EPA-540/1-86-049
                        Agency
   ce of Emergency and
   nedial Response
Washington DC 204.60
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
                        Superfund
&EPA
                         HEALTH  EFFECTS ASSESSMENT
                         FOR ASBESTOS
                              Do not remove. This document
                              should be retained in the EPA
                              Region 5 Library Collection.

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                                            EPA/540/1-86-049
                                            September 1984
       HEALTH  EFFECTS  ASSESSMENT
               FOR  ASBESTOS
    U.S. Environmental Protection Agency
     Office of Research and Development
Office of Health  and  Environmental Assessment
Environmental Criteria and Assessment  Office
            Cincinnati,  OH   45268
    U.S. Environmental Protection Agency
  Office of Emergency  and  Remedial Response
Office of Solid Waste and Emergency  Response
            Washington,  DC  20460
             U S. Environmental Protection Agwe»
             Region 5, library (PL-12J)
             I* West Jackson Boulevard, 12th r»i
             Chkago. »L  60604-3590

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                                  DISCLAIMER

    This  report  has  been funded  wholly  or  In  part by  the  United  States
Environmental  Protection  Agency under  Contract  No.  68-03-3112  to  Syracuse
Research Corporation.  It has been  subject  to  the Agency's peer and adminis-
trative review, and  It has been  approved  for  publication as an EPA document.
Mention of  trade  names or commercial  products  does  not  constitute  endorse-
ment or recommendation for use.
                                      11

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                                    PREFACE
    This  report  summarizes  and evaluates Information relevant  to  a prelimi-
nary  Interim  assessment  of  adverse health effects  associated  with asbestos.
All  estimates  of  acceptable  Intakes and  carcinogenic  potency  presented  In
this  document  should be  considered  as  preliminary  and reflect  limited  re-
sources allocated  to this project.  Pertinent  toxlcologlc  and environmental
data  were  located  through   on-Hne   literature  searches  of  the  Chemical
Abstracts,  TOXLINE,   CANCERLINE  and  the CHEMFATE/DATALOG  data bases.   The
basic   literature  searched   supporting   this   document  Is   current  up   to
September,  1984.   Secondary  sources  of  Information have  also been  relied
upon  1n  the  preparation of  this  report  and  represent  large-scale  health
assessment  efforts  that entail   extensive  peer  and  Agency  review.   The
following  Office  of  Health  and Environmental Assessment  (OHEA)  sources  have
been extensively utilized:


    U.S.  EPA.   1980b.   Ambient  Water  Quality  Criteria  for  Asbestos.
    Environmental  Criteria   and   Assessment   Office,   Cincinnati,  OH.
    EPA-440/5-80-022.  NTIS  PB 81-117335.

    U.S.  EPA.   1983a.  Reportable  Quantity  for Asbestos.   Prepared by
    the Environmental  Criteria and  Assessment  Office, Cincinnati,  OH,
    OHEA  for  the Office  of  Solid Waste  and  Emergency Response,  Wash-
    ington, DC.

    U.S.  EPA.  1983b.  Review of  Toxlcologlc Data  1n Support  of Evalua-
    tion  of  Carcinogenic  Potential   of  Asbestos.   Prepared  by  the
    Carcinogen Assessment Group,  OHEA, Washington,  DC  for  the  Office of
    Solid Waste and Emergency Response, Washington,  DC.

    U.S.  EPA.   1983c.   Technical Support  Document on the Ranking of
    Hazardous  Chemicals   Based  on Carc1nogen1c1ty.    Prepared  by  the
    Carcinogen Assessment Group,  OHEA, Washington,  DC  for  the  Office of
    Emergency and Remedial Response, Washington, DC.

    U.S.  EPA.   1985.  Drinking  Water Criteria  Document  for  Asbestos.
    Prepared  by  the  Environmental  Criteria   and   Assessment  Office,
  - Cincinnati, OH,  OHEA  for  the  Office of Drinking Water,  Washington,
    DC.  Final draft.


    The intent in these assessments is to  suggest acceptable  exposure  levels
whenever  sufficient  data  were available.   Values were  not derived or  larger
uncertainty factors  were employed  when  the  variable  data  were  limited  in
scope tending  to generate conservative (i.e., protective)  estimates.  Never-
theless,  the Interim  values  presented  reflect  the relative degree of  hazard
associated with exposure  or  risk to the chemical(s)  addressed.
                                      Hi

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    Whenever possible, two categories  of  values  have been estimated for sys-
temic toxicants  (toxicants for which  cancer  is  not  the endpoint of concern).
The  first,  the  AIS  or acceptable  intake subchronic,  is  an estimate  of  an
exposure  level   that  would  not  be expected  to  cause adverse  effects  when
exposure  occurs  during a  limited  time interval   (i.e.,  for  an  interval that
does  not  constitute a  significant portion of  the   lifespan).   This  type  of
exposure  estimate  has not been  extensively  used or  rigorously  defined,  as
previous  risk  assessment  efforts  have  been  primarily  directed  towards
exposures from  toxicants  1n  ambient air  or water where lifetime exposure  1s
assumed.   Animal data  used   for  AIS  estimates  generally  include  exposures
with  durations  of  30-90 days.   Subchronic  human data  are  rarely available.
Reported  exposures are  usually  from chronic  occupational exposure situations
or from reports of acute accidental exposure.

    The AIC,  acceptable  intake  chronic,  Is  similar  in  concept to  the  ADI
(acceptable  dally  intake).   It   is  an  estimate of  an exposure  level  that
would not be expected  to  cause adverse  effects when  exposure  occurs  for  a
significant portion  of  the  lifespan  [see U.S.   EPA  (1980a)  for  a discussion
of  this  concept].   The  AIC  is  route  specific  and estimates  acceptable
exposure  for  a  given  route   with  the  Implicit  assumption that  exposure  by
other routes is Insignificant.

    Composite  scores  (CSs)   for  noncarclnogens  have  also   been  calculated
where data  permitted.   These values are  used for ranking reportable quanti-
ties; the methodology for their development is explained in U.S. EPA (1983d).

    For  compounds for which  there  is  sufficient  evidence of cardnogenicHy,
AIS  and  AIC values  are not  derived.   For a  discussion of  risk assessment
methodology for  carcinogens  refer  to U.S. EPA  (1980a).   Since  cancer  is  a
process  that  is  not characterized  by  a  threshold,   any exposure contributes
an increment of  risk.   Consequently,  derivation of  AIS and  AIC values  would
be inappropriate.   For  carcinogens,  q-|*s have  been  computed based  on  oral
and Inhalation data 1f available.
                                      1v

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                                   ABSTRACT
    In  order  to  place  the  risk assessment  evaluation  In  proper  context,
refer  to  the preface  of   this  document.   The  preface outlines  limitations
applicable to all documents of this  series as well  as  the appropriate Inter-
pretation and use of the quantitative estimates  presented.

    Human data  clearly  Indicate  that asbestos exposure from  Inhalation  con-
tributes to excess  risk for  GI and  lung cancer,  and  peritoneal  mesothelioma
data  1n animals  are corroborative.  Evidence  for  the  cardnogenidty  of
asbestos  following   oral   exposure   is  equivocal.   Since  the  carcinogenic
potency of  asbestos appears  to  be  dependent  upon  fiber  size  and  shape,  a
carcinogenic potency estimate for "generic" asbestos is not proposed at  this
time.

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                               ACKNOWLEDGEMENTS


    The  Initial  draft  of  this  report  was  prepared  by  Syracuse  Research
Corporation under  Contract No.  68-03-3112  for EPA's  Environmental  Criteria
and  Assessment  Office,  Cincinnati,  OH.   Dr.  Christopher  DeRosa and  Karen
Blackburn were the Technical Project Monitors  and  Helen Ball  was the Project
Officer.  The final documents  In  this  series  were  prepared for the Office of
Emergency and Remedial Response, Washington, DC.

    Scientists from  the  following U.S. EPA offices  provided  review "comments
for this document series:

         Environmental Criteria and Assessment Office, Cincinnati, OH
         Carcinogen Assessment Group
         Office of Air Quality Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

Editorial review for the document series was provided by:

    Judith 01 sen and Erma Durden
    Environmental Criteria and Assessment Office
    Cincinnati, OH

Technical support services for the document series  was provided by:

    Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
    Environmental Criteria and Assessment Office
    Cincinnati, OH
                                      v1

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                              TABLE OF CONTENTS
1.
2.


3.








4.








5.
6.





7.
ENVIRONMENTAL CHEMISTRY AND FATE 	
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL . . '. 	
2.2. INHALATION 	
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	
3.1. SUBCHRONIC 	
3.1.1. Oral 	
3.1.2. Inhalation. . . .• 	
3.2. CHRONIC 	
3.2.1. Oral 	
3.2.2. Inhalation 	
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.4. TOXICANT INTERACTIONS 	
CARCINOGENICITY 	
4.1. HUMAN DATA 	
4.1.1. Oral 	
4.1.2. Inhalation 	
4.2. BIOASSAYS 	
4.2.1. Oral 	
4.2.2. Inhalation 	
4.3. OTHER RELEVANT DATA 	
4.4. WEIGHT OF EVIDENCE 	
REGULATORY STANDARDS AND CRITERIA 	
RISK ASSESSMENT 	
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 	
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 	
6.3. CARCINOGENIC POTENCY (q-j*) 	
6.3.1. Oral 	
6.3.2. Inhalation 	
REFERENCES 	
Page
1
4
. . 4
9
13
, . 13
. . . 13
13
15
. . . 15
15
. . . 18
18
, . . 21
, , . 21
. . . 22
, , . 24
29
. . . 29
33
. . . 38
39
. . , 42
, . . 43
. . . 43
. . . 43
43
. . . 43
, , , 44
. . . 45
APPENDIX: Summary Table for Asbestos .................    59

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LIST OF TABLES
No.
1-1
2-1
2-2
4-1
4-2
4-3
4-4
4-5
Title
Selected Physical and Chemical Properties of Asbestos ....
Asbestos Levels In Rats Fed 1% Asbestos for 6 Weeks 	
Distribution of Fiber at the Termination of Exposure 	
Recent Studies of Cancers Related to Asbestos in
Drinking Water 	
Ep1dem1olog1cal Studies: Human Cancers Associated with
Inhalation of Asbestos 	
Deaths Among 17,800 Asbestos Insulation Workers in the
United States and Canada 	
Summary of Experiments on the Effects of Oral
Administration of Asbestos 	
Carc1nogen1c1ty of Asbestos 1n Animals Exposed by
Inhalation 	
Paqe
2
8
11
23
25
27
30
34

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                             LIST  OF ABBREVIATIONS
ADI                     Acceptable dally Intake
AIC                     Acceptable Intake chronic
AIS                  .   Acceptable Intake subchronic
BaP                     Benzo(a)pyrene
bw                      Body weight
CHO                     Chinese hamster ovary
CS                      Composite score
GI                      Gastrointestinal
TEH                     Transmission electron microscope
TLV                     Threshold limit value
TWA                     Time-weighted  average
UICC                    International  Union Against Cancer
                                      1x

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                     1.   ENVIRONMENTAL  CHEMISTRY AND FATE

    Asbestos  Is  a  generic  term  applied  to  a  variety of  naturally formed
hydrated  silicates   containing  metal  cations  such  as  sodium,  magnesium,
calcium or Iron.  The two major groups of asbestos are  serpentine and amphl-
bole.  Chrysotile 1s  the only form of asbestos  that  belongs to the serpen-
tine group.  The  amphlbole  group  exists  In  five different classes:  actlno-
Ute, amosHe,  anthophylllte, croddollte  and  tremolHe.   Only chrysotHe,
amoslte, croddolHe  and anthophyllHe are  of  commercial Importance (IARC,
1973),   and  the  first   three  varieties   constituted  a  total  of   99.9%  of
asbestos, production  1n   1976  (Strelb,  1978).   A  few  selected  physical and
chemical  properties  of  chrysotlle,  amoslte and  croddolHe  asbestos are
shown In Table 1-1.
    Of   the  243,527  metric  tons  of asbestos  discharged  to the environment,
-1.5%  Is  discharged  1n  the  air  (U.S. EPA,  1980b).   Based  on  Its lack  of
reactivity  1n  aquatic media  (Callahan et al.,  1979),  It  1s  not Hkely  that
asbestos will  undergo any photochemical reaction or other  chemical  reactions
1n  air.   Both ralnouts  and dry  deposition  may  be primarily  responsible for
the  removal  of asbestos  from air.  The  lifetime  of  partlculate matter for
the physical removal mechanism 1s  dependent  on  the  particle  size.   The  exact
particle  size distribution of  atmospheric   asbestos  1s unknown,  but  It  1s
known  that  only  a  small  fraction  of   atmospheric  asbestos  has  particle
lengths of  >5 Mm  (U.S.  EPA,  1980b).   Based on  the half-life of other  atmo-
spheric metals  (although the particle shape may  be  different  from that  of
asbestos),  1t  1s  speculated that  the  half-life  of  submlcron  asbestos parti-
cles may  be several days.  The  aquatic  fate of asbestos  has been  discussed
by  Callahan  et  al.  (1979).    It  appears  from  this   report  that  asbestos
                                      -1-

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                                                     TABLE  1-1

                               Selected Physical and Chemical Properties of Asbestos3
ISJ
I
Property
CAS No.
Idealized formula
Specific gravity
Approximate dlam-

Chrysotlle
12001-29-5
M
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remains chemically  Inert  1n the aquatic  environment.   The only  significant
mechanism of  asbestos  transfer  from aquatic  phase  to  sediment  Is  through
coagulation  of asbestos or  other processes  of precipitation such as  adsorp-
tion  through  clay  and  subsequent  precipitation.   Although  the  estimated
half-life of asbestos  In  the  aquatic system 1s not known,  It  1s  expected  to
be quite long.
    Limited  Information regarding  the fate  of asbestos 1n  soil 1s  available
1n  the  literature.   Based  on Us  predicted  Inability  to  undergo  chemical
reactions,   degradation and  volatilization   from  water  (Callahan  et  al.,
1979),  none of  these  reactions  are expected  to  be   significant  1n  soil.
Based on Us solubility 1n  acidic  and basic media, leaching of asbestos  from
soils Is possible; however, the leaching process may destroy the  crystalline
structure of asbestos by  solubH1z1ng the  element  1n  the asbestos  structure.
                                     -3-

