EPA-540/1-86-036
                     Environmental Protection
                     Agency
Office of Emergency and
Remedial Response
Washington DC 20460
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 VINYL CHLORIDE

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                                                       EPA/540/1-86-036
                                                       September 1984
OO2\
                   HEALTH  EFFECTS  ASSESSMENT
                        FOR VINYL CHLORIDE
                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 Prote'ctlon  Agency

                            Region V,  Ubr^ry
                            2~G  ^>;>ih rrjrbcm Street
                            Ch,r-o, ll'^cis  60504

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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  1t 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  vinyl
chloride.   All   estimates   of  acceptable  Intakes  and  carcinogenic  potency
presented  In  this  document should be  considered as preliminary and  reflect
limited  resources   allocated   to  this  project.   Pertinent  toxlcologlc  and
environmental data  were located  through  on-Hne literature searches  of  the
Chemical Abstracts, TOXIINE, CANCERLINE  and  the CHEHFATE/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.   1980a.   Ambient  Water  Quality  Criteria   for  Vinyl
    Chloride.   Environmental   Criteria  and  Assessment  Office.  Cincin-
    nati, OH.  EPA 440/5-80-078.   NTIS PB 81-117889.

    U.S. EPA  1982.  Health and Environmental Effects  Profile  for  Vinyl
    Chloride.   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.   1983a.   Repor table Quantity Document for Vinyl  Chloride.
    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 Toxlcologlc Data  In. Support  of Evalua-
    tion for  Carcinogenic   Potential  of: Vinyl  Chloride.   Prepared  by
    the  Carcinogen  Assessment Group,   OHEA,  Washington,  DC  for  the
    Office of Solid Waste and Emergency Response, Washington,  DC.


    The Intent  1n 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.

    Whenever possible,  two categories of values  have been estimated for  sys-
temic toxicants  (toxicants  for which cancer 1s  not  the  endpolnt of  concern).
The  first,  the  AIS  or acceptable Intake  subchronlc,   1s 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  Hfespan).   This  type  of
exposure estimate  has  not   been  extensively  used  or  rigorously defined,  as
previous  risk  assessment   efforts   have  been   primarily   directed  towards
                                      111

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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.  Subchronlc  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,   1s  similar  1n  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 Hfespan [see  U.S.  EPA (1980b) for a  discussion
of  this  concept].   The  AIC  1s  route specific  and  estimates   acceptable
exposure  for  a given  route  with  the   Implicit  assumption  that exposure  by
other routes 1s Insignificant.

    Composite  scores  (CSs)  for  noncardnogens  have  also  been  calculated
where data  permitted.   These  values  are used for ranking  reportable  quanti-
ties; the methodology for their development 1s explained  1n U.S.  EPA (1983c).

    For compounds for which there 1s sufficient  evidence  of  carc1nogen1c1ty,
AIS  and AIC values  are not derived.   For a  discussion  of risk  assessment
methodology for  carcinogens  refer to  U.S. EPA  (1980b).   Since cancer  1s  a
process  that  1s  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.

    Vinyl  chloride  following  inhalation exposure   has  been  shown  to  be
carcinogenic  1n humans,  rats,  mice and hamsters.   Using data  for  tumor
Incidence  1n   rats,   a   q-|*   for  humans  of   2.5xlO~2  (mg/kg/day)"1   was
estimated.

    No  data  are  available concerning  oral  exposure In  humans  and  cancer
risk.   On the  basis  of  total  tumors  1n female rats  fed vinyl  chloride-
containing  diets,   a  human   q-j*  of  2.3 (mg/kg/day)'1  was  estimated  for
oral exposure.

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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  wastthe Project
Officer.  The final documents  1n this  series  were  prepared  for the Office of
Emergency and Remedial Response, Washington, OC.

    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 Olsen and Erraa 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
                                      vl

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TABLE OF CONTENTS

1.
2.


3.








ENVIRONMENTAL CHEMISTRY AND FATE 	
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL ... 	
INHALATION 	
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	
3.1.


3.2.


SUBCHRONIC 	
3.1.1. Oral 	
3.1.2. Inhalation 	
CHRONIC 	
3.2.1. Oral 	
3.2.2. Inhalation 	
Page
. . . 1
. . . 2
. . . 2
. ... 2
. . . 3
. . . 3
. . . 3
. . . 3
7
. . . 7
. . . 7



4.








5.


3.4.
3.3.1. Oral 	
3.3.2. Inhalation 	
TOXICANT INTERACTIONS 	
CARCINOGENICITY 	
4.1.


4.2.


4.3.
4.4.
HUMAN DATA 	
4.1.1. Oral 	
4.1.2. Inhalation 	
BIOASSAYS 	
4.2.1. Oral 	
4.2.2. Inhalation 	
OTHER RELEVANT DATA 	
WEIGHT OF EVIDENCE 	
REGULATORY STANDARDS AND CRITERIA . . .
	 10
	 	 	 10
	 J. . . . 11
	 12
. . . .• 	 12
	 12
	 12
	 15
	 15
	 20
	 32
	 33
	 35
       V11

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                           TABLE  OF  CONTENTS (cont.)

                                                                        Page

 6.  RISK ASSESSMENT	   37

     6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)  	   37
     6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)	   37
     6.3.   CARCINOGENIC POTENCY (q-j*)	   37

            6.3.1.   Oral	'.   37
            6.3.2.   Inhalation	   38

 7.  REFERENCES. .	   39

APPENDIX A: Summary Table for Vinyl Chloride  	   54

APPENDIX B: Cancer Data Sheet for Derivation of q*	   55

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                               LIST OF TABLES

No.                               Title                                Page

4-1     Epidemiology Studies on the Cardnogenlclty of
        Vinyl Chloride	   13

4-2     Type and Incidence of Statistically Significant Treatment-
        Related Changes In the Liver and Lung of Male Wlstar Rats
        Exposed to VCM 1n the Diet	   17

4-3     Type and Incidence of Statistically Significant Treatment-
        Related Changes 1n the Liver and Lung of Female Wlstar
        Rats Exposed to VCM 1n the Diet	   IS

4-4     Tumor Incidences 1n Sprague-Dawley Rats Dosed with
        Vinyl Chloride by Gavage	   19

4-5     Incidence of Tumors 1n Sprague-Dawley Rats Exposed
        4 Hours/Day, 5 Days/Week,  for 52 Weeks by Inhalation to
        Various Concentrations of  Vinyl Chloride:  Results after
        135 Weeks	   21

4-6     Tumor Incidences In Male Wlstar (Ar/IRE) Rats Exposed to
        30,000 ppm of Vinyl Chloride by Inhalation	   23

4-7     Tumor Incidences 1n Sprague-Dawley Rats Exposed to
        100-10,000 ppm of Vinyl Chloride	,. . .  .   24

4-8     Tumof Incidences 1n Sprague-Dawley Rats, Swiss Mice and
        Syrian Golden Hamsters Exposed to Various Concentrations
        of Vinyl Chloride by Inhalation 	   25
                                                   *

4-9     Tumor Incidences In CD Rats and CD-I Mice Exposed to
        50-1000 ppm of Vinyl Chloride by Inhalation 	   28

4-10    Tumor Incidences 1n CD Rats and CD-I Mice Exposed to
        Various Concentrations of  Vinyl Chloride by Inhalation. ...   30

5-1     Hygienic Standards for Occupational Exposure to Vinyl
        Chloride 1n Foreign Countries 	   36
                                     1x

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                             LIST  OF ABBREVIATIONS
ADI
AIC
AIS
bw
CAS
CNS
CS
PEL
GOT
GPT
LOAEL
NED
NOAEL
NOEL
ppm
PVC
TLV
TWA
VCM
Acceptable dally Intake
Acceptable Intake chronic
Acceptable Intake subchronlc
Body weight
Chemical abstract service
Central nervous system
Composite score
Frank-effect level
Glutamlc oxaloacetlc transamlnase
Glutamlc pyruvlc transamlnase
Lowest-observed-adverse-effect level
Minimum effective dose
No-observed-adverse-effect level
No-observed-effect level
Parts per million
Polyvlnyl chloride
Threshold limit value
Time-weighted average
Vinyl chloride monomer

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                     1.  ENVIRONMENTAL CHEMISTRY AND FATE
    The  relevant  physical  and chemical properties  and  environmental  fate of
vinyl  chloride (CAS  No.  75-01-4),  also  known as  chloroethene, are  given
below.
     Chemical class:                  halogenated aliphatic hydrocarbon
                                      (purgeable halocarbon)
     Molecular weight:                62.5
     Vapor pressure:                  2660 mm Hg at 25°C
                                      (Callahan et al.. 1979}
     Water solubility:                2760 mg/l at 25'C (Horvath, 1982)
                                      1100 mg/kg at 28"C
                                      (U.S. EPA, 1980a)
     Octanol/water partition
     coefficient:                      24 (estimated) (U.S. EPA, 1980a)
     Bloconcentratlon factor:         2.97 (estimated) (U.S. EPA, 1980a)
     Half-lives 1n
        Air:                          1.2 days (Singh et al., 1981)
        Water:                        several minutes to a few hours
                                      (Callahan et al., 1979)
                                      1-5 days (estimated)

    The estimated half-life  values  for  vinyl chloride 1n  aquatic  media have
been derived  from the reaeratlon rate  ratio (0.675) and  the  oxygen  reaera-
tlon rate of 0.19-0.96 day'* given by Habey et al.  (1981).
    The fate  of vinyl  chloride 1n soil 1s not  known  with certainty.   Evapo-
ration  Is  expected  to  be  the  predominant  loss  mechanism  from  the  soil
surface.   The half-life  for  soil   evaporation  should  be  longer  than  Its
evaporative half-life  from water.   Despite  Us expected low soil  sorptlon
rate and  Insignificant blodegradatlon  rate (Callahan et al.,  1979; Mabey  et
al., 1981), the probability of groundwater contamination  through leaching  of
vinyl  chloride from soil  Is low (Page,  1981).
                                     -1-

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           2.  ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1.   ORAL
    Although quantitative data are not available, WUhey  (1976) and Watanabe
et  al.  (1976a)  have  reported rapid  absorption  of  vinyl  chloride from  the
gastrointestinal tract Into the blood  of  dosed rats.
2.2.   INHALATION
    Rapid absorption .and equilibration of vinyl chloride  from  the  lungs  Into
the  bloodstream have  been  reported  for  rats exposed  to the  compound  by
Inhalation (Duprat et al., 1977; Watanabe et  al.,  1976b;  Bolt  et al.,  1977).
Within  10  minutes  following  Inhalation  exposure  of rats  to  20,000  ppm  of
[14C]  vinyl  chloride  for  5 minutes,  [14C]   was  found  1n several  tissues
of  the  exposed  animals  (Duprat et  al., 1977).  In a brief  review  of  a  study
regarding  the   Inhalation  uptake  of   vinyl   chloride  by  rats  (VJUhey  and
Collins, 1976), the  U.S.  EPA (1980a)  stated  that 1n 200  g  rats, the  concen-
                                                              j
tratlon of vinyl  chloride  1n blood produced  by 1ntak1ng  1.97  ppm  was  equiv-
alent  to  that   produced   by   gavage  treatment  with  4.5  mg/kg/day.    This
relationship held true for gavage doses ranging from"2-25  mg/kg/day.
                                      -2-

