greater        well-documented study; replica-     1984)                                 
radiographic            prevalence of small opacities     tion and confirmation desirable                                      
changes, and            among current smokers in 2                                                                             
pulmonary function      plants producing ordinary and                                                                          
(FVC, FEV1,             fine fibres; for non-smokers,                                                                          
FEV1/FVC, FEF 25-75,    greater prevalence observed                                                                           
RV, VC, TLC, DL,        in only 1 of these plants;                                                                             
DL/ALVOL)  in 1028      among smokers, prevalence of                                                                           
workers in 7 glass      small opacities increased                                                                              
wool and mineral        with increasing length of                                                                              
wool plants exposed     employment, and authors con-                                                                           
for a  median period    cluded that exposure to MMMF                                                                           
of 18 years to          with small diameters may lead                                                                          
median levels from      to low-level profusion of                                                                              
< 0.032 to 0.928        opacities                                                                                              
fibres/cm3                                                                                                                                                                                            

Table 21.  (contd.)
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                      
Survey of workers       Prevalence of breathlessness      No convincing evidence that        Moulin                    
with > 1 year           and nasal cavity symptoms         exposure to fibres affects          et al.                           
employment at 2         significantly higher in ex-       respiratory system                  (1987)                                 
glass wool factories    posed workers at factory A                                                                             
(A and B); age- and     only; no other significant                                                                             
smoking  habit-         differences; bronchitic symp-                                                                          
stratified sample       toms a little more frequent                                                                            
from factory A (n =     in both exposed groups ( P >                                                                           
367); all eligible      0.05); in nested case-control                                                                          
from factory B (n =     study, a significantly                                                                                 
157); respiratory       shorter mean period of employ-                                                                         
symptoms                ment for cases in factory A                                                                            
(questionnaire),                                                                                                                                                                                      
clinical                                                                                                                                                                                              
examinations, chest                                                                                                                                                                                   
radiography,                                                                                                                                                                                          
spirometry, CO-                                                                                                                                                                                       
transfer factor for                                                                                                                                                                                   
those working with                                                                                                                                                                                    
fibres compared with                                                                                                                                                                                  
those not exposed at                                                                                                                                                                                  
same factory                                                                                                                                                                                          
(factory A: 114,                                                                                                                                                                                      
factory B: 34)                                                                                                                                                                                        
                                                                                                                                                                                                      
Examination of          Positive association bet-         Evidence of errors in question-     Engholm &                     
exposure and            ween handling of MMMF and         naire-determined exposure to        Von                     
respiratory symptoms    bronchitis                        asbestos undermines interpreta-     Schmalensee                            
(determined by self-                                      tion of the association as causal   (1982)                                 
administered                                                                                                                                                                                          
questionnaire) in                                                                                                                                                                                     
135 000 male Swedish                                                                                                                                                                                  
construction                                                                                                                                                                                          
workers; separate                                                                                                                                                                                     
analysis for                                                                                                                                                                                          
"former", "never",                                                                                                                                                                                    
and present smokers;                                                                                                                                                                                  
control for age and                                                                                                                                                                                   
asbestos exposure                                                                                                                                                                                     

Table 21.  (contd.)
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                      
Examination of chest    No radiographic evidence          Radiological procedures not docu-   Carpenter &                      
radiograms of 84        attributable to mineral           mented adequately                   Spolyar                    
workers in a rock       wool exposure                                                         (1945)                                 
and slag wool plant                                                                                                                                                                                   
(exposure periods, 7                                                                                                                                                                                  
- 26 years)                                                                                                                                                                                           
                                                                                                                                                                                                      
Examination of          Wheezing and breathlessness       Effects of work-place exposure      Ernst                      
respiratory symptoms    related primarily to current      may have been underestimated        et al.                           
(determined by self-    smoking and asthmatic pre-        due to selective withdrawal         (1987)                                 
administered            disposition antedating work;      from the active work-force and                                       
questionnaire) in       these symptoms also related       to inaccuracies in exposure                                          
537 insulators          to occupational exposure in       (based on duration of employ-                                        
working in Quebec in    subjects with prior airways       ment only); not possible to                                          
1982 without            hyperreactivity                   separate exposure to asbestos,                                       
asbestosis; logistic                                      MMMF, and dust                                                       
regression analysis                                                                                                                                                                                   
with smoking,                                                                                                                                                                                         
reactivity before                                                                                                                                                                                     
employment and                                                                                                                                                                                        
occupational                                                                                                                                                                                          
exposure to dust and                                                                                                                                                                                  
mineral fibre as                                                                                                                                                                                      
risk factors                                                                                                                                                                                          
(workers without                                                                                                                                                                                      
asbestosis in 558                                                                                                                                                                                     
respondents out of                                                                                                                                                                                    
644 identified                                                                                                                                                                                        
subjects)                                                                                                                                                                                             

Table 21.  (contd.)
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                      
Examination of          7 cases of "work-related          No control data; cause of the       Finnegan                   
respiratory symptoms    asthma" identified                asthma not identified               et al.                           
(determined by                                                                                (1985)                                                                                                        
questionnaire) and                                                                                                                                                                                    
spirometry in 235                                                                                                                                                                                     
workers in a                                                                                                                                                                                          
continuous filament                                                                                                                                                                                   
glass fibre plant                                                                                                                                                                                     
(83% of the shop                                                                                                                                                                                      
floor workers and 21                                                                                                                                                                                  
others who were                                                                                                                                                                                       
infrequently or                                                                                                                                                                                       
never on the shop                                                                                                                                                                                     
floor); prick testing                                                                                                                                                                                 
and bronchial                                                                                                                                                                                         
challenge in some                                                                                                                                                                                     
workers identified                                                                                                                                                                                    
as having work-                                                                                                                                                                                       
related asthma                                                                                                                                                                                        
                                                                                                                                                                                                      
Examination of          No relationship between           Preliminary results of a longi-     Lockey                 
respiratory symptoms    chronic cough, phlegm,            tudinal investigation               (in press)                                 
(determined by ATS      dyspnoea, or effects on                                                                                
questionnaire) and      pulmonary function and                                                                                
pulmonary function      length of employment; res-                                                                             
(FVC, FEV1) in          piratory symptoms related                                                                              
> 4000 workers in       to smoking and pulmonary                                                                               
14 US and Canadian      function related to smoking                                                                           
fibrous glass (type     and age                                                                                                
unspecified) plants                                                                                                                                                                                   
exposed for a median                                                                                                                                                                                  
period of 7.7 years                                                                                                                                                                                   
(males) to < 0.5                                                                                                                                                                                     
fibres/cm3                                                                                                                                                                                            

Table 21.  (contd.)
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                      
Comparison of           Higher incidence of chronic                                           Maggioni                   
respiratory symptoms    and dysplastic pharyngo-                                              et al.                                 
(determined by          laryngitis in workers (> 5                                           (1980);                 
questionnaire),         years) exposed to highest                                             Saracci &                                 
radiographic            concentrations; skin disease                                           Simonato                  
changes, and            (mainly primary irritative                                            (1982)                                 
pulmonary function      dermatitis) in 14% of the                                                                              
in 467 glass wool       working population                                                                                     
workers (exposed for                                                                                                                                                                                  
a mean period of 13                                                                                                                                                                                   
years) and in                                                                                                                                                                                         
controls                                                                                                                                                                                              
                                                                                                                                                                                                      
Comparison of           No significant differences        Not possible to generalize from     Malmberg                   
respiratory symptoms    in pulmonary function bet-        careful, detailed physiology in     et al.                           
(determined by          ween exposed and control          only 21 subjects                    (1984)                                 
questionnaire) and      groups; some symptoms of                                                                               
pulmonary function      chronic bronchitis in ex-                                                                              
(lung volume,           posed group                                                                                           
airway resistance,                                                                                                                                                                                    
forced expiratory                                                                                                                                                                                     
flow, closing                                                                                                                                                                                         
volume, transfer                                                                                                                                                                                      
factor) in 21                                                                                                                                                                                         
employees (> 45                                                                                                                                                                                      
years old) of a rock                                                                                                                                                                                  
wool manufacturing                                                                                                                                                                                    
plant (mean exposure                                                                                                                                                                                  
for  17.6 years to                                                                                                                                                                                    
0.19 respirable                                                                                                                                                                                       
fibres/cm3) and in                                                                                                                                                                                    
43 controls (50 -70                                                                                                                                                                                   
years of age)                                                                                                                                                                                         
(values corrected                                                                                                                                                                                     
for differences in                                                                                                                                                                                    
age, body weight,                                                                                                                                                                                     
and smoking habits)                                                                                                                                                                                   

