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
-------
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
-------
' 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
-------
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
-------
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
-------
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.
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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-
-------
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
-------
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-
-------
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-
-------
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-
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1983.
Threshold Limit Values for Chemical Substances and Physical Agents In the
Workroom Environment with Intended Changes for 1984. Cincinnati, OH.
Anderson, D., M.C.E. Hodge and I.F.H. Purchase. 1976. Vinyl chloride:
Dominant lethal studies 1n male CO-1 mice. Mutat. Res. 40: 359-370.
(Cited In IARC, 1979)
Anderson, D., M.C.E. Hodge and I.F.H. Purchase. 1977. Dominant lethal
studies with the halogenated oleflns vinyl chloride and vlnylldene dlchlo-
Mde In male CD-I mice. Environ. Health Perspect. 21: 71-78. (Cited In
IARC, 1979)
Andrews, A.M., E.S. Zawlstowskl and C.R. Valentine. 1976. A comparison of
the mutagenlc properties of vinyl chloride and methyl chloride. Mutat. Res.
40: 273-276. (CHed 1n IARC, 1979)
Bartsch, H. and R. Montesano. 1975. Mutagenlc and carcinogenic effects of
vinyl chloride. Mutat. Res. 32: 93-114. (Cited 1n IARC, 1979)
Bartsch, H., C. Malavellle and R. Montesano. 1975. Human, rat and mouse
liver-mediated mutagenlclty of vinyl chloride 1n S. typhlmurlum strains.
Int. J. Cancer. 15: 429-437. (CHed 1n IARC, 1979)
-39-
-------
Bartsch, H., C. Malavellle, A. Barbln, H. Bresll, L. Tomatls and R.
Montesano. 1976. Mutagenlclty and metabolism of vinyl chloride and related
compounds. Environ. Health Perspect. 17: 193-198. (Cited 1n IARC, 1979)
Bartsch, H., C. Malavcllle. A. Barbln and 6. Planche. 1979. Mutagenlc and
alkylatlng metabolites of halo-ethylenes, chlorobutadlenes and dlchloro-
butenes produced by rodent or human liver tissues; evidence for oxlrane
formation by P450-I1nked mlcrosomal mono-oxygenases. Arch. Toxlcol. (In
press) (Cited 1n IARC, 1979)
Bertram, C.6. 1977. Minimizing emissions from vinyl chloride plants.
Environ. Sc1. Tech. 11: 864-868. (Cited 1n IARC, 1979)
Blendls, L.M., P.M. Smith, B.W. Lawrle, M.R. Stephens and W.D. Evans. 1978.
Portal hypertension 1n vinyl chloride monomer workers. A hemddynamlc study.
Gastroenterology. 75(2): 206-211. (CHed 1n U.S. EPA, 1983a)
*
Bolt, H.M., et al. 1977. Pharmacok1net1cs of vinyl chloride In the rat.
Toxlcol. 7: 179. (CHed 1n U.S. EPA. 1980a)
Byren, D., G. Engholm, A. Englund and P. Westerholm. 1976. Mortality and
cancer morbidity In a group of Swedish VCM and PVC production workers.
Environ. Health Perspect. 17: 167-170. {CHed 1n U.S. EPA, 1983b)
Callahan, M.A., M.W. SUmak, N.W. Gabel, et al. 1979. Water-related
environmental fate of 129 priority pollutants. Vol. II. Office of Water
Planning and Standards, Office of Water and Waste Management, U.S. EPA,
Washington, DC. EPA 440/4-79-029b.
-40-
-------
Carter, E.A. and K.J. Isselbacher. 1972. Hepatic mlcrosomal ethanol
oxidation; mechanism and physiologic significance. Lab. Invest. 27: 283.
(Cited 1n U.S. EPA, 1980a)
Code of Federal Regulations. 1981. OSHA Safety and Health Standards.
Vinyl Chloride. 29 CFR 1910.1017.
Cordler, J.M., et al. 1966. Acro-osteolyse et lesions cutanees assoclees
chez duez ouvrlers affectes au nettoyage d'autoclaves. Cahlers Med.
Travail. 4: 14. (Fre.) {CUed 1n U.S. EPA, 1980a, 1983a)
Dlnman, B.C., et al. 1971. Occupational acro-osteolysls. Arch. Environ.