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                3.  TOXICITY  IN  HUMANS  AND  EXPERIMENTAL  ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.  Feron  et  al. (1975) administered  vinyl chloride  monomer  by
gavage to groups of  15 male and 15  female Wlstar  rats  at a  level  of 0, 30,
100  or  300 mg/kg  bw,  6  days/week, for  13 weeks.   Both  males and  females
given  the  highest  dose   level  had   significantly  Increased  Hver-to-body
weight ratios  1n  the  absence  of  hepatic  damage.   Males  given the  highest
dose  level  also had  significantly decreased  adrenal-to-body weight  ratio.
Several  hematologlcal  and biochemical  changes were  reported,  but Feron  et
al.  (1975)  expressed  reservations  about  the  toxlcologlcal   significance  of
these changes.  The  reported hematologlcal and biochemical  changes Included
a  significantly decreased  number  of  leucocytes   In  the mid- and  high-dose
groups of females; significantly decreased blood sugar  In  the mid- and high-
dose groups of  both  sexes; and significantly  decreased  serum GOT,  serum GPT
                                                              j
and urinary GOT 1n the  high-dose group of  males.   Hepatocellular  rough endo-
plasmlc  retlculum  of both sexes  of high-dose  groups  was hyper trophic.   No
treatment-related  effects  were  reported  for  the  lowest  dose groups.   The
authors  considered 30  mg/kg to  be the NOEL  of  this  experiment but  also
stated that a somewhat higher no-effect level  could be expected.
3.1.2.   Inhalation.     Several   subchronlc  Inhalation   studies    of   vinyl
chloride have been summarized  by U.S.  EPA (1983a).  Due to  the  time  limita-
tions of this project,  the subchronlc  studies  discussed below were taken,  1n
part, from that document.
    A three-part  subchronlc  Inhalation  study  of  rats,  guinea pigs,  rabbits
and dogs revealed  toxic effects  1n  rats  and rabbits  exposed  to 50-500 ppm of
vinyl chloride, but not 1n guinea  pigs or  dogs (Torkelson  et al.,  1961).  In
the first part  of  the study, 10 male and  10 female  rats- were exposed to 500
                                      -3-

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ppm  (1278  mg/m3) of  vinyl  chloride for  7 hours/day,  5  days/week,  for  4.5
months.  Five unexposed  rats  of  each sex  served as  controls.   This exposure
level  resulted  In central  lobular  granular  degeneration 1n  the  liver  and
Interstitial and  tubular  changes 1n the  kidneys.   The average  liver weight
of both sexes of  experimental  animals  was Increased  over  controls; however,
this Increase was statistically significant 1n males only  (p=0.001).
    In the  second part  of the study, rats (20-24 males,  24  females), guinea
pigs  (10  male,  8 female),  rabbits  (3  male,  3 female) and  dogs (1  male,  1
female) were exposed  to 100  or  200  ppm (255.6  or  511.2  mg/m3)  of  vinyl
chloride for 7 hours/day, 5 days/week,  for 6  months.   In  addition,  groups of
five male  rats were  exposed to 100 or  200 ppm of vinyl chloride for  0.5, 1,
2  or  4  hours/  day,  5  days/week,  for 6  months.   Both  unexposed  and  air-
exposed controls  were used for  each species.  At  the 200 ppm,  7  hours/day
level,  the livers of  both sexes  of rabbits  were affected  by  exposure to
                                                              i
vinyl  chloride,  characterized by  central lobular  granular  degeneration In
both  sexes and  necrosis  with foamy  vacuolatlon 1n  males or  necrosis  with
perlportal  cellular  Infiltration  1n females.   Increased   mean  liver  weights
were  observed  In male  and  female rats  exposed  to 100 or 200  ppm of  vinyl
chloride for 7 hours/day  (p<0.005, as compared with controls).
    In  the third part of the  study,  rats (24 male,  24 female), guinea pigs
(12 male,  12 female),  rabbits  (3 male,  3  female)  and dogs (1 male,  1 female)
were  exposed to  50 ppm  (127.8 mg/m3)   of  vinyl  chloride   for 7  hours/day,  5
days/week,  for 6 months.   In  addition, groups of 10  male rats were exposed
to  50 ppm  of  vinyl  chloride  for  1, 2 or 4  hours/day,  5 days/week,  for  6
months.  Both unexposed  and air-exposed controls were used for  each  species.
                                      -4-

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For  all  species tested, there  was  no difference  between  treated or control
animals In regard  to mortality,  growth,  organ weights, or microscopic exami-
nation  of tissues.  This  study  suggests  a  NOEL  for  rats  of  50 ppm  and a
LOAEL  of  100 ppm  of vinyl  chloride for Increased liver weights,  and a NOEL
for dogs and guinea pigs of 200 ppm of vinyl chloride.
    A  total   of 27  CD-I  Charles  River  white  male  mice  were   exposed  to
2500-6000  ppm (6391  or  15,337  mg/ma) of  vinyl  chloride for 5  hours/day, 5
days/week, for  5 or  6  months (Suzuki,  1978).  Resultant alveologenlc tumors
1n mice  were examined  by  light and electron microscopy to characterize the
toxic  changes  that occur before  tumor  formation.   Suzuki  (1980)  reported a
series  of pathological  changes  Including  proliferation and hypertrophy  of
the  terminal  bronchlolar  cells  (ciliated  and  Clara  cells), hyperplasla  of
the  alveolar  epithelium,  degeneration  of  alveolar  septal  cells, and  occa-
sional perlbronchlolar  or  bronchlolar Inflammation.   These changes  occurred
                                                              *
1n the  lungs  of almost  all  of  the  treated mice,  regardless  of  whether they
were exposed to 2500 or 6000 ppm of  vinyl chloride.
    Sokal  et  al.  (1980)  Investigated  the  effects"  of chronic  Inhalation
exposure to vinyl  chloride  with male rats  (strain and number not reported).
The  rats  were exposed  to 0,  50, 500 or  20,000  ppm of  vinyl chloride  for 5
hours/day, 5  days/week,  for 10  months.   Morphological lesions  1n the  liver
and  testes,  depression  of  body weight  gain. Increased  organ  weights,  and
slight hematologlcal and biochemical  changes 1n  the blood were  observed  1n
treated animals.   The  abstract  of  this  study did  not distinguish  between
level  of  exposure  and  toxic effects, and the paper  was  not available  for
further review.
                                     -5-

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    Following  acute  toxlclty determinations  for vinyl  chloride,  Prodan  et
al.  (1975)  studied the  long-term  effects of  vinyl  chloride In guinea  pigs
(strain and  sex  not  reported)  1n  a subchronlc  Inhalation  study.  Groups  of
10 guinea  pigs were exposed  to 0  or  10%  (0  or 100,000  ppm;  0  or  255,624
mg/m3)  vinyl   chloride  vapors  for  2  hours/day  for  a  period  of 90  days.
There  was  a  statistically  significant   (p<0.01)  slowed  growth  1n  exposed
animals when compared  to controls.   Vinyl chloride had a  narcotic effect  on
treated animals,  resulting 1n  decreased  spontaneous  activity.   There was  a
significant Increase 1n  mean kidney weight  In those guinea pigs  exposed  to
10%  vinyl  chloride,  but  the  mean  liver  weight  was  similar to  that  of
controls.  Hepatocellular  lesions  covering  the entire lobule but  more dense
toward  the center, hepatocellular  necrosis, and  flbroblastlc and  Kupfferlan
proliferation  were observed  1n the  livers of  experimental animals  during
hlstopathologlcal  examination.   Moderate  lesions of  the  glomerull,  marked
lesions  In the  renal   tubules, a  strong  cellular  reaction *1n  the  spleen
(marked  by  almost total  disappearance  of  the red  pulp),  and  pulmonary
flbrosls were  also  noted  1n  guinea  pigs  exposed* to  10% vinyl  chloride.
Hematologlcal  parameters  of  treated  animals  paralleled  those  of  control
animals.
    In  another subchronlc  Inhalation  study,  Lester  et  al. (1963)  exposed
groups  of  15 male  and  15 female Sherman rats  to  0 or 2.0% (0  or 20,000 ppm;
0  or  51,125  mg/m3) vinyl  chloride  vapors for 8  hours/day,  5  days/week,  for
3  months.  No  differences  1n body weight, hemoglobin values,  hematocrU  and
prothrombln  values,  monocytes,  eoslnophlls,   or external  appearance  were
noted  between  experimental  and  control animals.  The only differences noted
1n rats  exposed  to 2% vinyl  chloride  1n comparison to those not  exposed  to
                                      -6-

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vinyl  chloride were  a  significant  Increase 1n  mean  liver  weight  and  a
significant  decrease   In  mean  spleen  weight.    There  was  no  evidence  of
tumor1genes1s 1n any organs or tissues examined  h1stopatholog1cally.
3.2.   CHRONIC
3.2.1.   Oral.  Feron  et  al.  (1981)  administered  vinyl  chloride  monomer  to
five  groups  of  60-80 male  and 60-80  female Wlstar  rats by  Incorporating
polyvlnyl chloride powder with a high content of  vinyl chloride  monomer Into
the diet  or  by gastric Intubation  of a 1054  vinyl chloride monomer  1n  soya-
bean oil.  The dietary levels of vinyl  chloride monomer  provided doses  of 0,
1.7, 5.0  and  14.1  mg/kg/day as  determined by measured food  consumption,  and
the gastric  Intubation dose level  was 300 mg/kg  bw  given  5  days/week.   Ani-
mals were  treated  for  their Hfespan.  A dose-related Increase  In mortality
was reported, with decreased  survival at  all  dose levels.  There was also an
Increase  1n  a  variety of  neoplastlc  and  non-neoplastlc  treatment-related
                                                              i
hepatic lesions at  all dose levels.  Other treatment-related effects at  the
14.1  mg/kg/day and  300  mg/kg  bw  levels  Included  shortened  blood-clotting
times, slightly Increased  serum  alpha-foetoproteln levels, hepatomegaly,  and
Increased  splenic  hematopoletic  activity.    Feron et al. (1981)  concluded
that the NOEL  for  vinyl chloride to rats  was  <1.7 mg/kg/day,  the lowest dose
tested 1n this study.
3.2.2.   Inhalation.  Numerous chronic  Inhalation  studies  of  vinyl  chloride
1n humans and  experimental animals  have been  summarized  by U.S.  EPA (1983a).
Due to  the time limitations  of  this project, the chronic studies discussed
below were taken,  1n part, from that document.
    There are  numerous clinical  Indications that  chronic Inhalation exposure
to  vinyl  chloride  1s toxic  to humans  (U.S.  EPA,  1980a).    Hepat1t1s-I1ke
changes,  angloneurosls,   Reynaud's  syndrome,  dermatitis,  acro-osteolysls,
                                      -7-