Table 21.  (contd.)
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                      
Spirometry and          Slightly increased elastic        Length or extent of exposure un-    Sixt                       
determination of        recoil in exposed subjects;       known; bias may have been intro-    et al.                           
lung volumes,           authors could not exclude         duced by low (47%) response rate,   (1983)                                 
closing volumes,        the possibility that fibrous      and hyper-critical inclusion                                         
slope of the            glass could cause a faint         criteria                                                             
alveolar plateau,       and probably harmless                                                                                  
maximum expiratory      fibrous reaction in the lung                                                                           
flow in air and         parenchymma                                                                                            
after helium-oxygen                                                                                                                                                                                   
breathing and                                                                                                                                                                                         
elastic recoil                                                                                                                                                                                        
pressures in 8 sheet                                                                                                                                                                                  
metal workers                                                                                                                                                                                         
exposed to fibrous                                                                                                                                                                                    
glass compared                                                                                                                                                                                        
with 7 sheet metal                                                                                                                                                                                    
workers "never                                                                                                                                                                                        
exposed" to fibrous                                                                                                                                                                                   
glass (workers with                                                                                                                                                                                   
no history of                                                                                                                                                                                         
smoking, pleural                                                                                                                                                                                      
plaques, or asbestos                                                                                                                                                                                  
exposure chosen from                                                                                                                                                                                  
251 respondents out                                                                                                                                                                                   
of 532 workers                                                                                                                                                                                        
surveyed)                                                                                                                                                                                             

Table 21.  (contd.)
--------------------------------------------------------------------------------------------------------
Study protocol          Results                           Comments                            Reference                        
--------------------------------------------------------------------------------------------------------
                                                                                                                                                                                                      
Examination of          In original study group,          Longer follow-up required to        Stahuljak-                       
pulmonary function      mean pre-shift values of FVC,     detect possible exposure-           Beritic                    
(FVC, FEV1, and MEF     FEV1, and MEF 50% signifi-        related lung function decre-        et al.                           
50%) in 162 rock        cantly lower than reference       ments                               (1982)                                 
wool workers            values, but no relation-                                                                               
(exposed to 0.003 -     ship with cumulative exposure;                                                                         
0.463 respirable        in second study, no change in                                                                          
fibres/cm3); 5 years    pulmonary function associated                                                                          
later, examination      with MMMF exposure                                                                                     
of pulmonary                                                                                                                                                                                          
function in 102                                                                                                                                                                                       
people from                                                                                                                                                                                           
original population                                                                                                                                                                                   
exposed only to MMMF                                                                                                                                                                                  
in the interval                                                                                                                
--------------------------------------------------------------------------------------------------------
a  Abbreviations
MRC = Medical Research Council (United Kingdom).
ATS = American Thoracic Society.
FEV1 = Forced expiratory volume in 1 second.
FVC = Forced vital capacity.
FEF 25-75 = Forced expiratory volume during the mid-half of the forced vital capacity.
RV = Residual volume.
VC = Vital capacity.
TLC = Total lung capacity.
DL = Diffusing capacity.
DL/ALVOL = Ratio of diffusing capacity to alveolar volume.
MEF 50% = Maximal expiratory flow rate at 50% of forced vital capacity.
    Hill   et  al.  (1973)  compared  radiographic  appearances,
reports  of respiratory symptoms, and lung function measurements
in  70  workers  who had been exposed at a glass wool factory in
England  for an average of nearly nearly 20 years, with those of
other  workers, matched for  sex, age, height,  and weight,  who
were from the same geographical area but had not been exposed to
fibrous  dust.  The frequency  of any abnormalities  among those
exposed  was no higher than in the controls.  Hill et al. (1984)
later  examined 74% of 340 workers and ex-employees, in the 55 -
74  year age group, who had been employed for more than 10 years
at  the  same  factory, and  also  samples  of other  groups  of
employees and ex-employees for whom participation rates were low
(121/250  overall).  The results  of the second  study indicated
some occupationally related chronic non-specific lung disease in
the  340  fibrous  glass workers  examined.   The  statistically
significant  impairment of lung function was reported to be more
severe among workers in occupational groups designated as likely
to  have had high exposure to fibres, but there was no relation-
ship  with length  of time  employed in  these  groups.   Eleven
percent  of all 340 workers studied had small opacities on their
chest radiographs of profusion category higher than 0/1  in  the
ILO  (1980)   international  classification.  A  subgroup of 161
men,  who had no history  of occupational exposure to  any dusts
other  than glass fibres, included 15 (9%)  with category 1/0 or
higher,  but there was no statistically significant relationship
between  the occurrence of these  signs and either intensity  or
duration  of exposure to glass fibres.  The factory concerned is
included  in  the  European  study  of  mortality  discussed  in
sections 8.1.2.2 and 8.3.

    Moulin  et al. (1987) conducted a cross-sectional survey  of
workers  in two glass  wool manufacturing plants  in France.   A
total  of  524  subjects (367 in factory A and 157 in factory B)
were  examined for respiratory symptoms,  radiological pulmonary
changes,   and  functional  respiratory  alterations.   In  each
factory, the prevalences of abnormalities among those exposed to
fibres   were  compared  with  findings   in  unexposed  workers
(administrative,  oven,  and  polystyrene  workers).   The  only
statistically  significant  differences  between the  two groups
were  higher prevalence rates of breathlessness and nasal cavity
symptoms in the exposed workers at factory A.  The prevalence of
chronic  bronchitis was increased slightly among exposed workers
at  both factories.  No  other exposure-related effects  on  the
respiratory system were observed.  The authors also used a case-
control  approach  in  which cases  were  the  subjects  in  the
quartile showing the worst results from the various examinations
and  the age-matched controls were chosen from among the others.
There was no difference as to duration of exposure in factory B,
while  cases had a  shorter period of  employment in factory  A.
The results of this study do not indicate any consistent effects
of exposure to glass wool fibres on the respiratory system.

    Weill et al. (1983, 1984) reported results based on  a  very
detailed  statistical  analysis  of  observations  on  1028  men
working  at  7  North  American  glass  wool  or  mineral   wool

factories.  All 7 factories were included in  the  comprehensive
US mortality study discussed in sections 8.1.2.2 and  8.1.3.   A
statistically  significant  increase  in the  chance  of finding
small  opacities (category 0/1 or higher) with increasing length
of  employment at the factories was found among some 450 current
cigarette  smokers.  The highest  profusion category on  the ILO
(1980)  scale,  as determined  from  the median  of  independent
assessments  by 3 readers on  6 films, was category  1/1.  There
was  no evidence in this study that exposure to fibres increased
the  prevalence of respiratory  symptoms or impairment  of  lung
function.

    Three  reports  refer  to separate  cross-sectional surveys,
carried  out at different times, of workers at one large factory
producing  continuous filament glass fibres  (Wright, 1968; Nasr
et  al., 1971; Utidjian & Cooper, 1976).  The last survey was of
a  stratified approximately 10% random sample of the workers and
included  the  use of  a  respiratory symptom  questionnaire and
measurement  of lung function.   The earliest of  these  studies
(Wright,  1968) did not include  those who had been  employed by
the  company for  less than  10 years,  but Nasr  et al.  (1971)
studied  nearly all  male employees  (N =  2028), including  196
office  workers.   Radiographic  appearances were  characterized
using different conventions.

    Wright   (1968)  did  not  find   any  unusual  radiological
patterns,  and the frequency of various radiological appearances
among  those characterized subjectively  as "likely to  have had
highest  exposure" was no  greater than in  those considered  to
have least exposure.  Nasr et al. (1971) reported  very  similar
prevalences  of radiographic abnormalities among  the office and
production workers (17% and 16%, respectively).  Mean  ages  and
mean  durations of employment  in 6 age  groups were  correlated
almost  perfectly, and these  mean values were  each  correlated
positively with the prevalence rates in the age  groups.   Thus,
there was almost total confounding between the average  age  and
duration of employment in the grouped data.