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           2.   ABSORPTION  FACTORS  IN HUMANS AND EXPERIMENTAL ANIMALS
2.1.   ORAL
    The weight of evidence suggests that  the  toxldty  and  cardnogenlcHy  of
asbestos  are  associated  with  the nature  of  the  asbestos  fibers and  their
actions upon  the  cells  with  which they come  in  contact  or  penetrate.   Since
asbestos  fibers are  neither  water nor I1p1d  soluble,  1t  seems  unlikely that
absorption  of asbestos  fibers  takes  place  either by  passive  diffusion  or
active  transport,  but  more  likely as  a result  of  the fibers  mechanically
penetrating a  tissue  barrier,  such as the epithelial  lining  of  the  GI  tract
(persorption).  Phagocytosis of asbestos  fibers  by macrophages,  monocytes  or
other  phagocytic  cells  Is probably  involved  in  absorption,  or  uptake,  and
subsequent  distribution  of  asbestos  fibers to  other  tissues.  Including  the
lymphatic  system  or  the  bloodstream, resulting  In  widespread body  distri-
bution.
    The evidence  for  GI uptake of  asbestos  fibers In humans 1s  highly sug-
gestive,  but  not  absolutely conclusive.   Fibers of  amphibole  asbestos (not
otherwise  specified)  were discovered in  Duluth, MN, drinking  water  (Carter
and Taylor, 1980).   The presence  of amphibole fibers, which  resembled  those
found  1n  the  drinking  water,  were  demonstrated  in  the liver,  jejunum  and
lung  specimens  from  deceased  Duluth  residents.   Among  96 tissue  specimens
from  32  deceased  Duluth residents, amphibole  fibers  were found  In  60, with
concentrations ranging  from 3-16xlOs  fibers  of  all  sizes/g  of tissue.   A
control cohort consisted  of  61 tissue  specimens from 21 deceased  residents
of Houston, TX,  and St.  Paul, MN.  Amphibole fibers were found  1n  only  two
tissue specimens  in the control cohort.   Since air sampling gave  no  evidence
of amphibole  air  concentrations  In Duluth,  these  authors concluded  that  the
                                      -4-

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presence of  amphlbole  fibers 1n these  tissues  Indicated  transmucosal  uptake
of  fibers  resulting  from 1ngest1on of  amph1bole-contam1nated  drinking water
1n Duluth, MN.
    Cook  and  Olson  (1979)  examined  the  urine  sediment  from  humans  who
Ingested drinking  water  1n  Ouluth, MN, contaminated  with  amphlbole asbestos
fibers.  Measured  concentrations of amphlbole  fibers  eliminated  In  the urine
averaged ~lxlO~3  times  the  concentration of  amphlbole fibers 1n the  drink-
Ing  water.   The  authors noted that  applying  adequate  filtration   to  the
drinking  water  removed   the  amphlbole  fibers  and  resulted  1n  a  gradual
disappearance of amphlbole fibers  from  the  urine.   They concluded  that these
observations  provided  direct  evidence  of  the  passage  of asbestos  fibers
through  normal  human GI  mucosa.  Furthermore,  they  emphasized that, since
some body  retention  of asbestos  fibers undoubtedly  occurs,  urinary  concen-
trations of asbestos  are an  underestimation of the actual uptake of  asbestos.
    Boatman et al. (1983) discovered  that drinking water  1n  the  Puget Sound
area had unusually high levels  of  asbestos, with tap  water from the homes of
seven  Individuals containing  230-383x10°  chrysotHe  fibers/a.   A  control
group consisted  of four  residents from the Seattle/Bellevue area  whose  tap
water  contained   1.2-3.1xl06  chrysotHe  f1bers/s..   The  content  of  chryso-
tlle fibers  In  the  urine of  long-term (>24  years)  residents  of  the Puget
Sound area was significantly (p=0.05)  higher  than  the  content  of  chrysotlle
fibers   1n  the urine  of short-term (1.5-2.8 years) residents.  There  was no
significant  difference,  however,  1n  the urinary  content  of chrysotlle  for
Puget  Sound  compared  to  that  from the  Seattle/Bellevue  residents.   These
authors, however,  reported  some difficulties  with  their  Nucleopore membrane
filters, which may have  resulted  1n  the  lack  of  statistically  significant
data generated 1n this  study.
                                      -5-

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    In animals,  a  substantial body  of  evidence also  exists  that  1s  highly
suggestive of  GI uptake  of asbestos  fibers,  but  some Investigators  doubt
that  this  phenomenon occurs.   An early  Investigation  Indicated that  fiber
uptake across  the  GI lining  did not occur  (Gross et  al.,  1974),  but  this
conclusion has  been  challenged by Cooper  and  Cooper  (1978), who  questioned
the sensitivity of  the analytical procedure used.
    Following  1ngest1on  of chrysotHe  or amoslte  asbestos  by  rats,  fibers
have been found  1n the colonlc mucosa  (Westlake  et al., 1965)  or penetrating
the  epithelial  cells of  the  jejuna!  mucosa  (Storeygard  and  Brown,  1977).
Kidney cortical  tissue  of  a  neonatal  baboon  fed  chrysotlle  for 9  days  was
found  to  contain   a  significant  (p=0.005)  excess   of  chrysotlle  fibers
compared  to  the kidney  cortical tissue  from an  untreated neonatal  baboon
(Patel-MandHk and  Hallenbeck, 1978).
    Patel-Mandlik and Millette  (1983a,b)  treated  20 Sprague-Oawley rats with
50  mg  chrysotile asbestos/kg by  gavage  2 times/week until natural  death or
sacrifice.   A  control group  of  rats was  maintained.   The test group  of 20
rats was  further divided  into four  groups of  five rats,  depending on age at
death  or  sacrifice.   The  four  groups  consisted  of rats  from  <200, 200-400,
400-600  or  >600  days   of  age   when  examined.    There  was  a  significant
(p<0.005)  difference in  the  kidney cortical  content  of  chrysotile between
the  different  treatment groups  of rats,  but  the  difference did not correlate
with   duration   of   treatment.   There  was  also  a  significant  difference
(p<0.005)  between  the  kidney  cortical  content  of chrysotlle  In  treatment
rats   (1.15  fibers/TEM  grid)  compared  with  control  rats  (0.05  fibers/TEM
grid).
                                      -6-

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    Following  pretreatment,  dietary  regimens  of  0  or  50  mg/day  of  UICC
chrysotlle A  for  30  days,  male MRC-hooded rats were  given single  oral  doses
of  50,  30  or 1  mg  or  10  or 0.1  pg of  UICC chrysotlle  A  or  "prepared"
chrysotHe  (>90%  of  fibers  <5  ym  1n   length)  (Welnzwelgh  and  Richards,
1983).  Control  rats  were  maintained.  The  portal  hepatic  vein was  Ugated
and blood samples were drawn for  analysis  of  chrysotlle at  2,  7  and 12 hours
after the single oral dose of  asbestos.   The  occurrence of  chrysotlle fibers
In  the  blood from control  rats  complicated  Interpretation  of  the  results.
Peak  levels  of  chrysotlle  1n  the blood  seemed to  occur  ~7  hours  after  the
single  oral  dose was  administered.   In  6 of  the  15  trials,  the  level  of
chrysotHe In the  blood  of  treated rats  was  significantly greater  than that
of  controls.   Fibrils detected  1n blood  were of  small  size  (97% <1  urn).
These authors suggested  that migration of  larger asbestos particles probably
does not occur as a result  of uptake Into  the portal  circulation.
    Cunningham et  al.  (1977)  fed  diets   containing  1% chrysotlle  asbestos
(22%  0.3-1.0  wm;  59%,  1.1-3.0  vm; 9%,   3.1-5.0  vm;   10%,   5.1-10  vm;
10%,  10.1-50.0 pm)  to 20 male Wlstar  rats  for  6  weeks.  To reduce  dust  and
the likelihood of  Inhalation of  asbestos, corn oil  or  molasses  was added to
the diet.   Control  rats  were  maintained.   The  rats were killed and tissues
were  examined;  the results are  summarized In  Table  2-1.   In treated  rats,
the  greatest tissue  content  of   chrysotlle  was  observed  1n  the  omentum,
followed by  the  brain and  lungs.   The fact  that growth depression occurred
In  all  treated  groups   Implied  that   1%  chrysotlle  1n the  diet   "had  some
biological  effect."  Food Intake figures were not  reported.
                                     -7-

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                                  TABLE 2-1
             Asbestos Levels  In Rats Fed 1% Asbestos for 6 Weeks
                               (fibers x 106/g)a
Tissue
Blood
Omen turn
Lung
Kidney
Liver
Brain
Controls
0
1
0
0
0
.00
.08
.29
.17
.13
0.22

+
+
+
+
+

0.
0.
0.
0.
0.

58
08
03
06
11
Asbestos
0
9
1
0
0
1
.57 ±
.66 ±
.02 ±
.36 +
.62 +
.25 ±
Treated
0
3
0
0
0
0
.43
.18b
.20C
.03C
.30
.34b
aSource: Cunningham et a!., 1977
bp<0.02  using  a   t-test  with  each  figure  representing   the  average  with
 standard error for 10 rats.
cp<0.01
                                      -8-

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    Meek  (1983),  however,  reported  that  no evidence  for  Intestinal mucosal
uptake  could  be  found  1n  rats   treated  with  amoslte.   This  Investigator
Injected  a 0.1 ma,  suspension  of  amoslte  In  physiological   saline  Into the
wall  of  the Intact GI  tract of male Wlstar rats  to  characterize  the granu-
lomatous  changes  expected  as  a result of  amoslte uptake.   Dense accumula-
tions of  macrophages  were observed In  the  Injection  site  as a result of the
Injected  amoslte.   Subsequently,  other  rats were  treated  by gavage  with 100
mg  UICC   amoslte  for  5 days  and   then  killed;  their   Intestinal  tracts  were
microscopically  examined   for   the  macrophaglc  Invasion   that  was  found  to
characterize the  response to amoslte.  A  lack of  evidence  of a macrophaglc
response  or other  pathological changes  In the  small Intestine  of treated
rats  was   Interpreted  to   mean  that  the  "gut  wall  of rats may  present  an
effective  barrier  to  the  penetration of asbestos	" Meek (1983)  acknowl-
edged  the  limitations  of  this  study  and  suggested  that   further  studies
should Involve electron microscopy of the mucosal cells.
    According  to  Bolton et  al. (1982), electron  microscopic  examination  of
the Intestinal mucosa of male  HAN  spf Wlstar  rats exposed to asbestos failed
to  reveal any  evidence of penetration  or  damage to  gut  tissues.  Exposure
was to UICC amoslte,  UICC  croddollte  or  UICC chrysotHe A,  at  levels  of 5
mg/g of margarine which was  fed ad libitum for at least 25 months.  Consump-
tion of asbestos  was  -250  mg/week.   The  result  of the electron microscopic
examination of  tissue  residues Indicated  no  widespread   penetration  and/or
dissemination of asbestos  fibers In treated rats.
2.2.   INHALATION
    Comparatively  few data  have been located  on the  absorption of  asbestos
following   Inhalation  exposure.   Whether   Inspired  asbestos  fibers  will  be
deposited  1n the lung depends strongly  upon their  diameter.   Timbrel!  (1965)
                                      -9-

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has shown  that  a  fiber, Independent  of  Us  length, behaves  aerodynamlcally
like a  particle  having a diameter 3  times as  great as Us actual  diameter.
Brain and Valberg (1974) Indicated that 50% of  particles  with a  median  diam-
eter of  <0.1  ym  will  be  deposited  on  nonclllated  pulmonary surfaces,  as
determined by a model  for  aerosol  deposition  based on  the  aerodynamic  char-
acteristics of  particles.   About 25% of  particles with  a  diameter of  1  v»m
and 0%  of  particles  with a  diameter  of  10 pm  would  be  expected  to  deposit
on  nondllated  respiratory  epithelium.   Once   Inhaled, a large fraction  of
the Inhaled  fibers  Is rapidly cleared by  mucodllary action, although  some
fibers  will remain 1n  the  lung and can be  found there decades after exposure
(Pooley,  1973;  Langer,  1974).    Particularly   large  fibers  trapped  in  the
lungs may become coated or  calcified  and  form  asbestos bodies.
    The  clearance  of asbestos from  the  respiratory  tract  of rats has  been
studied  directly  In  a series of  experiments  (Morgan  et  al.,  1975;  Evans  et
al., 1973).  Rats were exposed for 30 minutes  to different  varieties  of UICC
standard  asbestos samples,  made  radioactive  by  neutron  bombardment,  and
deposition  and   clearance   from  the  respiratory   tract   was   determined.
Subsequently,  distribution  among various  tissues  of  the body was  measured.
The results  are presented  In Table  2-2.   These data  Indicate the magnitude
of mucodllary clearance of asbestos  fibers from the lungs.
    A difference  In  the  pulmonary retention  of  various forms of asbestos  In
Wlstar   rats  exposed  to 10.1-10.6 mg/m3  for  7   hours/day, 5  days/week  for  24
months  was  reported  by Wagner  et al.  (1974).   These  authors  determined that
the amphlboles  studied  (amoslte,  anthrophyllHe and crocldolHe) accumulated
1n  the  lungs  ~7  times  as  heavily as  the  two  chrysotlles  (a  Canadian  and a
Rhodeslan sample).
                                     -10-

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                                   TABLE 2-2

             Distribution of Fiber at the Termination of Exposure
                           ('/. of Total  Deposited)*'5
Fiber
Chrysotile A
Chrysotile B
Amos He
CrocidolHe
AnthophyllHe
Fluoramphibole
Nasal
Passages
9
8
6
8
7
3
± 3
± 2
i 1
± 3
i 2
i 2
Esophagus GI Tract
2 i 1 51
2 + 1 54
2 ± 1 57
2 + 1 51
2 ± 1 61
1 i 1 67
± 9
± 5
± *
± 9
± 8
± 5
Lower
Respiratory
Tract
38
36
35
39
30
29
± 8
± 4
± 5
± 5
± 8
± *
aSource: Morgan et al., 1975

bMean and SO
                                     -11-

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    More  recently,  Barry  et  al.  (1983)   found  chrysotile  fibers  1n  the
alveolar  macrophages,  epithelium  and  Interstitial  perlalveolar  tissue  of
rats  exposed  to  9.06 mg  chrysotlle/m3  for  7  hours.   After  3  month?  of
exposure for 7  hours/day,  5  days/week,  numerous  fibers and cellular  changes
were observed 1n the alveolar epithelium and 1nterst1t1um.
    Phagocytosis by  macrophages was  considered  to  be the major  method  by
which chrysotHe fibers  Inhaled  by  guinea  pigs moved  through  the  parenchyma
of  the  lungs  to the pleura.   Macrophages that disintegrated  before  complet-
ing  the journey discharged  their contents  In the  lymphatic system  (Holt,
1983).
    In  an In  vitro study  of  the  toxldty of  several Inhaled  pollutants,
three forms of  UICC standard reference samples of asbestos fibers  (amosHe,
crocldollte and  Canadian chrysotile  B) were  seen  by  electron microscopy  to
be  Ingested by human bronchial epithelial  cells (Haugen et  al., 1982).
                                     -12-

