27754
DRAFT CRITERIA DOCUMENT
FOR' VINYL CHLORIDE
FEBRUARY 1984
HEALTH EFFECTS BRANCH
CRITERIA AND STANDARDS DIVISION
OFFICE OF DRINKING WATER
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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TABLE OF CONTENTS
"I. SUMMARY 1-1
II. INTRODUCTION II-l
III. PHYSICAL AND CHEMICAL PROPERTIES III-l
IV. PHARMACOKINETICS IV-1
A. Absorption IV-1
B. Metabolism IV-5
C. Excretion IV-8
V. HUMAN EXPOSURE* V-l
VI. HEALTH EFFECTS IN ANIMALS VI-1
A. Acute/Chronic Effects VI-1
B. Teratogenicity VI-3
C. Mutagenicity VI-4
D. Carcinogenicity VI-6
VII. HUMAN HEALTH EFFECTS VII-1
A. Non-Carcinogenic effects VII-1
B. Carcinogenic effects VII-6
VIII. MECHANISM OF TOXICITY VIII-1
IX. RISK ASSESSMENT IX-1
X. QUANTIFICATION OF TOXICOLOGICAL EFFECTS X-l
XI. REFERENCES XI-1
*Prepared by the Science and Technology Branch
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I. SUMMARY
Almost 7 billion pounds of vinyl chloride are produced"
in the United States annually. Most emissions into the environ-
ment originate from manufacturing plants which use the compound
for the production of polyvinyl chloride resins. The predomi-
nant route of exposure to the public living near these plants
is through inhalation, while the principal source of vinyl
chloride exposure for most Americans is probably from polyvinyl
chloride food containers. This source contributes approximately
1 ppb to the diet. Vinyl chloride has also been found in
drinking water. Three national surveys of drinking water have
demonstrated the presence of vinyl chloride at very low levels
(ug/1 range) in a small number of supplies.
•
Upon ingestion, vinyl chloride is rapidly absorbed from
the gastrointestinal tract and is distributed to the liver and
other organs. Several pathways may be involved in vinyl chloride
metabolism, which occurs primarily in the liver. The toxicity
of vinyl chloride appears to be attributable to its enzymatic
conversion to reactive polar metabolites such as chloroacetalde-
hyde or chloroethylene oxide. Several of these suspected meta-
bolites are mutagenic, while vinyl chloride itself is not, accord-
f
ing to available information. At low doses (e.g., 1 mg/kg) the
metabolites of vinyl choride are primarily excreted in the urine.
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1-2
At high doses (e.g., 100 mg/kg), most of the solvent is
expired as vinyl chloride.
Acute and chronic exposure to vinyl chloride can result
in toxicity in experimental animals and humans. In animals,
an inhalation exposure of approximately 100,000 ppm results
in death within several hours, with autopsies revealing
congestion and edema of the lungs and hyperemia of the
Kidneys and liver. ?est animals exposed to an inspired
air concentration below 100 ppm exhibit no pronounced adverse
health effects. Vinyl chloride does not appear to be terato-
genic in rats or rabbits, and insufficient data exists to
evaluate the teratogenicity of vinyl chloride in humans.
Studies on humans working in vinyl chloride plants sug-
gest that systemic toxic effects that are noncarcinogenic
in nature can be demonstrated at exposure levels below 50
ppm. Some plant workers may have been exposed to concentra-
tions exceeding 1000 ppm and occasionally approaching 10,000
ppm before OSHA standards were instituted in 1974. At these
levels, workers manifested dizziness, headaches, and/or
euphoria. Long-term exposure to these levels in vinyl chlor-
ide plants have resulted in a number of diseases (i.e.,
acroosteolysis, pulmonary insufficiency), cardiovascular
and gastrointestinal manifestations, and disturbances of
the central nervous system. Unfortunately, data regarding
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1-3
dose-response relationships in humans are very scarce because
of the virtual absence of air measurements of vinyl chloride
in the work environment before 1974.
Vinyl chloride is a proven carcinogen in mice, hamsters,
and rats. Animal studies have shown that vinyl chloride pro-
duces tumors of different types at different sites, and that
the incidence and relative distribution are influenced by
\
dose, age of the animal, and species and strain of animal used.
Angiosarcomas of the liver were found in all animals studied,
whereas some types of tumors such as brain tumors, hepatomas
and lung tumors were observed in one type of animal only. A
dose-response relationship was observed in most experiments.
Inhalation studies have shown the lowest dose of vinyl chloride
exposures to have a carcinogenic effect to be 50 ppm. A recent-
ly completed ingestion study demonstrated the occurrence of hepat-
ic angiosarcomas and pulmonary angiosarcomas in rats at levels
of 5.0 mg/kg bw/day or more, and the increased incidence of
• • .
foci of cellular alteration and liver cell tumors at the lowest
exposure level of 1.7 mg/kg/ bw/day.
Human data have been primarily obtained from workers
exposed to vinyl chloride. A number of epidemiologic studies
have linked vinyl chloride with angiosarcoma and other forms
of neoplasm. The reported frequency of angiosarcoma of the
liver is especially noteworthy because this is a very rare
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1-4
type of cancer (25 - 30 cases/year in the United States),
and it is reasonable to infer a causal relationship between
exposure to vinyl chloride and the development of this tumor.
Through 1977, a total of 64 cases of liver angiosarcoma have
been identified worldwide among vinyl chloride-exposed indus-
trial workers. Although rare, the carcinogenicity of vinyl
chloride to humans is unambiguous.
The International Agency for Research on Cancer (IARC)
analyzed the available data and concluded that exposure to
vinyl chloride results in an increased carcinogenic risk to
humans. The organs most likely to be affected were the
liver, brain, lung and hemato-and lymphopoietic systems.
The National Academy of Sciences (1983) also examined the
data and concluded that vinyl chloride is an established
carcinogen in humans and animals with older animals and
females appearing to be more susceptible.
The National Academy of Science (NAS) and EPA's Carcin-
ogen Assessment Group (CAG) have calculated projected incre-
mental excess cancer risks associated with the consumption
of a specific 'chemical via drinking water by mathematical,
extrapolation from high-dose animal studies. Using the risk
estimates generated by the NAS (1977-1979) where the linear
non-threshold multi-stage model was utilized, the range of
vinyl chloride concentrations were computed that would nomi-
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1-5
nally increase the risk of one excess cancer per million
(106), per hundred thousand (105). or per ten thousand (104)
people over a 70-year lifetime assuming daily consumption at
the stated exposure level. From the NAS model it is estimated
at the 95% confidence limit that consuming two liters per
day over a lifetime having a vinyl chloride concentration of
100 ug/1, 10 ug/1 or 1 ug/t would increase the risk of one
excess cancer per 10,000, 10.0,000 or 1,000,000 people exposed,
••
respectively. Using the revised GAG approach and the multi-
stage model, it was estimated at the 95% confidence limit
that consuming two liters per day over a lifetime having a .
vinyl chloride concentration of 200 ug/1, 20 ug/1 or 2 ug/1
would increase the risk of one excess cancer per 10,000,
•
*
100,000 or 1,000,000 people exposed respectively. The
numerical differences observed after utilizing the NAS and
GAG risk estimates are due to the selection of data for use
/
in the model. The NAS based its calculations on an ingestion
study by Maitoni et al. (1975) in which rats were exposed to
vinyl chloride by gavage, while the GAG used the same Maitoni
et al. (1975) study but based its estimate upon the increased
incidence of total tumors in rats exposed to vinyl chloride
through inhalation.
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II. INTRODUCTION
Vinyl chloride has been used foe over 40 years in the
production of poiyvinyl chloride (PVC)f the most widely used
material in the manufacture of plastics throughout the world.
About 25% of the estimated 18 billion pounds of vinyl chloride
produced worldwide in 1972 was manufactured in the United
States (Berk, et a_l., 1976). Between 1968 and 1973, vinyl
• " »
chloride production in the United States rose 14% annually,
reaching a production level of nearly 7 billion pounds in
•
1978 (U.S. Int. Trade Comm.). This increase in vinyl chloride
production was due to the growing dependence of virtually
every branch of industry and commerce upon products and
components fabricated from poiyvinyl chloride (U.S. EPA, 1974).
(For the location of vinyl chloride and poiyvinyl chloride
manufacturing and processing plants in the United States in
1978, refer to Figure II-l.)
Vinyl chloride is not known to occur in nature (National
Academy of Sciences, 1977). The compound is synthesized as
chlorinated olefinic hydrocarbon monomer from petrochemical
feedstock and chlorine. In 1975, vinyl chloride emissions
in the United States were found to originate from three major
sources: (1) 17 plants where vinyl chloride was commercially
synthesized (about 11 percent); (2) 41 PVC plants where the
vinyl chloride monomer was used in the production of PVC
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(Milby, 1978)
°Vinyl Chloride Plant Location
"Polyvinyl Chloride Plant Location
SOURCE: SRI.
°PUERTO RICO
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II-2
resins for various industrial purposes (about. 85 percent);
(3) about 8,000 PVC fabricating plants (U.S. EPA, 1975b).
Vinyl chloride and polyvinyl chloride are used as raw
materials in the rubber, paper, glass and automotive indus-
tries. In addition, vinyl chloride and polyvinyl chloride
are used in the manufacture of electrical wire insulation
and cables, piping, industrial and household equipment,
medical supplies, food packaging materials and'building and
construction products. Polyvinyl chloride and vinyl chloride
copolymers are distributed and processed in a variety of
forms, including dry resins, plastisol (dispersions in plasti-
cizers), organosol (dispersions in plasticizers plus volatile
solvent), and latex (a colloidal dispersion in water used to
coat paper, fabric or leather).
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II. PHYSICAL AND CHEMICAL PROPERTIES
The structure of vinyl chloride is as follows:
H2C = CHC1 Molecular Weight m 62.5
Vinyl chloride is highly flammable (limits of inflamma-
bility: 4.00-21.70%) and in sufficient concentrations (at
least 1200-2000 ppm) has a sweet, pleasant odor. The compound
has a boiling point of -13.3'C. Thus, at standard temperature
•'• .* ' ' \
and pressure, vinyl chloride exists as a gas. Vinyl chloride
is only sparingly soluble in water (0.11 g/100 g water at
28*C), but is soluble in alcohol and very soluble in ether
and carbon tetrachloride. The specific gravity of the chemical
is 0.91; thus it would tend to rise to the surface of water.
The vapor density of vinyl chloride is slightly more than
twice that of air (CRC Handbook of Chemistry and Physics,
1978-1979? Braker and Mossman, 1971).
The above information indicates that vinyl chloride is
volatile and readily passes from water into the gas phase
under most laboratory and environmental conditions. This was
confirmed in experiments where 16 mg/1 vinyl chloride was
added to distilled water in beakers and the concentration
determined with time (U.S. EPA, 1974). The data indicate
that if first order kinetics are assumed, the volatilization
half-life in quiescent water (unstirred) is 290 minutes and
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III-2
in continually stirred water is 25 .,8 minutes. Dilling, et
al. (1975) found similar values for the stirred water. As
Dilling, et al., note, predictions of vinyl chloride loss
from water at relatively high concentrations (e.g., 1 mg/1)
may not reflect the situation at very low concentrations.
Volatilization appears to be the most significant process
\
in the loss of vinyl chloride from the aquatic environment
(Hill, et al^ ,/. 1976).. Once in the atmosphere, vinyl chloride
undergoes rapid photochemical oxidation (Gay, et aj..,1976;
Lillian et al., 1975).
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IV. PHARMACOKINETICS
A. Absorption and Distribution
An investigation by Duprat et al. (1977) indicates
that inhaled vinyl chloride is rapidly absorbed by the lungs
and immediately accumulates in the liver. In this study,
rats were exposed in a chamber to 20,000 ppm 14C vinyl chlo-
ride for 5 minutes, and then the distribution of radioactive
'*
vinyl chloride in the various body organs was determined.
After 10 minutes exposure, radioactivity was found in the
liver, bile duct, digestive lumen, and kidneys. With increas-
ing time (up to 3 hours), 14C activity was detected in the
urinary system, salivary and lacrimal glands, skin and thymus.
•
*
Using male Wistar rats, Withey (1976) determined that
vinyl chloride is rapidly absorbed from the gastrointestinal
tract following gastric intubation of aqueous solutions
containing up to 2.0 mg/ml vinyl chloride. Vinyl chloride
uptake by this route was extremely rapid; peak concentrations
were found less than 10 minutes after the dose was administered.