    Utidjian   &  Cooper  (1976)   failed  to  demonstrate   any
significant differences in the prevalence of chronic respiratory
illness  or impairment of  lung function between  categories  of
workers  designated as likely to have had the highest and lowest
exposures  to  airborne  fibres  in  the  same  plant.  However,
neither  tabular  nor  graphical presentations  of  results were
included in their brief report.

    Engholm  &  Von  Schmalensee (1982)  collected data, through
self-administered  questionnaires,  on  occupational  histories,
smoking  habits, and respiratory symptoms in 135 000 men working
in  the Swedish construction  industry.  Reports of  respiratory
symptoms indicative of chronic bronchitis were grouped according
to  age,  duration  of exposure  to  MMMF,  smoking habits,  and
whether  or not  there had  been any  occupational  exposure  to
asbestos.  Standardized prevalence rates of bronchitic symptoms,
adjusted  for age  and for  histories of  exposure to  asbestos,

increased consistently with increasing years of exposure to MMMF
in each smoking category.  The authors discuss likely sources of
bias  in their results,  including the possibility  that factors
not considered in their analysis may have been  correlated  with
duration  of  exposure  to  MMMF  and  with  the  occurrence  of
bronchitic   symptoms  (confounding).   They  argue  that  their
results are unlikely to be explained in this way.  This argument
is  weakened  by their  observation  of a  possible  association
between  bronchitis and exposure to  asbestos in their data  and
subsequent  demonstration  of  substantial errors  in  the self-
administered-questionnaire-determined   exposures  for  asbestos
(Engholm et al., in press).

    Other studies listed in Table 20, with  apparently  negative
or  equivocal  results, are  even  more difficult  to  interpret
epidemiologically,  because  of:  the small  numbers  of persons
studied,  the selection criteria adopted to justify inclusion in
analyses,  the  absence of  information  on likely  intensity or
duration of exposure to fibres, or incomplete  documentation  of
study procedures and findings.

    In  summary, results from available  cross-sectional studies
indicate that occupational exposure to various types of MMMF may
be associated with adverse effects on the respiratory tract, but
no  consistent  pattern  has emerged.   Findings suggesting this
association  require  confirmation,  preferably in  longitudinal
investigations  of exposed cohorts, including  ex-employees.  In
particular,  follow-up of the  observed increased prevalence  of
small opacities in smokers exposed to MMMF would be valuable.

8.1.2.2.  Historical prospective studies

    The  design and results  of relevant historical  prospective
analytical  epidemiological studies are  presented in Table  22.
The  most  extensive  historical prospective  studies of disease
incidence and mortality in populations occupationally exposed in
the production of MMMF have been those conducted in the  USA  by
Enterline  et al.  (in press)  and in  7 European  countries  by
Simonato  et al. (1986a,b, in press).  The results of studies on
widely overlapping- or sub-cohorts of these 2  large  investiga-
tions  have  also been  reported  (Enterline &  Henderson, 1975;
Bayliss  et  al., 1976;  Robinson et al.,  1982; Morgan et  al.,
1984; Andersen & Langmark, 1986; Bertazzi et al., 1986; Claude &
Frentzel-Beyme,  1986; Gardner et al., 1986; Olsen et al., 1986;
Teppo & Kojonen, 1986; Westerholm & Bolander, 1986).  Discussion
will be restricted mainly to results of: the complete cohorts in
the  2 large investigations (Simonato et al., 1986a,b, in press;
Enterline  et  al.,  in press),  studies  of  two  smaller,  but
distinct,  cohorts of production  workers (Moulin et  al., 1986;
Shannon et al., in press), and a cohort and  case-control  study
of construction workers (Engholm et al., in press).


Table 22.  Historical prospective (cohort) and case-control studies of MMMF-exposed workers
--------------------------------------------------------------------------------------------------------
Study protocol         Resultsa                       Comments                            Reference     
--------------------------------------------------------------------------------------------------------
16 661 male workers    Compared with local rates,     Asbestos may have been used in      Enterline     
in 11 fibrous glass    no excess of mortality from    some of the mineral wool plants;    et al.        
(6 glass wool, 3       NMRD for glass wool or con-    race unknown for about 30% of       (1983,        
glass filament, and    tinuous filament workers,      the cohort, so white male death     in press);    
2 mixed) and 6         statistically nonsignifi-      rates used for expected values;     Enterline &   
mineral wool plants    cant excess in mineral         average exposure for glass fila-    Marsh         
in the USA employed    wool workers; significant      ment, 0.011 fibres/cm3; for glass   (1984)        
for 1 year (6 months   excess in all malignant        wool, 0.033 fibres/cm3; for mixed                 
at 2 plants) between   neoplasms and lung cancer      fibrous glass, 0.059 fibres/cm3;                  
1945 and 1963 (1940-   20 years or more after         and for mineral wool, 0.352                       
63 for 1 plant)        first employment (mal-         fibres/cm3; 147 of the 301 res-                   
followed up to 1982    ignant neoplasms, O:E =        piratory cancer deaths 20 years                   
(98% traced; 4986      735:678; lung cancer, O:E =    from first exposure occurred at                   
deaths; caused         288:255.5) compared with       one plant (validity of use of                     
determined for 97%     local rates; excess of res-    local rates for this plant ex-                    
of deaths);            piratory cancer greatest in    amined); smoking survey showed                    
comparison with age-   mineral wool workers (O:E =    smoking habits of MMMF workers                    
and calendar-          45:34.4 for those with > 20    similar to those of US white                      
adjusted mortality     years from first exposure);    males                                             
rates for males in     in workers with 30 years                                                         
the USA or county      from first exposure, ex-                                                         
(malignant neoplasms   cess of respiratory cancer                                                       
only); exposure        in all but continuous fila-                                                      
estimate based on      ment production (significant                                                     
environmental survey   only in mineral wool wor-                                                        
and information        kers); excess (nonsignificant)                                                   
concerning changes     of respiratory cancer among                                                      
in control over the    1015 workers "ever exposed"                                                      
study period           in the production of small                                                       
                       diameter fibres compared with                                                    
                       those "never exposed" in this                                                    
                       sector (O:E = 22:17.8; for                                                       
                       those with > 30 years after                                                      
                       first exposure, O:E =                                                            
                       6:3.03); little relationship                                                     
                       between respiratory cancer and                                                   

                                                                                                       
Table 22.  (contd.)                                                                                     
--------------------------------------------------------------------------------------------------------
Study protocol         Resultsa                       Comments                          Reference       
--------------------------------------------------------------------------------------------------------
                       duration of employment, time                                       Enterline     
                       from first exposure, or                                            et al.        
                       estimated cumulative exposure,                                     (1983,        
                       but sharp increase in mineral                                      in press);    
                       wool workers with date of                                          Enterline &   
                       hire; 3 unconfirmed meso-                                          Marsh         
                       theliomas in entire cohort                                         (1984)        
                       (within expected range)                                                          
                                                                                                        
Case-control study     Statistically significant                                          Enterline     
of all MMMF workers    relationship between esti-                                         et al.        
from above cohort      mated cumulative exposure                                          (in press)    
who died of NMRD or    and respiratory cancer in                                                        
respiratory cancer     mineral wool, but not in                                                         
between January 1950   fibrous glass workers after                                                      
and December 1982      control for smoking (deter-                                                      
(cases) and a 4%       mined by telephone interviews                                                    
random sample of       of workers or their families)                                                    
workers stratified                                                                                      
by plant and year of                                                                                    
birth (controls)                                                                                        
                                                                                                        
21 967 workers in 13   No excess in NMRD compared     Largest cohort studied to date;     Saracci       
MMMF plants  (7 rock   with national rates (O:E =     advantage that some cancer inci-    et al.        
wool, 4 glass wool,    165:164.9) in total cohort     dence data available; however,      (1984a,b);    
and 2 continuous       or any sector; significant     workers with < 1 year of employ-    Simonato      
filament) in 7         excess of mortality from       ment comprised about 1/3 of the     et al.        
European countries     all neoplasms (O:E =           cohort; past manufacture of glass   (1986a,b,     
followed from first    661:597.7), due mainly to      wool in one of the continuous       in press)     
employment (1900-55)   significant excess of          filament plants; in "early tech-                  
to 1982 (95% traced;   lung cancer (O:E = 189:151.2)  nological phase" of rock wool/                    
2719 deaths; causes    and non-significant excess     slag wool production, airborne                    
determined for 98.3%   in cancers of the buccal       fibre concentrations higher due                   
of deaths) (> 1 year   cavity and pharynx (O:E =      to absence of dust suppressing                    
employment in          13:10.6), rectum (O:E =        agents; for glass wool, however,                  
English and Swedish    33:27), larynx (O:E =          changes in airborne fibre con-                    
plants); comparison    9:6.3), and bladder (O:E =     centrations between early and                     
with national          24:17.9); no relationship      "intermediate technological                       