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thyroid Insufficiency, and  hepatomegaly  have  been reported (Cordler et al.,
1966;  Dlnman  et  al., 1971;  FHatova  et  al., 1958;  Harris  and Adams, 1967;
Marsteller  and  Lebach,  1975;  Trlbukh  et  al.,  1949;  Wedrychowlez,  1976;
Wilson et  al.,  1967).  Other  long-term  effects  Include functional  disturb-
ances of  the  CNS  with adrenerglc  sensory polyneuMtls {Smlrnova and Granlk,
1970);  thrombocytopenla,   splenomegaly,   Hver   malfunction  with   flbrosls,
pulmonary changes  (Lange  et al.,  1974); alterations  1n  serum enzyme  levels
(Makk et al., 1976);  portal  hypertension attributed  to an  abnormality  of  the
portal  vein  radicles,  or  hepatic  sinusoids  (Blendls  et  al.,  1978);   and
anglosarcoma or flbrosls  of the liver and acro-osteolysls, all of  which  are
accompanied by mlcrovascular abnormalities  (MaMcq et al.,  1976).
    Chronic  Inhalation  studies  of  experimental  animals  exposed  to vinyl
chloride  yield toxic  effects similar  to  those seen  1n humans,  Involving  the
liver,  spleen,  kidneys,  hematopoletlc  system   and  skeletal   system.   In  a
three-part  study, Feron et  al.  (1979a,b) and  Feron  and  Kroes  (1979) Investi-
gated  the  toxic  effects  of chronic Inhalation exposure  to vinyl  chloride 1n
Wlstar rats.  Groups  of 62  male and 62 female rats were exposed to 0 or  5000
ppm  (0 or  12, 781  mg/m3)  of  vinyl  chloride for  7 hours/day, 5  days/week,
for  52 weeks.  In the first part  of   the study,  growth, mortality, hematol-
ogy,  clinical chemistry  and  organ   weights  were  examined  (Feron et  al.,
1979a).   In rats exposed  to 5000 ppm of  vinyl  chloride,  treatment-related
toxic  effects Included slight  growth retardation;  slightly shortened blood
clotting  time;  Increased  potassium  contents of the blood serum;  Increased
blood  nitrogen  urea levels;  Increased  kidney, heart  and  spleen weights;
slight  signs  of  anemia; and mortality.  In  the  second part of  the  study,  the
experimental  animals  were examined for morphological changes  In the respira-
tory  tract, cerumlnous  glands, brain, kidneys,  heart and spleen  (Feron  and
                                      -8-

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Kroes,  1979).    Rats  exposed  to  5000 ppm  of  vinyl   chloride  had  tubular
nephrosls,  mild  focal  degeneration  of  the myocardium,  Increased  hemato-
poletlc activity  1n  the spleen, and  tumors  of the  brain,  lungs,  cerumlnous
glands and  nasal  cavity.   The third part of the  study.  In  which the morpho-
logical changes  1n the liver  were examined, Indicated  degenerative,  hyper-
plastic  and  neoplastlc  changes  (Including  hepatocellular  carcinoma)  1n
hepatic parenchyma, and anglosarcoma  of the liver 1n  rats  after exposure to
5000 ppm  of vinyl  chloride (Feron et al., 1979b).   It seems likely that the
mortality observed among  treated animals may  have been due  to  the carcino-
genic  response.   Neither  a NOEL nor  a  NOAEL for vinyl  chloride  In rats can
be  suggested from this  study, as  the only exposure level  tested  (5000 ppm)
was a PEL for Increased mortality, among other  effects.
    Viola (1970) exposed groups  of  25  male VMstar albino rats to 0 or 30,000
ppm of  vinyl  chloride (equivalent  to  0 or  76,690 mg/ma) for  4  hours/day,  5
                                                              j
days/week,  for  12 months.  H1stolog1cal  examination  was  performed on  the
paws,  brain,  liver,   kidneys   and  thyroid.   Metatarsal  bone  metaplasia  and
chondrold metaplasia  were  observed  1n treated  animals.  The skin covering
the paws  was affected by  epidermal  hyperkeratosls,  basal layer vacuollzatlon
and  degeneration, disappearance  of   the  cutaneous   adnexa,  and  epidermal
edema.  Diffuse  degenerative  lesions  of the  grey and  white matter of  the
brain and atrophy of the  granular  layer of  the  cerebellum were also observed
1n  animals  exposed  to 30,000  ppm  of  vinyl  chloride.   The  livers  of treated
animals  were  characterized   by  Increased  volume,   diffused  Interstitial
hepatitis,  abnormal  proliferation  of  Kupffer's  cells  (often hypertrophlc)
and partial  necrosis.   The kidneys were marked by signs of tubulonephrosls
that  were  sometimes  accompanied  by  chronic   Interstitial  nephritis.   The
thyroid was affected by  colloid  goiter  and an  Increase  1n  parafolllcular
                                      -9-

-------
cells.  Similar  hlstopathologlcal  changes  were not  seen  In the  skeleton  or
organs of  control animals.   The only  exposure level  tested  In  this  study
(30,000 ppm) also represents a PEL.
3.3.   TERATOGENICITY AND OTHER .REPRODUCTIVE EFFECTS
3.3.1.   Oral.   Pertinent  data  regarding  the  teratogenlclty   of   orally
administered vinyl chloride could not be located In  the available literature.
3.3.2.   Inhalation.   Vinyl  chloride was not  teratogenlc when  administered
by  Inhalation  to rats,  mice or  rabbits  (Ungvary  et al.,  1978;  John  et  al.,
1977, 1981).   The  discussion  of  these studies that  appears  below was taken,
In part,  from U.S. EPA (1983a).
    In a  teratogenlclty  study  In CFY  rats, Ungvary  et  al.  (1978)  exposed
groups  of  13-28  pregnant  rats  to 0  or  4000  mg/m3  (-1500  ppm)  vinyl
chloride  for   24 hours/day  during   days  1-9,  8-14  or 14-21  of  gestation.
 *
Significantly  Increased  (p-0.05)  fetal  mortality and  fetotoxlc  effects  were
observed 1n the  offspring of dams exposed to vinyl  chloride daring the first
third of  pregnancy (days 1-9  of  gestatton).  Similar effects were  not  seen
In  offspring  of  dams exposed  1n  the second or last* third  of  pregnancy.   No
teratologlcal  effects related  to vinyl  chloride  exposure were noted  1n  any
of the experimental groups.
    John et al.  (1977,  1981)  performed a teratogenlclty  study with  pregnant
CF1  mice,  Sprague-Dawley  rats and  New Zealand  white rabbits.   Initially,
groups of  30-40  bred mice,  20-35  bred rats  and   15-20  bred  rabbits  were
exposed  to  500  ppm  (-1278 mg/m3)  vinyl chloride  for 7  hours/day  on  days
6-15 '(mice  and rats) or  6-18  (rabbits)  of   gestation.  Using  the same expo-
sure  period,  mice were  subsequently exposed  to 50  ppm  (-128  mg/m3)  vinyl
chloride  and  rats and  rabbits  to  2500 ppm (-6390 mg/m3)  vinyl  chloride.
                                     -10-

-------
These exposures  resulted 1n maternal toxldty, but  no  significant embryonal
or  fetal  toxlclty or  gross teratogenlc abnormalities  were observed  1n  the
offspring of  exposed  dams.   There were excess occurrences  of  minor skeletal
abnormalities  and Increased  fetal  deaths at  the  higher  exposure  levels;
however,  neither  of  these  effects  occurred  at  a  statistically  significant
Increased Incidence when compared with respective control animals.
3.4.   TOXICANT INTERACTIONS,
    Metabolism of  vinyl  chloride by  rats  In  vivo  1s Inhibited  by pretreat-
ment with ethanol or  pyrazole,  which  1s  an  Inhibitor of alcohol  dehydro-
genase,  xanthlne  oxldase  and  other  enzymes (Hefner  et  al.t  1975; Carter  and
Isselbacher,  1972).   In  rats,  simultaneous chronic  1ngest1on  of  ethanol  and
Inhalation  exposure   to   vinyl  chloride  Increased  the  Incidence of  liver
tumors  and  tumors In other  sites  as compared to the Incidence  expected  for
exposure  to only  vinyl  chloride (Radlke et a!., 1977).   Jaeger  (1975)  found
that the  effects  on rats  of 4-hour  Inhalation  exposures to  2od ppm of vlnyl-
Idene chloride  and 1000  ppm of vinyl chloride were less severe  than  those
seen after  exposure  to  only 200  ppm of  vlnylldlner chloride.   The  toxlco-
loglcal   endpolnt  used  for comparison  was  serum  alanlne  a-ketoglutarate
transamlnase levels.
                                     -11-

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                             4.  CARCINOGENICITY
4.1.   HUMAN DATA
4.1.1.   Oral.   Pertinent  data  regarding   the   carclnogenlclty  of  oral
exposure to  vinyl  chloride 1n humans  could  not be located 1n  the  available
literature.
4.1.2.   Inhalation.  Numerous case reports  and epidemiology  studies on  the
carclnogenlclty  of  vinyl  chloride  to humans  have been  summarized by  IARC
(1979),  U.S.  EPA  (1980a,  1983b)  and  Infante  (1981).   For  the  purposes  of
this document, only  those  studies  presenting sufficient data on  the  exposed
population and a substantial  number of  cancer  cases  have been reviewed  for
the assessment of carcinogenic risk.  The exposure and  cancer  Incidence  data
are summarized 1n  Table  4-1.   These data have  been previously  summarized by
U.S. EPA (1983b).
    Infante  (1981)  reviewed ep1dem1olog1cal  data  that   Indicate  an assoda-
                                                             i
tlon between  liver  cancer, brain  cancer, lung  cancer,  and hematopoletic  and
lymphatic  cancers  and  vinyl   chloride  exposure.   Waxweller   et  al.  (1976)
reported that  7  of 136  deaths among  1287 workers e'xposed to  vinyl chloride
for  >5  years were  due  to  biliary  and  liver  cancer.  All  seven  deaths
occurred after a latency  period of 15 years.  The Incidence of  biliary  and
liver cancer  among  this  group  of  workers was considered to be  significantly
Increased  (p<0.01) when  compared to the  expected  number of 0.4  cases  1n  this
group.  Similarly, three brain and CNS cancers  were reported after  a  15-year
latency, while only 0.6  were  expected (p<0.05).   Respiratory  system  cancers
numbered 11,  while 5.7 were expected  (p<0.05).   Lymphatic and  hematopoletic
system cancer  occurred 1n  three workers exposed  to vinyl  chloride, which 1s
suggestive of an Increased Incidence  (1.7 expected) but 1s not  statistically
significant.
                                     -12-

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                                                                          TABLE 4-1
                                           Epidemiology Studies on Deaths due  to Cancer Among Vinyl Chloride Workers
Site of Slie of
Exposed Control
Population Population
12B7 U.S. death
rates






750 1969
Swedish
population
7409 death
rates for
England
i, and Males
1 161 161







Level of Duration of
Sex Exposure Exposure Target Organ
N.f NR >5 years liver and
biliary
brain and CNS

lymphatic and
hematopoletlc
respiratory
system
N periodically >10 years liver /pancreas
up to 15,000 <1 to >10 years brain
ppm <1 to >10 years lung
N <25 to >200 6-20 years liver
ppm


N NR NR liver and
biliary tract
brain
lung
digestive
lymphatic and
hematopotetlc
• system
Tumor
Type
cancer

cancer

cancer

cancer

cancer
cancer
cancer
cancer



cancer

cancer
cancer
cancer
cancer


Number
of Cases
Observed*
7

3

3

11

4
2
3
4



a

5
13
13
5


Number
of Cases
Expected
0.4

0.6

1.7

5.7

0.68
0.33
1.78
1.64



0.7

1.2
7.9
8.3
3.4


Relative
Risk Reference
(p value)
16.0 Maxweller
(p<0.01) et al.. 1976
5.0
(p<0.05)
1.8
(NS)
1.9
(p<0.05)
p<0.005 Bryen et al..
p<0.043 1976
p<0.26
2.44 Fox and
Collier, 1977


11.0 Nonson
et al., 1974
4.2
1.6
1.6
1.5


•Incidence of tumors after 15-year latency
NS - Not significant; NR - Not reported