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               3.  TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.    Pertinent  data   regarding   toxldty   associated   with   sub-
chronic oral  exposure to  asbestos  In  humans  could  not  be  located  1n  the
available literature.
    Jacobs et al.  (1978)  fed rats diets  containing 0.5  or  50 mg  of  chryso-
tlle  dally  for   14 months,  and subsequently  examined the  GI  tract by  both
light  and electron microscopy.   No  effects  were  noted  1n  the  esophagus,
stomach or  cecum,  but  "structural  changes  In  the  v1H1  of  the  Heum  were
quite evident at  both  dosage levels."
3.1.2.   Inhalation.   Only  one study  of  subchronlc  Inhalation  exposure  of
humans to asbestos was  located  1n the available literature.  Harless et  al.
(1978)  discovered  airflow  abnormalities  (not  further specified)  in  17/23
Individuals   examined   1.5  and  8.0   months   following an   Intense  5-month
exposure to asbestos.   Of the 17  affected Individuals, 12 were nonsmokers or
current  light   or  ex-light  smokers   (<10  pack-years).   The   obstructive
abnormalities were usually  observed  during  measurements  of  1-m1nute forced
expiratory volume and  of  closing  volume.
    Male  and  female  rats exposed  to  9.06 mg  chrysotlle/m3,  7 hours/day,  5
days/week for 3  months  showed  the presence  of chrysotlle fibers  and  consid-
erable  cellular  change  1n  the  alveolar  epithelial  and  Interstitial  cells
(Barry et al.,  1983).   Most noteworthy was a  57%  Increase  1n the  number  of
type  II   epithelial  cells  and a 90%  Increase In   their  average cellular
volume.   A  58%  Increase  1n  the  number  of  Interstitial  cells  and  a  40%
Increase  1n  their  average cellular  volume were also  observed.   Infiltration
                                     -13-

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with macrophages accounted  for  nearly all the Increase  in  Interstitial  cell
numbers.  Of cells that were observed  to  contain  chrysotHe fibers,  88% were
macrophages.  Eventually,  calcification  of these fibers  occurred  and cellu-
lar inclusions were thus formed.
    Wagner  (1963)  exposed  guinea pigs and  vervet monkeys  to  chrysotlle and
amoslte  dust  at  concentrations of  37,600 or  30,000 part1cles/m3,  respec-
tively,  for  8   hours/day,  5  days/week  for   49  weeks.    The  technique  of
asbestos  analysis  had the  limitation  of not  being able to  Identify "long"
asbestos  fibers.  Guinea   pigs  exposed  to  chrysotlle   developed  pulmonary
fibrosls, Interstitial pneumonitls, cuboldal  metaplasia  of  the epithelium of
the  alveolar  ducts  and cor  pulmonale.    Similar  lesions  but  a  more  rapid
onset were  noted In guinea  pigs  exposed  to amoslte  dust.  Deaths occurred in
monkeys exposed  to chrysotlle after 7, 10 and 22  months  of exposure.  Deaths
of  the  first  two  were  due to  gastroenteritis.   Deaths  occurred  in monkeys
exposed  to  amoslte  after   4,  12 and  14  months  of  exposure.   Pathological
changes  In  both  chrysotlle- and  amosite-exposed monkeys  included lung fibro-
sis  and  cor  pulmonale.  hlstologically  consistent   with  slight  to  moderate
human asbestosis.
    Subsequently, Wagner et al.  (1974) exposed groups of -20-25  Wistar  rats
to  amoslte, anthophyllite, crocidolite  and  chrysotile  to  establish a  dose
relationship  between  different  asbestos  dusts  and  pulmonary  malignancies.
Exposure  was  for 7 hours/day,  5 days/week for 3, 6, 12  or 24  months to air
containing  10-11  mg/m3.    Overall,  the  severity  of asbestosis  (fibrosis,
Increased numbers  of  type  II  pneumocytes)  correlated with  Increased length
of exposure.
                                     -14-

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3.2.   CHRONIC
    Most  studies  of the  chronic  exposure of  animals to asbestos  by either
the oral  or  Inhalation  route  have  been  for  the purpose of studying the abil-
ity of asbestos fibers  to  Initiate a  carcinogenic  response.   Therefore, most
long-term studies of exposure to asbestos will be discussed In Chapter 4.
3.2.1.   Oral.   Bolton  et  al.  (1982)  fed  margarine containing  5  mg  UICC
amoslte,  UICC  croddollte  or UICC  chrysotHe  A/g  of  margarine  to  groups  of
23  HAN spf  Wlstar  rats.   Negative  control  and  vehicle  control  rats  (fed
margarine without  asbestos)  were  maintained.  Margarine  containing asbestos
was  fed  ad^  libitum,  and  asbestos  Intake averaged  -250 mg/rat/week.   Rats
were  treated  for  25 months,  and the  majority  were  kept  for  the remainder  of
their lifespan.
    The animals tolerated  the experimental diets well.  Rats  given  access  to
margarine with or  without asbestos  consumed  -30% less  standard  laboratory
food and  weighed  consistently 25% more than rats  not given  access  to marga-
rine.  The resultant obesity  had no obvious  effect  on morbidity or  mortality
of the treated animals,  with the  majority surviving  beyond  700 days  of age.
Light  and electron  microscopic  examination of  many   tissues was  performed.
No penetration  or  damage  to  any  of the gut tissues  was  observed.   Although
occasional asbestos fibers were found in  several tissue  residues,  no  lesions
or  effects  of  treatment   were  seen.    Bolton  et al.  (1982)  concluded  that
there were no  significant  adverse  effects of  prolonged asbestos 1ngest1on  1n
healthy laboratory rats.
3.2.2.   Inhalation.   In  humans,  a   chronic,  progressive  pneumoconlosls
(asbestosls)   results  from long-term  Inhalation  of asbestos  fibers.    It  1s
characterized  by  Hbrosls  of  the lung  parenchyma,   which  usually  becomes
radlographlcally   discernible  10   years   after    the   first   exposure.
                                     -15-

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Radlographlc lesions are  usually  small,  Irregular opacities, usually  1n  the
lower and  middle  lung  fields.  Pleural  flbrosis  and thickening,  often  with
focal  areas of  calcification,  are  also  found.    Changes  can  occur  more
rapidly  1f exposure  1s  more  severe.   Shortness  of breath  Is the  primary
symptom,  cough  Is  somewhat  less  common,  and  signs such  as   rales,  finger
clubbing and weight  loss  occur  1n more  advanced  stages  of  the  disease.   The
disease was  first  reported by Murray  (1907),  and has since been  recognized
frequently among occupatlonally-exposed workers.
    It  has been estimated  that   50-80%  of workers  exposed  to asbestos  >20
years have  radlographlc evidence  of asbestosls (Sellkoff et al.  1965;  Mount
S1na1,  1976;  Lewlnsohn,   1972).    In  many  cases,  the  disease  progresses
following  cessation  of  exposure.   In  a  group   of  workers employed  1n  an
asbestos factory for  varying lengths  of time  between 1941 and 1954,  radio-
graphic  changes  were  observed years  after  exposures   as  short  as  1  week
(Sellkoff, n.d.).
    Restrictive pulmonary  dysfunction 1s  also seen  with asbestos  exposure
and may  be accompanied by dlffusional  defects or airway  obstruction  (Bader
et al.,  1961).   In the early  stages  of  asbestosis  there  is little  correla-
tion  between  pulmonary  function  tests  and  radlographlc  changes;  as  the
disease progresses,  the  degree of  correlation between  radlographlc  changes
and pulmonary dysfunction  Increases markedly (Bader et al.,  1961).
    Families of asbestos-exposed  workers can also be affected.   Anderson et
al.  (1976) demonstrated that 36%  of  626 family contacts of  workers  employed
sometime  between   1941  and  1954  at  an  asbestos   insulation  manufacturing
facility had radlographlc  evidence of exposure  to  asbestos.
                                     -16-

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    In  addition   to  disease  and  disablement  during  life,  asbestosls   has
accounted for  a   large  proportion  of  deaths  among  exposed  workers.  Early
Investigators (Aurlbault, 1906; Murray, 1907) attributed the death  of  entire
working  groups   to   severe  asbestosls.   Since  then,  Improvement  1n  dust
control has  markedly  reduced  the  Incidence of  mortality due to  asbestosls,
but workers  1n extremely dusty conditions, as 1n textile mills,  stand  a  >40%
probability of death because of asbestosls (Nicholson, 1976).  From 5-20% of
deaths may  be  attributed to asbestosls  In  groups  of workers 1n  occupations
where dust  1s controlled more  satisfactorily (Mount  Sinai,  1976;  Sellkoff et
al., 1979).
    The  BOHS (1968) estimated  that exposure  to  airborne  asbestos for  <50
years  at  an air  level  of  2  fibers (>5  vm In length)/cm3  would  result  In
asbestosls  In 5  vm  1n  length)/cm3 1n  air experienced  an
Increase  1n deaths  due to  respiratory  malignancies  (10  observed vs.  2.7
expected,  p<0.005)   and  respiratory  nonmallgnandes  (8  observed  vs.   3.2
expected, p<0.05).  Simultaneous exposure  to free  silica  dust also occurred,
but  reportedly  at  levels  below  OSHA   (Code  of  Federal   Regulations,  1981)
standards,  and these  Investigators (GUlam et  al.,  1976)  concluded that the
nonmallgnant respiratory  disease  was  caused primarily by  asbestos, possibly
assisted by  low levels of silica dust.
    The effects of  chronic exposure  of rats  to  asbestos  fibers  by Inhalation
was  Investigated  by  Reeves  et  al.  (1974), who  exposed  207 rats  to 47.9-50.2
mg  chrysotHe,  amoslte  or  croc1dol1te/m3 for  4  hours/day,  4 days/week for
                                     -17-

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2  years.    Only  0.08-1.82%  of  the  dusts  retained  fibrous  morphology  as
assessed by  light  microscopy following completion of  preparation  procedures
for dust generation.   A  marked  h1st1ocyt1c  and giant cell  response  occurred
1n  rats as  a response to  any of  the  forms  of asbestos;  pulmonary  flbrosls
and hyperplasla  were most severe  In  the croddollte-exposed  group  followed
by  the  amosHe-exposed group which was  greater than  the  chrysotile-exposed
group.   These  Investigators  also  reported   pulmonary  flbrosls   1n  mice,
gerblls, rabbits and guinea  pigs  exposed  to  asbestos by  the  same protocol.
Rats  exposed to  any  of  these  asbestos dusts  developed  lung  cancers  and
mesotheHomas.
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE  EFFECTS
    Pertinent data  regarding the  teratogenldty, fetotoxldty or  effects  on
reproduction  In humans or  animals  associated  with either  oral or  Inhalation
exposure  to  asbestos  could  not  be  located  In the  available  literature,
although  transplacental  transfer  of  asbestos  following  oral  exposure  has
been  demonstrated   (Pontefract   and  Cunningham,   1973;  Cunningham   and
Pontefract,  1974).
3.4.   TOXICANT INTERACTIONS
    Asbestos exposure and  cigarette smoking have been  shown to act synergls-
tlcally to produce dramatic  Increases 1n  lung  cancer  over  that from exposure
to  either agent alone.   In a prospective study  of 17,800  Insulation workers
exposed to asbestos, smoking histories were taken, and  a 10-year  observation
period  was   begun  (Hammond  et   al.,  1979).    Those   Insulation  workers  who
claimed  nonsmoker   status  experienced  higher  mortality  (8)  than  expected
(1.3)   based  on  age-, calendar- and  year-specific  cancer  rate   data  among
smokers  and  nonsmokers compiled  by the American Cancer  Society.   Insulation
workers  who  reported being  smokers  experienced 268  deaths compared  to  4.7
                                     -18-

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expected.  These  Investigators  concluded that exposure  to  asbestos  appeared
to multiply  the  risk  of death by 4-6  times.  The  combination  of  exposure to
asbestos and  the habit of  smoking  Increased  the likelihood of death  due to
lung cancer  by >50  times.   In an earlier study, Sellkoff  et al.  (1968)  sug-
gested that  the  risk of death  from  lung  cancer  1n  cigarette smoking asbestos
workers was 92 times that  of Individuals  exposed to neither pulmonary Insult.
    The  study by  Hammond   et  al.  (1979)  associated  Increased  deaths  from
cancer of  the larynx,  pharynx,  buccal  cavity  and esophagus  among  asbestos
workers  who  smoked  cigarettes.    Among asbestos  workers  1n  this  study,
cancers of the pleura,  peritoneum,  stomach,  colon and  rectum  were unrelated
to  smoking  habits.   Shettlgara  and  Morgan   (1975),  however,   found a  much
stronger association of  laryngeal cancer with asbestos  exposure  rather  than
with cigarette smoking.
    Berry et  al.  (1972) obtained  retrospective  smoking  histories  on a  group
of  asbestos  workers and  evaluated the  causes  of  mortality  over a 10-year
period.  They concluded  that the effects of  cigarette  smoking and  exposure
to  asbestos   were  multiplicative  rather  than   additive  1n   Increasing  the
Incidence of lung cancers.
    Some nonmallgnant  effects  of  asbestos  also appear  to  be  synerglstlcally
enhanced by cigarette smoking.  Among  a  cohort  of  factory  workers  exposed to
asbestos,  Weiss  (1971) found  that  radlographlcally-dlagnosed flbrosls  was
Increased  1n cigarette  smokers  compared  to  nonsmokers.   Hammond et  al.
(1979)  found that  deaths   due to  asbestosls appeared  to  be Increased  In
smokers compared  with nonsmokers.
    Simultaneous  exposure  to  BaP  and asbestos  seems  to  provide  convincing
data  that  these  two  agents  may  act  synerglstlcally  to  produce  malignant
tumors.  Pylev  and Shabad  (1973) reported  that  Intratracheal Injection  of
                                     -19-