In a study by Watanabe et al. (1976a), rats were given
single oral doses (gavage) of 0.05, 1, or 100 mg/kg of 14O
vinyl chloride dissolved in corn oil, and the routes and rates
of elimination of 14C activity were followed for 72 hours. The
percentage of the dose expired as vinyl chloride was 1, 2,
and 67%, respectively. The disposition of vinyl chloride to
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IV-3
Tissue
TABLE IV-1
*
Percentage of the Administered 14C Activity
per Gram of Tissue
After Administration of,(14C) Vinyl Chloride
by Gavage to Male Sprague-Dawley Rats3
(Watanabe et a_l., 1976a)
0.05
Dose (ma/kg)*1
1.0
100
Liver
Skin
Carcass
Plasma
Muscle
Lung
Pat
0.172 i 0.025&
0.070 + 0.023
• * »
Ol*027 + 0.007
0.041 + 0.004
0.028 i 0.003
0.050 +_ 0.003
0.030 + 0.004
0.182 + 0.005
0.076 + 0.010
0.046 + 0.002
0.053 + 0.007
0.031 + 0.003
0.061 i 0.003
0.045 + 0.008
0.029 + 0.002
0.010 +_ 0.002
0.007 + 0.001
0.006 + 0.001
0.011 + 0.001
0.006 + 0.001
a Remaining in the body after 72 hr.
" Mean ^ SE, five rats per dose
c Not detectable above background
d Vinyl chloride dissolved in corn oil
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IV- 4
TABLE IV- 2
Percentage of 1*C Activity
per Gram Tissue 72 hr Following an Inhalation
Exposure to (14C) Vinyl Chloride
For 6 hr in male Sprague-Dawley Rats
(Watanabe et aU , 1976b)
Percentage
activity
Exposure concentration
Tissue
Liver
Skin
Carcass
Plasma
Muscle
Lung
Fat
Kidney
0.139 +
0 ..141, +
0.072 +
0.073 7
0.048 +
0.049 7
0.051 +
0.052 7
0.052 +
0.053 +
0.065 +
0.066 +
0.026 +
0.026 7
0.079 +
0.080 7
10 ppm
0.009a (0:35)c
0.009&
0.004 (0.18)
0.004
0.004 (0.12)
0.004
0.001 (0.13)
0.001
0.005 (0.13)
0.005
0.007 (0.16)
0.007
0.006 (0.07)
0.006
0.003 (0.20)
0.003
1000 ppm
0.145 + 0.008a (9.63)c
0.165 + 0.009b
0.115 •»• 0,010 (7.64)
0.131 7 0.011
0.049 + 0.004 (3.26)
0.056 i 0.005
ND<3
0.038 + 0.003 (2.52)
0.043 + 0.003
0.046 + 0.001 (3.06)
0.052 i 0.001
NDd
0.057 + 0.005 (3.79)
0.065 + 0.006
a Expressed as percentage of total 14C activity per gram of
tissue. Uncorrected for expired VC:
dpm per g tissue
total dpm recovered
Mean ± SE from four rats.
b Expressed as percentage metabolized 14C activity per gram
tissue* Corrected for expired VC:
dpm per g of tissue
Total dpm recovered minus dpm of expired VC
Mean + SE from rats.
c Micrograra equivalents vinyl chloride per gram of tissue.
d Not detectable, detection limit for plasma and fat was 3
ug/g of tissue (3ppm)
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IV-5
hours in a closed system, the percentage incorporated as
radioactivity per g tissue was highest for kidney (2.13)
and liver (1.86).- The percent of incorporated activity
was 0.73 for the spleen and 0.17 for the brain. Forty-
eight hours after the beginning of exposure, labeled material
could still be detected in these tissues.
The percentage absorption of vinyl chloride from the
human gastrointestinal tract has not been established.
Because of the lack of data on percent absorption from the
gastrointestinal tract, the risk calculations in this
document will assume a 100% absorption factor.
B. Metabolism
Metabolism of vinyl chloride occurs primarily in the
liver by microsomal enzymes. There is strong evidence that
the toxicity of this compound is attributable to its
enzymatic oxidation to reactive polar metabolites. Several
of these suspected metabolites are strongly mutagenic,
while vinyl chloride itself is not (Bartsch and Montesano,
1975). Exposure to vinyl chloride leads to the reduction
of non-protein sulfhydryl levels in rat liver, suggesting
that the metabolites of vinyl chloride conjugate with
glutathione and/or cysteine (Hefner et al., 1975a). Hathway
(1977) reported in vitro depurination of calf thymus DNA by
chloroacetaldehyde identical to that observed in hepatocyte
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IV-6
DNA following administration of vinyl chloride to rats in
vivo. This suggests that vinyl chloride metabolites may
interact with some purine and pyrimidine residues of DNA,
providing a possible explanation for the oncogenic properties
associated with vinyl chloride.
In a review of the literature, Bartsch and Montesano
(1975) report two possible biotransformation schemes - one
•'•
involving alcohol dehydrogenase (Scheme I) and the other
involving the mixed function oxidase system (Scheme II).
These are indicated below:
Scheme I: C1HOCH2 >C1H2C-CH2OH >C1H2C-CHO >C1H2C-COOH
o
Scheme II: C1H=CH2 >[H2C-CHC1] >C1H2C-CHO >C1H2C-COOH
Evidence for biodegradation involving the alcohol
dehydrogenase pathway includes data which demonstrates that
pretreatment of rats with either ethanol or pyrazole (an
%
inhibitor of alcohol dehydrogenase) inhibits the metabolism
of vinyl chloride (Hefner et al., 1975a).
There is also ample evidence that the mixed function
oxidase (MFO) system is involved in the metabolism of vinyl
chloride. Pretreatment of rats with phenobarbital, which
which induces the MFO system, also enhances liver toxicity of
vinyl chloride (Jaeger et a_l., 1974). Rat liver microsomes
catalyze the covalent binding of vinyl chloride metabolites to
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IV-7
protein and nucleic acids (Kappus et al., 1975; 1976); chloro-
ethylene oxide, which is thought to be formed by the MFO system,
may be the primary microsomal metabolite capable of alkylating
these intra-cellular macromolecules (Laib and Bolt, 1977).
Several pathways may be involved in vinyl chloride metab-
olism, the predominant one depending on dose. Hefner et al.
(1975) performed an inhalation study in which rats were
exposed to vinyl chloride concentrations ranging from 50.5%
to 1167.0 ppm for 12 months time. The rate of metabolism,
as determined by measuring the declining level of vinyl
chloride in the chamber atmosphere, was three times greater
for seven separate exposures ranging from 50 to 105 ppm than
it was for five separate exposures ranging from 220 to 1167
ppm. This indicated that the predominant pathway at the
lower concentrations, probably involving alcohol dehydrogenase,
is saturable between 105 and 220 ppm. This group also found
evidence that oxidases in the microsomes may be involved in
metabolism at high level exposures. In another study, Bolt
et al. (1977) subjected rats to an inspired concentration
of 14C-vinyl chloride ranging from 200 to 1200 ppm in a closed
system, and measured the rate of decrease of vinyl chloride
levels in the chamber atmosphere. This group calculated
that saturation of the vinyl chloride-metabolizing enzymes
of the rat is achieved at 250 ppm.
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rv-8
C. Excretion
Excretion of ^C activity within 72 hours following
a single oral dose of 14C-labeled vinyl chloride (0*05,
1»0, or 100 mg/Tcg) is shown in Table IV-3 (Watanabe et al.,
1976a). As the dose increases, a markedly greater proportion
of vinyl chloride is expired unmetabolized, while the percent-
age of metabolite .in the urine decreases substantially.
•'•••'" \
Again, saturation kinetics are suggested. The table also
indicates that metabolites of vinyl chloride are predominantly
excreted via the urine. Administration of vinyl chloride by
inhalation produced almost identical results (Watanabe et al.,
1976b). Two major metabolites in the urine are identified
as indicated in Table IV-4.
Buchter et al. (1980) examined the metabolic elimination
of vinyl chloride in Rhesus monkeys. Rhesus monkeys were placed
in a closed exposure system into which vinyl chloride was in-
jected, and air samples taken to determine the decline of
vinyl chloride in the gas phase of the system. The results
showed that the metabolic elimination of vinyl chloride in
Rhesus monkeys is a dose-dependent, saturable process, as in
rats. Elimination was shown to obey a first-order law
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IV-9
TABLE IV- 3
Percentage of Administered c Activity Recovered
Following a Single Oral Dose of Vinyl Chloride*
(Watanabe et al., 197 6a)
Dose (mg/kg)
0.05
1.0
100
Expired:
As VC
As CO 2
Urine
Feces
1
8
68
2
.43
.96
.34
.39
± °
± °
+ 0
.*59
.54
.52
2
13
59
2
.13 +
.26 +
.30 +
.20 +
0.22
0.47
2.75
0.39
66
2
10
0
.64
.52
.84
.47
•f
+
+
+
0.67
0.13
0.95
0.06
Carcass and
tissues
Cage washc
Total recovery
10.13 +' 1.93 11.10 + 0.47
0 0.84 + 0.45
/ 91.25 + 2.47 88.83 + 1.98
1.83 + 0.14
0
82.30 + 0.43
a Percentage of dose excreted over 72 hr. Only the 14C
activity associated with the expired VC can be
attributed to VC per se.
b Mean + SE five rats per dose.
c Distilled water wash of metabolism cage at termination
of the study.
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IV-10
TABLE IV-4
14C-containing Urinary Metabolites
from Male Sprague-Dawley Rats
Given Vinyl Chloride by Gavagea
(Watanabe et al., 1976a)
Dose (mg/kg)
Compound 0.05(4)b 1.0(5) 100(5)
N-acetyl-S-(2-
hydroxyethyl-
cysteine) 30.4 + 2.0C 36.2 + 3.9 29.1 + 2.0
Thiodiglycolic acid 25.6 + 1.9 23.7+1.1 25.4+0.9
Unidentified 38.6 + 2.9 34.5 + 4.6 36.6 + 2.0
Total 94.6 94.6 91.1
Metabolites were separated and quantitated by high
pressure liquid chromatography. Values are expressed
as percentage of total urinary radioactivity.
( ) = Number of animals per dose
Mean + SE
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IV-11
below 200-300 ppm, and at high concentrations the maximal
velocity of metabolic elimination" of vinyl chloride was
about half that of rats when related to kg body weight.
Green and Hathway (1975) measured the excretion of 14O
vinyl chloride administered to rats by intragastricr
intravenous (femoral vein), or intraperitoneal routes. Two
doses were used.: 0.25 mg/kg and 450 mg/kg. The results
are shown in Table IV-5. During the first 24 hours after
treatment, more than 90 percent was excreted from the
animals for all three routes. Significant differences were
noted, however, in the manner of excretion for the 0.25
mg/kg dose. For the intragastric route, 71.5% was excreted
in the urine, whereas 99% was exhaled from the lungs when
vinyl chloride was administered intravenously. For the
intraperitoneal route, 43.2% was exhaled while 41.5% was
excreted in the urine. At the higher dose (450 mg/kg),
over 90% was exhaled as vinyl chloride in both intragastric
and intraperitoneal administered rats. The intragastric
values are consistent with the values reported in the oral
studies performed by Watanabe et al., (1976a) (see Table
IV-3).
Withey and Collins (1976) have developed a statistical
model for use in equating oral dose levels of vinyl chloride
to inhalation exposure levels in rats, using blood level
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IV-12
TABLE IV-5
(Green and Hathway, 1975)
TN OF RADIOACTIVITY IN RATS, GIVEN A SINGLE DOSE OF 114C]VINYL CHLORIDE
ere each dosed i.g. with 250ug of [^Clvinyl chloride per kg in corn oil solution, and another 4 rats were each
milarly with 450 mg of lUcjvinyl chloride per kg. 4 rats were each injected in the femoral vein with 250 ug of
tyl chloride per kg in N-(B-hydroxyethyl)lactamide. Four rats were each injected i.p. with 250 ug of [14C]vinyl
, per kg in N-(B-hydroxyethyl) lactamide, and another 4 animals were each injected similarly with 450 mg of l1401
loride.