-------
    In  a  cohort  study  of  750 workers  exposed  to  vinyl  chloride  for  >10
years,  Bryen  et al.  (1976)  reported four  Hver/pancreatlc  cancers,  two  of
which were  confirmed "liver  anglosarcomas,  compared  to  0.68 cases expected
(p=0.005).  An additional case of hepatic hemanglosarcoma  occurred after  the
data  were  compiled,  and was  therefore not  Included  1n  the reported  cases.
Two cases of brain cancer were reported compared  to  0.33  expected (p<0.043).
The  Increased  Incidence of  lung  cancer  {3  observed  vs.  1.78 expected)  was
not statistically significant.
    Fox and Collier  (1977) examined  the mortality  of  7409  workers exposed to
vinyl chloride  1n the production of  polyvlnyl  chloride  1n  eight factories.
A  total  of  four deaths due  to  liver cancer were  reported,  compared  to  1.64
expected.  Three  of  these cases occurred  In a factory engaged  1n  polyvlnyl
chloride production  since  1944  (the longest period of those factories  exam-
ined),  while  only 0.13 would have  been  expected (p<0.01)  (Infante,  1981).
                                                              i
It was  noted,  however,  that  75% of this  study cohort had  been  employed  for
<10  years,  which does not allow  for a sufficient latency  period and there-
fore  underestimates the observed risk of cancer.
    Of  161 deaths among vinyl  chloride workers,  there were 8 liver and bili-
ary  cancers  (0.7  expected;  11.0 risk ratio), 5  brain cancers  (1.2 expected;
4.2  risk  ratio), 13  lung  cancers  (7.9 expected;  1.6  risk  ratio),  13 diges-
tive  tract cancers  (8.3 expected;  1.6 risk  ratio), and 5 lymphatic and hema-
topoletlc cancers (3.4  expected; 1.5 risk  ratio)  (Monson  et al., 1974).   The
authors  did  not report statistical  comparisons  of these  data,  but  did  note
an  excess  frequency  of  liver, lung  and brain  cancers.  It was  also reported
that  the  frequency  of all  cancers  Increased  with  length of  exposure  and
latency  {Monson et al., 1974).
                                     -14-

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4.2.   BIOASSAYS
4.2.1.   Oral.  An  oral  study (Feron et al.,  1981)  1n which  vinyl  chloride
was given 1n  the  diet  or  by gavage was used by the U.S. EPA (1984) to derive
a  q,* for  oral  exposure.   In  the dietary  study  groups  of  60 male  and 60
female 5-week-old Wlstar  rats were  fed  diets containing 10% PVC powder (PVC,
containing  not more than  0.3 ppm), which acted as a  carrier  for liquid VCM.
A  control  group  of 80 males  and  80 females was given  a  diet  containing PVC
without added VCM.  The VCM used  In this  study was >99.97X pure.  Diets were
prepared  dally  and offered  for   6 hours  each  day.   In  addition,  another
control group (80 males and 80  females) was fed diets containing PVC without
VCM ad  libitum  and an additional  treatment group (60  males and 60 females)
was given VCM 1n  soya  oil at 300  mg/kg bw/day.  A vehicle control (soya oil)
group was  not used  In this experiment.  The  feeding trials  lasted  for  135
weeks for males and 144 weeks for  females.   Gavage treatment  was performed 5
days/week for 83 weeks.
    Body weights  and food consumptions  were measured  periodically throughout
the study.  Fecal VCM  was subtracted  from VCM  Intake's on the assumption that
H represented VCM  enclosed 1n PVC granules and  not available  to  the body.
Dietary levels of VCM  of 0,  20,  60 and 200 ppm resulted  In actual  exposure
of 0, 1.7,  5.0 and  14.1 mg VCM/kg bw/day.   Complete  hlstopathologlcal exami-
nations were performed on tissues and organs of 20 males and  20 females from
the control (restricted feeding), high-dose  diet and  gavage groups  at termi-
nation.  In addition,  all gross lesions and tumors were hlstopathologlcally
examined as were  selected  tissues  from 10  males  and 10  females  from these
groups sacrificed at 26 and 52 weeks.
                                     -15-

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    A  statistically  significant  dose-related  decrease  1n  survival  became
evident In rats fed diets containing VCM  at  80  weeks  of treatment.   Sur-vlval
was also  reduced  1n  gavage-treated  rats  but statistical  analyses  were  not
performed because a vehicle control group had not  been  maintained.   The U.S.
EPA (1984) reported the  Incidences  of  liver and lung tumors by  type  and the
q * associated  with  each Individual  tumor  1n  rats fed  VCM  In the  diet.
These data are  presented 1n Tables  4-2  (males) and 4-3  (females).   A dose-
related Increased Incidence of hepatocellular carcinomas,  and  liver  and lung
anglosarcomas were  noted  1n  rats  of both sexes.   A high  Incidence  of anglo-
sarcoma of the  lung  (19/60 males.  23/60  females)  was also noted 1n  gavage-
treated  rats.   A  significantly  Increased   Incidence  (p<0.05  at  the  two
highest dose  levels;  Fisher  Exact Test)  of liver  anglosarcomas was  seen 1n
Sprague-Dawley  rats  (40/sex/dose  level)  given vinyl  chloride  by  gastric
Intubation (1n  olive  oil) at  levels of  0,   3.33,  16.65 or 50 mg/kg  bw,  4-5
times/week, for  52  weeks (Maltonl, 1977a;  Maltonl et al., 1975).   Survival
at 85 weeks after the beginning of  treatment was 35 control,  39  low-dose, 32
mid-dose and  23  high-dose animals.  After  120 weeks,*  the  number  and  types of
tumors  reported  were  1  Zymbal gland  tumor  1n  the  control  group;   1  1ntra-
abdomlnal  anglosarcoma  1n  the  low-dose  group;   9  liver anglosarcomas,  2
Zymbal gland  carcinomas,  and 3 nephroblastomas  1n  the mid-dose group; and 16
liver anglosarcomas.  2 nephroblastomas,  1  Zymbal  gland carcinoma,  1  thymlc
anglosarcoma,  and  1  1ntra-abdom1nal  anglosarcoma 1n  the high-dose  group.
The Individual  Incidences  for  each  sex were  not segregated  1n the  available
summaries  of  this  study  (IARC,  1979;  U.S.  EPA,  1983b).  The  Incidences of
hepatic anglosarcoma and renal nephroblastoma are summarized 1n Table 4-4.
                                     -16-

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                                   TABLE  4-2

   Type and Incidence of  Statistically Significant Treatment-Related Changes
     1n the Liver  and Lung of Male Wlstar Rats  Exposed to VCM 1n the Diet.
                Values of q-j* and Concentration from Multistage
                         Extrapolation Model Included3
Treatment Group (mg/kq/day)

Number of rats examined0
Liver
Neoplastlc nodules
Hepatocellular carcinomas
Anglosarcomas
Total liver tumorsd
Lung
Anglosarcomas
Total animals with tumors
0
55
0
0
0
0

0
0
1.7
58
1
1
0
2

0
2
5.0
56
7
2
6
13

4
17
14.1
59
23
8
27
50
*
19
58
(mg/kg/day)'1

2.1 x lO'i
8.8 x 10"2
; 1.3 x 10"1
3.0 x 10'1

1.1 x 10'1
2.9 x 10"1
aSource: Adapted from Feron et al., 1981

bHuman equivalent q-j* » qi*{a)(WnWa)1/3 1n (mg/kg/day)~i

cFound dead or killed 1n extremis or terminally

dSum of neoplastlc nodules and liver anglosarcomas
                                     -17-

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                                  TABLE 4-3

  Type and  Incidence of Statistically Significant Treatment-Related  Changes
    1n the Liver and Lung of Female Wlstar  Rats  Exposed  to VCM  In  the Diet.
               Values of q-j* and Concentration  from Multistage
                        Extrapolation Model  Included3
Treatment Group (mq/kq/dav)

Number of rats examined0
Liver
Neoplastlc nodules
Hepatocellular carcinomas
Anglosarcomas
Total liver tumorsd
Lung
Anglosarcomas
Total animals with tumors
0
57

2
0
0
2

0
2
1.7
58

26
4
0
26

0
26
5.0
59

39
19
2
41

1
42
qi*°
14.1 (mg/kg/day T1
57

44 1.3
29 5.0 x 10'1
9 8.8 x 10~2
53 1.9

5 5.8 x 10~2
56 2.3
aSource: Adapted from Feron et al., 1981

bHuman equivalent q-j* « qi*(a)(WnWa)1/3 1n (mg/kg/day)'1

cFound dead or killed 1n extremis or terminally

dSum of neoplastlc nodules and liver anglosarcomas
                                     -18-

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                                                 TABLE 4-4
                Tumor Incidences  In  Spragtre-Dawley  Rats Dosed with  Vinyl  Chloride by Gavagea
Dose or
Sex Exposure1*
Img/kg)
NR 50
^ NR 16.5
i
H,F 0.0
Duration of
Treatment
(weeks)
52
52
52
Duration
of Study
(weeks)
136
136
136
Purity
of
Compound
NR
NR
NA
Vehicle or
Physical
State
olive oil
olive oil
olive oil
only
Target
Organ
liver
kidney
liver
kidney
liver
kidney
Tumor Type
anglosarcoma
nephroblastoma
anglosarcoma
nephroblastoma
anglosarcoma
nephroblastoma
Tumor
Incidence
(p value)
16/80
(p<0.05)c
2/80
9/80
(p<0.05)c
3/80
0/150
0/150
aSource: Haltonl. 19776
^Exposure to vinyl chloride by gavage was once dally In olive oil  4-5 days/week for 52 weeks
cF1sher exact test was performed by Syracuse Research Corporation
NA = Not applicable; NR = Not reported

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              atlon.   There are numerous  Inhalation  studies  on the  cardno-
            vlnyl chloride In-experimental animals.   Inhalation exposures  to
           ride  have  resulted   In  Increased  Incidences  of  various  tumors,
          pulmonary adenomas and adenocarclnomas, anglosarcomas of  the  liver
        er  sites, lymphomas, mammary carcinomas, and neuroblastomas of  the
brain,  1n  mice,  rats  and hamsters  (Wagoner,  19S3).   Inhalation exposure  to
vinyl chloride at  concentrations  as low  as  10 ppm have  resulted  In hepatic
and  extrahepatlc  anglosarcomas,  whereas  mammary  carcinomas  are produced  at
even  lower  concentrations  (e.g.,  1  or  5 ppm)  (Wagoner,  1983).   Due to  the
limitations  of  this  project,   only  the  most  substantial  studies  will  be
reviewed and  used as  a basis  for   evaluating  carcinogenic  risk  associated
with  Inhalation  exposure  to  vinyl chloride.   The reader  1s referred to  the
summaries by U.S. EPA (1980a, 1982,  1983b) and IARC  (1979).
    Maltonl  and  Lefemlne  (1974a,b,  1975)   Investigated  the carcinogenic
                                                              t
effects of  Inhaled vinyl  chloride In rats exposed to concentrations ranging
from  50-10,000 ppm for  5 days/week,  for  52 weeks. The animals were observed
for  tumor  development  for  their Hfespan (length of*experiment equal to 135
weeks).  The  total  tumor  Incidences after 135  weeks,  reported by  U.S.  EPA
(1980a) as  the  basis  for deriving  a human cancer based  criterion  for  vinyl
chloride,  were  6/58  controls,  10/59 at  the  50 ppm  level,  16/59  at  the  250
ppm  level,  22/59 at the 500  ppm level,  32/59  at the  2500  ppm level. 31/60 at
the  6000  ppm  level,   and  38/61  at  the 10,000 ppm  level.   Differential
responses  between  the  sexes  were not  reported.  The  tumor  types  Included
hepatic  anglosarcomas,  renal nephroblastomas,  Zymbal gland  carcinomas,  and
others  unspecified.  These tumor Incidences are summarized 1n Table 4-5.
                                     -20-

-------
                                                                   TABLE  4-5

                    Incidence of Tutors tn Sprague-Dauley Rats  Exposed 4  Hours/Day.  S Days/Week,  for  52 Weeks by Inhalation
                                     to Various Concentrations of Vinyl Chloride:  Results after 135 Weeks*