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6 mg chrysotHe, upon which 0.144 mg BaP had been adsorbed, and 2 mg chryso-
tlle simultaneously with 5 mg  BaP  resulted  1n  malignancies In 29 and 54% of
the treated  rats,  respectively.   Administration  of  6 mg  chrysotlle  or  5 mg
BaP alone yielded no tumors.
    Miller et  al.  (1965) showed that  Intratracheal  Injection of chrysotlle
with BaP  Increased  the  tumor  yield over that  of  BaP  alone.   In this study,
amoslte appeared to have IHtle effect.
                                     -20-

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                              4.   CARCINOGENICITY
4.1.   HUMAN DATA
    For an  In-depth  review  of the literature the  reader  1s  referred  to U.S.
EPA  (1985).   The modern  history of  asbestos disease  dates from  the  early
1900s  when  two reports documented  uncontrolled  dust conditions  1n asbestos
textile factories.   Murray  (1907) described  severe  pulmonary  flbrosls  found
at  necropsy  In  a  cohort of  deceased workers  who had worked  10-14  years In  a
carding room.   Aurlbault  (1906)  discussed  the  deaths  of  50 men  In  a  short
period  (unspecified)  following the opening  of  an  asbestos  weaving  mill  In
France.
    Two clinical  reports  associated  lung cancer  with  exposure  to asbestos
(Lynch  and  Smith, 1935;  Gloyne, 1935).   Merewether (1947) clearly  related
lung cancer  to  asbestos exposure  when  he  demonstrated  that 13% of a group of
asbestos workers, who  had died  of  asbestosis,  also had  bronchogenlc carci-
nomas.  Mesothelloma,  a rare tumor involving the  pleura  or peritoneum,  was
first  described  in  an asbestos  worker  in  1953  (Weiss,  1953),  was  subse-
quently found  to  be  frequently associated with exposure  to  asbestos  (Wagner
et  al.,  1960), and  later,  was  unequivocally related  to asbestos  exposure
(Newhouse and Thomson,  1965).
    Gastrointestinal   cancer  was  also  found  to   be  related  to  asbestos
exposure among  Insulation workers (Sellkoff  et al.,  1964),  probably  because
a  large  fraction  of  Inhaled  asbestos  is  cleared  from  the respiratory  tract
and subsequently  swallowed  (see  Section 2.2.).   Gastrointestinal cancers  may
also result  from  Ingestion of asbestos  fibers in food  or drinking water.   In
this  document,  the  cardnogenlcity  of asbestos  associated with  inhalation
will  be considered  separately  from  cardnogenlcity  associated  with  oral
exposure,   in spite  of the  fact that  a   substantial  proportion  of  inhaled
asbestos fibers are ultimately swallowed.

                                     -21-

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4.1.1.   Oral.   Historically,  oral  exposure of  humans  to  asbestos  fibers
has  been  through  the drinking  water,  resulting  either  from contact  with
asbestos  deposits  or  transmission   through asbestos  cement  water  mains.
Several  studies  of  carclnogenicity   in  humans  associated  with asbestos  in
drinking water are summarized in Table 4-1.
    Polissar et al.  (1983) reported  a  slightly  elevated Incidence  of pharyn-
geal  and  stomach  cancers  in males  living in  the  Everett,  WA, area,  whose
watershed  is  the  Sultan  River  which  reportedly   contains  unusually  high
asbestos  levels   (~200xl06   fiber/a).   Since   only   males   seemed   to  be
affected, and  since  the  population   studied  was  small,  these  Investigators
concluded that the  higher  than  expected incidence of  stomach  and  pharyngeal
cancer was probably not related  to asbestos intake.
    Harrington et  al.  (1978)  and Meigs  (1983)  investigated the  incidence  of
cancer of the  61  tract and peritoneum related  to asbestos  in  drinking water
1n  several   Connecticut  communities,  resulting  from  the  use  of  asbestos
cement pipe.  No relationship was  established between  asbestos  in  the drink-
ing water and the incidence of GI or  peritoneal  tumors.
    The incidence of  death due  to  cancer of  the digestive tract or lungs,  or
tumors  of  all sites  was  elevated  16-49% in Duluth,   MN residents  compared
with  residents of  other  Minnesota cities.    Duluth drinking water  originates
from  Lake  Superior,  which   is  contaminated  with  fibrous   tailings  from
iron-ore processing  in the area.  More  recently,  Sigurdson  (1983)  observed
significant  increases in deaths  due  to tumors of  the peritoneum (p<0.05),  61
tract  (p<0.01)  or  prostate  (p<0.01)  in  Duluth   residents  compared  with
residents of other Minnesota  cities.
                                     -22-

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                                                                   TABLE 4-1
                                        Recent Studies of Cancers Related to Asbestos  tn Drinking Water
Watershed
Everett,
Washington

Various,
Connecticut
to
i
Eseambla
County,
Florida
Duluth.
Minnesota

Level of Duration of
Exposure Exposure
(fibers/4) (years)
-200x10* 23X; >30

"few hundred <5 to >30
thousand*
0.2-32.7x10* NR
1-65x10* NR

Target
Organ
Gl tract

peritoneum
Gl tract
several
peritoneum
Gl tract
prostate
Tumor Type
pharyngeal cancer
(males)
stomach cancer
(males)
peritoneal
mesothelloma
NR
several
total tumors
total tumors
total tumors
Number
of Tumors
Observed
NR
NR
NR
NR
NR
4.3/100.000
2.8/100,000
90.4/100.000
Number
of Tumors
Expected
NR
NR
NR
NS
NR
1.4/100,000
0.3/100,000
69.3/100,000
Relative
Risk
(positive)
p<0.05
p<0.05
NS
NS
p<0.05
p<0.01
p<0.01
Reference
Pollssar
et al., 1983

Helgs, 1983
Mlllette
et al.. 1983
Slgurdson,
1983

NR - Not reported; NS = not significant

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    Cooper et al. (1978) reported on  the  Incidence  of  death due to cancer In
721  census  tracts of  the  five  Bay Area  counties  In  California  associated
with  the  chrysotile  asbestos   fiber  concentrations   1n   drinking  water.
ChrysotHe  content   ranged  from not  detectable   to   36xl06  fibers/8..   By
grouping  population   tracts according  to  a  gradient   of  asbestos  counts,
statistically  significant   dose-related  trends were  noted  for  white  males
(lung and  stomach cancer)  and  white females  (gall bladder,  esophageal  and
peritoneal cancer).
4.1.2.   Inhalation.   Many ep1dem1olog1cal  studies  have clearly  Implicated
asbestos  as  a cause  of bronchogenlc  cancers and  pleural  mesothellomas  In
exposed  workers   (U.S.  EPA, 1980b).   The  more  significant  ep1dem1olog1cal
studies are summarized 1n Table 4-2.
    Without exception, the  Incidence of deaths due  to  cancer  1s  In excess of
the  expected  cancer-associated  death  rates  for  large  control  populations.
The occurrence of excess deaths  due to cancer ranges  from a low of 1.9 times
the  expected  rate for  lung cancers  and   pleural  mesothellomas  1n  asbestos
factory workers  In  England (Peto et  al.,  1977),  to a  high of  28 times  the
expected  rate for  lung  and  pleural cancers  In  women 1n  asbestos  textile
manufacturing 1n England (p<0.001) (Newhouse et al., 1972).
    6111am et  al. (1976)  reported  significant excess   mortality from malig-
nancies  Involving the  respiratory  tract  1n  mine  workers exposed  to amoslte
at  average  concentrations  of   4.82  fibers/cm3.   The observed  number  of
deaths due to respiratory  malignancies was  10/440,  compared with an expected
Incidence of 2.7 (p<0.01).
    A study of the incidence of  mesothelloma and  non-neoplast1c  lesions in a
region of Turkey  with  very high environmental levels of naturally occurring
asbestos was  performed by  Baris  et  al.  (1979).  The occurrence  of 148 cases
                                     -24-

-------
                                                                               TABLE  4-2


                                             Epldemlologlcal  Studies:  Human  Cancers Associated  with  Inhalation of  Asbestos
in
i
Size of
Exposed
Population
165
557
239
126
440
143
963
632
370
Site of
Control
Population
Northern
Ireland
death rate
death rates
for England
and Wales
South
Dakota
general
population
national
death
rates
national
death
rates
U.S. death
rate data
U.S. death
rate data
Level of
Sex Exposure
N NR
F severe
F severe
F low to
moderate .
N 4.82
fibers/cm*
M 10-15a
fibers/cm'
H/F 2.9-13.3C
fibers /cm1
H NR
N NR
Duration of
Exposure
5-50*- years
<2 years
<2 years
any exposure
time
>60 months
>20 years
>10 years
>20 years
>20 years
Target Organ
lower
respiratory
system
lung and pleura
lung and pleura
lung and pleura
respiratory
system
lung
lung
lung, stomach,
colon, rectum
lung, stomach,
colon, rectum
Tumor
Type
cancer
cancer
cancer
cancer
malignant
cancer
cancer
cancer
cancer
cancer
cancer
Number of
Tumors
Observed
28
6
14
2
10
35b
36*>
42
29
47
14
Number of
Tumors
Expected
1.64
1.0
0.5
0.3
2.7
4.54
19.3
6.02
9.71
6.18
3.92
Relative
Risk
(p value)
NR
p<0.001
p<0.001
p<0.05
p<0.01
p<0.001
p<0.001
NR
NR
NR
NR
Reference
Elmes and
Simpson, 1971
Newhouse
et al., 1972
Gil lam et al..
1976
Peto et al.,
1977
Peto et al.,
1977
Sellkoff
et al., 1964
Sellkoff, 1976
    aWorkers exposed prior to 1933.  Exposure was estimated.


    ''Lung cancers and pleural mesothellomas


    cWorkers exposed after 1933.  Exposure measurements varied over the period measured.  Actual measurements of asbestos dust were reported since 1951.


    NR = Not reported

-------
of malignant  pleura!  mesothelioma (92  In  males,  56 In  females)  was  associ-
ated with the occurrence of asbestos  fibers  1n  the  water,  fields  and  streets
of  this  region.   In  1  year,  11/18  deaths  were  due  to  malignant  pleural
mesothelloma 1n a town of 604 Inhabitants.
    An extensive study by Sellkoff et al.  (1979) demonstrated  the full  spec-
trum  of  disease associated  with asbestos  exposure.   The mortality  experi-
ences  of  a  cohort  of 17,800  United States  and  Canadian asbestos workers,
which  occurred  over  a  10-year  period  (1967-1976), were  compared to  those
expected  based   on  data  compiled by  the   U.S.  National  Center   for  Health
Statistics.  Prior  to 1940,  these workers  were exposed  primarily to  chryso-
tlle, and subsequently,   to a  mixture  of chrysotlle  and  amosHe.   During this
10-year period,  2271  deaths  occurred.   The causes  of these  deaths as deter-
mined  from  death certificates  or  from  "best evidence"  (clinical,  surgical,
necropsy),  and  the expected  Incidences of  deaths  from these cancers,  are
detailed 1n Table 4-3.
    Lung tumors  were  the most  common cause of death and  accounted for -20%
of the deaths.   Pleural  and peritoneal  mesothellomas, ordinarily  rare enough
so that expected deaths  due to  this  cause  have not  been projected, accounted
for  ~8%  of  the  2271  deaths.   Considerable  discrepancy exists   between  the
Incidences  of  mesothellomas  as  determined  by "best evidence" compared with
the  Incidence of mesothellomas reported on death certificates.   Sellkoff  et
al.   (1979) judged  that  diagnosis based on  "best evidence" 1s  more likely to
be accurate, particularly 1n  cases  of  rarely occurring  tumors  such as  meso-
thellomas.  Cancers of the  GI tract also appeared  to be strongly associated
with Industrial  exposure to  asbestos.
    In  addition   to  the  Increase  In  lung  cancers,  mesothellomas  and  GI
cancers,   recent   case reports  have  associated exposure  to  asbestos  with
                                     -26-

-------
                   TABLE  4-3

Deaths Among 17,800 Asbestos Insulation Workers
      1n the United States and Canadaa«b'c
      (January 1,  1967 -  January 1,  1977)
Observed
Underlying Cause of Death

Total deaths, all causes
Total cancer, all sites
Cancer of lung
Pleural mesothelioma
Peritoneal mesothelioma
Mesothelioma
Cancer of esophagus
Cancer of stomach
Cancer of colon-rectum
Cancer of larynx
Cancer of pharynx, buccal
Cancer of kidney
Deaths of less common
malignant neoplasms
Pancreas
Liver, biliary passages
Bladder
Testes
Prostate
Leukemia
Lymphoma
Skin
Brain
All other cancer
Expected

1658.9
319.7
105.6
NAd
NAd
NAd
7.1
14.2
38.1
4.7
10.1
8.1


17.5
7.2
9.1
1.9
20.4
13.1
20.1
6.6
10.4
25.5

BEd
2271
995
468
63
112
0
18
22
59
11
21
19


23
5
9
2
30
15
19
12
14
55

DCe
2271
922
429
25
24
55
18
18
58
9
16
18


49
19
7
1
28
15
16
8
17
92
Ratio
Observed/
Expected

BEd
1.37
3.11
4.60
NR
NR
NR
2.53
1.54
1.55
2.34
2.08
2.36


1.32
0.70
0.99
NR
1.47
1.15
0.95
1.82
1.35
2.16

DCe
1.37
2.88
4.06
NR
NR
NR
2.53
1.26
1.52
1.91
1.59
2.23


2.81
2.65
0.77
NR
1.37
1.15
0.80
1.22
1.63
3.61
                     -27-

-------
                              TABLE 4-3  (cont.)
Observed
Underlying Cause of Death Expected
Nonlnfectlous pulmonary
diseases total
Asbestosls
All other causes

59.0
NAd
1280.2
BEd

212
168
1064
oce

188
78
1161
Ratio
Observed/
Expected
BEd -

3.59
NR
0.83
DCe

3.19
NR
0.91
aSource: Adapted from Sellkoff et al.t 1979

bExpected deaths  are based  upon  white male  age-specific  mortality data  of
 the U.S. National Center for Health  Statistics  for  1967-1975  and extrapola-
 tion to 1976.

cHan-Years of Observation:   166,853

dRates  are  not  available,  but  these  have been  rare  causes  of death  1n  the
 general population.