Time Radioactivity excreted (% of dose)3
(h) :
Intragastric Intravenous Intraperitoneal
Exhaled air Urine Fe/»s Exhaled air Urine Feces Exhaled air Urine Fecea
Vinyl (X>2 Vinyl 002 Vinyl 002
chloride chloride chloride
kg 0-24 3.7 + 1.2 12,6 + 1.1 71.5 + 5.6 2.8 + 2.5 99.0 + 0.8 0.1 0.5 0.1 43.2 + 4.6 10.3 + 2.2 41.5 + 4.8 1.6
24-48 ~ 0.9" 3.3 1.6 -. 0.7 1.6 0.2^
48-72 0.3 ' *' 0.2
Total 3.7 + 1.2 13.5 + 1.3 75.1 + 4.2. 4.6 + 3.0 99.0 + 0.8 0.1 0.5 0.1 43.2 + 4.611.0 + 1.2 43.1 + 5.71.8
kg 0-2491.9 + 2.5 0.6 4.5 +2.3 0.4 96.2+4.10.7 2.5 +.0.90.1
24-48 0.1 0.8 0.3 0.1
48-72 0.1
Total 91.9 +_ 2.5 0.7 5.4 +_ 2.2 0.7 96.2 + 4.1 0.7 2.6 +_ 0.9 0.1
;s shown are the means + S.O. 'of those means.
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IV-13
time curves. The authors concluded that "if the total daily
liquid intake contained 20 ppra vinyl chloride, then the area
generated under the blood level time curve, for rats, would
be equivalent to an inhalation exposure of about 2 ppm for
24 hours." Thus, according to this model, inhalation exposure
is ten times more efficient than oral exposure.
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VI- HEALTH EFFECTS IN ANIMALS
A. Acute/Chronic Effects
Acute toxicity tests with vinyl chloride were carried
out by Patty et al. (1930) of the Bureau of Mines, Department
of Commerce. Single exposure of guinea pigs to vinyl chloride
gas, 10 percent in air (100,00 ppm), resulted in narcosis and
death within 30 to 60 minutes. Inhalation of lower concentra-
.'• '• ' • *
tions resulted in'ataxia and narcosis. Pathological findings
at necropsy were congestion and edema of the lungs and hypere-
of the kidneys and liver. A number of investigators have
similar observations when examining the acute inhalation
Affects of vinyl chloride in mice, rats, guinea pigs, rabbits,
cats, dogs (Peoples and Leake, 1933; Lester et al., 1963;
Mastromatteo et a_l., 1960; Haley, 1975; Prodan et al., 1975).
animal studies, LCSO's at 2 hours ranged from 117,500 ppm
mice to 230,800 ppm for rabbits.
Marsteller et al. (1975) reviewed and summarized the
findings of previous studies on vinyl chloride exposure in
laboratory animals. Torkelson et al. (1961) exposed test
animals to concentrations ranging from 50 to 500 ppm. Rats
e«posed to 100 ppm (2 hours/day for 6 months) were judged
normal on the basis of appearance, mortality, growth,
hematological examination and other factors. However, a
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VI-2
slight increase in the liver weight was observed. Rats,
guinea pigs, rabbits, and dogs exposed to 50 ppra (7 hours/day,
130 times in 189.days) appeared to be normal in appearance,
mortality, and growth, and the increase in weight of the
rat livers did not occur at this concentration. Basalaev
et al. (1972) administered gaseous vinyl chloride to rats
and rabbits at a concentration of 0.03-0.04 mg/1 for 4
hours/day for § months. Cardiovascular disorders, changes
in the bioelectric activity of the hypothalamus,
hyperadrenalinemia, osteoporosis and resorption of bone
tissue were observed.
Jaeger (1975) conducted experiments with rats to
determine the interaction between vinylidene chloride (1,1-
DCE) and vinyl chloride. In this study, hepatotoxicity was
measured by the. elevation of serum alanine-oC-fcetoglutarate
transaminase (AKT). When fasted rats were exposed to 0.02%
(V/V), 1,_1-DCE, serum AKT activity was elevated about 50-
fold, two hours after the termination of a 4-hour inhalation
exposure. No elevation was observed when 0.1% vinyl chloride
was administered alone. When the two chemicals were
administered simultaneously at the levels indicated, no
elevation of serum AKT occurred. Thus, the vinyl chloride
was protective. These two monomers are used together in the
production of vinyl copolymers, and exposure to both agents
in the workplace was reported by Kramer and Mutchler (1972).
-------
VI-3
B. Teratogenicity
John et al. (1977) examined the effects of vinyl
chloride inhalation on the fetuses of mice, rats, and
rabbits. The pregnant animals were exposed 7 hours daily
to concentrations of 50 or 500 ppm for mice and 500 or 2500
ppm for rats and rabbits. Mice and rats were exposed on
days 6 to 15 of gestation, and rabbits on days 6 to 18.
•* •*
Ho teratogenic effects were observed at 2500 ppm in rats
and rabbits, except that a greater incidence of dilated
ureters were noted in rats. Indeed, vinyl chloride exposure
at this level actually decreased the incidence of certain
skeletal anomalies in rats compared to controls (e.g.,
*
delayed ossification of the bones of the skull, and unfused
centers of ossification of the skull and sternebrae). Mice
i
were the most sensitive to vinyl chloride. No teratogenic
| /
effects were noted in the fetuses of mice exposed to 50
iPprn, but a .significantly greater incidence of unfused
sternebrae and delayed ossification of sternebrae (no. 5)
and bones of the skull were observed among litters of mice
exposed to 500 ppm compared to unexposed controls.
Embryotoxic effects were not generally noted, but some
decrease in fetal body weight and crown-rump length was
observed in rats and mice.
-------
VI-4
Radike et al. (1977a) did not observe gross (nonmicro-
•
scopic) abnormalities in the offspring of rats exposed 4
hours daily on the 9th to the 21st "day of gestation by inha-
lation of 600 or'6000 ppm vinyl chloride. A small increase
in the incidence of minor skeletal abnormalities, including
wavy ribs, extra 14th ribs and delayed calcification of
small bones, were observed in the offspring of the exposed
animals. However, the investigators concluded that such a
small incidence* is difficult tJb distinguish from a sporadic
occurrence, and should be considered to be skeletal variants
and not malformations.
Groups of pregnant CF-1 mice, Sprague-Dawley rats and
New Zealand white rabbits were exposed to doses of vinyl
chloride ranging from 50 to 2500 ppm by inhalation. Exposure
to these concentrations of vinyl chloride did not cause any
significant embryonal or fetal toxicity and vas not teratogenic
i
in any of the three species tested. (John et al., 1981).
C. Mutagenicity
Vinyl chloride is mutagenic in a number of biological
systems. The mutagenic action of vinyl chloride appears to
be dependent upon its metabolic conversion to chemically
reactive metabolites (e.g., chloroethylene oxide, 2 chloro-
acetaldehyde). The mutagenic effects of vinyl chloride have
been demonstrated in: (1) nsetabclically activated systems
-------
VI-5
using Salmonella typhimuriuro (Bartsch et al., 1975; McCann
et al., 1975; Elmore et al., 1976; Rannug et al./ 1974;
Garro et al., 1976) developed by Ames et al. (1973) in which
the genetic indicator refers to histidine prototrophy by
base-pair substitutions! or by base-pair insertions or dele-
tions; (2) Escherichia coli K12 bioauxotrophic strain with
back mutation system arginine + (Greim et a_l., 1975); (3)
several species; o£ yeast inducing forward mutations and gene
\
conversions at specific loci (Loprieno et aJL., 1976, 1977);
(4) in germ cells of Drosophila (Verburgt and Vogel, 1977)
and (5) Chinese hamster V79 cells (Huberman et al., 1975).
The literature on the mutagenic effects of vinyl chloride
were reviewed by Bartsch and Montesano (1975).
The mutagenic activity of inhaled vinyl chloride (3000,
10,000 or 30,000 ppm for 6 hours a day for 5 days) was
.'
assessed in infertile male CD-I strain mice with the dominant
lethal assay (Anderson et al ., 1976). At these concentrations,
vinyl chloride was not mutagenic as judged by scoring of
post-implantation fetal deaths, pre-implantation egg losses
and reduction in fertility. Positive control tests indicated
that the dominant lethal effect was expressed in the CD-I
mice used in these experiments.
Anderson and Richardson (1976) conducted a cytogenic
study investigating mutagenic effects in the bone marrow
-------
VI-6
cells of rats after exposure to paradichlorobenzene at various
dose levels. In this study, benzene and vinyl chloride were
used as positive controls. The results of the vinyl chloride
control showed that vinyl chloride was effective in producing
chromosome damage in rat bone marrow after the multiple
exposure regime.
D. Carcinogenicity
Eviden.ce"has been accumulated in recent years impli-
cating vinyl chloride as a human and animal carcinogen.
The first four human cases of liver angiosarcoma in workers
employed by a vinyl chloride plant were reported by Creech
and Johnson in 1974. The first experimental data on the
carcinogenic effect of vinyl chloride in rats were published
by Viola et al., in 197i; preliminary results of an investi-
gation concerned with the oncogenic potential of vinyl chloride
in experimental animals followed (Maltoni and Lefemine, 1974).
These initial reports spurred a series of retrospective epidemi-
ologic investigations of workers in the vinyl chloride industry
and supportive experimental studies in animals. Several compre-
hensive reviews and symposium proceedings have been published
on the subject (e.g., Selikoff and Hammond, 1975; Proceedings
of the Royal Society of Medicine, 1976; U.S. EPA, 1975c;
Milby, 1978).
-------
VI-7
In animal studies, Viola et aJL. (1971) reported the
carcinogenic response of male rats (AR/IRE Wistar strain)
exposed to vinyl chloride by inhalation (Table VI-1). Skin
tumors were first noted at approximately 10 months; tumors
in the lungs and bones were observed at about 11 months.
Caputo et al. (1974) exposed male and female rats (A and
IRE Winstar strain) by inhalation to various concentrations
of vinyl chloride* Carcinomas and sarcomas were observed
- .•
in all groups except those exposed to 50 ppm (Table VI-2).
As can be observed, a dose response relationship exists
between exposure of 50 to 20,000 ppm. Tumors appeared
between 8 and 13 months from the beginning of the inhalation
treatment. These investigations also exposed rabbits by
inhalation to 10,000 ppm vinyl chloride, for 15 months (Table
VI-2) and reported the occurrence of lung and skin carcinomas.
Recent inhalation studies with albino CD-I mice and CD
rats (Charles River Breeding Lab) confirm the carcinogenicity
of vinyl chloride at concentrations as low as 50 ppm (Lee
e_t a_l., 1977, 1978). Liver angiosarcomas as well as other
forms of cancers were found in both species.
An extensive examination of vinyl chloride in experimental
animals has been conducted by Maltoni (1981). A summary of
these results are presented in Tables VI-*3 - VI-19. Vinyl
-------
VI-8
chloride was shown to cause tumors in all the animal systems
tested (i.e., mice, rats and hamsters) both through inhalation
and ingestion exposure. A clear-cut dose-response relationship
was shown to exist, with carcinogenic effects being seen at
exposures as low as 50 ppm. Newborn animals appeared to be
especially sensitive to the development of hepatocarcinomas and
angiosarcomaa and carcinogenic effects on the embryo via the
placenta were demonstrated. Table VI-20 indicates the tumor
\
types that have been correlated to vinyl chloride exposure in
experimental animals.
TABLE VI-1
Oncogenic Effects of Inhaled Vinyl Chloride
(Viola et al.« 1971)
Cone. VC
(pprn)
4 hrs/day,
5 days/wk
12 months
30,000
No treatment
Number
Rats
26
25
Skin
Epider-
moid Carci-
nomas
17
-
Lung
Adenocarci-
nomas &
Squamous cell
Carcinomas
6
'
Bones
Osteo-
chondroma
5
-
-------
VI-9
TABLE VI-2
Incidence of Tuners in Rats and Rabbits
Exposed to Vinyl Chloride by Irfcalation
(Caputo et al., 1974)
(ppn)
4 hrs/day
5 days/vdc
12 months
20,000
10,000
5,000
2,000
500
50
No
Treatment
10,000
No
Treatment
# of
Aniirals
Rats
150
200
200
200
150
200
200
Rabbits
40
20
Liver
Angiosaroonas
Cholangianas
31
16
12
10
4
-
*•
Lung Skin Squa-
Adeno- ncus Cell
Alveolar Carcinana
Cardnonas AcanthonB
21 67
16 34
4 20
8 6
3
-
6 12
— «
Other
7
8
2
6
-
—
-
-
-------
VI-10
Table VI-3
Zzptrincot BTL*
Animtli •with tamori.
TomonOOO
Gram and-
MT
BT LAS LA ELAS EIA taoaa
Hep*- Kephro- titan- Zymbal
BL BL GLCt
Skin
EpT
Ton-
stomach
PmAAe
mar?