Table 22.  (contd.)                                                                                     
--------------------------------------------------------------------------------------------------------
Study protocol         Resultsa                       Comments                          Reference       
--------------------------------------------------------------------------------------------------------
mortality and, where   with time since first expo-    phase" less marked due to                         
available, incidence   sure for any of the tumour     opposing effects on airborne                  
specific for           types except lung cancer       fibre levels of use of dust sup-              
calendar period,       (O:E = 29:16.8 for > 30        pressants and reduction of fibre              
sex, and age, and      years from first exposure)     diameters; in the "early techno-              
adjusted, in some      and bladder cancer; in-        logical phase" of rock wool/                  
cases, for local       crease in mortality from       slag wool production, use of                      
variations;            lung cancer for all sectors    arsenic-containing slags, and                     
historical             (continuous filament, glass    poor ventilation (resulting in                    
environmental          wool, and rock wool/slag       potential exposure to PAHs);                      
investigation          wool) compared with national   data on smoking habits not                        
                       rates with relation with       available; some use of asbestos                   
                       time from first exposure for   in some plants                                    
                       rock wool/slag wool and glass                                                    
                       wool subcohorts; when ad-                                                        
                       justed for local rates, in-                                                      
                       crease in mortality from                                                         
                       lung cancer for rock wool/                                                       
                       slag wool workers, only,                                                         
                       related to time from first                                                       
                       exposure; no relationship                                                        
                       of lung cancer with duration                                                     
                       of employment; excess of lung                                                    
                       cancer greatest in rock wool/                                                    
                       slag wool workers employed 
                       in the "early technological                                                      
                       phase" (SMRs = 257 and 214                                                       
                       for comparison with local and                                                    
                       national rates, respectively);                                                   
                       for bladder cancer, excess in                                                    
                       glass wool and rock wool/slag                                                    
                       wool workers related to time                                                     
                       from first exposure in rock                                                      
                       wool/slag wool production;                                                       
                       lung cancer incidence increased                                                  
                       in rock wool/slag wool sub-                                                      
                       cohort related to time from
--------------------------------------------------------------------------------------------------------
                                                                                                        
Table 22.  (contd.)                                                                                 
--------------------------------------------------------------------------------------------------------
Study protocol         Resultsa                       Comments                          Reference       
--------------------------------------------------------------------------------------------------------
                       first exposure and the early                                     Saracci   
                       technological phase; sig-                                        et al.    
                       nificant excess incidence                                        (1984a,b);
                       of cancer of the buccal                                          Simonato  
                       cavity and pharynx in rock                                       et al.    
                       wool/slag wool production                                        (1986a,b,       
                       sector with some (nonsignifi-                                    in press)       
                       cant) relationship with time                                                     
                       from first exposure; one case                                                    
                       of mesothelioma in the cohort                                                    
                       (within number expected and                                                      
                       worker employed for < 1 year)                                                    
                                                                                                        
2557 men with > 90     Deaths from NMRD fewer         Data on smoking not available,    Shannon                     
days employment in a   than expected; significant     but increase probably too large   et al.                      
glass wool plant       excess of lung cancer (O:E =   to be attributable solely to      (1984a,b,                   
between 1955 and       19:9.5) among "plant only"     this cause; local mortality       in press)                   
1977 followed to       employees not related to       rates for lung cancer similar                                 
1984 (97% traced;      duration of, or time since     to those of Ontario and Canada;                               
155 deaths);           first, exposure                no historical exposure data                                   
comparison with age-                                                                                                
and calendar-                                                                                                       
specific death rates                                                                                                
of Ontario males                                                                                                    
                                                                                                                    
                                                                                     
---------------------------------------------------------------------------------------------------------
                                                                                                         
Table 22.  (contd.)                                                                                                 
---------------------------------------------------------------------------------------------------------
Study protocol         Resultsa                       Comments                          Reference        
---------------------------------------------------------------------------------------------------------
135 026 Swedish male   Mortality from NMRD lower      Possible selection bias ("sur-    Engholm          
construction workers   than expected; significant     vivor population"); exposure      et al.           
examined by the        increase in cancer inci-       estimates based on job category   (1984,           
Construction           dence for pleural mesothel-    and self-reported inform-         in press)        
Industry               ioma (O:E = 23:10.8)           ation only; construction wor-                      
Organization for                                      kers frequently exposed to many                    
Working Environment,                                  dusts and difficulty in charac-                    
Safety and Health                                     terizing intermittent exposure                     
between 1971 and                                                                                         
1974 and  followed                                                                                       
up to 1983 (99.9%                                                                                        
traced; 7356                                                                                             
deaths); comparison                                                                                      
of cancer mortality                                                                                      
and incidence with                                                                                       
age-specific                                                                                             
national rates;                                                                                          
smoking habits and                                                                                       
place of residence                                                                                       
taken into account                                                                                       
in the analyses                                                                                          

Case-control study     Smoking and population         May be selection bias since pos-  Engholm          
of 518 construction    adjusted relative risk         sibly a "survivor population";    et al.           
workers with           for MMMF exposure (adjusted    construction workers frequently   (1984,           
respiratory cancer     for asbestos exposure) -       exposed to many dusts and trem-   in press)        
from above cohort      1.21 and for asbestos expo-    endous difficulty in character-                    
compared with          sure (adjusted for MMMF        izing exposure that was inter-                     
maximum of 5           exposure) - 2.53               mittent, varied in intensity,                      
controls each                                         and based largely on worker re-                    
matched for age,                                      call                                               
time of first check-                                                                                     
up, and survival;                                                                                        
smoking habits and                                                                                       
residence (urban/                                                                                        
rural) taken into                                                                                        
account in the                                                                                           
analyses                                                                                                 

Table 22.  (contd.)                                                                                      
---------------------------------------------------------------------------------------------------------
Study protocol         Resultsa                       Comments                          Reference                         
---------------------------------------------------------------------------------------------------------
1374 men with > 1      Significantly higher inci-     Large loss to follow-up; those    Moulin                      
year employment in a   dence of cancers of the        lost were considered to be        et al.                                  
glass wool factory     larynx (SIR = 2.3),            alive; authors reported that      (1986)                                  
between 1975 and       pharynx (SIR = 1.4), and       mortality in region where plant                                           
1984 followed up to    buccal cavity (SIR = 3) in     located did not differ signifi-                                           
1984 (92.7% traced);   production but not in          ficantly from comparison regions,                                         
comparison with age-   administration and main-       but did not indicate basis for                                            
and calendar-          tenance workers; some rel-     the conclusion; it was also                                               
specific incidence     ationship between SIRs and     reported that tobacco smoking                                             
for 3 regional         duration of exposure (not      no more frequent in cohort than                                           
French cancer          statistically significant)     in general population (based on                                           
directories (not                                      estimates in workers in 1983);                                          
including population                                  mean time since first exposure,                                         
in the region where                                   17.6 years; number of expected                                          
the plant was                                         lung cancers in workers with                                            
located)                                              more than 20 years exposure                                             
                                                      small; study conducted due to                                           
                                                      observation by an industrial                                            
                                                      physician of an excess of can-                                          
                                                      cers of the upper respiratory                                           
                                                      and alimentary tracts - essen-                                          
                                                      tially confirmation of a case                                           
                                                      report                                                                  
                                                                                                         
--------------------------------------------------------------------------------------------------------
a   Excesses  that  were  statistically signficant at  P < 0.05 are described as "significant"; all other 
    excesses were not statistically signficant.
NMRD = Non-malignant respiratory disease.
MRD = Malignant respiratory disease.
SMR = Standardized mortality ratio.
SIR = Standardized incidence ratio.
    Standardized  Mortality  Ratios  (SMRs)  for   non-malignant
respiratory  disease and their  statistical significance at  the
conventional  level of  P = 0.05 for  the main  results  in  the
European  and  US studies  are presented in  Table 23.  In  both
studies,  the  authors  preferred the  use  of  local  rates  to
national  rates  for the  purposes  of comparison  and presented
evidence  of  the  reasons for  this  in  fibrous glass  workers
(Gardner et al., 1986; Enterline et al., in press).