BE  = Best  evidence.   Number of  deaths   categorized  after review of  best
 available Information (autopsy, surgical, clinical)
                i
DC = Number  of deaths as recorded from death certificate Information only

NA = Not available; NR = not reported
                                     -28-

-------
leukemia and  myeloma  (Kagan et  a!.,  1979; Haidak  et  al.,  1979; Rouhler  et
al., 1982).   Kagan et  al.  (1979) and Haidak et al.  (1979)  reported  cases  of
Individuals with  multiple  myeloma and  chronic  lymphocytlc leukemia  concur-
rent  with   pulmonary  asbestosls.   A  third patient with  multiple  myeloma
developed a massive pleural mesothelloma  (Kagan et  al.,  1979;  Haidak et al.,
1979).  Another patient, who had been occupatlonally exposed  to  asbestos for
30  years,  developed  malignant  alpha-chain disease,  and was  found   to  have
malignant  lymphoma  (Rouhler  et  al.,  1982).   All of  these  cases  showed
lesions of  asbestosls 1n addition to the diagnosed malignancies.
4.2.   BIOASSAYS
4.2.1.   Oral.  Several studies  of  the  cardnogenlcHy of  asbestos  adminis-
tered1 orally  to animals have been  found 1n the  available  literature (Table
4-4).  These  data  have  severe  limitations: the numbers  1n  each  experimental
group were  small;  the doses of  asbestos  administered were  limited;  Important
Information on  experimental  procedures   1s  lacking;  and  systemic hlstopatho-
loglcal examinations  were performed only on a few experimental animals.
    Smith  (1973)  discounted the significance  of  a single neoplasm  of  the
colonlc mesentery  in 1  of  45 hamsters  fed a diet  containing 1% chrysotlle or
amoslte  for an unspecified length of  time because  asbestos  fibers  were not
found  1n sections of  the  tumor.  The  finding of  asbestos fibers  1n tumor
tissue  seems  unlikely,  and, since  mesenterlc  tumors  1n hamsters are rare,
this result should not be disregarded arbitrarily.
    The  data  summarized by Gross  et al.  (1974)  were  the  results  of unpub-
lished  studies  from  three  laboratories  over  a  10-year   period.    Lack  of
Information about  experimental  detail and lack  of systemic  histopathologlcal
examination of  all treated animals  renders Interpretation of  these limited
data difficult.
                                     -29-

-------
                               1ABLE 4-4
Summary of Experiments  on the Effects of  Oral  Administration  of  Asbestos
Species/Strain
Rats/Ulstar
Rats/Wlstar
Rats/Wlstar
Kats/W1star
SPF
(!o Rats/Wlstar
o SPF
Rats/Wlstar
SPF
Rats
Rats
"laboratory"
Rats/Wlstar
SPF
Rats/MUtar
SPF
Rats/Mlstar
SPF
Rats/Wlstar
SPF
No. /Sex
2SN, 25F
25H. 25F
25H, 25F
32/NR
32/NR
16/NR
10H
5/NR
31 /NR
33/NR
34/NR
24/NR
Material
Administered
asbestos filter
material containing
52.6* chrysotlle
talc
control
U1CC Canadian
chrysotlle In
malted milk powder
Italian talc
control
ball-milled chry-
sotlle mixed with
laboratory food
control
Rhodeslan
chrysotlle
0.2X-0.4X
croc Idol He In
butter 0.2-0.4X
mixture
croc Idol He In
butter 0.2-0.4X
mixture
control (butter)
Dosage
50 mg/kg bw/day
In the diet for
life
SO mg/kg bw/day
In the diet for
life
control
100 rag/day. 5
days /week for
100 days
100 rag/day. 5
days/week for
100 days
control
5X by weight of
feed mix for 21
months
control
10 nig weekly for
16 weeks
5 mg weekly for
for 16 weeks
10 mg weekly for
16 weeks
control
Animals Examined Findings
for Tumors (malignant tumors)
42 4 kidney carcinomas
3 retlculosarcomas
4 liver -cell carcinomas
1 lung carcinoma
45 3 liver-cell carcinomas
49 2 liver -cell carcinomas
32 1 gastric lelomyosarcoma
32 1 gastric lelomyosarcoma
16 none
10 none
5 none
31 less "a few* 2 mammary carcinomas
33 less "a few" none
34 less "a few" 1 lymphoma
(24?) 3 mammary carcinomas
1 thigh sarcoma
Average
Survival
lime (days)
441
649
702
618
614
641
sacrificed
sacrificed
NR
NR
NR
NR
Reference
Glbel
et al..
Glbel
et al..
Glbel
et al..
Wagner
et al..
Wagner
et al..
Wagner
et al..
Gross
et al..
Gross
et al..
Gross
et al.,
Gross
et al..
Gross
et al..
Gross
et al..
1976
1976
1976
1977
1977
1977
1974
1974
1974
1974
1974
1974

-------
                                                                      TABLE 4-4 (cont.)
Species/Strain No. /Sex
Rats/Hlstar 35/NR
SPF

Rats/Wlstar 28/NR
SPF

Rats/MUtar 24/NR
SPF
Rats/Wlstar ION





Rats/W1star 10H
i
CJ
1 Rats/Wlstar 40N









Rats/Wlstar 40M






Hamsters/NR 45/NR


Material
Administered
NU Cape crocldo-
Itte In butter
(0.2-0.4X)
Transvaal crocldo-
llte In butter
(0.2-0.4X)
control (butter)

IX chrysotlle





control

1% chrysotlle









control






chrysotlle or
amosHe

Animals Examined findings
Dosage for Tumors (malignant tumors)
10 mg weekly for 35 less "a feu* none
18 weeks

10 mg weekly for 28 less "a few* none
for 18 weeks

control (24?) none

In diet 7 2 kidney
1 peritoneal
1 lymphoma
1 fibrosarcoma
1 brain
1 pituitary
NA 81 peritoneal
fibrosarcoma
In diet 36 3 thyroid
1 bone
1 liver
1 jugular body
2 leukemta/lymphoma
1 adrenal
1 large Intestine
anaplastlc carcinoma
1 small Intestine
fibrosarcoma
NA 38 1 thyroid
1 liver
2 adrenals
1 kidney
nephroblastoma
1 leukemia/ lymphoma
5 subcutaneous tissue
IX In diet for 45 1 mesenterlc neoplasm*
unspecified
period of time
Average
Survival Reference
Time (days)
NR Gross
et al., 1974

NR Gross
et al.. 1974

NR Gross
et al., 1974
NR Cunningham
et al.. 1977




NR Cunningham
et al.. 1977
NR Cunningham
et al.. 1977








NR Cunningham
et al., 1977





NR Smith. 1973


'From text, Impossible to state whether tumor was  benign or  malignant.
NA = Not applicable; NR = not reported

-------
    Because of concern  about  the use of filter material  containing asbestos
1n  the  purification of  wine  products,  Gibe!  et  al.  (1976)  fed  rats  diets
containing  asbestos  filter material.    Treatments  continued throughout  the
natural   Hfespan  of the  animals; untreated  controls were maintained.   The
finding of four malignant kidney  tumors  1n  treated  rats  1s accorded particu-
lar significance In view of the  finding  of  an elevated risk of  kidney cancer
among asbestos Insulation workers  (Sellkoff et al.,  1979}  and  a  high excre-
tion  of  asbestos  1n  the urine  of  humans  exposed  to  asbestos-contaminated
drinking water  (Cook  and Olson,  1979).   The  presence of  sulfated cellulose
and condensation  resin  In  the filter material  complicates  Interpretation of
these results.
    Cunningham et  al.  (1977)  fed  diets  containing  1% chrysotlle  to  10  male
Wlstar rats  for  up  to  24  months.  Control  rats were  maintained.  In  the
treated group,  seven  malignancies were  fpund,  while in  the  10 control  rats
only one malignancy was  found.   In a second trial,  40 treated and 40 control
male Wlstar  rats  were  studied using the same  experimental  protocol.   After
24 months of exposure,  11 malignancies were found 1n the treatment group and
11 malignancies were  found  1n the control  rats,  which  considerably  reduces
the apparent  relevance  of  the  large number  of malignancies 1n  the  earlier
study.
    The U.S. EPA (1985) concluded  a  review  of  the available published animal
data with the following statement:
    In animal  populations,  the  majority of  the  experimental  evidence
    suggests  that  chronic,  high-level  1ngest1on  exposures  to  asbestos
    fibers failed  to produce  any definite,  reproducible,  organ-specific
    carcinogenic effect.
                                     -32-

-------
    In addition to the published  literature, U.S.  EPA  (1985)  presents  a sum-
mary of  the  data  from a draft NTP  (1984) report.   In  this  study  no evidence
of carc1nogen1c1ty was  found following feeding  of short-range (98% <10  vm)
chrysotlle asbestos fibers to either male or female rats.   In contrast, male
rats  Ingesting  Intermediate-range  chrysotile  fibers  (65%  >10 vm  with  -14%
>100  jjtn) at  a 1% dietary  level  showed  an  Incidence  of  3.6%  for  benign
epithelial neoplasms  1n  the  large  Intestine.   U.S.  EPA  (1985)  quotes  NTP
(1984) as follows:

    Although  not  statistically   significant   (p=0.08)   compared  with
    concurrent  controls  (0/85),   the  Incidence  of  these neoplasms  was
    highly significant  (p=0.003)  when  compared with  the  Incidence  of
    epithelial  neoplasms  (benign and malignant  combined)  of  the large
    Intestine In  the  pooled  control groups  (male) of all  the NTP  oral
    asbestos lifetime studies (3/524, 0.6%).

This study should  be re-examined  following peer review and final publication.
4.2.2.   Inhalation.   Several assays  of the carclnogenldty  of asbestos  1n
laboratory animals  exposed  via  Inhalation  have  been  conducted.    Data  from
some of the more pertinent studies are summarized 1n Table 4-5.
    Lynch  et al.  (1957)  administered  chrysotHe  dust   (150-300xl06  parti-
cles/ft3,  -5297-10,595xl06   part1cles/m3.)   8-12   hours/day,  5   days/week
for  19  months  to  AxC F,  mice.    Although  a  higher  Incidence of  pulmonary
adenomas  was  reported   In  the   exposed  group  (58/127)  than  1n  controls
(80/222), these results  were  not  statistically  significant.
    Exposure  to 86 mg  chrysotHe  dust/m3  for  30  hours/week for  16  months
resulted 1n  lung  tumors  1n 24/72 rats  (Gross  et al.,  1967).   No  lung  tumors
were found 1n 39 control  rats.
                                     -33-

-------
                         TABLE  4-5



CarclnogenUUy of Asbestos In Animals  Exposed by Inhalation
Species/
Strain
Mice



Mice

Rat/white

Rat/white

Rat/Charles
River CD
i
CO
» Rat/Charles
River CD

Rat/Charles
River CD
Rat/Charles
River CD
House/Swiss

House/Swiss


House/Swiss


Mouse/Swiss

Sex
H/F



H/F

M

M

H/F



H/F


H/F

M/F

M/F

M/F


M/F


M/F

Dose/Exposure
150-300xlO«a
particles/ft*
(B-12 hours/day;
5 days/week)
untreated

86 mg/m»c

0.0 rag

48.6 mg/ro*e
(4 hours/day;
4 days/week)

47.9 mg/m»c
(4 hours/day;
4 days/week)
50.2 mg/m»f
(4 hours/day;
0.0 rog/m»

48.6 mg/m*e
(4 hours/day;
4 days/week)
47.9 mg/m»h
(4 hours/day;
4 days/week)
50.2 mg/m*f
(4 hours/day;
4 days/week)
0.0 mg/m1

Duration
of
Treatment
19 months



NA

62 weeks

NA

24 months



24 months


24 months

24 months

24 months

24 months


24 months


24 months

Duration
of Study
19 months



19 months

>16 months
(lifetime)
lifetime

24 months



24 months


24 months

24 months

24 months

24 months


24 months


24 months

Purity of Vehicle or
Compound Physical
State
92.6-9B.8Xb dust



NA untreated

milled dust

NA untreated

NR dust



NR dust


NR dust

NA untreated

NR dust

NR dust


NR dust


NA untreated

Target
Organ
lung



lung

lung and
pleura
lung

lung and
pleura


lung and
pleura

lung and
pleura
no tumors

no tumors

no tumors


bronchial


bronchial

Tumor
Type
adenoma



adenoma

cancer

cancer

various



various


various

NA

NA

NA


carcinoma


carcinoma

Tumor
Incidence
58/127
(NS)


80/222

24/72d

0/39

3/46



3/43


5/469

0/5

0/17

0/19


2/18


1/6

Reference
Lynch
et al.,


Lynch
et al.,
Gross
et al..
Gross
et al..
Reeves
et al.,


Reeves
et al.,

Reeves
et al.,
Reeves
et al..
Reeves
et al..

Reeves
et al..

Reeves
et al..

Reeves
et al..