1
1






Concentration
(PP»)

10.000
6.000
2.500
500
250
50
No treatment
Number

Total


69
72
74
67
67
64
68
of Animals

Corrected


61
60
59
59
59
59
58
Liver

Anglo-
sarcomas

9
13
13
7
4
1
0

Average
Latency
(weeks)
64
70
• 78
81
79
135
0
Kidney

Nephro-
blastomas

5
4
6
4
6
1
0

Average
latency
(weeks)
59
65
74
83
80
135
0
Zvmbal Gland

Carcinomas


16
7
2
4
0
0
0

Average
Latency
(weeks)
50
62
33
79
0
0
0

Other


25
19
IB
11
9
12
10
Total Number of
Rats with One
or More Tumors

38
31
32
22
16
10
6
•Source:  Hal ton1  and lefemlne.  1975

-------
    Viola et al.  (1971)  reported  an Increased Incidence of  skin  carcinomas,
lung carcinomas and  osteochondromas  In  Wlstar rats exposed  to  30,000  ppm of
vinyl  chloride by   Inhalation.   Since  then, studies  by  Maltonl  (1977b),
Maltonl et  al.  (1981),  Lee et 41.  (1978) and Hong  et  al.  (1981)  have  also
provided evidence  of the cardnogenlclty  of  vinyl chloride  1n  experimental
animals.  These five studies are  summarized 1n Tables  4-6  through 4-10.
    Maltonl (1977b)  reported  an  Increased Incidence of hepatic  anglosarcoma
and  renal   nephroblastoma  1n Sprague-Dawley rats  exposed  by  Inhalation.
Kidney nephroblastomas were seen 1n animals exposed to  6000  or  10,000  ppm of
vinyl  chloride,  whereas  an  Increased  Incidence  of  liver  anglosarcoma  was
reported  1n groups  exposed  to   concentrations  as  low  as   100  ppm.    More
recently, Naltonl  et al.  (1981) reported  kidney  nephroblastomas  In groups of
rats exposed by Inhalation  to 25 ppm of  vinyl chloride, while control  groups
had  none.   Liver  anglosarcomas were evident  1n rats exposed to  100  ppm of
vinyl chloride by  Inhalation.  Similar  tumors were not seen 1n  rats exposed
to  0,  1 or 5  ppm of vinyl chloride.   For groups of  Swiss  mice  exposed by
Inhalation  to  50, 250,  500,  2500,  6000  or  10,000* ppm  of   vinyl  chloride,
Maltonl  et al.  (1981)  reported  a dose-related   Incidence  of  liver  anglo-
sarcomas and  lung tumors.  In  Golden  hamsters  exposed  at  the  same levels,
paplllomas and acanthomas of  the forestomach  were  produced by vinyl chloride
exposure.
    In  groups  of  36 male and 36  female CD  rats,  lung and  liver hemanglo-
sarcomas were  produced  1n groups  of animals  exposed by Inhalation to  250 or
1000  ppm of vinyl chloride (Lee  et al.,  1978).   This  study  Indicated  that
females  of  this  strain were  more  susceptible to  the carcinogenic effect of
vinyl  chloride.   Rats  treated with  0  or  5'0  ppm  of  vinyl  chloride did  not
                                     -22-

-------
                                                      TABLE  4-6
        Tumor  Incidences  In Hale VHstar (Ar/IRE) Rats Exposed to 30,000 ppm of Vinyl Chloride by Inhalation8
CO
Dose or
Exposure''
(ppm)
30,000
0
Duration
of
Treatment
12 months
NA
Duration
of Study
>12 months
>12 months
Purity
of
Compound
99X
NA
Vehicle or
Physical
State
vapor/air
air only
Target
Organ
skin
lung
bone
skin
lung
bone
Tumor Type
epldermold carcinoma
carcinoma
osteochondroma
epldermold carcinoma
carcinoma
osteochondroma
Tumor
Incidence
15/26
6/26
5/26
0/25
0/25
0/25
    aSource: Viola et al., 1971
    Exposure was for 4 hours/day, 5 days/week for 12 months.
    NA = Not applicable

-------
                                                 TABLE 4-7
            Tumor Incidences In Sprague-Dawley Rats Exposed to 100-10,000 ppm of Vinyl Chloride3
Exposure
Route
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
NA
Dose or
Exposure**
(ppm)
10,000
6.000
200
150
100
0
Duration of
Treatment
(weeks)
52
52
52
52
52
52
Duration
of Study
(weeks)
155
155
143
143
143
143-155
Vehicle or
Physical
State
vapor /air
vapor /air
vapor /air
vapor /air
vapor /air
air only
Target
Organ
liver
kidney
liver
kidney
liver
liver
liver
liver
kidney
Tumor Type
anglosarcoma
nephroblastoma
anglosarcoma
nephroblastoma
anglosarcoma
anglosarcoma
anglosarcoma
anglosarcoma
nephroblastoma
Tumor
Incidence
9/60
5/60
13/60
4/60
12/120
5/120
1/120
0/500
0/120
^Source: Maltonl, 1977b
^Exposure to vinyl chloride by Inhalation  was  for  4 hours/day,  5  days/week  for  52 weeks
NA = Not applicable; NR = Not reported

-------
                                                                            TABLE 4-6


                         TiMor Incidences In Sprague-Dawley Rats. Swiss Nice and Syrian Golden Hamsters Exposed to Various Concentrations
                                                               of Vinyl Chloride by Inhalation'**
en
i
Sex

H.F
H.F
H.F
H.F
H.F
H.F
H.F
H.F
H.F
H.F
H.F
Dose or
Exposure0

-------
                                                                        TABLE 4-8 (cont.)
o>
I
Sex

H.F
H.F
H.F
H.F

H.F
H.F
H.F
H.F
H.F
H.F
H.F
Dose or
Exposure*
(PP»)

10
5
1
0

10.000
6.000
2.500
500
250
50
0
Duration of
Treatment
(weeks)

52
52
52
MA

30
30
30
30
30
30
NA
Duration
of Study
(weeks)

147
147
147
135-147

81
81
81
81
81
81
81
Vehicle or
Physical
State
HATS (cont.)
air/vapor
air/vapor
air/vapor
air only
HICf
air/vapor
air/vapor
air/vapor
alr/vaper
air/vapor
air/vapor
air only
Target Organ

liver
kidney
liver
kidney
liver
kidney
liver
kidney

liver
Tung
liver
lung
liver
lung
liver
lung
liver
lung
liver
lung
liver
lung
Tumor Type

anglosarcoM
nephroblastoM
anglosarcoM
nephroblastoM
angtosarcoM
nephroblastoM
anglosarcoM
nephroblastoM

anglosarcoM
tumor
angiosarcoM
tumor
anglosarcoM
tumor
anglosarcoM
tumor
anglosarcoM
tumor
anglosarcoM
tumor
anglosarcoM
tumor
Tumor
Incidence

1/119
0/119
0/119
0/119
0/118
0/118
0/363
0/363

10/56
46/56
13/60
47/60
16/59
40/59
14/60
50/60
18/60
41/60
1/60
6/60
0/150
15/150

-------
                                                               TABLE 4-8 (conl.)
Sex

H.F
H.F
H.F
H.F
H.f
H.F
H.F
'Source
i
-J DPur1ty
Dose or Duration of
Exposure0 Treatment
(ppM) (weeks)

10.000
6.000
2,500
500
250
50
0
: Hal ton 1 et al.. 1981
of compound was >99.9X

30
30
30
30
30
30
NA

Duration
of Study
(weeks)

109
109
109
109
109
109
109

Vehicle or
Physical
State
HAHSTERS
air /vapor
air/vapor
air/vapor
air/vapor
air/vapor
air/vapor
air only

Target Organ
I

forestoMch
forestnuch
forestoMch
forestomach
fores touch
forestoMch
forestoMch

Tumor Type

papl 1 loM/acanthoiu
papllloM/acanthowi
paptlloM/acanthoM
papt 1 loiu/acanthoma
papllloma/acanthoiM
paplHoM/acanthona
papl 1 lona/acanthoma

Timor
Incidence

10/30
10/30
17/30
9/30
4/30
3/30
3/60

cExposure was for 4 hours/day, 5 days/week
NA - Not applicable; NR - Not reported

-------
                                            TABLE  4-9
                                                        t


Tumor Incidences In CD Rats  and CD-I Nice  Exposed  to 50-1000 ppm of Vinyl  Chloride by Inhalation'












1
no
CD
l






Dose or
Sex Exposure0
(PP»)

N 50

F 50

N 250

F 250


N 1000


F 1000


N 0

F 0

Duration of
Treatment
(months)

12

12

12

12


12


12


NA

NA

Duration
of Study
(months)

12

12

12

12


12


12


12

12

Purity
of
Compound

99. 8X

AA Bmf
99. BX

99. 8X

99. W


99. W


99. 8X

1
NA

NA*

Vehicle or
Physical
State
RATS
vapor /air

vapor/air

vapor /air

vapor /air


vapor/air


vapor /air


air only

air only

Target Organ

liver
lung
liver
lung
liver
lung
liver

lung
liver
lung

liver

lung
liver
lung
liver
lung
Tumor Type0

hemanglosarcoma
hemanglosarcoma
hemanglosarcoma
hemanglosarcoma
hemanglosarcoma
hemanglosarcoma
hemanglosarcoma

hemanglosarcoma
hemanglosarcoma
hemanglosarcoma

hemanglosarcoma

hemanglosarcoma
hemanglosarcoma
hemanglosarcoma
hemanglosarcoma
hemanglosarcoma
Tumor
Incidence
(p value)

0/36
0/36
0/36
0/36
2/36
0/36
10/34
(p<0.05)
3/34
6/34
4/34

15/36
(p<0.05)
9/36
0/35
0/35
0/35
0/35

-------
                                                               TABLE  4-9  (cent.)