    There  has been little  evidence of an  excess of  mortality
from  non-malignant respiratory disease (NMRD) in the cohort and
case-control  studies  conducted  to  date.   In  the  extensive
European study of 21 967 production workers, there was no excess
mortality  from NMRD  in the  total cohort,  in  any  production
sector (i.e., continuous filament, glass wool, or rock wool/slag
wool), or on analysis according to time from first  exposure  or
duration of employment (Simonato et al., 1986a,b, in press).  In
the  large cohort of 16 661 production workers in the USA, there
was no excess mortality from NMRD in glass wool workers compared
with  local  ratesa (O  =  144, SMR =  103), though there  was a
statistically  significant  excess compared  with national rates
(O =  158,  SMR =  134).  In mineral  wool workers, there  was a
statistically  nonsignificant excess of NMRD  compared with both
local  (O = 31,  SMR = 140)  (Enterline et al.,  in  press)  and
national  rates  (O  = 31,  SMR  =  145) (Enterline  & Marsh, in
press).   In continuous filament  workers, there was  no  excess
compared  with either local (O = 35, SMR = 98) or national rates
(O = 41, SMR = 90).
---------------------------------------------------------------------
a   In  the US  study, SMRs  based on  local rates  are for  the
    period  1960-82; SMRs based  on national rates  are for  the
    period 1946-82.

Table 23.  Non-malignant respiratory disease mortality - epidemiological
studies of MMMF production workersa
-------------------------------------------------------------------------
Feature        Study                    Fibre type                     
                            Glass        Glass           Rock wool/
                            filament     woolb,c       slag wool
---------------------------------------------------------------------------
Number of      USA          35           144             31
deaths from    Europe       13           93              59
non-malignant  ----------------------------------------------------------
respiratory    Standardized mortality ratios compared with local ratesd,e
disease                                  

Non-malignant  USA          98           102             140
respiratory    Europe       96           105             94
disease        (national)
mortality

Time since     USA          0/124/110/69 52/92/118/93    0/230/134/123
first expo-    Europe       0/145/159/0  63/118/115/113  101/90/72/142
sure (< 10/    (national)
10-19/20-29/
30+ years)

Duration of    USA                 116/78                136/118
employment     Europe       240/0        121/71          90/114
(< 20/20+      (national)
years) (> 20
years since
first exposure)

Estimated      USA          97/130/107/0 126/79/74/95    158/141/160/117
cumulative
exposure (in-
creasing in-
tervals of
fibre/cm3
x months)

Small dia-     USA
meter fibres
- ever/never                -            110/97          -
  exposed

- by time                   -            0/44/164/113    -
  since first
  exposure
  (ever ex-
  posed)
-------------------------------------------------------------------------
a  IARC (1985) and Enterline & Marsh (in press).
b  Data for "fibrous glass-both" and "fibrous glass-wool" plants in the 
   USA study combined.
c  In  the only additional relevant study of a much smaller cohort of 
   glass wool  production  workers, there  was no excess  of mortality 
   from  non-malignant respiratory disease (O = 4, SMR = 55) compared 
   with provincial rates (Shannon et al., in press). 
d  Local rates, unless otherwise specified.
e  No  SMRs nor trends shown in this table are statistically significant 
   at the conventional  P = 0.05 level.

    The results  of analyses of NMRD mortality  with  time  from
first  exposure, or duration  of exposure, or  cumulative  fibre
exposure  did not showed any trends for either the glass wool or
rock wool workers.  Among glass wool workers "ever  exposed"  to
small diameter fibres, there was no excess of NMRD mortality but
a  slight statistically insignificant  increase with time  since
first exposure.

    Shannon  et al. (in press)  studied 2557 glass wool  workers
with  more than 90 days employment and found 4 deaths from NMRD,
whereas 7.3 would have been expected (SMR = 55).  Engholm et al.
(in  press),  in their  study  of 135 026  Swedish  construction
workers  potentially  exposed to  MMMF  and asbestos,  found 193
deaths  from  NMRD  compared with  418  expected;  this gave  an
unusually low SMR of 46.

8.1.3.  Carcinogenicity

    Standardized  mortality ratios (SMRs) and  their statistical
significance  at the conventional level of  P = 0.05 for the main
results  in the European and  US studies are presented  in Table
24.   In both studies,  the authors preferred  the use of  local
rates  to national  rates for  the purposes  of  comparison  and
presented  evidence of  the reasons  for this  in fibrous  glass
workers (Gardner et al., 1986; Enterline et al., in press).

8.1.3.1.  Glass wool

    In  the European study (Simonato et al., 1986a,b, in press),
there  was no significant excess  of mortality from lung  cancer
(O =  93, SMR = 103)  among glass wool production  workers, when
compared  with  local mortality  rates.   However, there  was  a
statistically  non-significant relationship between  lung cancer
mortality  and  time from  first  exposure.  When  compared with
national  mortality rates, there was a statistically significant
excess  of lung cancer that was related (O = 93, SMR = 127) (not
statistically significantly) to time from first exposure.  There
was no relationship between lung cancer mortality  and  duration
of employment.  No excess was discernible among workers employed
in the "early technological phase", whichever reference rate was
used.

    In  the  USA  glass wool  subcohort  (Enterline  et al.,  in
press),  the SMR for lung cancer was 109 (O = 267, statistically
nonsignificant),  based  on  local rates,  and  116  (O  =  267,
statistically  significant), based on national  reference rates.
After  20 years  from the  onset of  exposure, the  SMR was  not
statistically  significant compared with  local rates (111)  but
was  statistically  significant  compared with  US  rates (124),
based   on  207  observed  cases.   There  was  a  statistically
nonsignificant  increase with time since first exposure, but the
rend was less evident when local rates were used.  There was no
relationship  between respiratory cancer mortality  and duration
of  exposure, or cumulative fibre  exposure.  There was also  an
excess  (not statistically significant) of mortality due to lung
cancer among 1015 workers "ever exposed"  in the  production  of

fibres  of  nominal  diameter < 3 m  (O = 22, SMR = 124), where
measured  fibre  levels were  higher  than in  other  production
sectors,  compared with those  "never exposed" in  this  sector.
The excess showed an increasing but non-significant relationship
with time from first exposure.

Table 24.  Lung cancer mortality - epidemiological studies of MMMF
production workersa
-------------------------------------------------------------------------
Feature         Study                  Fibre type                   
                           Glass          Glass          Rock/slag
                           filament       woolb,c      wool
---------------------------------------------------------------------------
Number of       USA        64             267            60
deaths from     Europe     15             93             81
lung cancer     ---------------------------------------------------------
                 Standardized mortality ratios compared with local rates

Lung cancer     USA        92             109            134 ( P < 0.05)
mortality       Europe     97             103            124

Time since      USA        104/53/119/80  92/108/108/114 90/157/127/135
first expo-     Europe     176/76/0/0     68/113/100/138 104/122/124/185
sure (< 10/
10-19/20-29/
30+ years)

Duration of     USA           110/106d                 145/111
employment      Europe     0/0            118/60         143/141
(< 20/20+
years) (> 20
years since
first exposure)

Estimated       USA        96/51/109/63   120/109/81/108 185/164/119/104
cumulative
exposure (in-
creasing
intervals of
fibre/cm3
x months)

Technological   Europe
phase
- early/inter-             -              92/111/77      257/141/111
  mediate/late                                           ( P < 0.05)e

- by time since            -              108/70/80/121  0/0/317/295
  first exposure
  (early phase)

Small dia-      USA
meter fibres
- ever/never               -              124/105        -
  exposed
-------------------------------------------------------------------------

Table 24.  (contd.)
--------------------------------------------------------------------------
Feature         Study                  Fibre type                   
                           Glass          Glass          Rock/slag
                           filament       woolb,c      wool
---------------------------------------------------------------------------
                 Standardized mortality ratios compared with local rates
                   
- by time                  -              61/128/105/198 -
  since first
  exposure
  (ever ex-
  posed)

Estimated con-  USA        lower          intermediate   higher
centrations of                            (highest in
respirable                                small diameter
fibres                                    fibre produc-
                                          tion facilities)
-------------------------------------------------------------------------
a  Modified from: IARC (in press).
b  Data for "fibrous glass-both" and "fibrous glass-wool" plants in the 
   USA study combined.
c  In the only additional relevant study of a much smaller cohort of 
   glass wool production workers, there was a statistically significant 
   excess of lung  cancer  mortality compared  with provincial rates  (O 
   = 19,  SMR = 199),  which was not related  to time from first  
   exposure (< 10  years, SMR = 241; 10+ years, SMR = 195) or duration of 
   employment (<  5  years, SMR = 291; > 5 years, SMR = 174) (Shannon et 
   al., in press). 
d  Data reported for "fibrous glass" (type unspecified) subcohort.
e  Statistical test for linear trend.