1957



1957

1967

1967

1974



1974


1974

1974
1974


1974


1974


1974

-------
TABIf 4-5 (cont.)
Species/
Strain
Rat/
nonspecific
Rat/
nonspecific
Rat/
nonspecific
Rat/Wlstar
Rat/Wlstar
Rat/Hi star
co
en
1 Rat/Wlstar
Rat/Wlstar
Rat/Wlstar
Rat/Wlstar
Rat/Wlstar
Rat/Wlstar
Rat/Wlstar
Sex
H/F
H/F
H/F
H/F
H/F
H/F
H/F
H/F
H/F
H/F
H/F
H/F
H/F
Duration
Dose/Exposure of
Treatment
47.4-47.9 ng/m»l 2 years
(4 hours/day;
4 days/week)
48.2-48.6 mg/m*J 2 years
(4 hours/day;
4 days/week)
48.7-50.2 mg/m** 2 years
(4 hours/day;
4 days/week)
14.1 mg/m* 1 day
7 hours/day6
12.8 mg/m* 1 day
7 hours/day™
12.5 mg/m* 1 day
7 hours/day'
9.7 mg/m» 1 day
7 hours/day0
14.7 mg/in* 1 day
7 hours/day"
0.0 mg/m* NA
7 hours/day
12.4 mg/m* 3 months
7 hours/day
5 days/week6
13.5 mg/m* 3 months
7 hours/day
5 days/week1"
12.6 mg/m* 3 months
7 hours/day
5 days/week''
12.1 mg/m* 3 months
7 hours/day
5 days/week0
Duration
of Study
2 years
2 years
2 years
804 days
806 days
795 days
763 days
753 days
803 days
771 days
823 days
817 days
790 days
Purity of Vehicle or Target
Compound Physical Organ
State
NR dust lung and
pleura
NR dust lung and
pleura
NR dust lung and
pleura
NR dust lung
NR dust lung
NR dust lung
NR dust lung
NR dust lung
NA untreated lung
NR dust lung
NR dust lung
NR dust lung
NR dust lung
Tumor
Type
various
various
various
various1!
various1
various^
various1
various1
adenoma
various1
various1
various1
various1
Tumor
Incidence
3/54
3/61
7/50
3/45
2/44
6/43
1/42
5/45
4/44
10/37
6/37
14/36
18/34
Reference
Reeves,
Reeves,
Reeves,
Wagner
ct al.,
Wagner
et al.,
Wagner
et al..
Wagner
et al..
Wagner
et al.,
Wagner
et al.,
Wagner
et al..
Wagner
et al.,
Wagner
et al..
Wagner
et al..
1976
1976
1976
1974
1974
1974
1974
1974
1974
1974
1974
1974
1974

-------
TABLE 4-5 (cont.)
Species/
Strain
Rat/Wlstar


Rat/Utstar

Rat/Wlstar


Rat/Wlstar


Rat/Wlstar

o? Rat/Wlstar
i

Rat/Mlstar


Rat/Wlstar


Rat/Wlstar


Rat/Wlstar


Rat/Wlstar


Rat/Wlstar


Sex
H/F


M/F

H/F


H/F


H/F

H/F


H/F


H/F


H/F


H/F


H/F


H/F


Dose/Exposure
12.3 mg/m»
7 hours/day
5 days/week"
0.0 mg/m»

11.2 mg/m*
7 hours/day
5 days/week*
10.9 mg/m*
7 hours/day
5 days/week1"
10.7 mg/m*
7 hours/day
5 days/week'
10.2 mg/m*
7 hours/day
5 days/week0
10.7 mg/m*
7 hours/day
5 days/week"
10. 8 rng/n*
7 hours/day
5 days/week6
11.4 mg/m'
7 hours/day
5 days/week™
10.6 mg/m*
7 hours/day
5 days/weekf
10.7 mg/n*
7 hours/day
5 days/weekc
10.9 mg/m1
7 hours/day
5 days/week"
Duration Duration
oF of Study
Treatment
3 months 857 days


NA 793 days

6 months 763 days


6 months 686 days


6 months 788 days

6 months 669 days


6 months 766 days


12 months 692 days


12 months 759 days


12 months 776 days


12 months 778 days


12 months 826 days


Purity of
Compound
NR


NA

NR


NR


NR

NR


NR


NR


NR


NR


NR


NR


Vehicle or
Physical
State
dust


untreated

dust


dust


dust

dust


dust


dust


dust


dust


dust


dust


Target
Organ
lung


lung

lung


lung


lung

lung


lung
•

lung


lung


lung


lung


Tung


Tumor
Type
various1


adenoma

various1


various1


various1

various1


various1


various1


various1


various1


various1


various1


Tumor
Incidence
16/36


3/40

2/18


6/18


4/18

5/17


8/19


10/25


20/28


18/26


11/23


19/27


Reference
Wagner
et al..

Wagner
et al.,
Wagner
et al..

Wagner
et al..

Wagner
et al..
Wagner
et al..

Wagner
et al..

Wagner
et al.,

Wagner
et al..

Wagner
et al..

Wagner
et al..

Wagner
et al.,


1974


1974

1974


1974


1974

1974


1974


1974


1974


1974


1974


1974


-------
                                                                      TABLE  4-5 (conl.)
Species/
Strain Sex Dose/Exposure
Rat/Histar N/F 10.6 rag/m*
7 hours/day
5 days/week6
Rat/Ulstar H/F 10.6 mg/m»
7 hours/day
5 days/week1"
Rat/Ulstar N/F 10.3 mg/ra*
7 hours/day
5 days/week'
Rat/Utstar H/F 10.1 mg/m»
7 hours/day
S days/week0
Rat/Ulstar N/F 10.1 mg/m*
7 hours /day
i S days/week"
CO
T' Rat/Utstar N/F 0.0 mg/n»

Duration Duration
of of Study
Treatment
24 months 807 days


24 months 778 days


24 months 756 days


24 months 585 days


24 months 758 days



NA 754 days

Purity of Vehicle or Target Tumor
Compound Physical Organ Type
State
NR dust lung various1


NR dust lung various1


NR dust lung < various1


NR dust lung various1


NR dust lung various1



NA untreated lung various1

Tumor
Incidence Reference
13/21 Uagner
et al.,

16/18 Uagner
et al.,

13/18 Uagner
et al..

10/21 Uagner
et al.,

11/17 Uagner
et al..


0/42 Uagner
et al.,

1974


1974


1974


1974


1974



1974
aChrysot11e (very fine, low fiber content:  Canadian)
°S102 (37.12-43.36X). HgO (39.54-43.90X).  H20 (12-15X),  FeO (0-6X).  Fe203 (1-5X),  A1203 (0.2-1.5X),  CaO (0-0.3X).   Pure  chrysotlle  .  3NgO-2S102-
cChrysot11e (Canadian)
dExcluslve of lymphoblastomas, since this  tumor  type  Is  known  to  occur  spontaneously In those rats.
                                                                                                                                               2H20
eAmos1te
 Crocldollte
94 carcinomas of the lung; 1 adenocarclnoma of the lung
Chrysotlle
 Chrysollle - fiber count measured as 54 million fibers/in1
^ Amos He - fiber count measured as 864 million flbers/m3
 Crocldollte - fiber count measured as 1105 million fibers/in'
 Adenoma, adenomatosls, adenocarclnoma, squamous carcinoma
mAnthophyl11te
"Chrysotlle (Rhodeslan)
NR = Not reported; NA = not applicable; NS « not statistically significant
f


-------
    Reeves  et  al.  (1974)  tested  the  carclnogenlclty of  various  forms  of
asbestos 1n rats, mice,  rabbits,  guinea  pigs  and gerblls.   Dusts of chryso-
tHe, crorldolHe and amoslte were prepared by ban-milling, a process noted
for destroying much of the fibrous character of asbestos.  Exposures were up
to  24  months  to  air  concentrations  of 47.9-50.2 mg/m3.   Fiber  counts  were
54  fibers/ma  (chrysotHe),   864   fibers/ml   (amoslte)  and  1105  fibers/ml
(croddolHe).   Neoplasms were detected only In rats and mice.  Rats exposed
to  crocldolHe,  chrysotHe and  amoslte developed lung tumors  1n  5/46,  3/43
and  3/46,  respectively.   Papillary  carcinomas  developed  In  mice  (2/18)
exposed to crocldolHe.  Subsequently,  Reeves  (1976) exposed rats to chryso-
tlle, crocldolHe and amoslte, using the protocol previously described for a
2-year  treatment  period.   Fiber counts were  as  reported  previously (Reeves
et  al., 1974).   CrocldolHe,  with  the  highest fiber count, also Induced the
highest  Incidence of  tumors (7/50),  while  chrysotlle  (3/54)  and  amoslte
(3/61) were associated with fewer  tumors  1n  treated  animals.
    Wagner  et  al. (1974) exposed  CO  Wlstar  rats  to  amoslte,  croddolHe,
anthophylllte,  Canadian chrysotHe or Rhodeslan chrysotlle at concentrations
of  9.7-14.7  mg/m3 for  1 day,  3,  6,  12 or  24 months  for 7  hours/day,  5
days/week.   Exposure  to  all  forms  of  asbestos  was  associated  with  an
Increased Incidence  of  lung  carcinomas and mesotheHomas  after  3  months  of
exposure.  No mesotheHomas  were found  1n  rats  exposed  to  Rhodeslan chryso-
t1le for any length  of time.
4.3.   OTHER RELEVANT DATA
    MutagenlcHy testing of  chrysotHe,  amoslte,  anthophylllte  or superfine
chrysotHe gave  negative  results  1n  several  strains (unspecified)  of Esche-
rlchla coll and Salmonella typhlmurlum assay systems (Chamberlain and Tarmy,
1977).  The  authors  recognized  that since  prokaryotlc  cells do  not phago-
cytlze particles as  do eukaryotlc cells, a positive  response was not likely.

                                     -38-

-------
    Slncock and Seabrlght (1975) reported  finding chromosomal  aberrations  In
CHO cells  cultured  In a  medium containing  0.01  mg/m2. of either  chrysotlle
or croddolHe.  In a more extensive series  of  experiments,  both  morphologic
transformation and positive genetic responses resulted  from  the  Inclusion  of
several chrysotHe or croddolHe samples  In the  culture  medium  of CHO cells
(Slncock,  1977).   Very fine  glass  fibers  produced  the  same  abnormalities,
but  chemically  leached   asbestos   produced  fewer   abnormalities  than  did
unleached asbestos.
4.4.   WEIGHT OF EVIDENCE
    Evidence  Indicates that  Ingested  asbestos  fibers may  cause  an excessive
incidence of  cancers of the 61  tract.   Pollssar  et  al.  (1983)  found a slight
but significant (p<0.05)  Increase 1n the  Incidence  of  pharyngeal  and stomach
cancers  1n males drinking asbestos-contaminated  water  from the Sultan River,
considered to be  one of  the  most  highly  contaminated  water supplies  In  the
country.   Slgurdson  (1983)  reported a significant Increase  1n the Incidence
of  peritoneal  tumors  (p<0.05) and  tumors  of the GI tract  (p<0.01)  1n resi-
dents of Duluth, MM, whose drinking water contained  l-65x!06 fibers/8,.
    Other  Investigators  failed  to  find  a  positive  association  between
Ingested asbestos and  cancer  1n humans.   Harrington et al.  (1978) and Melgs
(1983)  Investigated  the  Incidence  of  GI  and  peritoneal cancers  In several
Connecticut communities 1n which concrete-asbestos  water  mains are used.   No
relationship  was established  between  asbestos  1n the  drinking water and  the
Incidence of  these tumors.
    Cooper et al.   (1978)  failed  to find  a dose-related trend  In the Inci-
dence of cancer 1n  721 census tracts  of five Bay Area  counties of California
by  examining  the  mortality data and  ranking the census  tracts  according to
the level of  asbestos 1n  the  drinking water.
                                     -39-

-------
    Evidence for a  carcinogenic  role for asbestos  1n  orally  exposed animals
Is  also  not convincing.   The data  generated  have severe  limitations:   the
numbers  of  animals  tested  were  small,  the  doses  of  asbestos  used  were
limited, and systematic  histopathologlcal  examination  of  all  animals was not
always  performed.   The most  convincing  data suggesting  a  carcinogenic  role
for orally-administered  asbestos  were  provided 1n  the  study  by  G1bel  et al.
(1976), who fed rats  diets containing  asbestos  filter  material  which Is  used
to  clarify  wine products.   The  finding of  four  kidney  carcinomas  among  50
rats  treated throughout  their  lifetimes  was  considered a  significant finding
In  view  of  the fact  that  Selikoff  et  al.  (1979)  found an  Increased risk  of
kidney cancer  associated with asbestos  Insulation  workers.   The  presence  of
sulfated cellulose  and  condensation resin  1n the filter  material  fed  to the
test  rats  complicates Interpretation of these results.   Additional  data are
available in the form of a draft NTP (1984) report (see Section  4.2.1.).
    The case for cardnogen1c1ty  of  asbestos  1n humans exposed  by Inhalation
Is  considerably  more  convincing.   Many ep1demolog1cal  studies have  demon-
strated  significant  Increases  in  the  Incidence  of  deaths  due  to  cancer
associated with  inhalation (particularly occupational) exposure  to  asbestos
(see Table 4-2).  Peto et  al.  (1977) and Newhouse et  al.  (1972) have clearly
shown that exposure to asbestos in  the  workplace  is related to  a significant
(p<0.001) increase  In  the  likelihood of  death  due  to  cancers  of the  lung and
pleura.   GiUam' et  al.  (1976)   associated  malignancies   of  the  lung  with
exposure to asbestos mining operations.  Selikoff  (1976) and  Selikoff  et al.
(1964, 1979) have  shown that working  with asbestos insulation may  dramati-
cally  elevate  the  likelihood  of  death  due  to cancer  of the  lung,  pleura,
peritoneum and  GI  tract.
                                     -40-

-------
    The animal data  substantiate  the  observation  of cancers In  humans  asso-
ciated  with   Inhalation  exposure  to  asbestos.   Although  several  bloassays
strongly suggest the cardnogenldty of Inhaled asbestos fibers,  the  data  of
Wagner et  al.  (1974) best Illustrate  this  phenomenon.   This complex  study,
which employed five  forms of asbestos  and treatment  times  of  from 1  day to 2
years followed by  varied post-exposure times,  Is  presented 1n  tabular  form
In Section  4.2.2.   This  study  did not present  statistical analysis of  the
tumor Incidence data.
    In  light  of  the  sufficient  evidence  Indicating  cardnogenldty   of
asbestos 1n  humans  exposed by  Inhalation,  which Is  well corroborated by  the
animal bloassay  data, asbestos  1s most appropriately classlfed  as a  Group A
substance  by  application  of  the  classification  criteria  devised  by  the
Carcinogen Assessment Group of  the U.S. EPA  {Federal Register,  1984).
                                     -41-

-------
                    5.  REGULATORY STANDARDS AND CRITERIA

    The  OSHA  standard  for  asbestos   fibers  (defined  as   fibers  >5  vm  In
length) In workplace  air  was set In 1972 at  5  fibers/cm3  TWA for an  8-hour
day.   In  1976,  this  standard  was  reduced  to  2  fibers/cm3  for  an  8-hour
TWA.   A  celling  concentration  of  10  fibers/cm3  was  set  (Code  of  Federal
Regulations,  1981).
    The AC6IH  (1980) recommended TWA-TLVs for asbestos as  follows:   amosHe,
0.5  fiber/cm3;  chrysotHe,   2.0  fibers/cm3;   croddolHe,   0.2   fiber/cm3;
other  forms,  2.0  fibers/cm3.   In  Great  Britain,  the  BOHS  (1968)  also
suggested  a  TWA  of  2.0  fibers/cm3,  although  Peto  (1978)  suggested  that
exposure to this  level may result 1n the death  of  10% of workers  exposed for
a lifetime.
    Standards for asbestos 1n foods or beverages could not  be located 1n the
available literature.
    The U.S.  EPA  (1980b) has recommended criteria  for ambient  water  based on
estimated levels  of asbestos  that  would  result  1n  increased  lifetime  cancer
risks  of  10~5,  10~«  and   10~7   as   300,000,   30,000  and  3000   fibers,
respectively.  These criteria were derived from the association of GI  cancer
with occupational exposure to asbestos dusts and by applying  several  assump-
tions.  Primary among these  assumptions  is  that virtually all of  the asbes-
tos  1s  ultimately swallowed, and  Is  therefore capable  of causing  lesions,
including  neoplasms,  in the  GI tract.  Estimates of  occupational  exposure
levels were matched with  observed  incidence  of  death due to  GI cancers  from
several  epidemiological  studies.  A  linear  relationship  between  increased
cancer risk and exposure level was  also assumed.
                                     -42-