HI
10,000 ppm
U
8L7 flJ 1L7
6.0
•0.0
6.0 6.0 1.7 IX 11.7 26.7
a/so) (3*0) wean wreo) a«o) ae/so]
22.0 14 S.1 6J L7 15 6.1 11.9 14 L7
(IS/59) #39) (3/59) (4/59) (1*9) (6/59) (3/59) (7/69) (2/59) (1/69)
5.0
— -"• rr^
m
2500 ppm
IV
600 ppm
jfljQ -_
VI
60 ppm
VII
(eoBtnl)
6LS
5LT
30.0
16.0
lit
20.0
• us
25.0
86.7
413
n.7
03*0)
10.0
(WO)
6.1
(8/69)
L7
..
4.0
(3/60)
L7
,0*0)
L7 N 14
0/69) (2/59)
L7
(1/60)
. —
IS
L7
0*0)
13
a/en
14
aw
is
(2/60)
(5*0)
L7
(1/69)
•
—
10.0
(&»)
10.0
(6/60)
16
(6/59)
L7
(1«)
•
6.7 IS
(4/60) (2/60)
6.7
(4/60)
— —
— —
1.7
(1/60)
L7
(1*0)
14
8/59)
1.7
0*0)
1.7
0/58)
13
(2*0)
L7
(1*60)
3.4
a»)
L7 IS
(1/60) (2/80)
- -
•Expanut by inhilition to VC in iir tt 10,000, 6000, 2500, 600, 250, ud 50 ppm; 4 hr/day, 6 d«yVw««k, for 62 wteki.
Spr««u^D«wley nu, M «nd F, 13 «Mks old. RaalU after 135 wwka (cad of experiment).
Table VIT4
Experiment BTZ.*
Animala with tumon. %
Group and
TumonOOO
animala
MT
BT LAS LA ELAS ELA tomaa
Fort- Min>-
Hepa- Nephro- Neuro- Zymfaal Skin itomach mary
BL BL GLC* EpT PaAAc MT
I
200 ppm
U .
160 ppm
HI
mJT
Kotmtmeat
(oontni)
35.0
35.0
2L7
16.7
2L7
25.0
T1A
2L6
10.0
(12020)
6.0
(8019)
(L8
(1020)
_
18
(4020)
.
OJ
0020)
«.
0.8
(1020)
.
_
LI
O085)
as
(1/120)
as
a/itt)
.
«.
16
(8020)
_
—
.
6.8
(7020)
9^
ani9)
u —
(10/120)
_ _
13
(4O20)
14
(47119)
0.8
(1020)
LI
(2085)
4.2
(6020)
14
(4019)
0.8
(1020)
LI
(Z085)
6.0
(6020)
1.7 5.0
(2019) (6019)
13 13
(4020) (4020)
1.6 1.0
(3/185) (2085)
•Ezpoture by inhalation to VC in air at 200. 160, 100 ppm; 4 hr/diy, S dayi/week, for 52 weeka. Sprague-Dawley nta, M and F, 13
w«eka old. Result* after 143 vteka (cad of experiment).
Source: Maltoni, 1981.
-------
VI-11
Table VI-5
Experiment BTS.*
i with tnroort. %
Tunora/100
Group nd ^^~~~~~~> H«p»- Nephro- Nemo» Zynbil Skin ttotnaeh any
MMirtTitinn MT BT LAS LA ELAS ELA toau BL BL GLCa EpT PsAAc XT
i IOOQ 5J!oioioLT LTto LT I LT SO LT IO is
90,000 ppa (1&60) (L«0) (MO) (SfiO) (1/50) (I/GO) (3SGO) (1^0) (1I«0) W80)
•Eapo«iT»bymhal«tioBtoVCia«irit30,OOOppm;4hr/d»y. S dtyt/wcck, for 52 weeks. Spngue-Dtwleyr»U, MandF, 17w««la
old. Ruufti after 68 wMks (end of cxpchaoit).
Table VI-6
Aninala irith unnor».
Bepa- Kephro- Neuro- Zymbal Skin itomacfa mary
MT BT IAS LA ELAS ELA tout BL BL GLCa EpT PiAAe MT
•53—53—IS S Zi 5!? I S3 I u To o.4 21.7
(8094)
. -««ft _
nt &0 «.w -
(euuuul)
" •rT««. hy if.K^i«. «• ve fa .fa. «t M ppm 4 hr/div. 6 diyi/week. for 52 wtekt. Sprague-Dtwley r»t». M «nd F. 13 wcek« old.
Kcnlu «ftcr 142 vecks («d of czpemtutX
Source: Maltoni, 1981.
-------
VI-12
•TABLE VI-7
ExperiaortBllS.*
Animals with tenors. *
TraxnOOO
Ton- Mun-
Qnnpnd
•OCB&BtMQ
I
IS ppm
„»
10 ppm
m
ippm
IV
Ippm
No trauma*
(eootnt)
MT BT LAS
I3y jgj 4.2
(&020)
«L7 534 0.8
0/119)
SSJ 86,0
'
y* K 44.2 —
254 17.S '-
LA
0.8.
a/i20)
_
.,
_
— m
ELAS
_
LT
(2019)
_
_
—
\
Hep*- Kephro- N«aro>
2LA tcnm BL BL
2.5
O020)
2.5
(3019)
•
—
0.8
(1020)
0.8
a/i2o)
• —
— _
— —
^ ^
_
—
.
_
^
CLCa
8.3
(4020)
1.7
(2O19)
0.8
0/119)
0.8
o/iis)
L7
(2020)
Skin
EpT
_
—
0.8
(1019)
0.8
(1/118)
—
•tomadb maiy
Pa&Ac MT
15.0
O7020)
17.6
(21019)
18.5
(22019)
12.7
(15018)
6.8
(7020)
txpenrt by mhaktian to VC in sir it 25,10,5,1 ppm; 4 hr/day, 5 diytfwMk, for 52 veekt. Spngw-Dtwley nu, 11 and F, 13
Mb «ld. Eeculu after 147 wwks (end of uperiacBtX.
TABLE VI-8
Experiment BT1.*
Animal*
TmoonOOO
Grocpmd
CODOEOtntMO
I
10,000 ppm
n
(000 ppm
H
tSOOppo
IV
SO ppm
VI
No treatment
(eoBtreD
•Cxno*m* bv i
MT
45.0
A3
4L7
15.0
n.7
14.7
nhilitiofl
BT
20.0
25.0
85.0
S6.0
25.0
26.0
20.0
to VC
LAS
L7
L7
OAO)
L7
—
-
-
in air at
LA
-
-
L7
O/S9)
L7
OA8)
-
10,000,
ELAS
- '
-
~
0.6
0090)
ELA
1.7
(1^8)
8.S
-
L7
(1A9)
L7
0/58)
-
6000, 2500, 500,
Hep*- Nephr>
tomaa BL
1.7
1.7
8.8
(ZfiO)
—
-
L7
0/58)
1.7
(1/60)
8.3
<2«0)
(609)
Ut
(8/58)
-
Fore-
Mara-
Neuro Zyrabat Skin Romach mary
BL • GLCt EpT Pa&Ac MT
15.5
(9^8)
20.0
(12*60)
8.3
(SW)
I
-
15.6 8.6 1,7
(9^8) (5/53) 0/53)
16.0 8.3 3.3
(9/60) (6*0) (2/60)
11.7 8.3
1.7
wan
1.7 - 5.1
(1/59) (3/59)
1.7
0/58)
1.0 0.5
(2090) OO90)
250. and 50 ppm; 4 hr/diy, 5 daya(*eek, for
1.7
(1/58)
1.7
6.7
5.0
(S*0)
1.7
(1/B9)
1.7
(1/58)
2.6
(5090)
17 weeka.
.ley »u, H aad F. 12 weeka old. R*«uHa aft«r 156 week* (end at experiment).
Source: Maltoni, 1981.
-------
VI-13
TABLE VI-9
Experiment BT10.*
Greopand
""•'•"•"MI
I
10,000 ppo
u
"V
10,000 ppo
IV
6000 nn
y*-
10,000 ppo
VI
6000 ppn
NotrcatasBt
(coatnO
•AH!
MT
RS
80.0
3SJ
*
• • *
304'
4L7
fy f
18.6
aak
BT
4L7
4fi.O
45.0
39.2
45.0
£0.8
4LO
LAS
as
a/118)
•
0.8
(1/119)
2.5
(SOU)
OJ
(1119)
0.8
a/120)
^
LA ELAS
_ _
OJ
a/120)
L7
(2019)
L7
«018)
L7
aou)
L7 0.8
(2020) 0/120)
— —
ELA
0.8
OA18)
L7
(2020)
OJ
a/ii9)
•
OJ
a/u9)
•
0.4
(12ST)
Aninuli with tureon. *
Bcpa-
tOBUft
0.8
oau)
_
^
••
•
L7
C2020)
^
Nephra.
BL
»
0.8
0/120)
•
0.8
0/119)
0.8
(1/120)
—
• Neun>-
BL
_
OJ
(1020)
_
0.8
(1/119)
.
—
Zytnbal
GLCa
7.6
(9018)
7.5
0020)
7.6
(9/119)
4£
(5/118)
6.7
(8019)
7.5
CiO20)
—
Skin
EpT
_
•
IS
OO19)
8.4
(4/118)
0.8
(1119)
_
0.9
(2227)
Fort- Man-
stomach nary
Pa*Ac MT
2.5 11.0
(3/118) (13/118)
1.7 10.8
(2020) (13020)
2.5 13.4
(3/119) (16019)
1.7 9.3
(2018) (Iini8)
0.8 16J
(1019) (20019)
0.8 10.0
(1020) (12020)
2.2 7.5
(5^27) (17«7)
•Expomn far Jnh»l*tioo to VC fe iir « 10,000, 6000, ppm; 4 hr/day, 5 feyi/week, for 5 weeks (groupt I and II) or 1 hr/diy. 4
uyvwcek, for*2S w««k« (group* III and IV) or 4 hr/day, one* weekly, tor 25 week* (froupi V and VI) (100 hr). Sprague-Dawley fits.
» «nd F, 18 vaekt old. Result* after 154 weeks (end of experiment).
TABLE VI-10
Experiment BT5.*
Tumon/lOO
Animats with tumon. *
Group and
eonecatnta
Hepe- Nephro> Neuro- Zynbal
tomas BL BL GICa
Skin
EpT
Fore- Mini-
itomach nur>-
Pa&Ac MT
9.8 . ±0 2.0
(5V51) (USD (1/51)
9.4 3.1 3.1 6.2
(3/32) (1/32) (1/32) (2/32)^
Source: Maltoni, 1981.
-------
VI-14
TABLE VI-11
Experiment BT14."
T«Baan/100 Animali with tcnora, »
•amah Fore- Man>
Groop ad ————. Hepa- Nephro- Ktoro- Zymbil Skin itomacb marjr
MT BT LAS LA ELAS ELA tonu BL BL GLCa EpT PaAAc MT
I
10,000 pptn 16.7 6S.7
(breeder*)
n
60001
ni
10,000 ppm 100.0 KJ> 84.1 «J 45.4 - 13 13 - -
(newborn) " •' OW4) , (&/44) (20/44) (1/44) (1/44)
IV *
«000pn 10U UL1 405 2.4 14 14 <7.« . 4.8 4.8 - 14
Q7/42) CWO (1/42} (1/42) (20/42) (2/42) (2/42) (1/48
•Ezpocurt by jafaaiidon to VC in air «t 10,000 «nd 6000 ppm, 4 hr/dty, 5 dayVwcck, for 5 weeks (from 1 d»r to 5 weeki of •(•)•
Spngue-Dawley nta, M tnd F, 21 weeJcs old (breeder*) (groups I and II) md newborn (group* III and IV). Result* after 124 wetb
VW*^M 04 VA|Mi* m
TABLE VI-12
Ezpcrimcnt BT7.'
Group and
coneentntioB
Ttnion/100
XT
60.0
63-J
26.7
80.0
13J
16.7
15.0
BT
10.0
20.0
UL8
10.0
16.7
6.7
15.0
Animals with tornon,
LAS
29.6
(8/27)
11.5
(306)
12.0
(805)
10.7
(808)
8.7
007)
_
—
LA
-
7.7
(206)
8.6
(108)
—
•
—
ELAS
-
8.8
(1O6)
4.0
OOS)
—
8.7
(107)
-.
16
(V38)
ELA
-
8.8
(106)
—
—
8.7
007)
—
,
_
Hipa-
tanas
-
7.7
(206)
4.0
O05)
—
^m
—
.