1
to
us
1



Dose or
Sex Exposure'1
(PP»>

H 0
F 0 '
N 50
F 50
N 250
F 250
N 1000
F 1000
Duration of Duration
Treatment of Study
(•onths) (Booths)

NA 12
NA 12
12 12
12 12
12 12
12 12
12 12
12 12
Purity
of
Compound

NA
NA
99. 6X
99. 8X
99. BX
99. OX
99'. BX
99. BX
Vehicle or
Physical
State
NICE
air only
air only
vapor /air
vapor /air
vapor /air
vapor /air
vapor/air
vapor /air
Target Organ

respiratory
tract
liver
respiratory
tract
liver
respiratory
tract
liver
respiratory
tract
liver
respiratory
tract
liver
respiratory
tract
liver
respiratory
tract
liver
respiratory
tract
liver
Timor Type0

bronchloloalveolar
adenoma
hemanglosarcoma
bronchloloalveolar
adenoma
hemanglosarcoma
bronchloloalveolar
adenoma
hemanglosarcoma
bronchloloalveolar
adenoma
hemanglosarcoma
bronchloloalveolar
adenoma
hemanglosarcoma
bronchloloalveolar
adenoma
hemanglosarcoma
bronchloloalveolar
adenoma
hemanglosarcoma
bronchloloalveolar
adenoma
hemanglosarcoma
Tumor
Incidence
(p value)

1/26
0/26
0/36
0/36
8/29
3/29
4/34
0/34
10/29
7/29
(p<0.05)
12/34
16/34
(p<0.05)
22/33
13/33
(p<0.05)
26/36
IB/36
(p<0.05)
'Source: Lee et al.. 1978
DExposure was for 6 hours/day, 5 days/week
NA * Not applicable

-------
                                                                            TABLE  4-10


                           Timor Incidences In CO Rats and CD-I Nice Exposed to Various Concentrations  of  Vinyl  Chloride by Inhalation'
o
I
Dose or Duration of Duration
Sex Exposure0 Treatment of Study
(ppm) (months) (months)

N.F 50 6 or 10d 18 or 22d





N.F 250 6 or 10d 18 or 22d





N.F 1000 6 or 10d 18 or 22d





N.F 0 6 or 10d 18 or 22d




-

N.F 50 1 13


N.F 250 1 13


N.F 1000 1 13


Purity Vehicle or
of Physical
Compound State
RATS
99. ex air/vapor





99.8X air/vapor





99. 8X air/vapor





99. OX air/vapor

t



NICE
99. 8X *" air/vapor


99. 8X air/vapor


99. 8X air/vapor


Target
Organ

liver


lung


liver


lung


liver


lung


liver


lung



lung

liver
lung

liver
lung

liver
Tumor Typec

hepatocellular
carcinoma
hemanglosarcoma
bronchloloalveolar.
tumor
hemanglosarcoma
hepatocellular
carcinoma
hemanglosarcoma
bronchloloalveolar
tumor
hemangtosarcoma
hepatocellular
carcinoma
hemanglosarcoma
bronchloloalveolar
tumor
hemanglosarcoma
hepatocellular
carcinoma
hemanglosarcoma
bronchloloalveolar
tumor
hemanglosarcoma

bronchloloalveolar
tumor
hemanglosarcoma
bronchloloalveolar
tumor
hemanglosarcoma
bronchloloalveolar
tumor
hemanglosarcoma
Tumor
Incidence

0/66

0/66
0/66

0/66
2/68

5/68
2/68

2/68
7/72

14/72
4/72

7/72
1/72

0/72
0/72

0/72

3/32

1/32
19/32

0/32
20/32

0/32

-------
                                                                        TABLE 4-10 (cent.)
i
cs
Dose or
Sex Exposure'*
(PP")

H.f 0


N.F 50


N.f 250


H.f 1000


H,F 0


H.f SO


H.F 250


H.F 1000


H.F 0


Duration of
Treatment
(Months)

1


3


a


3


3


6


6


6


6


Duration
of Study
(months)

13


15


15


15


15


18


18


18


18


Purity
of
Compound
NICE
99. OX
i

99. OX


99. 8X


99. BX


99.8X


99. 8X


99. 8X

*
99. 8X


99. 8X


Vehicle or
Physical
State
(cont.)
air/vapor


air/vapor


air/vapor


air/vapor


air/ vapor


air/vapor


air/vapor


air/vapor


air/vapor


Target
Organ

lung

liver
lung

liver
lung

liver
lung

liver
lung

liver
lung

liver
lung

liver
lung

liver
lung

liver
Timor Typec

bronchloloalveolar
tiMor
henanglosarcoM
bronchloloalveolar
tumor
hemangtosarcoma
bronchloloalveolar
tumor
hemanglosarcoma
bronchloloalveolar
tumor
hcmanglosarcona
bronchloloalveolar
tumor
hemanglosarcoma
bronchloloalveolar
tumor
hemanglosarcoma
bronchloloalveolar
tumor
hemanglosarcoma
bronchloloalveolar
tumor
hemanglosarcoma
bronchloloalveolar
tumor
hemanglosarcoma
Tumor
Incidence

3/32

0/32
12/32

0/32
21/32

4/32
5/20

16/20
2/32

0/32
3/16

1/16
12/20

9/20
14/24

13/24
11/56

1/56
          'Source:  Hong et  al..  1981
          '•Exposure for 6 hours/day,  5 days/week
          cShowed dose-related response;  significant at p<0.05
          ^Duration of exposure was  for  6  or 10 months,  followed by  a  12-month latency period.   The  results  presented are for  the combined  treatment-
           duration group.

-------
develop similar tumors.  Lee  et  al.  (1978) also reported an  Increased  Inci-
dence of  bronchloalveolar  adenoma and  hepatic  hemanglosarcomas  In male  and
female CD-I mice exposed to 50,  250 or  1000  ppm of  vinyl  chloride  by  Inhala-
tion for 6 hours/day,  5 days/week.
    In  a   study  examining  the  carcinogenic effect  of  vinyl  chloride  at
various doses  (50,  250 or 1000  ppm)  by Inhalation for various  durations  of
treatment (6 or 10 months treatment period for  rats;  1,  3 or  6 months treat-
ment period for mice).  Hong  et al. (1981) reported elevated  numbers  of lung
and liver  hemanglosarcomas, hepatocellular carcinomas  and bronchloloalveolar
tumors  In  rats treated with  250 ppm  of vinyl   chloride  for  6 or  10 months
duration.  All  four  tumor types  showed a significant dose-related response
In  rats.   In  mice,  only  hemanglosarcomas  showed  a  dose-related  response.
One month  of  exposure  to  250 or  1000 ppm  of  vinyl  chloride for  6  hours/day,
5  days/week,   followed by  a  12-month  latency period,  was  sufficient  to
produce an Increased Incidence of bronchloloalveolar tumors 1n'm1ce.
4.3^   OTHER RELEVANT DATA
    The mutagenlclty  of  vinyl  chloride  has  been  reviewed  by  IARC  (1979),
U.S.  EPA  (1980a),  Bartsch and Montesano  (1975),  Bartsch et  al.  (1976)  and
Flshbeln  (1976).   Vapors  of  vinyl   chloride  Induced  reverse mutations  1n
Salmonella  tvph1mur1um 1n the  presence of  a 9000 x  g supernatant  from rat
liver  (Andrews et  al.,  1976;  Bartsch  et al.,  1975; Garro  et  al.,  1976;
Malavellle  et al.,  1975;  McCann  et  al., 1975; Rannug  et  al.,  1974) from
mouse  liver  (Bartsch  et  al., 1975;  Garro et al.,  1976; Malavellle  et al.,
1975),  and from human liver  biopsy  specimens   (Bartsch  et al.,  1975,  1979;
Malavellle et  al., 1975).  Vinyl chloride vapors Induced mutations In  the S.
typhlmurlum  assay  without metabolic  activation, but  the mutagenlc  response
was  much  higher  with metabolic  activation (Andrews et  a.!.,  1976;  Bartsch et
al.,  1975; McCann et al., 1975).

                                     -32-

-------
     When  tested  1n  aqueous  or   methanollc   solution,  vinyl  chloride  was
 negative  1n  the  S.  tvphlmurlum test system  (Bartsch  et  al.,  1975;  Rannug et
 al.,  1974}  but Induced reverse mutations  1n Escherlchla coll  K12  (Grelm et
 al.,  1975),  forward mutations In  Schlzosaccharomyces pombe and mltotlc  gene
 conversions   1n   Saccharomyces  cerevlslae   1n  the  presence  of  mammalian
 metabolic activation (Loprleno et al., 1976, 1977).
     Both  vapors and an  ethanol  solution  of  vinyl  chloride  were negative 1n a
 mutagenldty  assay  with Neurospora  crassa.  regardless  of whether  metabolic
 activation  was  present  or  not  (Orozdowlcz  and  Huang,  1977).    Forward
 mutations were Induced  1n  V79  Chinese  hamster  cells by vinyl  chloride 1n the
 presence  of  a mammalian metabolic activation  system (Drevon  et  al.,  1977).
 Vinyl  chloride  vapors  Induced a significantly  Increased frequency  of  reces-
 sive  lethals  1n  DrosophUa  melanoqaster  (Magnusson and  Ramel, 1976; Verburgt
 and Vogel,  1977)  but not dominant lethals,  translocatVons or sex-chromosome
                                                               »
 loss  (Verburgt and  Vogel,  1977).   No dominant  lethal  mutations were observed
 In male  CD-I  mice exposed to various  levels  of vinyl chloride by Inhalation
 {Anderson et al., 1976, 1977).
 4.4.   WEIGHT OF EVIDENCE
     Vinyl  chloride  has  been  shown  to  be  a  carcinogen  1n  rats,  mice  and
 hamsters.   It produces a  high Incidence  of  liver,  kidney,   lung  and  brain
 tumors  In a  dose-related  response when administered  by oral  or  Inhalation
 routes.   Similar  carcinogenic  effects have been  reported  In  workers  exposed
 to vinyl  chloride.  The predominant  target  organs are the  liver, brain,  lung
 and  Iympho-hematopo1et1c   system,  but  a general  non-specific  carcinogenic
' effect  has  been  suggested.  IARC  (1982)  concluded that there 1s  sufficient
 evidence  for  carclnogenldty  1n  both  humans   and  experimental  animals.
                                      -33-

-------
Applying  the  criteria  for  evaluating  the  overall  weight  of  evidence  of
cardnogenlclty to humans proposed by the Carcinogen Assessment Group of the
U.S.  EPA  (Federal  Register,   1984)   vinyl   chloride  1s  most  appropriately
classified as  a chemical  1n  Group  A - Human  Carcinogen.
                                     -34-

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

    ACGIH  (1983)  has established  a TLV-TWA  of  5  ppm  (10  mg/m3) of  vinyl
chloride.  The  standards adopted by OSHA  In  1981 are  1 ppm  (2.6  mg/m3)  of
vinyl chloride  as  an 8-hour TWA  and  5 ppm  (13 mg/m3)  of vinyl  chloride  as
a celling  concentration  limit  average over any period  of <15 minutes  (Code
of Federal Regulations,  1981).   Similar hygienic standards  for occupational
exposures 1n foreign countries  exist;  these are summarized  1n Table 5-1.
    In the United States, vinyl chloride has  been used 1n  limited quantities
as an  aerosol  propellant, but  In  1974 1t was  banned  from use  1n  pesticide
aerosol products (U.S. EPA,  1974),  1n  self-pressurized household containers,
and as  an Ingredient of drug  and  cosmetic  products  (U.S.  Consumer  Product
Safety Commission,  1974a,b).
                                     -35-

-------
                                  TABLE 5-1

               Hygienic Standards for Occupational Exposure to
                     Vinyl  Chloride  1n  Foreign Countries*
Country
Canada
Finland
Italy
The Netherlands
Norway
Sweden
USSR
France
existing factories
new factories
Denmark
Belgium
Federal Republic of Germany
existing factories
new factories
United Kingdom
Switzerland
Concentration
(ppm)
10
25
5
10
50
10
1
5
1
5
12
5
15
1
5
1
5
15
5
15
2
15
10
30
10
Standard
8-hour TWA
15-mlnute celling
8-hour TWA
I0-m1nute celling
8-hour TWA
8-hour TWA
8-hour TWA
15-mlnute celling
8-hour TWA
15-mlnute celling
NR'
1-week TWA
celling
1-week TWA
celling
8-hour TWA
1-week TWA
celling
1-week TWA
1-hour celling
1-week TWA
1-hour celling
8-hour TWA
celling (maximum)
1-week TWA
*Sources: IARC, 1979; Bertram, 1977; Thomas, 1977