-------
                              6.   RISK  ASSESSMENT
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
    Asbestos Is  a  substance  that Is known to  be  carcinogenic.   Although the
U.S.  EPA  (1983c)  determined  that  H  1s Inappropriate  to  derive a  potency
factor for  asbestos  because  Us  carcinogenic potency 1s  related  to  specific
fiber shapes,  sizes  and air  concentrations,  the  U.S. EPA  (1980b)  estimated
unit carcinogenic risks for asbestos based on  human  epidemologlcal  data.  It
1s  Inappropriate,  therefore,  to  consider   an  oral  or   Inhalation  AIS  for
asbestos.
6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)
    Asbestos 1s  a  substance  that 1s known to  be  carcinogenic.   The  U.S. EPA
(1983c)  determined that  1t 1s Inappropriate  to  derive a potency  factor for
asbestos  because  Us  carcinogenic  potency  Is   related  to  specific  fiber
shapes,  sizes and air concentrations.
6.3.   CARCINOGENIC POTENCY (q^)
6.3.1.   Oral.    As reviewed   In  Section  4.1.1.,  oral  exposure  of humans  to
asbestos  1n drinking  water   has  not   been  conclusively   shown  to result  In
Increased  risk  of  cancer.  Pollssar  et  al.  (1983)  associated an  Increased
Incidence  of  stomach  and  pharyngeal   cancers  with a  high  concentration  of
asbestos  fibers  1n drinking  water  in  the Everett,  WA area.   Epldemlologlc
evaluations  of  cancer  Incidence  1n residents  of  the five  Bay  Area  counties
of  California  (Cooper  et  al.,  1978)   Indicated a  dose-related trend  In the
Incidence  of  lung  and  stomach  cancer  (males) and gall   bladder,  esophageal
and peritoneal  cancer  (females).  Other  epldemiologlc studies  (Melgs,  1983;
MUlette et al.,  1983) have  failed to relate increased   risk of  cancer  with
exposure to  asbestos.
                                     -43-

-------
    Animal  bloassays  have not  clearly established  a  carcinogenic role  for
asbestos administered by the oral  route (see Section  4,1.2.}.
    The U.S.  EPA  (1980b)  used human  Inhalation  data to derive a  risk  esti-
mate 1n order  to  develop  ambient  water quality criteria for asbestos.   In  a
later evaluation,  the  U.S.  EPA (1983c)  suggested  that  1t  may not  be  appro-
priate  to  calculate  a  potency factor  for  asbestos because Us  carcinogenic
potency is  related to  the size and  shape of  asbestos  particles  as well as
Its  concentration  1n  the  air.   This  Issue Is  currently  undergoing  review
(U.S. EPA,  1985).  The risk  assessment portion of U.S. EPA (1985)  Is  not as
yet final.  When  completed,  U.S.  EPA (1985), as a more extensive  evaluation
of the asbestos Issue,  should supercede any recommendations  1n  this document.
6.3.2.    Inhalation.   The carclnogenlcHy  of asbestos  for  humans  exposed by
the  Inhalation  route  has  been  well  established   (Elmes and  Simpson,  1971;
Newhouse et al.,  1972; Glllam et al.,  1976;  Peto  et a!.,  1977; SeHkoff et
a!., 1964, 1979;  Sellkoff,  1976).
    Animal bloassays  confirm the carclnogenlcHy of  asbestos administered by
Inhalation (Gross et  al., 1967; Reeves  et  al., 1974; Reeves, 1976; Wagner et
al., 1974).  According to U.S.  EPA  (1983c), H 1s Inappropriate to derive  a
potency factor for asbestos  because  the carcinogenic potency  of asbestos Is
related to specific fiber  shapes,  sizes  and air concentrations.
                                     -44-

-------
                                7.   REFERENCES







ACGIH  (American  Conference  of  Governmental  Industrial  Hygienists).   1980.



Documentation of the Threshold Limit Values,  4th  ed.   (Includes  Supplemental



Documentation, 1981,  1982,  1983).   Cincinnati, OH.  p.  27-30.







Anderson,  H.A.,  R.  LIHs,  S.M.  Daum,  A.S.  Fischbein  and  1.3.  Selikoff.



1976.   Household-contact   asbestos  neoplastic  risk.  Ann.   NY  Acad.  Sd.



271: 311-315.  (Cited 1n U.S. EPA,  1980b)







Aurlbault,  M.   1906.   Sur  1'hygiene  et  la securlte  des  ouvriers.   Jji:



Bulletin  de  1'Inspection  du  Travail,   p. 120-132.   (Fre.)   (Cited in  U.S.



EPA, 1980b)







Bader,  M.E.,  R.A.  Bader  and 1.3.  Selikoff.  1961.   Pulmonary  function  in



asbestosis of the  lung.  An  alveolar-capillary block syndrome.  Am. 3.  Med.



30: 235-242.  (Cited  in U.S.  EPA,  1980b)







Baris, Y.I.,  M. Artivinll  and A.A.  Sahin.   1979.   Environmental  mesothelioma



1n Turkey.  Ann.  NY Acad.  Sci.  330: 423-432.  (Cited in  U.S.  EPA,  1983b)







Barry, B.E.,  K.C.  Wong, A.R. Brody, and 3.D.  Crapo.  1983.   Reaction  of rat



lungs  to  Inhaled  chrysotile asbestos   following  acute  and subchronic  expo-



sure.  Exp. Lung Res.  5(1):  1-21.







Berry, G.,  M.L.  Newhouse  and M. Turok.  1972.  Combined effect  of  asbestos



exposure  and smoking  on   mortality from  lung  cancer   in  factory  workers.



Lancet.  2: 476-479.   (Cited  1n  U.S. EPA,  1980b)





                                     -45-

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Boatman,  E.S.,   T.  Merrill,  A.  O'Neill,   L.  Pollssar  and  J.R.   MUlette.
1983.  Use of quantitative  analysis  of urine to assess  exposure to asbestos
fibers  1n  drinking  water   In  the  Puget  Sound  region.    Environ.  Health
Perspect.  53: 131-139.

BOHS  (British Occupational  Hygiene Society).   1968.   Hygiene standards  for
chrysotlle asbestos dust.  Ann. Occup. Hyg.  11: 47-69.  (Cited  1n  U.S.  EPA,
1980b)

Bolton,  R.E., J.M.  Davis and  D.  Lamb.   1982.   The pathological effects  of
prolonged asbestos 1ngest1on In rats.   Environ.  Res.   29(1):  134-150.

Brain, J.O. and  P.A Valberg.   1974.   Models of  lung retention based on  ICRP
task  group report.   Arch.  Environ. Health.  28:  1-11.   (Cited 1n  U.S.  EPA,
1980b)

Callahan, M.A.,   M.W.  SUmak and  N.W.  Gabel.   1979.  Water-Related  Environ-
mental Fate of  129  Priority Pollutants.   Vol.  I.  U.S.  EPA,  Office  of Water
Planning  and  Standards,  Office  of Water  and  Waste Management, Washington,
DC.  EPA 440-4-79-029.

Carter, R.E.  and  W.G. Taylor.   1980.   Identification  of a particular  amphl-
bole  asbestos fiber  In  tissues of persons  exposed  to  a high oral  Intake  of
the mineral.   Environ.  Res.  21:  85-93.   (Cited  1n  U.S.  EPA,  1980b)

Chamberlain,  M.   and E.M. Tarmy.   1977.   Asbestos and  glass  fibres  1n  bac-
terial mutation  tests.  Mutat.  Res.   43:  159-164.   (Cited 1n U.S. EPA,  1980b)
                                     -46-

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Code  of  Federal  Regulations.  1981.   OSHA  Safety  and Health  Standards.   29
CFR 1910.1001.

Cook,  P.M.  and G.F. Olson.   1979.   Ingested mineral fibers:  Elimination  1n
human urine.  Science.  204: 195-198.  (Cited In U.S. EPA, 1980b)

Cooper,  R.C.  and  W.C.  Cooper.   1978.   Public  health  aspects  of  asbestos
fibers 1n  drinking water.   J. Am.  Water  Works Assoc.   72:  338-340.   (CHed
1n U.S. EPA, 1980b)

Cooper,  R.C.,  M.   Kanarek,  J.  Murchlo, et  al.   1978.   Asbestos  1n  domestic
water  supplies 1n five  California counties.   Progress  report for  period
April  25,  1977 to June 30,  1978,  under  U.S.  EPA  Contract No.  R804366-02.
(Cited 1n U.S. EPA, 1980b)

Cunningham, H.M.  and  R.D.  Pontefract.  1974.   Placental transfer of  asbes-
tos.  Nature.   249: 177-178.  (CHed 1n U.S. EPA,  1980b)

Cunningham, H.M.,  C.A.  Moodle,  6.A.  Lawrence and  R.D. Pontefract.   1977.
Chronic  effects   of  Ingested  asbestos   1n  rats.   Arch.  Environ.   Contam.
Toxlcol.   6(4):  507-513.

Elmes, P.C. and M.J.  Simpson.  1971.   Insulation  workers In  Belfast.   III.
Mortality  1940-1966.  Br.  3. Ind.  Med.   28:  226-236.   (Cited  1n U.S.  EPA,
1983b)
                                     -47-

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Evans, J.C., R.J. Evans, A. Holmes, et al.  1973.  Studies  on  the deposition
of  Inhaled  fibrous  material  1n  the  respiratory  tract  of  the  rat  and  Us
subsequent clearance using radioactive tracer techniques.   1.  UICC croddo-
IHe asbestos.   Environ.  Res.  6:   180-201.   (Cited  1n  U.S.  EPA, 1980b)

Federal   Register.    1984.   Environmental   Protection  Agency.   Proposed
guidelines for  carcinogenic risk  assessment.   49  FR 46294-46299.

Gibel,  W.,   K.H.  Lohs,  K.H.  Horn,  G.P.  WHdner and  F.  Hoffmann.    1976.
T1erexper1mentelle Untersuchungen  uber elne  kanzerogene Wlrkung von  Asbest-
fntermaterlal    nach    oraler  Aufnahme.   Arch.    Geschwulstforsch.    46:
437-442.  (Ger.)  (Cited 1n U.S.  EPA,  1980b)

Glllam, J.D.,  J.H.  Dement, R.A.  Lemen,  J.K.  Wagoner,  V.E. Archer  and  H.P.
Bleler.  1976.   Mortality patterns among hard rock gold miners exposed  to an
asbestlform mineral.  Ann. NY Acad. Scl.   271: 336-344.   (Cited  In U.S.  EPA,
1980b)

Gloyne, S.R.  1935.  Two cases of squamous carcinoma  of  the  lung  occurring 1n
asbestosls.   Tubercle.   17: 5-10.  (Cited 1n U.S.  EPA,  1980b)

Gross,  P.,   R.T.P.  deTrevllle,   E.B.  Tolker,  M.  Kaschak  and  M.A.   Babyak.
1967.  Experimental  asbestosls:  The development  of  lung cancer 1n rats  with
pulmonary deposits of chrysotlle asbestos dust.   Arch.  Environ.  Health.   15:
343-355.  (Cited In  U.S. EPA,  1983b)
                                     -48-

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Gross,  P.,   R.A.  Harley,  L.M.  Swlnborne,   J.M.G.  Davis  and  W.B.  Greene.
1974.   Ingested mineral  fibers.   Do they penetrate  tissue or  cause  cancer?
Arch. Environ. Health.   29:  341-347.   (Cited In U.S.  EPA,  1980b)

Haidak, D.J., E.  Kagan,  R.J.  Jacobson,  K.Y. Yeung and  G.H.  Nachnanl.   1979.
Immuno- and   Iympho-prol1ferat1ve  neoplasms   associated   with   exposure   to
asbestos  (ETA)  (Meeting  Abstract).   Proc.  Am.  Assoc.  Cancer Res.  20:  417.
(Cited 1n U.S. EPA,  1983b)

Hammond,  E.C.,  1.3.  Sellkoff and  H.  Seldman.   1979.   Asbestos  exposure,
cigarette smoking and death rates.  Ann.  NY Acad.  Scl.   330:  473.   (Cited 1n
U.S. EPA, 1980b)

Harless, K.W.,  S. Watanabe  and A.D.  Renzettl,  Jr.  1978.   The  acute  effects
of  chrysotlle  asbestos   exposure  on   lung function.   Environ.  Res.   16:
360-372.  (Cited 1n  U.S.  EPA,  1980b)

Harrington, J.M., G.F. Graun,  J.W.  Melgs,  P.J. Landrlgan,  J.T.  Flannery  and
R.S. Woodhull.   1978.   An Investigation  of the use of asbestos  cement  pipe
for  public  water supply and  the Incidence of  gastrointestinal  cancer  In
Connecticut,  1935-1973.   Am.   J.  Ep1dem1ol.   107: 96-103.   (Cited  In  U.S.
EPA, 1980b)

Haugen, A., P.W. Schafer  and 3.F. Lechner.   1982.   Cellular  1ngest1on, toxic
effects, and  lesions observed  In human  bronchial  epithelial  tissue  and cells
cultured with asbestos  and glass  fibers.  Int.  J.  Cancer.   30(3):  265-272.
                                     -49-

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Holt,  P.P.   1983.   Translocatlon of  Inhaled dust  to  the pleura.   Environ.



Res.  31(1):  212-220.







IARC  (International  Agency for Research  on  Cancer).   1973.  Some  Inorganic



and OrganometalUc compounds.  IARC Monographs on  the  Evaluation  of  Carcino-



genic Risk of Chemicals to Man.  WHO,  IARC,  Lyon,  France.   Vol.  2,  p.  17-47.







Jacobs, R.,  J.  Humphry*,  K.S. Dodgson  and  R.G.  Richards.  1978.  Light  and



electron microscope  studies  of the rat digestive tract  following  prolonged



and short-term  1ngest1on  of  chrysotHe asbestos.   Br.  J. Exp.  Pathol.   59:



443-453.  (Cited 1n U.S. EPA,  1980b)







Kagan, E.,  R.J.  Jacobson,  K.Y.  Yeung,  D.J.  Haldak and G.H. Nachnanl.   1979.



Asbestos-associated  neoplasms  of  B  cell   lineage.   Am.  J.   Med.    67(2):



325-330.  (Cited 1n U.S. EPA,  1983b)







Langer, A.M.  1974.  Inorganic particles  1n  human  tissues  and their  associa-



tion  with  neoplastlc  disease.    Environ.   Health Perspect.   9:   229-233.