Nephro*
BL
3.7
7.7
—
7.1
COS)
^
8.6
(1O8)
.
*
Neuro-
BL
11.1
(SOT)
8.8
(1O6)
4.0
(105)
—
"
—
•
Zymbal
GLCa
7.4
C2O7)
7.7
(206)
"
•
•"
-
Skin
EpT
••^•••^•^
^
*
4.0
(105)
*•
3.7
(107)
—
-
•MMMM^.^
i «/:_..
Fore-
stomach
PaiAc
^^•MMeMBBM
^
^
"*
™"
-
^•••••••••••iKB
.-.». U
"•Expowr* by inhalation to VCfa*ir it 10.000,6000,2500,500,2M.*nd 50 ppm;4hr/day,5day»^reek.for«weeks. Wistar rat.. M,
U vtekt old. Remit* after 165 week* (end of experiment).
Source: Maltoni, 1981.
-------
VI-15
TABLE VI-13
Groopnd
BT
7«~ IA r-t .c T-T . Htp*' Nepfaro- N«uro- Zymial Skin •touch
***» 1-A ELAS SLA isau SL BL GLCt EpT ^^
294
No
1.0 8.0 6,0 LO
0/99) (8/99) (S/99) (1/99)
±0
(control)
mo
12
(3*4)
1.1
(1/94)
'S*^
TABLE VJ-14
Experiment BT4.*
Animils vith toman, %
Tisnen/IOO nails
Groopnd
cofKcnmtm
I
10,000 pom
n
6000 pan
m
2900 ppa
WOppo
V
250 ppo
VI
60 ppa
VU
We fj-Lj»TT»gMt
(eaotroO
HimTTUTT Slnp
MT
60.0
68.7
684
684
04
284
14.7
BT
984
100.0
90.0
1034
984
nit
14.7
LAS
174
(10/56)
21.7
(1&60)
27.1
284
(14«0)
80.0
OSfiO)
1.7
(WO)
•
•
LA
10.7
(6/56)
11.7
(7/50)
8.S
84
(WO)
184
(11/50)
• 1.7
0*0)
•
ELAS
14
U/56)
L7
(W80)
18.5
1L7
(7)60)
6.0
(X130)
L7
(1/60)
0.7
(V160)
ELA
7.1
(4^6)
6.0
(8/60)
1.7
(1^9)
6.0
(MO)
6.0
(8fiO)
84
(6ASO)
0.7
(inso)
LangT
82.1
(4606)
784
(47/60)
674
(40/59)
834
(SOW)
684
(41/60)
10.0
(6«0)
10.0
(1M50)
Ca
234
aa«)
134
(MO)
18.6
OVS9)
18.3
CB/60)
20.0
(12/60)
20.0
(1ZW)
0.7
0/150)
EpT
7.1
(4^6)
11.7
6.8
(4/S9)
8.3
(2/60)
1.7
(1/60)
_
14
Fora-
ttonsch
Pa&Ae
14
(1/56)
1.7
1.7
(1/59)
L7
(1/60)
1.7
(1/60)
«.
•Eipotan by inhiktion to VC fa tir at 10,000,6000,2500.600,250, tnd 50 ppm; 4 hr/d*y. 5
-------
VI-16
TABLE VI -15
ExperiflMot BTC.*
animals
Group and
•oocotmioa
10,000 pern
n
WOO ppm
III
2500 pea
IV
B00vpp»
250 Ppm
vj
SOppn
jrn
(control}
MT
10.0
40.0
4SJ
B-J,
30.0
10.0
20.0
BT
73J
«34
U&3
63.3
•
413
40.0
46.7
LAS
-
84
(WO)
_
v 4.7
800)
•
•«.
LA
8.3
(WO)
8.3
(WO)
6.7
000)
—
—
•
^
•
ZLA
6.7
•
—
SJ
00))
13
(WO)
•
^
Animals with tmnon. %
Hep*- Giolan- Cholan-
tenaa fio-Ca guana
8.7 18.3
(2/30) (4/30)
3JJ 6.7 16.7
(WO) (ZOO) (5/30)
26.7
(8/30)
20.0
(600)
20.0
(630)
2U
(7/30)
86.7
Acoustic
Duet
EpT
13
(WO)
6.7
(200)
S.3
(WO)
10.0
(3^0)
.
—
Skin
EpT
±3.3
'sj
(WO)
10.0
(3^0)
23.3
(7/30)
10.0
(3^0)
80.0
(8/30)
5.0
Mela-
nftmsi
3.3
(WO)
6.7
C230)
3.3
(WO)
.
3.3
(WO)
3J
(WO)
—
Fort-
•tomachLeukae-
PaeUc
83.3
do/so)
33.3
(10/30)
56.7
(17/30)
30.0
(9/30)
13.3
(430)
10.0
(130)
6.0
jni^j*
16.7
(oV30)
20.0
(600)
30.0
(9^0)
16.7
(5«))
20.0
(630)
20.0
(6/30)
18.3
(8/60)
*Ezpo«uc by inhatrtion to VC in «r «t 10,000, 6000, 2500. 600. 250, and 50 ppm; 4 hr/day, S dayVwcek. for 30 weeks. Gotten
uten, K, 11 week* old. Result* after 109 weeks (end of experiment).
'Latency tint in vt*ki: Group 1.16.7; Group II. 27.2; Group III. 30.8; Group IV. 19.0; Group V. 22.5; Group VI, 35.3; Group VII.
TABLE VI-16
Eiperimeni BTXL*
ISmm/lOO
Group tad
1
60.00 of /kff
n
16.65 Of/Iff
Ul
8b38ag)kf
IV
Olhwcd
(eootnl)
Mim»«t«
XT
88.7
80.0
iao
13.7
BT LAS LA
85.0 2LZ 3.7
(17/80) (3/80)
17.5 ITS
(1£VW)
25.0
tg,5 . .
Aninula with tumors. %
Repe>
ELAS ELA toaM
2.5 2.5
(2/80) (2/80)
_ ,, ~
2.5 U! -
(2/80) (WO)
• • •
Nepkro- Keuro* Zvmbal
BL BL GLCa
2.5 - U
OBO) (WO)
3.7 . 2.5
(SflO) (240)
« • .
- - L2
(WO)
Skin
EpT
1.2
(WO)
^
_
L2
(WO)
Fore- Uara-
stomach miry
FalAc MT
Z5 5.0
(2'80) (4/80)
1.2 7.5
(WO) (6V80)
3.7
(3/80)
5.0
(490)
*Expoeure by taration (itomadi tube) of VC b olive oil at 50.00. 16. 65 and S.33 m«Vr hodv weMit. ana dailv. <-5 At v*/w*«k far .w
,
SpnciM-Dawley rata. If and T. 13 week* old. Resulta aiUr 136 weeks (end of experiment).
Source: Maltoni, 1981.
-------
VI -17
TABLE VI -17
Experiment BT27.*
Group sad
I
LOnsAf
O
Otlmffef
III
0.08 mg>kt
IV
OSvtofl
(COBttflQ
am
2fT
24.7
12J
18.0
•16.0
•
uk
BT
2U
28.0
8U
2B.7
LAS
2.0
O/149)
0.7
0/148)
•
_
LA ELAS
0.7
(1/149)
0,7
(1/148)
• —
. \ .
Aninula -with tssen. *
Repa-
yH,/y tomss
a?
0.7
0/148)
• •
. .
%Tm»iti.Mii_ *•
J^CpATT^ {iVUfX^
BL BL
— —
•• —
• —
•
- .
Zymbal
GLCa
jj
(S/149)
_
•
0.7
(W50)
Sttn
EpT
^
0.7
(M48)
0.7
O/1SO)
_
For*.
ttomach
PaiAc
2.0
1J
(2/148)
0.7
(1/150)
L8
(2aso)
Msav
aarj
MT
8.0
(unw
2.7
(4n4B)
9.3
U4/1SO)
4.7
(7/1SO)
*Cxpatun by incntioa (ftoruch tube) of VC in ofive ofl st LO, 0.3.0.03 mflyr body wticht, once daily, 4-5 diyVwcek, for 59 w««kx
opniue-Otwicj nti, 1C and Ff 10 w«ek» old. SesuiU after 136 vetka (tad of uperiacnt).
TABLE VI-18
Experiment BT12.*
Tumors/100
Cnwpand
Animals with tumors. %
MT BT LAS LA ELAS
Fore* Mam-
Hepa* Nephro- N«uro- Zymbal Skin stomach mary
BL BL GLCa EpT PafcAc MT
1
4-2Smj x<
11
*JSttjx3
ni
**5mjx2
IV
g mt
V^
tamni;
^r-r
18J 25.0 - - '- - -
16.7 OJ - L9
Q/S3)
1L7 184 L8
OA6)
20.0 88.0 - LI
0/55)
&* M.7
• — m
_ — _
_, _ _
1.8
0/55)
_ _ _
1.8
(LW)
1.9
(1/53)
1.8
U/B6)
8.6
(2^5)
8.6
&SS)
1.8
(L/5£)
L9
(IAS)
5.3
(3/56)
8.6
(2^5)
••
^•we by imnperitoneal injection of VC. 4^5 me » olive oil (1 ml), 4. 8, 2 times, st two month intervals or once only.
"•Owley rats, II and F, 17 weeks old. RwaJts afUr 144 we*ks (end
Source: Maltoni, 1981.
-------
VI-18
TABLE VI-19
Tumori/100
aniznali
Experiment BTU.*
Animals with tumors. «i
Fore- Mam-
Heps- Nephro- Neuro- Zymbal Skin stomach mary
LAS LA ELAS ELA tanas BL BL GLCa £pT Pa4Ac JiT
174
S6.T
LS
(1/75)
U
(1/75)
L8
0/75)
4.0
(V75)
1.3
(1/75)
injection of VC, 4^5 mg, in div* oil (1 ol), lingie do*e. Spn
-------
TABLE VI-20
Tumors Presently correlated to VC Exposure (by inhalation) on Experimental Rodents
(Haltoni, 1981)
Seba- Other Fore-
Lym- ceous cuta- stomach
Anglo- phcroas cuta neous Mam- papillomas
sarcomas Tumors Tumors and neous epi- mary and
of oE of leu- Hepa- Angio- Nephrb- car- thelial car- acan- Mela-
Species liver brain lung kemias tanas sarcomas blastemas cinemas tumors cinemas thcmas ncmas
\ *
Rat '4- 4- 4- + + * (4-) 4 4-
Mouse 14- 4- 4- {+) 4 (+
Hamster 1 4- (-«-) (+) (+) •»•
-------
VI-20
Maltoni (1981) concludes from the available data that
lnyl chloride may produce tumors of different types at
ifferent sites and that the incidence and relative distribution
e greatly influenced by dose, age of the animal, and species
strain of animal used.
A recently completed study by Peron et al. (1981) examined
oral toxicity of vinyl chloride in Wistar rats. This
was carried out over the lifespan of the rats, and
•
°nsisted of incorporating polyvinyl chloride powder containing
hi9h content of vinyl chloride monomer in the diet, or using
8tric intubation of a 10% vinyl chloride monomer in soya-
eari oil. The vinyl chloride monomer doses (actual exposures)
Were 0, 1.7, 5.0 and i4.i.mg/kg bw.through the diet or 300
9/kg Dw by gastric intubation. The results showed that rats
**Poaed to vinyl chloride monomer at levels of 5.0 mg/kg
W A
a*y or more demonstrated hepatic angiosarcomas, pulmonary
Sioaarcomas, and at the higher levels, a few primary extra-
V
P*tic abdominal angiosarcomas. At the lowest exposure
*Vft1 of 1.7 mg vinyl chloride monomer/kg bw/day, liver-cell
Ult>0rB and an increased incidence of foci of cellular alteration
noted. (Tables VI-21 and VI-22).
-------
TABLE VI-2I- Type and incidence of treatment-related histqpathological changes in the liver of rats exposed
orally to VCM
(Feron et al. , 1981)
Incidence of change
Males
Type of Treatment group
change* (mg VCM/kg/day) . . .
0
1.7
5.0
14.1
300t
0
Females
1.7
5.0
14.1
300t
Animals killed after 26 wk
\ No.
Clear-cell foci
of rats examined...
10
0
§
—
_.
—
\ Animals killed -after
i
i
1 No.
Clear-cell foci
Basophilic focd
Bosinophilic foci
Neoplastic nodule
of rats examined...
Hepatocellular carcinoma
Cystic proliferation
No.
Clear-cell foci
of bile ducts
Animals
of rates examined.