Health. 22: 61. (Cited In U.S. EPA, 1980a, 1983a)
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-
ference of Environmental Mutagens, Edinburgh, p. 150. (Abstract) (CUed
1n IARC, 1979)
Orozdowlcz, B.Z. and P.C. Huang. 1977. Lack of mutagenldty of vinyl chlo-
ride 1n two strains of Neurospora crassa. Mutat. Res. 48: 43-50. (Cited
In IARC, 1979)
Ouprat, P., et al. 1977. Metabolic approach to Industrial poisoning: Blood
kinetics and distribution of I4C-v1nyl chloride monomer (VCM). Toxlcol.
Pharmacol. Suppl. 142. (Cited In U.S. EPA, 1980a)
-41-
-------
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-
tory tract, cerumlnous glands, brain, kidney, heart, and spleen. Toxicol-
ogy. 13: 131-141. (Cited 1n U.S. EPA, 1983a)
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
Inhalation toxldty study of vinyl chloride 1n rats. I. Growth, mortality,
*
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.
Toxlcol. 19: 317-333. (Cited In U.S. EPA, 1984)
-42-
-------
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:
2013-2017. (CHed 1n IARC, 1979)
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-
-------
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.
IARC (International Agency for Research on Cancer). 1979. Vinyl chloride.
in: Vinyl Chloride, Polyvlnyl Chloride, and Vinyl Chloride-Vinyl Acetate
Copolymers. IARC Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Humans. IARC, WHO, Lyon, France. Vol. 19, p. 377-438.
IARC (International Agency for Research on Cancer). 1982. \{1nyl chloride.
In: Chemicals, Industrial Processes and Industries Associated with Cancer 1n
Humans. IARC Monographs on the Evaluation of the Carcinogenic Risk of
»
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-
-------
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:
171-177. (CHed In U.S. EPA, 1983a)
Lange, C.E., S. June, G. Stein and G. Veltman. 1974. The so-called vinyl
chloride sickness, an occupation related systemic sclerosis? Int. Arch.
Arbeltsmed. 32: 1-32. (CHed 1n U.S. EPA, 1980a, 1983a)
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.
J. Toxlcol. Environ. Health. 4: 15-30. (CHed 1n UVS. EPA, 1983b)
Lester, D., L.A. Greenberg and W.R. Adams. 1963. Effects of single and
repeated exposures of humans and rats to vinyl chloride. Am. Ind. Hyg.
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-
-------
Loprleno, N., R. Barale, S. BaroncelH, et al. 1977. Induction of gene
mutations and gene conversions by vinyl chloride metabolites In yeast.
Cancer Res. 36: 253-257. (Cited In IARC, 1979)
Mabey, W.R., J.H. Smith, R.T. Podoll, et al. 1981. Aquatic Fate Process
Data for Organic Priority Pollutants. Monitoring and Data Support Division,
Office of Water Regulations and Standards, Washington, DC. EPA 440/4-81-014.
Magnusson, J. and C. Ramel. 1976. Mutagenlc effects of vinyl chloride 1n
Drosophlla melanogaster (Abstr. No. 27). Mutat. Res. 38: 115. (Cited In
IARC, 1979)
Makk, L., F. Delmore, J.L. Creech, Jr., et al. 1976. Clinical and morpho-
logic features of hepatic anglosarcoma In vinyl chloride wockers. Cancer.
37: 149-163. (Cited 1n U.S. EPA, 1980a, 1983a)
•
Malavellle, C., H. Bartsch, A. Barbln, et al. 1975. Hutagenlclty of vinyl
chloride, chloroethyleneoxlde, chloroacetaldehyde, and chloroethanol.
Blochem. Blophys. Res. Commun. 63: 363-370. (Cited 1n IARC, 1979)
Maltonl, C. 1977a. Vinyl chloride carclnogenlcHy: An experimental model
for cardnogenesls studies. In.: Origins of Human Cancer, Book A, H.H.
H1att, J.D. Watson and J.A. Wlnsten, Ed. Cold Spring Harbor, NY.
p. 119-146. (Cited 1n IARC, 1979)
Maltonl, C. 1977b. Recent findings on the carclnogenlcHy of chlorinated
oleflns. Environ. Health Perspect. 21: 1-5. (CHed 1n U.S. EPA, 1983b)
-46-
-------
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-
-------
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-
-------
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-
mer. Environ. Res. 16: 285-301. (Cited 1n U.S. EPA, 1983a)
Suzuki, Y. 1980. Nonneoplastlc effects of vinyl chloride In mouse lung.