(Cited 1n U.S. EPA, 1980b)







Lewlnsohn,   H.C.   1972.   The  medical  surveillance of  asbestos  workers.   R.



Soc. Health J.  92: 69-77.  (Cited  1n U.S. EPA, 1980b)







Lynch, K.M.  and  W.A.  Smith.   1935.  Pulmonary asbestosls III:  Carcinoma  of



lung 1n asbesto-sHlcosls.  Am. 3. Cancer.   24:  56-64.   (Cited 1n U.S. EPA,



1980b)
                                     -50-

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Lynch,  K.M.,  F.A.  Mclver  and  J.R.  Cain.   1957.   Pulmonary  tumors in  mice
exposed to  asbestos  dust.   Arch.  Ind.  Health.  15:  207-224.   (Cited  1n  U.S.
EPA, 1983b)

Meek,  M.E.    1983.   Transmigration  of  Ingested  asbestos.   Environ.  Health
Perspect.   53: 149-152.

Melgs,  J.W.   1983.   Assessment of studies  on cancer risks from  asbestos  In
Connecticut drinking water.  Environ. Health Perspect.   53:  107-108.

Merewether, E.R.A.  1947.  Annual report of the chief  Inspector  of  factories
for the year  1947.  Her  Majesty's Stationery  Office, London.   (Cited  1n  U.S.
EPA, 1980b)

Miller,  L.,  W.E.   Smith  and  S.W.   Berliner.   1965.   Tests  for  effect  of
asbestos on benzo(a)pyrene cardnogenesls In  the  respiratory  tract.  Ann.  NY
Acad. Scl.  132: 489-500.  (Cited 1n  U.S.  EPA, 1980b)

M1llette,  J.R.,  G.F.  Craun,  J.A. Stober, et  al.   1983.  Epidemiology  study
of the  use of asbestos-cement  pipe for  the  distribution  of  drinking water  1n
Escambla County, Florida.  Environ. Health  Perspect.  53: 91-98.

Morgan, A., J.C.  Evans,  R.J.  Evans,  R.F.  Hounam, A. Holmes and  S.G.  Doyle.
1975.  Studies on the deposition of  Inhaled fibrous  material  In  the respira-
tory tract of the  rat  and Us subsequent clearance  using radioactive  tracer
techniques.    II.  Deposition  of  the  UICC  standard  reference  samples  of
asbestos.   Environ.  Res.   10: 196-207.   (Cited 1n  U.S.  EPA,  1980b)
                                     -51-

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Mount Sinai.   1976.   Rapport  final  comHe  d'etude  sur  la  salubrlte1  dans
Tlndustrle de  Tamlante.   Montreal,  Canada.  Annexe,  p. 151-160.  (Fre.)
(Cited In U.S.  EPA,  1980b)

Murray,   H.M.   1907.   Report  of  the departmental  committee  on compensation
for Industrial disease.  Her Majesty's Stationery Office, London.  (Cited 1n
U.S. EPA, 1980b)

Newhouse, M.L.  and H. Thomson.  1965.  Mesothelloma of pleura and  peritoneum
following  exposure  to  asbestos In  the  London area.  Br. J.  Ind.  Med.   22:
261-269.  (Cited In  U.S.  EPA,  1980b)

Newhouse, M.L., G. Berry, J.C. Wagner and M.E. Turok.   1972.  A study of the
mortality  of   female  asbestos  workers.    Br.  0.  Ind.  Med.    29: 134-141.
(Cited 1n U.S.  EPA,  1980b)

Nicholson, W.J.   1976.   Case  study  1:  Asbestos  - the TLV approach.  Ann. NY
Acad.  Sc1.  271:  152-169.   (Cited  In U.S.  EPA, 1980b)

NTP  (National   Toxicology  Program).   1984.   NTP  technical  report on  the
toxicology and cardnogenesls studies of chrysotHe asbestos.  NTP Publ. No.
84-2551, NTP-83-173.

Patel-MandHk,   K.  and W.  Hallenbeck.   1978.   Fate  of  Ingested  chrysotlle
asbestos fiber In the newborn baboon.  Report.  EPA 600/1-78-069.  (Cited In
U.S. EPA, 1980b)
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Patel-MandHk,  K.J.   and   J.R.  Millette.   1983a.   Chrysotile  asbestos   In
kidney cortex  of  chronically  gavaged  rats.   Arch. Environ. Contam.  Toxlcol.
12(2): 247-255.

Paiel-MandHk,  K.J.  and  J.R.  Millette.   1983b.   Accumulation  of  Ingested
asbestos fibers  1n  rat tissues  over  time.    Environ.  Health  Perspect.   53:
197-200.

Peto, 0.  1978.  The hygiene standard for asbestos.   Lancet.   8062:  484-489.
(Cited 1n U.S. EPA,  1980b)

Peto, J.,  R.  Doll,  S.V.  Howard,  L.J. Klnlen and  H.C.  Lewlnsohn.   1977.   A
mortality study among  workers  1n an  English  asbestos factory.  Br. J.  Ind.
Med.  34: 169-173.  (Cited 1n  U.S.  EPA,  1980b)

Pollssar,  L.,   R.K.  Severson   and  E.S.  Boatman.   1983.   Cancer  risk  from
asbestos In  drinking  water:  Summary  of  the  case-control  study In Western
Washington.  Environ.  Health Perspect.  53:  57-60.

Pontefract,  R.D.   and  H.M.  Cunningham.    1973.   Penetration  of   asbestos
through the digestive tract of rats.  Nature.  243:  352-353.   (Cited In  U.S.
EPA, 1980b)

Pooley,   F.D.   1973.   Mesothelloma 1n relation  to exposure,  in:  Biological
Effects   of  Asbestos,  P.  Bogovskl  et a!.,   Ed.    IARC,  Lyon,  France.    IARC
Sc1. Publ.  No. 8.   p.  222-225.   (Cited 1n  U.S. EPA, 1980b)
                                     -53-

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' •',,.*.
                                           APPENDIX

                                  Summary Table for Asbestos
        Carcinogenic
          Potency
Species
Experimental
Dose/Exposure
Effect
           
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Weiss,  A.    1953.   Pleurakrebs  be1  lungenasbestose,  j_n v_1_vo  morphologlsch
geslchert.   Medlzlnlsche.  2: 93.  (Ger.)  (Cited In U.S. EPA, 1980b)

Weiss, W.  1971.   Cigarette smoking,  asbestosis and  pulmonary flbrosls.   Am.
Rev. Resp.   DIs.   104: 223.  (Cited 1n U.S. EPA, 1980b)

Westlake,  G.E.,  H.J.  Splut  and  M.N. Smith.   1965.   Penetration  of colonlc
mucosa  by  asbestos particles.   An  electron  microscopic study  In  rats  fed
asbestos dust.  Lab. Invest.  14: 2029-2033.  (Cited In U.S. EPA, 1980b)
                                               	    _  60604-3590
                                     -58-

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U.S. EPA.  1983d.  Methodology and  Guidelines  for  Reportable  Quantity  Deter-
minations  Based  on  Chronic  Toxlclty  Data.    Prepared  by the  Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA  for  the  Office  of Solid
Waste and Emergency Response, Washington,  DC.

U.S. EPA.   1985.   Drinking  Water  Criteria  Document for  Asbestos.   Prepared
by  the  Environmental  Criteria  and Assessment  Office,  Cincinnati,  OH,  OHEA
for the Office of Drinking Water,  Washington,  DC.   Final draft.

Wagner, J.C.   1963.   Asbestosls  1n experimental  animals.   Br.  J. Ind.  Med.
20: 1-12.  (Cited In U.S.  EPA,  1983a)

Wagner,  O.C.,  C.A.  Sleggs  and P.  Harchand.    1960.   Diffuse pleura!  meso-
theHoma and asbestos  exposure  In  the Norwestern Cape  Provlce.   Br.  J.  Ind.
Med.  17: 260-271.   (Cited 1n U.S.  EPA, 1980b)

Wagner, J.C.,  6.  Berry, J.W. Skldmore  and  V.   Timbrel!.  1974.   The effects
of the  Inhalation of asbestos  In rats.  Br.  J. Cancer.   29:  252-269.  (CUed
1n U.S. EPA, 1983b)

Wagner,  J.C.,  G.  Berry,  T.J.  Cooke,  R.J.  H111  and  J.W.  Skldmore.   1977.
Animal   experiments  with talc.  In:  Inhaled Particles  and  Vapors,  IV,  W.C.
Walton, Ed.  Pergamon Press,  NY.   (In  press)  (Cited 1n U.S.  EPA,  1980b)

We1nzwe1gh, M. and R.G. Richards.   1983.  Quantitative  assessment of chryso-
tlle fibrils   1n  the  bloodstream  of   rats  which have  Ingested  the  mineral
under different dietary conditions.  Environ.  Res.  31(2): 245-255.
                                     -57-

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Strelb,  W.C.    1978.   Asbestos.  ln_:  K1rk-0thmer  Encyclopedia  of  Chemical
Technology,  3rd ed..  Vol.  3.  M.  Grayson,  Ed.   John Wiley  and Sons,  New
York.  p. 267-283.

Tlmbrell,  V.   1965.   The  Inhalation  of fibrous  dusts.   Ann. NY  Acad.  Sc1.
132: 255-273.  (Cited 1n U.S.  EPA, 1980b)

U.S. EPA.   1980a.    Guidelines  and  Methodology  Used  1n  the Preparation  of
Health  Effects  Assessment  Chapters  of  the  Consent  Decree  Water  Quality
Criteria.  Federal  Register.  45: 79347-79357.

U.S. EPA.   1980b.    Ambient  Water  Quality  Criteria for Asbestos.   Environ-
mental  Criteria  and Assessment  Office, Cincinnati,  OH.   EPA  440/5-80-022.
NTIS PB 81-117335.

U.S.  EPA.    1983a.    Reportable  Quantity   for  Asbestos.   Prepared  by  the
Environmental  Criteria  and  Assessment  Office,  Cincinnati,  OH,  OHEA  for  the
Office of Solid Waste and Emergency  Response, Washington,  DC.

U.S. EPA.   1983b.   Review  of  Tox1colog1c   Data  1n Support of Evaluation  of
Carcinogenic Potential  of Asbestos.   Prepared  by  the Carcinogen  Assessment
Group,  OHEA,  Washington,  DC  for  the  Office  of  Solid  Waste and  Emergency
Response, Washington, DC.

U.S. EPA.   1983c.   Technical Support  Document on  the Ranking of  Hazardous
Chemicals  Based  on  CarclnogenlcHy.   Prepared  by  the Carcinogen  Assessment
Group,  OHEA,  Washington,  DC   for  the  Office  of  Emergency  and  Remedial
Response, Washington, DC.

                                     -56-

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Sellkoff, I.J., et al.   1968.  Asbestos  exposure,  smoking  and  neoplasla.   J.
Am. Med. Assoc.  204: 106.  (Cited In U.S. EPA, 1980b)

Sellkoff, I.J., E.G. Hammond and  H.  Seldman.   1979.   Mortality experience of
Insulation  workers   1n  the United  States  and Canada,  1943-1977.   Ann.  NY
Acad. Scl.  330: 91.   (Cited 1n U.S.  EPA, 1980b)

Shettlgara,  P.T.  and R.W.  Morgan.   1975.  Asbestos,  smoking,  and  laryngeal
carcinoma.  Arch.  Environ. Health.   30(10):   517-519.   (Cited 1n U.S.  EPA,
1983b)

Slgurdson,  E.E.   1983.   Observations of cancer  Incidence  surveillance  In
Duluth, Minnesota.  Environ. Health Perspect.   59:  61-67.

Slncock,  A.M.   1977.   Iji  vitro   chromosomal  effects  of  asbestos and  other
materials.  |n_: Origins  of  Human-Cancer.   Cold Spring Harbour, 1976.   (Cited
1n U.S. EPA, 1980b)

Slncock,  A.  and  M.  Seabrlght.   1975.   Induction  of  chromosome changes  1n
Chinese hamster cells  by exposure to asbestos  fibers.   Nature.   257:  56-58.
(Cited 1n U.S. EPA,  1980b)

Smith,  W.E.   1973.    Asbestos, talc,  and  nitrates  1n  relation to  gastric
cancer.  Am. Ind.  Hyg. Assoc.  J.   33: 227.  (Cited  1n U.S.  EPA, 1980b)

Storeygard,  A.R. and A.L.  Brown.   1977.   Penetration  of  the  small Intestinal
mucosa by asbestos  fibers.  Mayo  Cl1n.  Proc.   52: 809-812.   (Cited  1n  U.S.
EPA, 1980b)

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 Pylev,  L.N.  and  L.M.  Shabad.   1973.   Some  results  of experimental  studies  1n
 asbestos  cardnogenesls.   In:  Biological Effects of  Asbestos,,  P.  Bogovski  et
 al.,  Ed.   IARC,  Lyon,  France.   Sc1.  Publ.  No.  8.   p. 99-105.   (Cited 1n U.S.
 EPA,  1980b)

 Reeves,  A.L.  1976.   The carcinogenic  effect of  Inhaled asbestos  fibers.
 Ann.  CUn. Lab. Sd. . 6: 459-466.  {Cited 1n U.S.  EPA, 1983b)

 Reeves,  A.L.,  H.E.  Puro  and  R.G.  Smith.   1974.   Inhalation  cardnogenesls
 from  various forms  of  asbestos.  Environ.  Res.  8:  178-202.   (Cited  1n U.S.
 EPA,  1980b)

 Rouhler, 0., C. Andre,  D.  Allard,  J.  Glllon  and R.  Brette.  1982.   Malignant
 alpha  chain  disease  and  exposure  to  asbestos.    Environ.   Res.    27(1):
 222-225.  (Cited 1n U.S. EPA, 1983b)

 Sellkoff, I.J.   n.d.  Personal  communications.   (Cited In  U.S..  EPA,  1980b)

 Sellkoff,  I.J.   1976.   Lung  cancer and mesothelloma  during prospective sur-
 veillance  of 1,249 asbestos  Insulation workers,  1963-1974.   Ann.  NY  Acad.
 Sd.  271: 448.  (Cited 1n U.S. EPA, 1980b)

Sellkoff, I.J., et al.  1964.   Asbestos exposure and  neoplasla.  J.  Am. Med.
Assoc.  188:  22.   (Cited 1n U.S. EPA, 1980b)

Sellkoff, I.J., et al.  1965.   The  occurrence  of asbestosls among Insulation
workers 1n the United States.   Ann.  NY  Acad. Sd.  132: 139.   (Cited  In U.S.
 EPA, 1980b)

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