Basophilic: foci
Eosinophilic foci
Necplastic: nodule
Hepatocellular cardnora
Angiosarccna
, 9
1
0
0
0
0
0
found
..55
0
8
3
0
0
0
^Ml»
—
dead or
58
9**
18
23***
1
1
0
- -
—
—
—
—
—
—
killed
56
16***
21*
27***
7**
2
6*
10
1
52 wk
10
8**
0
2
1
1
0
9
1 .
9
0
0
0
0
0
0
in extremis
59
21***
22**
33***
23***
8**
27***
55
9
12
11
3
1
27
10
*~ 0
9
0
0
0
0
0
0
—
— -
--..i
—
— .
—
—
—
—
_
—
__
—
—
— —
—
—
— —
10
5**
'10
a**
4
5**
2
1
4*
10
2
8
0
1
0
0
0
0
or terminally
57
4
0
8
2
0
0
58
24***
33***
35***
26**
4
0
59
22***
17
20*
39***
19**
2
57
36***
28***
29***
44***
29***
9**
54
10
19
6
2
0
29
-------
TABLE VI-21 (Continued)
VI-22
Proliferation of atypical
sinusoidal cells only
Extensive necrosis
Cysts
Liver-cell polymorphism
Centrilobular degeneration
Focal haenatcpoiesis
2
4
2
4
0
0
0
4
3
16*
0
1
4
8
4
28***
0
0
7
23***
16***
42***
1
10**
6
21
3
36
1
8
4
5
9
34
1
1
6
6
30***
51*
2
3
3
19***
41***
38
3
1
4
27***
49***
41
1
6
7
24
3
41
18
12
'Specific hepatocellular lesions were classified according to Squire & Levitt (1975).
VThe figures of this group were not evaluated statistically because no corresponding control group was included
in the study*
§Not examined.
Hie initial number of animals was 60/sex/group. A nuntoer of rats could not be examined because of cannibalism or
advanced autolysis.
Values narked with asteriks differ significantly from those of the controls according to the chi-square tests
*P
-------
TABLE VT-22- Site, type and incidence of tumours in organs other than the liver* in rats exposed orally to VCM for
over 2-5 yr (Feron et al., 1991)
Incidence of tumours
Site and Treatment group
type of tumour (rag VCM/kg/day) . . .
Effective no. of rats**.
No. of rats with primary tumours. . .
Lungs
Angiosarccna
Adencnu
Zymbal glands
Squamouu-cell cardncma
Adenomi
Abdomen
Mesothelioma
Angioaarcoma
\Fxbaro3aroana
Osteosarccna
Isaroona
Reticulum-cell sarcoma
'Schwann-cell tumour '
Unclassified
Spleen
Haemangioendotheliosarccma
Lymphcearccma
Nose
Squanous-cell cardncma
Brain
Granular-cell royoblastcma
Oligoctendrcglicma
Plexus papillcma
Glial-cell tumour
Ependyroona
Mesodermal tumour
Pancreas
Adenocardnoma
Thorax
Mesothelioma
Thyroid
Parafollicular-cell aderaona
Parafollicular-cell cardncma
Follieular-cell adenoma
0
55
38
0
0
0
0
3
0
0
0
0
0
0
0
0
0
0
1
1
0
0
0
0
0
1
4
1
0
1.7
58
50
0
0
0
0
1
0
0
0
0
1
0
0
1
0
0
1
0
0
0
0
0
0
0
12*
0
0
Males
5.0
56
49
4*
0
2
0
7
0
0
0
3
0
0
0
0
0
0
0
0
0
2
0
1
0
o
10
1
0
Females
14.1
59
52
.
19***
0.. -
0 -
0 '
8
0
3
"0
1
0
0
0
0
0
1
0
0
0
0
1
0
0
0
3
0
1
300t
55
44
19
1
1
0
1
1
0
1
0
1
0
0
0
0
0
0
0
0
1
0
0
0
0
3
0
0
0
57
54
0
0
0
0
1
0
1
0
0
0
0
2
0
0
0
0
0
0
0
0
0
1
0
7
0
1
1.7
58
56
0
0
0
0
6*
0
2
0
0
0
1
0
0
0
0
1
0
1
0
0
0
2
0
10
0
0
5.0
59
55
1
0
0
0
3
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
1
0
3
0
0
14.1
57
57
5*
0
0
0
3
2
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
0
1
300*
54
47
23
0
1
1
0
1.
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
-------
TABLE VI-22 (continued)
Incidence
Site and
type of Treatment group
tumour (ing VCM/kg/day)
Adrenals
Cortical adenoma
Etiaeochronocytcna
Pituitary
Adenona
Carcinoma
Blood
Leukemia
Heart
Endocardia! disease'
Haerangioendotheliosarocma
Kidneys
Nephroblastoma
Clear-cell tumour
LipomatouEi tumour
Unclassified epithelial tumour
Thymus
Fibrosarocna
Reticulum-cell sarcoma
Mesenteric lymph nodes
Reticulumr-cell sarcona
Skin
Squamous-cell carcinona
Subcutis
Fibroma.
Fribrosarccma
Mesenchyiml tumour
Skeletal muscle
RhabdomycHarcana
0
18
11
12
1
1
2
1
1
0
0
0
0
0
0
2
2
0
0
0
1.7
25
21
25**
0
0
0
0
0
0
0
0
1
0
0
3
1
1
0
0
Males
5.0
17
8
6
1
1
2
0
0
0
1
0
0
0
0
3
1
1
0
0
of Tumours
Females
14.1
10
4
2**
0
1
2
0
1
0
0
0
0
0
0
1
1
0
0
1
300t
9
6
0
0
3
1
0
0
0
0
o
0
1
1
0
1
0
0
1
0
26
2
14
3
1
1
0
O
0
0
1
0
0
0
0
3
1
1
1
1.7
30
1
• . •
16
Of
2
0
Q-
0
0
0
0
0
1
0
0
3
1
0
0
5.0
20
2
10
2
1
0
0
0
0
0
0
0
1
0
0
1
0
0
0
14.1
17
O
5*
O
0
0
0
0
1
0
0
0
0
0
1
0
0
0
0
300t
14
2
3
0
1
1
0
0
0
0
0 .
0
0
0
0
0
0
0
0
-------
TABLE VI-22 (continued)
Incidence
Site and
type of Treatment group
tumour (rag VCM/kg/day)
Skull
Osteoma
Mesenchyroal tumour
Ear region
Adenocarclnom of unknown origin
Urinary bladder
Unclassified epithelial tumour
Preputial glands
Squanous-cell carcdnona
Mammary glands
1 Adenoma
\ Fibroadencna
' Adenocarcinona
'.Anaplastic carcinona
Testes
'Interstitial-cell tumour
Uterus
Adenocarcincma
of Tumours
Males
0
1
0
0
0
0
0
0
0
0
3
1.7 5.0
0 0
0 0
0 1
0 1
0 1
0 0
0 0
1 0
0 0
0 0
14.1
0
0
0
0
0
0
0
2
-o
1
3oot
0
0
0
0
0
0
0
0
0
1
Malignant f ibroadenomatous tunour
Leicmycma
Cervix
Mesenchynal type of tunour
Adenocarcinona
Ovaries
Theca-cell tumour
0
0
0
0
0
0
0
21
3
0
6
0
0
2
0
0
Females
1.7
0
1
0
0
0
0
25
£
0
3
1
0
0
1
0
; ; — r-
5.0
0
0
0
0
0
0
12**
4
1
1
0
1
1
0
1
14.1
0
0
0
0
0
2
4**
7
0
1
0
0
0
0
0
300t
0
0
0
0
0
0
7
7
0
0
0
0
0
0
0
one Kupffer-cell sarcoma, three reticulum-cell sarcomas, two flbrcsaroomas, one haenangioendothelioma and one
mesenchynel tumour.
figurtss for this group were not evaluated statistically, because no corresponding control group was included
in the study.
§In several, cases the neoplastic character of the lesion was doubtful.
Values narked with asteriks differ significantly from those of the controls according to the chi-square test:
*P<0.05; **P<0.01j ***P<0.001.
-------
VI-26
Feron et al. (1981) concluded that vinyl chloride monomer
is a carcinogen when administered by the oral route, and that
the tumor response seems to shift from the exclusive development
of angiosarcomas at very high levels to the exclusive induction
of hepatocellular tumors at low levels of exposure. Feron et
al. have also initiated a similar lifespan oral carcinogenicity
study with vinyl chloride in rats, using three different dose
levels (0.017, 0.1*7 and 1.7 mg'vinyl chloride monomer/Teg bw
day) and two control groups. This study is currently in
progress and the results are not yet available.
-------
VII. HUMAN HEALTH EFFECTS
A. Non-Carcinogenic Effects
Vinyl chloride can produce a number of pathological
consequences in humans in addition to its carcinogenic effect.
These effects can be from acute or chronic exposure to vinyl
chloride. Unfortunately, data regarding dose-response relation-
ships in humans ajre very scarce because of the virtual absence
of air measurements of vinyl chloride in the work environment
of vinyl chloride manufacturing and polymerization plants
before 1975 (Mancuso, 1975). According to OSHA (39 FR 12342,
April 5, 1974), several facilities revealed vinyl chloride
concentrations for some job classifications as high as 229
ppra. Rowe (1975) commented that before I960, a few jobs
resulted in exposures in the range of 100 to 385 ppm, but
these measurements /could be high because the method of quanti-
fication measured total halogens rather than vinyl chloride
alone. Nicholson et al. (1975) reported that vinyl chloride
in polymerization reactors may often have exceeded 1000 ppm
and occasionally may have approached 10,000 ppm before OSHA
standards were instituted. At these levels, workers experi-
enced dizziness, headaches and/or euphoria during work periods.
Several instances of acute exposure have occurred in
vinyl Chloride plants. Deaths of two Canadian workers were
-------
VI1-2
reported by Danziger in 1960 following acute exposures to vinyl
chloride gas. At autopsy, there was congestion of the liver,
spleen and kidneys. In another study reported by Suciu et al.
M975), exposure of workers to high concentrations of vinyl
chloride produced euphoria, intoxication and narcosis. In
this study, the investigators found a dose-response relationship
for acute and subacute cases of "occupational disease" from
•• x
air concentrations ranging from 2,298 mg/m3 (about 900 ppm)
to about 100 mg/m3 (about 40 ppm).
In another investigation, Spirtas et al. (1975) conducted
a survey of 200 vinyl chloride workers and 89 rubber plant
workers (controls) where information was sought on the frequency
of eight symptoms, including dizziness, loss of consciousness,
headaches, etc. The vinyl chloride workers were categorized
into low and high exposure groups. Because the exposure
limits had been markedly decreased a short time before the
survey, the high exposure group consisted of workers who
were exposed to vinyl chloride concentrations of over 200
ppm before the standard, and 20-30 ppm subsequently. The
low exposure group consisted of workers who were exposed to
0-50 ppm before the standard and 0-10 ppm subsequent to it.
Examination of the differences among the three groups indicated
a statistically significant dose-response relationship for
five of the eight symptoms (i.e., frequency of symptoms in the
high exposure group < low exposure group < rubber workers), and
-------
VI1-3
a similar but non-significant trend in two of the remaining
symptom categories. Thus there appears to be a dose-response
relationship between certain acute symptoms (predominantly
Qeurological) and level of vinyl chloride exposure. The data
also suggest that vinyl chloride levels below 50 ppm can
produce health effects.
The earliest reports of hepatotoxicity in vinyl chloride
workers were noted by Tribukh vet al. (1949); however, the
«ffects were attributed to plasticizers added in the manufac-
turing process. The observed concentrations of vinyl chloride
ranged from 1 to 470 ppm. Since that time, impaired liver
function has been noted by other investigators (Marstellar et
£i- 1 1975; Lilis et a]L. , 1975; Popper and Thomas, 1975;
r, 1975).
Another effect from chronic vinyl chloride exposure is
a condition known as acroosteolysis, which involves bone
lesions in the distal phalanges of the hands and feet and
8cleroderma-like skin lesions. Also associated with this
c°ndition are Raynaud's syndrome, pseudoclubbing of fingers,
numerous other symptoms. Many cases of acroosteolysis
been reported and characterized and most involve autoclave
w°rkers in vinyl chloride plants (Wilson et al. , 1967; Dinman
S£ Si-, 1971; Harris and Adams, 1967; Lilis et al. , 1975).