    A case-control study nested in the US cohort  was  conducted
by  Enterline et al.  (in press) with  an initial number  of 211
respiratory   cancer   cases   among   "fibrous   glass"   (type
unspecified)  workers and 374  controls.  The logistic  analysis
performed  indicated  a  statistically  significant  association
between  lung cancer and the  smoking habits of workers  but not
between lung cancer and cumulative fibre dose.

    In  a glass wool plant in Ontario, there was a statistically
significant  (2-fold)  excess  of mortality  from  lung  cancer,
compared   with  provincial  rates,  among   2557  "plant  only"
employees  with more than 90 days employment (O = 19, SMR = 199)
(Shannon  et al.,  in press).   The lung  cancer rates  did  not
appear  to be related to time from first exposure or duration of
employment.

    The rate of mesothelioma in glass wool production workers in
the  large US study was not excessive.  Two cases were reported.
No  cases in glass  wool workers were  reported in the  European
study.

    Moulin  et al. (1986)  reported a statistically  significant
higher  incidence  of  cancers of  the  buccal  cavity (O  =  9,
Standardized  Incidence Ratio (SIR) = 301) in production workers
with more than 1 year of employment in a glass wool  factory  in
France; the excess was related to duration of exposure  but  not
significantly  so.   This  study  was  conducted  following   an
observation by an industrial physician of an excess  of  cancers
of  the  upper  respiratory  and  alimentary  tracts  and  must,
therefore, be considered to be essentially a confirmation  of  a
case  report.  On their  own, therefore, these  findings do  not
constitute convincing evidence of a real association.  Moreover,
the reported SIRs were based on comparison with rates of regions
other than the one in which the plant was located.

    A  statistically nonsignificant excess  of mortality due  to
laryngeal  cancer was observed  in a subcohort  of the  European
study among 1098 Italian workers employed for at least 1 year in
a plant manufacturing glass wool (Bertazzi et al., 1986).  There
was  some relationship with  time from first  exposure, but  the
number  of  cases  was small (O = 4, SMR = 190).  These findings
were limited to the Italian plant and were not  consistent  with
either  the results  of the  complete European  or  US  studies.
Moulin   et  al.  (1986)  also  reported  a  statistically  non-
significant excess in the incidence of cancer of the larynx (O =
5,  SIR  = 230)  in their cohort  of 1374 glass  wool production
workers  with more  than 1  year of  employment.  However,  this
observation  should be interpreted  with caution, owing  to  the
limitations of this study mentioned earlier.

8.1.3.2.  Rock wool and slag wool

    In  the European subcohort of rock wool/slag wool production
workers,  there  was  a statistically  nonsignificant  excess of
mortality  from lung cancer,  which was the  same compared  with
either  local or national mortality  rates (O = 81,  SMR = 124).
There  was a statistically nonsignificant relationship with time
from first exposure (Simonato et al., 1986a,b, in press) but not
with  duration of employment.  The excess was concentrated among
workers employed in the "early technological phase"  (with large
SMRs  of  257  and  214  for  local  and  national  comparisons,
respectively,  both  statistically  significant and  based on 10
observed cases), in which airborne fibre levels  were  estimated
to  have been much  higher.  The use  of copper slag  containing
arsenic  was also reported in one factory during this period and
ventilation  was  generally  poor, possibly  resulting  in  some
exposure  to polycyclic aromatic  hydrocarbons (PAHs)  from  the
furnaces.   Other environmental contaminants that might have had
an  influence on the lung cancer mortality excess have also been
analysed.   A statistically significant increase  in lung cancer
mortality  after 20 years  since first exposure  was  associated
with  the  use  of slag  (O =  23, SMR  = 189).   However, these
findings  are difficult to interpret due to the wide overlapping
between  the period of use  of slag and the  early technological
phase.  Neither the use of bitumen and pitch nor the presence of
asbestos  in some products explained  the excess of lung  cancer

(Simonato  et al., in press). The results of analysis of data on
lung  cancer incidence in  the European cohort  were similar  to
those reported for mortality.

    Enterline et al. (in press) studied a cohort of  1846  white
male  workers from 6 US  plants that produced slag  wool or rock
wool/slag wool.  The SMRs for respiratory cancer were 134 (local
rates) and 148 (national rates), both statistically significant,
based on 60 observed cases. After 20 years since first exposure,
the  SMRs were 131 (local  rates) and 146 (national  rates), the
latter  being  statistically  significant, based  on 45 observed
cases.  No clear trend with time since first exposure was found,
and  there was no relationship  with duration of employment,  or
with estimated cumulative exposure in this subcohort of  the  US
study.   It was reported that  one of the plants  studied used a
copper slag containing arsenic.

    A  case-control study nested in  the US rock wool/slag  wool
production  subcohort  was  also  carried  out  using  the  same
methodology  as that for the glass wool production workers.  The
study  comprised 45 respiratory  cancer cases and  49  controls.
Only  the  relationship  between  lung  cancer  and  smoking was
statistically  significant ( P <  0.001).  In a further analysis,
using  38  cases  and 43  controls,  there  was a  statistically
significant  relationship  between  lung  cancer  and  estimated
cumulative fibre dose ( P <  0.01), after controlling  for  years
of  smoking, time since starting to smoke, and interaction terms
between smoking and exposure.  Reservations about the model used
for  this  analysis  complicate  the  interpretation  of   these
results.

    Only  one case of pleural  mesothelioma was reported in  the
rock  wool/slag  wool  production  workers  in  the  US  cohort.
Similarly,  in  the  large  European  cohort  (Simonato  et al.,
1986a,b,  in press), only one pleural mesothelioma occurred in a
rock wool/slag wool production plant with a brief latency period
following  a relatively short  exposure time.  This  single case
does not represent an excess.

    In the European study, there was a statistically significant
excess  in the  incidence of  cancer of  the buccal  cavity  and
pharynx  (O  =  22, SIR  =  180),  which showed  a statistically
nonsignificant relationship with time from first exposure.  Also
observed   in  the  European  study  was  a  statistically  non-
significant  excess in bladder cancer  mortality (O = 13,  SMR =
137)  in the rock wool/slag  wool production sectors, which  was
related  at a statistically significant level to time from first
exposure (IARC, 1985).  In neither of these cases was  there  an
association with the early technological phase when fibre levels
were estimated to be higher.

8.1.3.3.  Glass filament

    In the glass filament subcohort of the European study, there
was  no excess of mortality from lung cancer compared with local

mortality  rates  (O =  15, SMR =  97), but a  small excess (not
statistically significant) compared with national rates (O = 15,
SMR  = 120), which was  not related to time  from first exposure
(Simonato  et al., 1986a,b,  in press).  However,  it should  be
noted  that the length of  follow-up of the continuous  filament
workers in this study was short.

    No excess for lung cancer was reported by Enterline  et  al.
(in  press)  from  the follow-up  of  3435  white  male  workers
employed  in glass filament  production in the  large US  study.
The  SMRs for respiratory cancer  were 92 (local rates)   and 95
(national  rates), based  on 64  observed cases.   There was  no
relationship with time since first exposure, or  with  estimated
cumulative fibre dose.

8.1.3.4.  Mixed exposures

    Engholm  et  al.  (in press)  reported  the  results of  the
follow-up of a large cohort of construction workers  in  Sweden.
The SIR for lung cancer was 91 based on 440 observed cases.  The
authors  also investigated the possible influence of exposure to
asbestos  and  to MMMF  using  a nested  case-referent approach.
After  adjusting for asbestos  exposure, the relative  risk  for
exposure  to  MMMF  was 1.21 (95% CI: 0.60 - 2.47), while it was
2.53  (95% CI: 0.77 -  8.32) for asbestos after  controlling for
potential  MMMF exposure.  A  wide overlapping of  asbestos  and
MMMF  exposures  makes the  analysis  and interpretation  of the
results of this study difficult.