Environ. Res. 21: 235-253. (Cited 1n U.S. EPA, 1983a)
Thomas, J.C. 1977. PVC and security, European regulations (Fr.). Caoutch.
Plast. 571: 33-38. (Cited 1n IARC, 1979)
-49-
-------
Torkelson. M.S.. F. Oyen and V.K. Rowe. 1961. The toxlclty of vinyl
chloride as determined by repeated exposure of laboratory animals. Am. Ind.
Hyg. Assoc. J. 22: 354-361. (Cited 1n U.S. EPA, 1983a)
TMbukh, S.L., et al. 1949. Working conditions and measures for their
sanitation 1n the production and utilization of vinyl chloride plastics.
Gig. Sanlt. 10: 38. (Cited 1n U.S. EPA, 1980a, 1983a)
Ungvary, G.Y., A. Hudak, E. Tatral, M. Lorlncz and 6. Folly. 1978. Effects
of vinyl chloride exposure alone and 1n combination with trypan blue —
Applied systematically during all thirds of pregnancy on the fetuses of CFY
rats. Toxicology. 11: 45-54. (Cited 1n U.S. EPA, 1983a)
U.S. Consumer Product Safety Commission. 1974a. Self-pressurized household
substances containing vinyl chloride monomer, classification as banned
hazardous substance. Fed. Reg. 39: 30112-30114. (Cited 1n IARC, 1979)
U.S. Consumer Product Safety Commission. 1974b. Vinyl chloride as an
Ingredient of drug and cosmetic aerosol products. Fed. Reg. 39: 30830.
(Cited 1n IARC. 1979)
U.S. EPA. 1974. EPA bans use of certain vinyl chloride pesticides. Envi-
ronmental News, 24 April, p. 1-2. (Cited 1n IARC, 1979)
U.S. EPA. 1980a. Ambient Water Quality Criteria for Vinyl Chloride. Envi-
ronmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-078.
NTIS PB 81-117889.
-50-
-------
t
I
U.S. EPA. 1980b. Guidelines and Methodology Used In the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. Federal Register. 45: 79347-79357.
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. Reportable Quantity Document for Vinyl Chloride. Pre-
pared 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 1n Support of,Evaluation 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
U.S. EPA. 1983c. 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. 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-
-------
Verburgt, F.6. and E. Vogel. 1977. Vinyl chloride mutagenesls 1n Droso-
phlla melanogaster. Mutat. Res. 48: 327-336. (Cited 1n IARC, 1979)
Viola, P.L. 1970. Pathology of vinyl chloride. Med. Lavoro. 61: 174-180.
V-
(CHed 1n U.S. EPA, 1983a)
Viola, P.L., A. Blgottl and A. Caputo. 1971. Oncogenlc response of rat
skin, lungs, and bones to vinyl chloride. Cancer Res. 31: 516-522. (CHed
1n U.S. EPA, 19835)
.J Wagoner, J.K. 1983. Tox1c1ty of vinyl chloride and poly(v1nyl chloride): A
critical review. Environ. Health Perspect. 52: 61-66.
Watanabe, P.G., G.R. McGowan and P.J. Gehrlng. 1976a. ,Fate of (14C)
vinyl chloride after single oral administration 1n rats. Toxlcol. Appl.
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.
Appl. Pharmacol. 37: 49-59. (Cited 1n U.S. EPA, 1980a)
Waxweller, R.J., W. Stringer, J.K. Wagoner, J. Jones, H. Falk and C. Carter.
1976. Neoplastlc risk among workers exposed to vinyl chloride. Ann. NY
Acad. Sc1. 271: 40-48. (CHed 1n U.S. EPA, 1983b)
-52-
-------
"Wedrychowlez, A. 1976. Preliminary results of studies on the state of
health of workers exposed to the action of vinyl chloride. Przeglad
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-
-------
DATE DUE
41
e
i
r- O
25
flj ttj
O. VI
X O
u
a>
Q.
Carcinoge
Potency
un
T3 f-
0»
«- e
Jl
0> 0.
o •
k.
HI
o
X
vn
«0
rx
f§
O VD
O
15
tJ
-------
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-
------- |