NR = Not reported
                                     -36-

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                              6.   RISK ASSESSMENT
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
    Vinyl chloride 1s a  chemical  that 1s a known human and animal carcinogen
and  data are  sufficient  for  calculation  of  a  q  *.   It  1s  Inappropriate,
therefore, to calculate an AIS for vinyl chloride.
6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)
    Vinyl chloride 1s. a  chemical  that 1s a known human and animal carcinogen
and  data are  sufficient  for  calculation  of  a  q,*.   It  Is  Inappropriate,
therefore, to calculate an AIC for vinyl chloride.
6.3.   CARCINOGENIC POTENCY (q^)
6.3.1.   Oral.  A dose-related  Increased Incidence of neoplastlc  nodules  of
the liver, hepatocellular  carcinomas  and anglosarcomas of  the  liver  and the
lung were  observed  1n both male  and  female rats fed  diets containing vinyl
chloride for  135 weeks  (males)  or 144 weeks  (females)  (Feron  et al., 1981).
The  Incidences  of  each  tumor   type and the  associated  human  q.*  were
presented  1n  Tables  4-2  and  4-3 for  males and  females,  respectively.   The
q,*  values   ranged  from  8.8xlO~2   to   1.3   (mg/kgYday)"1  for  Individual
tumor types.   A  q *  was also  calculated for rats  of  each sex  based on the
Incidence  of  total  animals  with  tumors.  The  Incidence  of  hepatocellular
carcinoma was not Included 1n these tallies because 1t was assumed that rats
having hepatocellular carcinoma also  bore neoplastlc  nodules,  since neoplas-
tlc modules are considered to be  preneoplastlc  forerunners of  hepatocellular
carcinomas.  Furthermore,  the total number of animals bearing  tumors 1n the
high-dose groups was  arbitrarily reduced  to  one less than  the  total number
of animals  examined,  so  that  the resulting data  would  fit the  linear  non-
threshold model adopted  by the U.S.  EPA (1980b) for  estimation  of carcino-
genic  potency.   The  human   q  *s  resulting   from  this   manipulation  were
                                     -37-

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2.9X10"1  (mg/kg/day)"1   (males)   and   2.3  (mg/kg/day)'1   (females).    The
q * of  2.3  (mg/kg/day)"1  associated with  total  tumors  1n  female rats  was
chosen  by  the  U.S.  EPA  (1984)   as  most  conservatively  representing  the
carcinogenic potency of vinyl  chloride.
6.3.2.   Inhalation.   The U.S. EPA  (1980a)  derived a  q^  for  humans  for
oral  exposure  from the  Incidence  of total tumors  1n  rats exposed ,to  vinyl
chloride  by Inhalation  (Maltonl  and  Lefemlne,  1975).   This  q^  has  been
superseded  by  a  q,*  for oral  exposure  based  on  the  Incidence  of  total
tumors  In  female  rats  fed   diets  containing  vinyl chloride  (see  Section
6.3.1.).   The  tumor  Incidence data  1n rats  exposed  by  Inhalation 1n  the
Maltonl and  Lefemlne  (1975) study may more  appropriately  be  used  to derive a
q * for humans exposed by Inhalation.
    Using the linear  non-threshold model adopted by  the  U.S.  EPA  (1980b) and
the data  from  the Maltonl and Lefemlne (1975) study summarized  1n Appendix
B,  a  human  q*  of  2.5xlO"2  (mg/kg/day)'1  1s   calculated'.    This  slope
value,  1n  transformed  units,  1s  the  same as  that developed  In  U.S.  EPA
(1980a) without Inclusion  of  the empirically  derived1 factor  to  estimate oral
exposure  from  Inhalation  data.  U.S.  EPA  (1980a)  estimated a unit  risk of
6.80xlO"»  (ppm)"1  based  on  the  rat  Inhalation  data.   Assuming  that  rats
breathe  0.223  mVday  (U.S.  EPA,  1980b) and  weigh  0.35  kg, this  unit risk
can  be  converted  to an animal  q^  of   4.2xlO~a  (mg/kg/day)"1.   Estima-
tion  of  an  equivalent human  q,*  was  accomplished  by  using a  surface area
                             1/3
approximation:      (70/0.35)    ,     I.e.,      4.2xlO"3     (mg/kg/day)"1    x
 (70/0.35)173 « 2.5xlO"2  (mg/kg/day)"1 (U.S. EPA, 1980b).
                                     -38-

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                                7.  REFERENCES

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Threshold  Limit  Values for  Chemical  Substances and  Physical  Agents  In  the
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Anderson,  D.,  M.C.E.  Hodge  and   I.F.H.  Purchase.   1976.   Vinyl  chloride:
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Anderson,  D.,  M.C.E.  Hodge  and   I.F.H.  Purchase.   1977.   Dominant  lethal
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Andrews, A.M., E.S.  Zawlstowskl and  C.R.  Valentine.  1976.  A  comparison  of
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Bartsch, H. and  R.  Montesano.   1975.   Mutagenlc and carcinogenic  effects  of
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Bartsch, H.,  C.  Malavellle and  R. Montesano.   1975.   Human,  rat  and  mouse
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                                     -39-

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Bartsch,   H.,   C.   Malavellle,  A.  Barbln,  H.  Bresll,   L.  Tomatls  and  R.
Montesano.  1976.   Mutagenlclty and metabolism of vinyl chloride and related
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Bartsch,  H., C. Malavcllle. A.  Barbln  and 6. Planche.  1979.  Mutagenlc and
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Bertram,   C.6.   1977.    Minimizing  emissions  from  vinyl chloride  plants.
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Blendls,  L.M., P.M. Smith, B.W. Lawrle, M.R.  Stephens and W.D. Evans.   1978.
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                                                     *
Bolt,  H.M.,  et al.   1977.   Pharmacok1net1cs of vinyl  chloride  In the  rat.
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Byren, D.,  G.  Engholm,  A.  Englund  and P. Westerholm.  1976.  Mortality and
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                                     -40-

-------
Carter,  E.A.  and  K.J.   Isselbacher.    1972.    Hepatic  mlcrosomal  ethanol
oxidation; mechanism  and  physiologic significance.   Lab.  Invest.  27:  283.
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Code  of   Federal  Regulations.   1981.    OSHA  Safety  and  Health  Standards.
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Dlnman,  B.C.,  et  al.  1971.   Occupational  acro-osteolysls.  Arch. Environ.
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Drevon, C., T. Kurokl and  R.  Montesano.  1977.   Mlcrosome-medlated mutagene-
                                                 •
sis of a  Chinese  hamster  cell line  by various chemicals.   In: 2nd Int.  Con-
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1n IARC,  1979)

Orozdowlcz, B.Z. and P.C. Huang.   1977.  Lack of mutagenldty of  vinyl  chlo-
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Ouprat, P., et al.  1977.  Metabolic approach to Industrial  poisoning:  Blood
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                                     -41-

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

Feron, V.J. and R. Kroes.  1979.  One-year time-sequence Inhalation toxldty
study of vinyl chloride  In  rats.   II.  Morphological changes In the respira-
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Feron, V.J.,  A.J. Speek,  H.I.  Will ems,   D.  Van Battum  and A.P.  De  Groot.
1975.   Observations   on  the  oral   administration  and  toxldty  of  vinyl
chloride 1n rats.   Food. Cosmet. Toxlcol.   13:  633.

Feron,  V.J.,   A.   Kruysse and  H.P.  Til.   1979a.    One-year  time-sequence
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                                      *
hematology, clinical  chemistry  and organ  weights.   Toxicology.   13:  25-28.
(Cited In U.S. EPA, 1983a)

Feron,  V.J.,  B.J. Spit,  H.R.  Immel and  R. Kroes.   1979b.  One-year time-
sequence Inhalation toxldty study  of  vinyl  chloride  In rats.  III.  Morpho-
logical  changes  In the liver.   Toxicology.   13:  143-154.   (Cited  1n  U.S.
EPA,  1983a)

Feron,  V.J.,  C.F.M.  Hendrlksen,  A.J.  Speek, H.P.  Til  and  B.J. SpH.  1981.
Llfespan  oral  toxldty  study  of  vinyl   chloride  1n  rats.   Food  Cosmet.
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                                     -42-

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Fllatova,  V.S..  et al.   1958.   Hygienic  characteristics  of vinyl  chloride
production.  G1g. Truda Prof.  Zab.   2:6.   (CUed  1n  U.S.  EPA,  1980a,  1983a)

F1shbe1n,  L.   1976.   Industrial mutagens  and  potential  mutagens.  I. Halo-
genated  aliphatic  derivatives.   Mutat. Res.   32: 267-308.   (Cited 1n IARC,
1979)

Fox, A.J.  and  P.F.  Collier.   1977.   Mortality experience of workers  exposed
to vinyl  chloride monomer  In  the manufacture of polyvlnyl chloride  1n Great
Britain.  Br. J.  Ind.  Med.   34:  1-10.   (CUed 1n  U.S.  EPA,  1983b)

Garro, A.J., Guttenplan, O.B. and P. MHvy.  1976.  Vinyl  chloride dependent
mutagenesls: Effects of  liver extracts and free  radicals.  Mutat. Res.  38:
81-88.   (Cited 1n IARC, 1979)                                 ,

Grelm, H.,  G.  Bonse.  Z.  Radwan, D.  Relchert and 0. Henschler.  1975.  Muta-
                                                    •
genldty In  vitro and  potential cardnogenlclty  of  chlorinated ethylenes as
a  function  of  metabolic  oxlrane  formation.   Blochem.   Pharmacol.   24:
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Harris,  O.K.  and  W.G.  Adams.   1967.   Acro-osteolys1s  occurring   1n  men
engaged  1n  the  polymerization   of  vinyl  chloride.   Br.  Med.  J.   3:  712.
(CUed 1n U.S.  EPA,  1980a,  1983a)

Hefner,  R..E.,  Jr.,  P.G.  Watanabe  and  P.J.  Gehrlng.   1975.    Preliminary
studies  of  the fate  of Inhaled vinyl  chloride monomer  In rats.   Ann.  NY
Acad. Sc1.  246:  135-148.  (CUed In U.S. EPA,  1980a)
                                     -43-

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 Hong, C.B., J.M.  Winston,  L.P.  Thornburg and  J.S.  Woods.   1981.   Follow-up
 study on  the  cardnogenlcUy of  vinyl  chloride and  vinylldene  chloride  1n
 rats and  mice:  Tumor  Incidence  and  mortality subsequent  to  exposure.   J.
 Toxlcol.  Environ.  Health.   7(6):.  909-924.   (Cited  1n U.S. EPA,  1983b)

 Horvath,  A.L.   1982.  Halogenated Hydrocarbons  Solubility.  M1sc1bliHy  with
 Water.   Marcel Dekker,  Inc.,  NY.   p.  494.

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                                                     »
 Chemicals to Humans.  IARC, WHO,  Lyon, France.   Suppl. 4, p. 260-261.