8.1.3.5.  Refractory fibres

    No published epidemiological studies are available.

8.2.  General Population

    With the exclusion of isolated case reports  of  respiratory
symptoms  and dermatitis associated with exposure to MMMF in the
home  and  office  environments, and  2  limited cross-sectional
studies  of  ocular  and  respiratory  effects  in  offices  and
schools, adverse effects on the general population have not been
reported.   For  example,  Newball &  Brahim  (1976)  attributed
respiratory  symptoms in members  of a family  to fibrous  glass
exposure from a residential air conditioning system.  Dermatitis
has  been  observed in  individuals  exposed to  disturbed  MMMF
insulation  in office buildings  (Verbeck et al.,  1981; Farkas,
1983)  and to clothing contaminated during laundering with MMMF-
containing materials (Lucas, 1976).

    A  significant increase in  the incidence of  "smarting" and
watering  eyes, swollen eyelids, disturbance  of sight, conjunc-
tival  hyperaemia, and "smarting" of the nose was observed in 39
persons  working in buildings  with ceilings made  of compressed
mineral  wool  compared  with a  control  group  of 23  persons,
matched  for age, sex, and  smoking habits, who were  working in

buildings  with plaster ceilings.  In  5 of the exposed  indivi-
duals,  mineral fibres were  present in the  conjunctival mucous
threads  compared with  0 in  the control  group.  It  was  also
reported  that  the  occurrence  of  symptoms  and  conjunctival
hyperaemia  were significantly reduced  by surface treatment  of
the mineral wool ceiling (Alsbirk et al., 1983).

    The  association  between  various  signs  and  symptoms  of
disease  and  exposure  to MMMF  in  adults  and children  in 24
kindergartens  was investigated in  one Danish county  in Autumn
1984 (Rindel et al., 1987).  In 10 kindergartens,  the  ceilings
were covered with MMMF products with water-soluble binder (Group
A), 6 had resin-bound ceiling covering material (Group B), and 8
had  ceilings  on which  MMMF was not  apparent (Group C).   The
investigation included questionnaires for the adults (n  =  200,
92%  response)  concerning  health  and  socio-economic  status,
smoking habits, and contact lens use (mode of administration not
stated);  questionnaires for children  (n = 900,  90%  response)
were  completed by their  parents.  In addition,  for 3  months,
daily  records were kept  by the adults  of their own  signs and
symptoms  of disease and  those of the  children.  All  subjects
were  also clinically examined  by a doctor.   Concentrations of
fibres  and dust, carbon dioxide  levels, temperature, humidity,
and  air speed were also  determined.  Mean total airborne  MMMF
levels  were similar  in Groups  A and  B (23  fibres/m3 and  40
fibres/m3, respectively), but ranged from 0 to 77  fibres/m3  in
Group  C.   Among children,  there  was no  correlation  between
disease  symptoms  and  MMMF concentrations.   For  adults,  eye
irritation  was significantly related to  respirable ( P =  0.03)
and  non-respirable ( P =  0.004)  MMMF.  The presence of settled
MMMF  on surfaces was correlated with adult skin irritation ( P =
0.005).  However, the authors concluded that the total  MMMF  in
air  derived from ceiling coverings did not explain the reported
symptoms and diseases.  Unless the adults were not  informed  of
the   hypothesis  to  be  tested,  and  the  physician  involved
"blinded",  it is  difficult to  see how  bias could  have  been
avoided.

    There  have  not  been  any  mortality  or  cancer morbidity
studies concerning exposure to MMMF in the general population.

9.  EVALUATION OF HUMAN HEALTH RISKS

    Whenever  possible, emphasis is  placed on data  obtained in
epidemiological  studies of human  populations exposed to  MMMF,
though  few data on quantitative exposure-response relationships
are  available.  Information from animal and  in vitro studies is
used  mainly in  the comparative  assessment of  the potency  of
various   fibre  types  and   sizes,  particularly  when   human
epidemiological studies are lacking or the results are not clear
cut, as is the case for some MMMF.

9.1.  Occupationally Exposed Populations

    There  have  been isolated  reports  of dermatitis  and  eye
irritation in workers exposed to MMMF (section 8.1.1).  However,
no  human  data  are available  concerning the exposure-response
relationship for these effects, and animal studies have not been
conducted to evaluate either of them specifically.

    In addition, there has been some suggestion of non-malignant
respiratory effects (e.g., decrements in lung function) in MMMF-
exposed  workers (section 8.1.2), but some of these studies have
been methodologically weak.  In the study regarded as  the  best
to  date, a slight  excess of small  radiological opacities  was
observed,  but this was not accompanied by ventilatory decrement
or increase in respiratory symptoms. The results of experimental
animal  studies have indicated  that MMMF might  be  potentially
fibrogenic,   especially  when  introduced  into  body  cavities
(pleural   and   peritoneal)  (section   7.1.1.1).   However,  a
significant  fibrogenic response has not been seen in inhalation
studies, to date, though it should be noted that the information
in  this regard is more complete for glass fibres than for other
MMMF.   Thus, it is not possible, on the basis of available data
from  human epidemiological and experimental  animal studies, to
draw  definite conclusions concerning  the nature and  extent of
the  possible non-malignant hazards  for the respiratory  system
resulting from exposure to MMMF.

    An  important concern  is the  potential risk  of cancer  in
workers  exposed to MMMF.   Although there is  no evidence  that
pleural  or peritoneal mesotheliomas  have been associated  with
occupational exposure in the production of various  MMMF,  there
have been indications of increases in lung cancer mortality from
the main epidemiological studies of workers in some  sectors  of
MMMF production, including the two most extensive investigations
of workers in Europe and the USA (section 8.1.3).

    In   the  rock  wool/slag  wool   production  industry,  the
standardized  mortality  ratios for  lung  cancer in  the  large
European and US cohorts were 124 and 134, respectively (Simonato
et  al., 1986a,b, in press; Enterline et al., in press).  In the
glass  wool production industry, the corresponding SMRs were 103
and  109, respectively.   There has  been no  increase  in  lung
cancer mortality in continuous filament production workers; SMRs
in  the European and  US studies were  97 and 92,  respectively.

However,  available data are too few to establish a quantitative
exposure-response  relationship  for  lung cancer  mortality  in
relation to airborne fibre concentrations.

    There  has been some suggestion  in these cohort studies  of
increases in cancer at sites other than the lung, but, it is not
possible,  on  the  basis of  the  available  data, to  draw any
conclusions   concerning  the  possible  role   of  occupational
exposure during MMMF production in the etiology of  these  other
malignant diseases.

    It  has been  suggested that  other factors  present in  the
work-place  may have contributed  to the increased  lung  cancer
mortality  observed, such as the presence of contaminants in the
slag  used, particularly  in the  early phase  of  mineral  wool
production  in the European study.   However, where it has  been
possible  to  study  such contaminants,  including  asbestos and
arsenic in copper slag, the lung cancer excess was not explained
by  their presence. Furthermore, it is not likely that any known
potential   confounding  factors  for  lung   cancer  mortality,
including  cigarette  smoking,  could  explain  the  high  rates
observed  in the early technological phase of the rock wool/slag
wool industry in Europe.  The hypothesis that the airborne fibre
concentrations  are  the  most important  determinants  of  lung
cancer  risk is supported  by the observation  of a  qualitative
relationship  between the standardized mortality ratios and past
estimated  airborne fibre levels  in the various  sectors  (rock
wool/slag  wool,  glass wool,  and  continuous filament)  of the
production   industry.    Moreover,   while  not   statistically
significant, there was a rise in lung cancer risk that increased
with  length of time since first exposure in workers involved in
the production of smaller diameter (< 3 m)  glass  wool  fibres
in the USA.  Airborne fibre levels measured in this  sector  are
higher  than those  in the  rest of  the glass  wool  production
sector.   However, it should  be emphasized that,  at the  lower
fibre  concentrations  associated  with the  improved production
conditions  of the late technological  phase, no excess of  lung
cancer   mortality  has  been  observed  in  the  European  rock
wool/slag wool workers.