-------
VI1-4
Other long-term effects induce disturbances of the
central nervous system, pulmonary insufficiency, cardiovascular
manifestations, and several gastrointestinal symptoms (Miller
et al., 1975; Suciu et al., 1975). These and other vinyl
chloride-induced health effects are reviewed in the New York
Academy of Sciences report "Toxicity of Vinyl Chloride-Polyvinyl
Chloride" (Selikoff and Hammond, 1975).
Reproductive effects have also been noted. According to
a study by Infante (Infante, 1976; Infante et al^, 1976a),
the incidence of birth defects for three small communities
in Ohio in which vinyl chloride polymerization plants are
located were significantly higher (P<0.001) than those in
*
either the counties in which these communities are located
or the State of Ohio in general. Significant excesses were
observed for clubfoot and defects of the central nervous
/
system, upper alimentary tract, and genital organs. A follow-
up study by Edmonds et al. (1975) identified a moderate increase
in central nervous system malformations, but no association
could be found with vinyl chloride exposure. In another
epidemiologic study by Infante et al. (1976b), there was a
significant excess fetal loss (P<0.05) in wives whose husbands
were vinyl chloride polymerization workers compared to controls
(wives of polyvinyl chloride fabrication and rubber workers).
The Infante studies suggest an association between vinyl
-------
VI1-5
chloride and birth defects/fetal loss, but they are not yet
supported by animal data.
Cytogenic studies have also been conducted. Picciano et
al. (1977) reported no statistically significant differences
in chromatid and chromosomal aberrations or proportion of
abnormal cells, in a group of 209 vinyl chloride exposed
workers. These workers were exposed for periods ranging from
" -' ' \
1 to 332 months to time-weighted average (TWA) levels of vinyl
chloride ranging from 0.3 to 15.2 ppm. Killian et al. (1975)
have also reported a lack of evidence for excess chromosome
breakage in a population of vinyl chloride exposed workers.
In contrast, Ducatman et al. (1975) and Purchase et al. (1975)
have reported increased incidence of chromosomal breakage
among vinyl chloride exposed workers.
Heath et al. ('1977) examined cytogenic effects in three
groups of industrial workers: PVC polymerization workers
(presumed high exposure), PVC processing workers (presumed
low exposure) and rubber and tire manufacture workers (presumed
negligible exposure). Actual vinyl chloride levels were not
measured. Chromosome breakage in all three groups was signi-
ficantly greater than in non-industrial controls, and overall
breakage levels were simlar in all three groups. The authors
concluded that other agents in addition to vinyl chloride
may cause cytogenic damage in workers employed in the rubber/
plastics industry.
-------
VI1-6
B. Carcinogenic Effects
The primary effect associated with vinyl chloride
exposure in man is an increased risk of cancer in several
organ systems including angiosarcoma of the liver. Human
data have been obtained primarily from occupational exposure
of workers to vinyl chloride.
Epidemiologic studies of vinyl chloride exposed workers
have focused on cases of angiosarcoma of the liver, a type of
cancer which occurs infrequently in the general population,
about 25-30 cases per year in the United States (Heath et al.,
1975). Because of its rare occurrence, it is possible to
infer a causal relationship between exposure to vinyl chloride
and the development of this tumor. The epidemiologic evidence
linking vinyl chloride to other types of cancers is more
tenuous.
The first study associating vinyl chloride exposure in
humans with cancer was conducted by Creech and Johnson, 1974.
Three cases of angiosarcoma in workers at a polymerization
plant in Louisville, Kentucky, were described. The remaining
portion of this section describes some of the epidemiologic
studies linking vinyl chloride with angiosarcoma and other
types of cancer.
-------
VI1-7
Tabershaw and Gaffey (1974) conducted a mortality study
ayl chloride workers. Mortality calculations included
those workers who could be traced, i.e., 7,128 of 8,384
rs. These individuals were from 33 different facilities
11 had been exposed to vinyl chloride for at least 1
The mean employment duration for the group of workers
study was 80 months. Among the workers, there were
ith exposures of 20 years, or longer and 1,640 exposed
more years.
Compared to the general male U.S. population, the overall
lity rate among vinyl chloride workers was found to be
, i.e., 75 percent of the expected rate. The favorable
11 mortality rate is a phenomenon commonly observed in
Ing populations. Standarized mortality ratios (the
of the number of observed deaths in the study population
ne number of deaths expected in a comparable population)
alignant neoplasms increased with increasing exposure
1 and/or longer duration. In the group identified as the
exposure group, there were increases in liver cancer
narily angiosarcoma), respiratory system cancers, and
n cancers. These differences were not statistically
ificant.
Dow Chemical Co. (Holder, 1974) conducted a mortality study
94 workers in a single plant exposed to vinyl chloride
-------
VII-10
Ott et al. (1975) have re-examined much of the mortality
data reported by Tabershaw and Gaffey (1974) and have included
more clearly defined exposure levels and .follow-up of former
company employees. The basic findings remain unchanged; no
increase over expected in malignant neoplasms was found in
the low exposure group (TWA from 10 to 100 ppm) and an increase
in deaths due to malignant neoplasms was observed in the high
exposure group.(TWA of greater than 200 ppm).
.• \
Chiazze et al.(1977) have reported a cross-sectional
mortality study of 4,341 employees from 17 PVC plants who died
between 1964 and 1973. No angiosarcoma deaths were identified.
Total cancer deaths increased in white employees (especially
due to cancer of the digestive sy-tem). In white women
employees, deaths from cancer of the breast and urinary organs
were greater than expected.
/
In contrast, in a mortality study of 7,000 British
workers exposed to vinyl chloride between 1940 and 1974, the
investigators found no evidence of increased cancer mortality
other than from liver cancer. In this study, four cases of
malignant liver tumor were diagnosed, and two of these were
confirmed to be angiosarcoma. Both cases were in men exposed
to high levels of vinyl chloride (Pox and Collier, 1977).
-------
VII-11
In addition, Byren et al. (197-6) traced 750 of 771
Swedish vinyl chloride plant workers. A four- to five-
fold increase over expected in pancreas and liver tumors was
found, and two cases were diagnosed as angiosarcoraa. The
numbers of other tumors did not deviate significantly from
expected.
v
Ten cases of. hepatic angiosarcoma have been found
•'•
among the relatively small work force employed at a vinyl
chloride polymerization plant in Quebec. This is the largest
number of cases to be diagnosed in a single plant (Makk et
al.i 1976). As a result, Delorme and Theriault (1978) have
retrieved more detailed information on these employees. The
authors suggest that the cases of hepatic angiosarcoma appear
to be associated with high vinyl chloride exposure levels and
overtime work hours. No correlation was found between occurrence
/
of this tumor and alcohol consumption or cigarette smoking.
In workers engaged in the polymerization of vinyl chloride
who were studied by Popper and Thomas (1975), the characteristic
hepatic fibrosis was present in all cases of angiosarcoma.
*
Although the relation of fibrotic lesions to the development
of angiosarcomas requires further study, a transition from
the fibrotic stage to angiosarcoma is suggested by the focal
proliferation of the sinusoidal lining cells and of the
-------
VII-12
hepatocytes that are seen in the fibrotic stage but which
becomes even more pronounced in the initial stages of angio-
sarcoma development. These findings suggest that the
fibrotic lesions without angiosarcomas, frequently observed
in workers exposed to vinyl chloride (Lilis et al., 1975),
might be the prestage of developing neoplastic lesions.
The diagnosis of the fibrotic lesions in these workers may
imply a longer;, latency period for tumor initiation based
on a lower exposure level. The series of changes observed
in the liver appear to represent a multi-centric development
of angiosarcoma and are similar to the changes induced by
Thorotrast and inorganic arsenicals (Berk et al., 1976).
In the most recent update of the NIOSH register (Spirtas
and Kaminaski, 1978) a total of 64 cases of hepatic angio-
sarcoma have been identified worldwide among vinyl chloride
exposed industrial 'workers. A listing of all documented
cases by country is presented in Table VII-1. The number
of cases per year is depicted in Figure VII-1. Of the 64
cases, 23 have been reported in the United States. The
authors reported that both the age at diagnosis and the
latency period for cancer induction appear to be increasing.
They suggest three explanations for these phenomena:
(1) early cases may have heavier exposures; (2) the initial
cases represented more biologically susceptible individuals;
-------
VI1-13
and (3) random fluctuation. If the trend of increased age
at diagnosis and the longer latent period for hepatic
angiosarcoma induction are indeed related- to lower levels of
occupational exposure, then the latent period for cancer
induction as a result of these low levels of exposure may be
longer than previously anticipated, i.e., it would be many
years before the ultimate outcome of these exposures will be
known.
It has been hypothesized that inhalation of low levels
of vinyl chloride by the general public in the vicinity of
vinyl chloride/PVC manufacturing plants could be responsible
for an increased risk of angiosarcoma of the liver development.
Brady et al. (1977) examined annual rates of hepatic angic—
sarcoma from 1970 through 1975 in residents of the State of
New York (excluding New York City). Exposures to arsenic,
/
vinyl chloride, or thorium dioxide were suggested to be
significant factors in the etiology of these tumors. Direct
exposure to these agents could not be demonstrated in 19 of
the 26 study cases. Five of the 19 patients lived closer to
vinyl chloride plants than did their matched controls. This
may lend some support to the idea that "indirect modes of
exposure, not specifically related to occupation, might be
insportant in the etiology of this disorder" (Brady et al.,
1971).
-------
VI1-14
The International Agency for Research on Cancer (1979)
examined the available data on humans and concluded that ex-
posure to vinyl chloride results in an increased carcinogenic
risk to humans. The organ systems most likely to be affected
were the liver, brain, lung, and hemato and lymphopoietic
systems.
-------
Anglosarcona of the lAver in Vinyl Chloride/PSJC Vtorker
(Spirtaa an3 Kamlnaki, 1978)
Country
Belgium
Canada
Canada
Canada
Canada
Canada
Canada
Canada
Canada
Canada
Canada
Czechoslovakia
Czedhos lovakia
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Garmany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
France
France
France
France
France
France
France
vrance
reat Britain
reat Britain
Case
No.
01
01*
02*
03*
04*
05*
06*
07*
08
09
10
01*
02*
01*
02*
04
05*
07*
08*
09*
10*
11*
01*
02
03*
04*
05*
06*
07
08*
01*
03
Birth
Date
OO-OO-OO
12-15-13
03-O6-14
08-26-19
04-05-19
05-07-11
12-15-19
11-09-19
05-13-20
07-19-21
05-16-15
00-OO-28
00-OO-26
06-04-30
07-26-31
09-O4-30
O1-O1-32
09-29-26
10-19-17
12-13-34
07-25-29
12-29-36
04-15-24
06-03-11
00-00-19
01-27-27
01-29-38
04-14-34
00-00-27
04-O1-34
04-20-01
06-O2-37
1st VC
of PVC
Exposure
00-00-00
00-OO-44
00-OO-43"
00-00-41
00-00-45
00-OO-44
00-OO-47
00-00-46
00-00-61
00-00-46
00-00-53
00-00-57
00-00-51
10-01-56
10-14-57
04-16-57
12-16-62
04-15-54
04-19-54
12-02-59
10-10-55
01-02-61
01-00-46
07-O6-59
00-00-46
1O-19-49
OO-00-65
00-OO-58
07-01-50
05-23-57
00-00-44
02-OO-66
Diagnosis of
Angiosarcona
00-00-00
00-00-55
00-00-57
00-OO-62
00-00-67
00-OO-68
00-00-71
00-00-72
00-00-73
00-00-74
00-00-76
00-00-73
00-OO-66
09^19-68
09-25-70
00-00-74
00-00-75
00-00-75
00-00-75
06-16-76
06-28-77
00-00-77
02-18-67
01-08-75
01-OO-75
01-04-76
04-00-76
09-00-76
07-00-76
12-03-76
12-00-72
12-OO-74
Age at
Diagnosis
00
41
43
42
48
57
51
53
53
53
61
46
40
38
39
44
43
49
58
42
47
41
43
63
55
49
38
42
49
42
71
37
Years from
1st Exposure
to Diagnosis
00
11
14
21
22
24
24
26
12
28
23
16
15
12
13
17
13
21
22
17
22
16
21
15
29
26
11
18
26
19
28
09
Total
Years of
Exposure
00
11
14
20
22
05
23
25
05
26
14
16
15
12
12
17
12
12
21
15
22
10
19
12
29
26
10
17
23
19
22
04
Date
of
Death
06-29-76
09-02-55
12-21-55
03-22-62
01-21-68
07-05-68
04-10-71
12-24-72
06-12-73
09-04-74
04-00-77
00-00-74
00-OO-66
01-25-69
12-14-71
11-25-74
01-09-75
11-13-75
12-25-75
Alive
06-28-77
03-07-77
02-19-67
01-24-75
06-29-75
01-04-76
05-13-76
09-12-76
07-O2-76
01-30-77
12-00-72
12-24-74
-------
Country
Italy
Italy
Japan
Norway
Sweden
Sweden
Sweden
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S. A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
Yugoslavia
Yugoslavia
Case
No.