 Infante,  P.F.   1981.   Observations  of  the site-specific carclnogenldty  of
 vinyl  chloride  to  humans.   Environ. Health  Perspect.   41:  89.   (Cited  1n
 U.S. EPA, 1983b)

 Jaeger,  R.J.   1975.   Vinyl  chloride monomer:  Comments  on Its  hepatoxldty
 and  Interaction  with  I,l-d1chloroethylene.   Ann. NY  Acad. Sc1.   246:  150.
. (Cited 1n U.S. EPA, 1980a)
                                      -44-

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John,  R.J.,  F.A.  Smith,  B.K.J. Leong  and  B.A.  Schwetz.  1977.  The effects
of  maternally  Inhaled  vinyl  chloride on embryonal  and  fetal development  1n
mice,  rats and  rabbits.   Toxlcol.  Appl.  Pharmacol.   39: 497-513.  (CHed  1n
U.S. EPA, 1980a)

John,  J.A.,  F.A.  Smith and B.A.  Schwetz.  1981.  Vinyl chloride:  Inhalation
teratology study  1n mice,  rats and rabbits.   Environ. Health Perspect.  41:
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Lange,  C.E.,  S.  June,  G.  Stein and  G.  Veltman.  1974.   The so-called vinyl
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Lee,  C.C.,  J.C.  BhandaM, J.H. Winston,  W.B.   House,  R.L. D1xon  and J.S.
        »
Woods.   1978.   Carclnogenlclty of  vinyl chloride  and  vlnylldene chloride.
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Lester,  D.,  L.A.  Greenberg and  W.R.  Adams.   1963.  Effects  of single and
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Assoc. J.  24: 265-275.   {CHed 1n  U.S. EPA, 1983a)

LopMeno, N.,  R.  Barale,  S.   Baroncelll, et  al.   1976.  Evaluation  of the
genetic  effects  Induced  by   vinyl  chloride   monomer  (VCM)  under  mammalian
metabolic activation:  Studies  in vitro and In vivo.   Mutat.  Res.  40: 85-96.
(CHed 1n IARC,  1979)
                                     -45-

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Loprleno, N.,  R.  Barale,  S.  BaroncelH,  et  al.  1977.   Induction  of  gene
mutations and   gene  conversions  by  vinyl  chloride  metabolites  In  yeast.
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Mabey, W.R.,  J.H.  Smith,   R.T.  Podoll,  et al.   1981.   Aquatic Fate  Process
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Magnusson, J.  and  C.  Ramel.  1976.   Mutagenlc  effects  of  vinyl chloride  1n
Drosophlla melanogaster (Abstr. No.  27).  Mutat. Res.   38: 115.  (Cited  In
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Makk, L., F. Delmore,  J.L. Creech,  Jr.,  et al.  1976.   Clinical and morpho-
logic features  of  hepatic  anglosarcoma  In  vinyl chloride  wockers.   Cancer.
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                                                    •
Malavellle,  C., H.  Bartsch, A.  Barbln,  et al.   1975.   Hutagenlclty  of vinyl
chloride,   chloroethyleneoxlde,   chloroacetaldehyde,    and   chloroethanol.
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Maltonl,  C.   1977a.  Vinyl  chloride  carclnogenlcHy:  An  experimental  model
for  cardnogenesls  studies.   In.:  Origins  of  Human Cancer,   Book  A,  H.H.
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Maltonl,  C.   1977b.  Recent  findings  on the carclnogenlcHy  of  chlorinated
oleflns.  Environ. Health  Perspect.   21:  1-5.   (CHed 1n U.S.  EPA,  1983b)
                                     -46-

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Maltonl,  C.  and  6.  Lefemlne.   1974a.   CardnogenlcHy  bloassays of  vinyl
chloride.  I.  Research  plan  and early results.  Environ. Res.   7:  387-405.
(Cited 1n U.S.  EPA,  1980a}

Maltonl, C. and G. Lefemlne.   1974b.   La potentiality del  saggl  sper1mental1
mella predlzlon;  del  Mschl  oncogenl  amblental:  Un esemplo: 11  chlorure  d1
vlnlle.   Acad.  Natl. L1nce1.   56: 1.   (Fre.)  (CHed 1n U.S.  EPA,  1980a)

Maltonl,  C.  and  6.   Lefemlne.   1975.  CardnogenlcHy  bloassays  of  vinyl
chloride:  Current  results.   Ann. NY  Acad.  Sc1.   246:  195-218.   (CHed  1n
U.S. EPA, 1980a)

Maltonl, C., A. C1l1bert1, L. 61ann1  and  P.  Chleco.   1975.   CardnogenlcHy
of  vinyl  chloride administered  by  the  oral  route  1n  rats ;(Ital.).   Osp.
VHa.  2: 102-109.  (CHed  1n  IARC. 1979)
                                         0
                                                   •
Maltonl,  C., G.  Lefemlne, A.  CHIbertl.  G. Cottl and  D.  Carrettl.   1981.
CardnogenlcHy bloassay of vinyl chloride monomer: A model  of risk  assess-
ment on  an experimental  basis.  Environ.  Health Perspect.  41:  3-29.   (CHed
1n U.S.  EPA,  1983b)

Marlcq,  H.R., M.N. Johnson, C.L. Whetstone and  E.C. LeRoy.   1976.  Capillary
abnormalities 1n  polyvlnyl chloride production workers.   J.  Am.  Med.  Assoc.
236(12): 1368-1371.  (CHed 1n U.S. EPA, 1983a)
                                    -47-

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Marsteller,  H.J.   and  W.K.   Lebach.    1975.    Unusual   splenomegallc   liver
disease as  evidenced  by perltoneoscopy and guided  liver  biopsy among  poly-
vinyl chloride production workers.  Ann.  NY  Acad.  Sc1.   246: 95.   (Cited  In
U.S. EPA,  1980a,  1983a)

McCann, 3.,  V.  Simmon,  D. Stre1tw1eser and  B.N.  Ames.   1975.   MutagenlcHy
of  chloroacetaldehyde,  a possible  metabolic  product  of  l,2-d1chloroethane
(ethylene  d1chlor1de),  chloroethanol  (ethylene chlorohydrln),  vinyl  chlo-
ride, and  cyclophosphamlde.   Proc. Natl. Acad.  Sc1.  (Wash.).  72:  3190-3193.
(Cited In IARC, 1979)

Monson, R.R.,  J.M. Peters and  M.N.  Johnson.   1974.  Proportional  mortality
among  vinyl-chloride workers.   Lancet.   2:  397-398.    (Cited  1n  U.S.  EPA,
1983b)                                                        i

Page,  G.W.   1981.   Comparison  of groundwater  and surface  water  for  patterns
and  levels  of  contamination by  toxic substances.   Environ. Sc1.  Technol.
15:  1475-1481.

Prodan, L.,  I.  Suclu, V. PHaru. E.  Ilea  and  L.  Pascu.   1975.   Experimental
chronic  poisoning  with vinyl  chloride (monochloroethane).  Ann.  NY  Acad.
Sc1.   246:  159-163.   (Cited 1n U.S. EPA, 1983a)

Radlke,  M.J., K.L.  Stemmer,  P.G.  Brown,  E.  Larson and  E.  Blngham.   1977.
Effect  of  ethanol  and vinyl  chloride on  the Induction  of  liver  tumors:
Preliminary report.   Environ.  Health  Perspect.   21:  153-155.  (Cited 1n U.S.
EPA,  1980a}
                                     -48-

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Rannug, U., A.  Johansson,  C.  Ramel  and C.A. Wachtmelster.   1974.   The  muta-
genldty of vinyl  chloride after metabolic activation.  Amblo.   3:  194-197.
(Cited 1n IARC, 1979)

Singh, H.B.,  L.J.  Salas,  A.J. Smith  and  H. Shlgelshl.  1981.   Measurements
of  some  potentially  hazardous  organic  chemicals  1n  urban  environments.
Atmos. Environ.  15: .601-612.

Smlrnova,  N.A.  and  N.P.   Granlk.   1970.    Long-term  side   effects  of  acute
occupational poisoning by  certain  hydrocarbons and their  derivatives.   G1g.
Tr. Prof. Zabol.  14: 50.   (Cited 1n U.S.  EPA,  1980a,  1983a)

Sokal, J.A.,  B.  Baranskl,  J.  Majka,  et  al.  1980.  Experimental  studies  on
the  chronic  effects  of  vinyl  chloride  In  rats.    J.   Hyg.   Ep1dem1ol.
M1crob1o1. Immunol.  24(3): 285-294.  (Cited In U.S.  EPA, 1983a)
                                                    •
Suzuki, Y.  1978.   Pulmonary  tumors Induced 1n mice by  vinyl  chloride  mono-
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Suzuki,  Y.  1980.   Nonneoplastlc effects  of  vinyl  chloride In mouse  lung.
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                                     -49-

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Torkelson.  M.S..  F.  Oyen  and  V.K.  Rowe.   1961.   The  toxlclty  of  vinyl
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                                     -50-

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 t
I
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                                                             *
         Emergency Response, Washington, DC

         U.S. EPA.   1983c.   Methodology and  Guidelines  for  Reportable Quantity Deter-
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         U.S.  EPA.   1984.   Review  of   a carc1nogen1c1ty  study  on  vinyl  chloride.
         Prepared by  the Carcinogen  Assessment  Group,  OHEA,  Washington,  DC  for  the
                                                                                           \/
         Office  of  Drinking  Water,  Washington,  DC.   Memorandum  from Larry Anderson
         and Steven Bayard to Joseph Cotruvo.  January 6.
                                              -51-

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        Verburgt,  F.6. and  E.  Vogel.  1977.   Vinyl  chloride mutagenesls  1n Droso-
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V-
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    .J   Wagoner,  J.K.  1983.   Tox1c1ty of vinyl chloride and poly(v1nyl chloride): A
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        Watanabe,  P.G.,  G.R.  McGowan  and  P.J.  Gehrlng.   1976a.  ,Fate  of   (14C)
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        Pharmacol.   36:  339-352.   (Cited 1n U.S.  EPA,  19803),

        Watanabe, P.G., G.R. MeGown,  E.O.  Madrid and P.J.  Gehrlng.  1976b.  Fate  of
        (14C)   vinyl  chloride  following   Inhalation  exposure   In  rats.   Toxlcol.
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        Waxweller,  R.J., W. Stringer, J.K.  Wagoner,  J. Jones, H.  Falk  and C. Carter.
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        Acad.  Sc1.   271: 40-48.  (CHed 1n  U.S. EPA,  1983b)
                                             -52-

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"Wedrychowlez,  A.    1976.   Preliminary  results  of  studies  on  the  state  of
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Lekarskl.  33: 936.  (Cited In U.S. EPA, 1980a, 1983a)

WHson,  R.H.,  W.E. McCormlck,  C.F.  Tatum  and  J.L. Creech.   1967.   Occupa-
tional  acroosteolysls.   Report  of  31  cases.   J.  Am.  Med.  Assoc.   201:
577-581.  (Cited 1n U.S. EPA, 1980a, 1983a)

Wlthey,  J.R.   1976.   Pharmacodynamlcs  and  uptake of  vinyl  chloride monomer
administered  by  various routes  to rats.   J.  Toxlcol. Environ.  Health.   1:  L-
381-394.  (Cited 1n U.S. EPA. 1980a)

Wlthey,  J.R.   and  B.T.  Collins.   1976.   A  statistical  assessment of  the
quantitative  uptake of  vinyl  chloride  monomer  from  aqueons  solution.   J.
Toxlcol. Environ.  Health.  2: 311.  (Cited 1n U.S. EPA, 1980a)J.
                                     -53-

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          DATE DUE
                        41



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                                  25
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                                  APPENDIX B
                    Cancer  Data  Sheet  for  Derivation  of  q-|*

Compound:  Vinyl chloride
Reference:  Maltonl and Lefemlne, 1975
Species, strain, sex:  rats, Sprague-Dawley, male and female
Body weight:  0.35 kg (assumed)
Length of exposure (le) » 52 weeks, 4 hours/day, 5 days/week
Length of experiment (Le) = 104  weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type:  total tumors
Route, vehicle:  Inhalation
Experimental
(ppm)
0
50
250
500
2,500
6000
10.000
Doses or Exposures
(mg/m3)
0
127.8
639.1
1.278.1
6.390.6
15,337.4
25.562.4

Transformed
Dose*
(mg/kg/day)
0
4.9
23.9
47.8
239.1
573.8
956.4
Incut
Incidence
No. Responding/No. Tested
(or Examined)
6/58
10/59
16/59
22/59
32/59
31/60
38/61
"^Assumes   rats   breathe   0.223  mVday,   reflects  time-weighted   average
 exposure  Incorporating  factors of 4  hours/24 hours,  5  days/7 days  and  52
 weeks/104 weeks
Unadjusted q^* from study = 4.2xlO"3 (mg/kg/day)"1
Human q-j* = 2.5xlO~2 (mg/kg/day)"1
                                     -55-

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