    Airborne  MMMF  concentrations  present in  work-places with
good work practices are generally of the order of, or less than,
1 fibre/cm3  (section 5).  However,  data  reviewed in section 5
indicate that mean airborne fibre levels for some workers in the
ceramic  fibre and  small diameter  (< 1 m)   glass wool  fibre
manufacturing sectors may be similar to those to  which  workers
were exposed in the early production phase.  Therefore, although
only  a  small  proportion of  workers  are  employed  in  these
segments  of  the  industry,  their  lung  cancer   risk   could
potentially  be elevated.  However, epidemiological data are not
yet   available  on  workers  in  the  ceramic  fibre  industry.
Elevated  average concentrations of fibres during the blowing or
spraying  of insulation wool in  confined spaces have also  been
recorded  and,  though  the time-weighted  average  exposure for

individual  workers may not be  as high (section 5),  their lung
cancer   risk  could  similarly  be   increased,  if  protective
equipment is not used.

    The  results of animal  studies,  in toto, indicate that  the
excess of lung cancer observed in the epidemiological studies in
some  sectors of the  MMMF production industry  is  biologically
plausible   (section  7.1).   Although  in   inhalation  studies
(probably  the most relevant studies for risk assessment in man)
conducted  to  date,  MMMF  have  not  induced   a   significant
carcinogenic  response, the carcinogenic potential  of many MMMF
has  been demonstrated when  they have been  introduced directly
into  the pleural and peritoneal cavities.  The results of these
studies  clearly show that the carcinogenic potential in animals
is  directly related to fibre size and durability.  In addition,
glass  fibres have been  shown to cause  chromosomal alterations
and  cell  transformation  in  vitro, but   little information in
this regard is available for the other MMMF (section 7.2).

9.2.  General Population

    There  have  been  isolated  case  reports  of   respiratory
symptoms  and dermatitis associated with exposure to MMMF in the
home  and office environments (section 8.2).  However, available
epidemiological  data are not sufficient to draw any conclusions
in this respect.  As with occupationally-exposed populations, it
is the potential risk of lung cancer at low levels  of  exposure
that  is of most  concern, but no  direct evidence is  available
from which to draw conclusions.

    Available data on occupationally-exposed populations are not
yet  sufficient to estimate  quantitatively, by extrapolation to
low  levels, the risk of  lung cancer in the  general population
associated  with exposure to MMMF in the environment.  Moreover,
the available information is inadequate to characterize exposure
to  MMMF in the general environment.  However, levels of MMMF in
the typical indoor and general environments, measured  to  date,
are very low compared with present levels in most sectors of the
production  and  user  industry  and  certainly  much  lower (by
several orders of magnitude) (sections 5.1.1.2 and 5.1.1.3) than
some  past occupational exposure  levels associated with  raised
lung  cancer risks.  It should also be noted that such increases
in  lung  cancer  risk have  not  been  observed  among  workers
employed under the improved conditions of the late technological
phase and followed up for a sufficient length of time.

    The overall picture indicates that the possible risk of lung
cancer  among the general public is very low, if there is any at
all,  and  should  not be a cause for concern if the current low
levels of exposure continue.

10.  RECOMMENDATIONS

10.1.  Further Research Needs

10.1.1.  Analytical methods

    The  current reference scheme  for the measurement  of  MMMF
concentrations  in the occupational environment  by the membrane
filter  optical and scanning electron microscopic methods should
continue.

    There is also a need to standardize methods  of  measurement
of  MMMF in ambient and indoor air; ideally, such methods should
determine both the total mass of dust and the number  of  fibres
likely  to  be  deposited  in  the  respiratory  system.   Where
scanning  electron or transmission electron microscopy are used,
fibre  size distribution should be fully characterized.  Greater
standardization  of  sample preparation  and measurement methods
for   the  determination  of  MMMF  in  other  media,  including
biological tissues, is also desirable.

    Further  research  on  the development  of  automated  fibre
counting methods, which may improve the consistency  of  results
obtained  in different laboratories,  should be conducted.   The
development of cheaper and more practical methods of determining
fibrous particulates is also desirable.

    For  fibrous  dusts  with  the  potential  for  causing non-
malignant  and  malignant  diseases  of  the  airways  and  lung
parenchyma,   attention  should,  in  future,  be  paid  to  the
measurement and study of the effects of the fraction  of  fibres
(inhalable)  that is  mainly deposited  on the  surface  of  the
airways  as well  as the  fraction ("respirable")  with  a  high
efficiency   for  airway  penetration  and   deposition  in  the
alveoli.

10.1.2.  Environmental exposure levels

    There  is  a  need  to  determine  levels  of  MMMF  in  the
environment   that  are  representative  of  general  population
exposure, and it is recommended that respirable levels  of  MMMF
in  ambient and indoor air should be measured by appropriate and
preferably   standardized  methods  of  sampling  and  analysis.
Analysis  of the MMMF contents of tissues in both occupationally
exposed groups and the general population is also recommended.

10.1.3.  Studies on animals

    Standardized reference samples of MMMF products as  well  as
size-selected  fibre  samples should  be  developed for  use  in
experimental  animal  studies.   Complete  characterization  and
reporting of the fibre size distributions of MMMF used  in  such
investigations is also essential.

    Research  to  investigate  the  relative  potencies  of  the
various  MMMF  types  (preferably  by  routes  of  exposure that
simulate  those of man, e.g., inhalation)  should continue.  The
effects  of fibre  coating on  the potential  of MMMF  to  cause
disease  should be further  examined and investigations  of  the
effects  of  concomitant exposure  to  MMMF and  other  airborne
pollutants (such as tobacco smoke) should be conducted.

    Studies   should  be  undertaken  to   examine  further  the
mechanisms   by   which   fibrous   materials   cause   disease.
Particularly  relevant  for  the assessment  of risks associated
with exposure to the MMMF is the examination of  the  biological
significance of the durability of fibres in tissue.  Development
of  short-term  models of  durability are needed,  as well as  a
comparison of durability in different locations in the body.

    Studies  on the relationship  of fibrogenicity and  carcino-
genicity  are of special importance as is a better understanding
of  the mechanisms of fibre toxicity, especially at the cellular
level  (interaction  of  macrophages, etc.).   Cytotoxicity  and
genotoxicity studies should be extended to all  MMMF  (currently
available only on glass fibres).

    As  new fibres are  developed, they should  be subjected  to
systematic  investigation for the  assessment of health  hazard.
It  would  be  desirable to  develop  a  standard set  of  study
protocols for use in this regard.

10.1.4.  Studies on man

    Further  study  of  the  prevalence  of  dermatitis  and eye
irritation  in  populations  exposed occupationally  to  MMMF is
warranted.   The respiratory effects observed in cross-sectional
studies  of MMMF workers  should be further  investigated  using
standardized   methods   to   measure  effects,   including  the
International  Classification of Radiographs  of Pneumoconiosis,
in appropriately designed epidemiological studies (WHO, 1983b).

    Follow-up of MMMF-exposed workers examined in the historical
prospective  studies  reported  to date  should  continue.   The
possibilities  of  extending these  investigations to meaningful
studies  (in terms, for  example, of size  and time since  first
exposure)  on workers who have  entered the glass wool  and rock
wool  industries  more  recently, those  working with refractory
(including  ceramic)  fibres, special  purpose fibres, or  other
new  fibres,  and  workers in  the  user  industries  should  be
explored.  These studies should be accompanied by the collection
of  agreed comprehensive industrial  hygiene data in  advance of
the   epidemiological   analyses.   Where   possible,  continued
attempts should be made to control for confounding factors, such
as  cigarette smoking (perhaps by  nested case-referent studies)
and  past exposure  to asbestos  (perhaps by  lung fibre  burden
studies).

10.2.  Other Recommendations

10.2.1.  Classification of MMMF products

    There is a need for setting up a systematic scheme  for  the
classification of the various MMMF products manufactured.

    There  is  also  a need  to  give  guidance  concerning  the
potential  for fibre  release from  MMMF products.   As a  first
step,  information on fibre  diameters in the  bulk material  is
essential.

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    See Also:
       Toxicological Abbreviations
       Man-made Mineral Fibres (IARC Summary & Evaluation, Volume 43, 1988)