02*
03*
01
01*
01*
03*
04*
01*
02*
03*
04*
05*
06*
07*
08*
09*
10*
11*
12*
13*
16*
17*
18*
19*
20*
21*
22*
23*
24*
25*
01*
02*
Birth of PVC
Date Exposure
11-13-29
03-14-20
08-01-22
12-23-15
06-23-27
06-10-10
11-16-14
10-17-23
08-19-33
05-25-15
01-15-24
01-25-12
11-23-28
05-03-22
05-O6-20
11-08-31
08-16-13
05-27-O9
11-17-lfl
12-01-21
11-04-27
05-06-31
04-22-28
00-00-15
08-31-17
09-02-09
10-02-23
00-00-23
05-07-17
08-O7-10
04-O5-14
11-15-31
00-00-57
00-00-53
04-00-53
03-OO-50
08-14-51
05-00-47
OO-00-46
12-09-48
11-15-55
11-28-45
07-06-52
06-19-^14
01-17-62
08-27-44
10-07-46
05-28-45
Q6-12-51
10-14-46
09-13-49
12-11-42
05-08-50
06-23-55
09-15-54
00-00-43
00-00-55
12-00-46
07-11-47
09-00-58
00-00-39
02-00-47
00-OO-53
00-00-50
Diagnosis of
Angiosarcora
12-13-72
07-10-75
08-21-74
12-20-71
08-00-74
03-19-76
05-12-77
03-O3-73
05-OO-70
12-19-73
08-19-67
04-O9-64
02-00-74
00-00-68
08-OO-61
03-01-74
05-00-68
03-OO-70
05-02-69
05-OO-74
00-OO-69
10-11-74
00-OO-75
06-19-75
01-30-76
00-00-77
01-00-76
04-06-73
05-27-77
03-10-77
04-08-73
07-12-73
at
Diagnosis
43
55
52
56
43
65
62
49
37
58
43
52
46
45
41
43
55
61
50
52
41
43
46
60
58
67
52
50
60
67
59
42
1st Exposure
to Diagnosis
15
22
22
22
19
29
31
24
14
28
15
20
12
24
15
29
17
23
20
32
19
19
21
32
21
30
29
15
38
30
20
23
Years of
Exposure
06
21
22
21
18
21
31
21
13
28
15
20
12
17
15
24
17
23
19
26
04
19
11
22
18
21
28
14
26
20
20
18
of
Death
12-00-72
07-10-75
1O-24-75
01-O4-72
10-20-70
03-19-76
05-12-77
03-03-73
09-28-71
12-19-73
01-07-68
04-09-64
07-24-75
03-23-68
08-29-61
03-00-75
05-10-68
03-16-70
05-O2-69
07-04-74
03-27-69
Alive
11-02-75
04-06-76
01-30-77
01-O2-77
12-04-76
04-06-73
05-27-77
03-10-77
04-08-73
07-12-73
Total Reported
Cases
64
-------
VII-17
Figure VII-1
Number of cases of vinyl chloride/PVC related angiosarcomas
reported to NIOSH by year of diagnosis (representing only 63
of the 64 cases known to NIOSH since information on diagnosis
is missing for one case) (Spirtas and Kaminski, 1978).
1-50 I'S
TCAR OF DIAGNOSIS
ho ITS
-------
VIII. MECHANISMS OF TOXICITY
The mechanisms of non-carcinogenic injury of vinyl
chloride are not Tcnown. It is theorized that the toxicity of
this compound is attributable to its enzymatic oxidation to
reactive polar metabolites, possibly chloroethylene oxide or
chloroacetaldehyde (see Pharmacokinetics section).
Ward et al. (1976) hypothesized that an inununological
mechanism is responsible for the non-carcinogenic pathological
effects of vinyl chloride exposure. According to this model/
a metabolite of vinyl chloride binds to plasma protein,
producing an antibody response. The antigen and resulting
immunoglobulin interact to produce a soluble complex which
causes vascular occlusion, platelet aggregation, and other
adverse effects which explain the observed symptoms of the
disease. An investigation of workers with "vinyl chloride
disease" showed the presence of circulating immune complexes
in 19 of 28 patients. Abnormalities were also detected in
some workers' exposed to vinyl chloride who had few or no overt
clinical signs.
Over the past several decades, scientists have conducted
ft great deal of research in an effort to establish the
nechanism(s) by which chemical substances exert their
carcinogenicity. The somatic cell mutation theory of
carcinogenicity suggests that for a carcinogenic response to
occur, an irreversible change must occur in the cell which
-------
VIII-2
in proliferation of a neoplasm. This change reflects
4 wutational event in the DNA of that cell, suggesting that
^e chemical carcinogen must interact directly with or
ot*erwise alter the DNA to intiate the change. In recent years,
how«~
^ever, some substances have been shown to be carcinogenic,
ut by mechanisms in which there apparently is no direct
n*eraction with or alteration of the DNA of the cell by the
^stance. Presumably, these compounds are not capable of
i-tiating the alteration of a normal cell to a neoplastic one,
ut can facilitate expression of a neoplastic response in
Ut«
cells. On the basis of these purported differences in
c«anisras, carcinogens now are often classified into two broad
te9ories: genotoxic and epigenetic or nongenotoxic.
The mechanisms by which a compound exerts its carcinogenicity
can be determined by the chronic testing of whole
such as is done in the NTP bioassay. Thus, a large
tober of short-term in vitro and in vivo assay systems have
be
n Developed for the purpose of elucidating mechanisms.
Sin
nce most of the in vitro testing systems measure mutational
entsr and many carcinogens are mutagens, it is suggested
tha*
*<- positive results in certain of these test sytems indicate
^otox The decision as to whether a substance is
6t*otoxic may be made qualitatively on the basis of several
1) a reliable, positive demonstration of genotoxicity
n Appropriate prokaryotic and eulcaryotic systems in vitro y
-------
VIII-3
studies on binding to DNA and 3) evidence of biochemical
biologic consequences of DNA damage (Weisburger and
^Uians, 1981).
No single test system appears capable .of detecting all
rcinogens that are genotoxic. Therefore, a number of
Dentists have proposed testing batteries such that results
r°m each test within the battery when evaluated as a whole,
il allow one to make a conclusion about the mechanism of
ar°inogenicity of a particular ^compound. Vinyl chloride has
n '' *
°* been systematically studied in any specific battery of
stsf but has been evaluated in a number of test systems
*t have been proposed for inclusion in one or more batteries.
"le Vlli-i summarizes some of the mutagenicity studies on vinyl
*oride which have demonstrated the chemical to have genotoxic
t
. The studies have been divided according to the
criteria for genotoxicity (Weisburger and Williams,
98 1) outlined above.
/
When considering all of the data on vinyl chloride, it
is '
Probable that vinyl chloride exerts its carcinogenicity
r°ugh genotoxic mechanisms.
-------
VIII-4
TABLE VIII-1 - Results of Vinyl Chloride Mutagenicdty Studies
A. Assay system
Results
In Vitro prdkaryotic and eukaryotic systems
Metabolically activated +
Salmonella tyghiirurium
system lAraes/
Escherichia coli KL2 +
bioauxotrophic strain
Yeast
Germ cells of Drosochilia +
Chinese hamster V79 cells +
B. DNA Binding Studies
Mouse tissues (brain, lung, +
liver, kidney, spleen, (Irreversible
pancreas and testes) in binding to
vitro and DNA)
Rat liver microscnes,
reconstituted cytochrcnB
P-450 systems and isolated
hepatocytes
Rat liver microscnes with
NADPH
(Irreversible
binding to
protein and DNA)
(Alkylation
of FNA)
References
Bartsch et al. , 1975
McCann et al. , 1975
Elrore et al, 1976
Rannug et al, 1974
Garro et al. 1976
Greimetal., 1975
Loprieno et al. 1976, 1977
Verburgt and Vogel, 1977
Huberoan et al. , 1975
Bergman, 1982
Guengerich et al. , 1981
and Holt, 1977
C. Biochemical or biologic consequences of DNA damage
Bone marrow cells of
rats (in vivo)
Bone marrow cells of
Chinese hamsters (in vivo)
(Q
damage)
Anderson and Richardson,
1976
Basler and Rohrborn, 1980
aberrations and
sister-chrcnatid-
exchanges)
Cultured peripheral lympho-
cytes in humans (vinyl (Chronosomal
Purchase et al. , 1978
chloride exposed workers) abnormalities) Purchase et al. , 1975
Ducatman et al., 1975
-------
IX-1
IX. RISK ASSESSMENT
Because vinyl chloride rarely occurs in nature, virtually
all of the compound found in the aquatic environment appears
to be in discharge water from vinyl chloride production and
.polymerization plants, and leachates from disposal sites. Up
to 20 ppm has been found in samples of discharge water (U.S.
EPA, 1974). Because of its low solubility in water and high
volatility, vinyl chloride would not be expected to persist
,: .. ' • v
in the aquatic environment (Hill e_t aJL., 1976). It nevertheless
has been detected in the potable water of several cities and
towns in at least two national surveys (U.S. EPA, 1975a and 1977).
Interactions of Vinyl Chloride with other Chemicals
Vinyl Chloride has been demonstrated to have interactions
with other chemicals. Radike e_t al. (1981) investigated the effect
of ingested ethanol on the induction of liver tumors in rats. Male
Sprague-Dawley rats were exposed to 600 ppm vinyl chloride by inha-
lation, 4 hours/day, 5 days/week for 1 year. Half of the group
received 5% ethanol in their drinking water four weeks before the
beginning of the vinyl chloride exposure and continued for life or
termination of the study. The results showed that the incidence
of angiosarcoma in vinyl chloride-ethanol dosed rats (50%) was
-------
IX-2
Bore than double that resulting from vinyl chloride exposure alone
'23%). vinyl chloride-ethanol also induced a greater number of
hepatocellular carcinomas (60%) than occurred in vinyl chloride
treated animals (44%). Thus, ethanol was shown to potentiate
the toxicity of vinyl chloride.
An experiment to determine the interaction between vinylidene
chloride (1,1-DCE) and vinyl ^chloride was carred out by Jaeger
• " »
(1975). This'study measured hepatotoxicity by the elevation of
serum alanine-c(-ketoglutarate transaminase (ART). When fasted
rats were exposed to 0.02% 1,1-DCE, serum ART activity was eleva-
ted about 50-fold, two hours after the termination of a 4-hour
inhalation exposure. No elevation was observed when 0.1% vinyl
chloride was administered alone. When the two chemicals were
a<3ninistered simultaneously at the levels indicated, no elevation
°f serum ART occurred. These results were interpreted to suggest
that vinyl chloride shows protective effects when administered
with vinylidene chloride.
Sensitive Populations
Sensitive populations are subgroups within the general popula-
tion which are at greater than average risk upon exposure to a
chemical. For vinyl chloride, several animal studies have suggested
that sensitive groups may exist in the general population.
-------
IX-3
Groth et al. (1981) exposed adult Sprague-Dawley rats to
ppm vinyl chloride by inhalation for 7 hours/day, 5 days/week
*or 24 weeks. Four different age groups of animals were used (6,
?8» 32 and 52 weeks), and the results showed that adult animals
and females are more susceptible to the angiosarcoma inducing
effects of vinyl chloride than are young adult animals and males,
respectively.
Maltoni, et al. (1981) carr>d out a series of carcinogenicity
studies on mice, hamsters and rats (See Health Effects in Animals
section). These studies demonstrated that newborn animals appeared
to be extremely sensitive to the carcinogenic effect of vinyl chlo-
ride, with the development of both hepatocarcinomas and angiosar-
°omas. in addition, evidence for transplacental carcinogenesis was
seen.
As discussed above, Radike ejt al. (1981) showed that exposure
to vinyl chloride and ethanol together produced more hepatocellu-
*ar carcinomas and angiosarcomas than exposure to vinyl chloride
alone. Thus, these results indicate that ethanol potentiates the
fc°xicity of vinyl chloride.
In summary, animal studies have suggested that older individ-
uals, females, newborns and alcohol consumers may be particularly
8ensitive to the effects of vinyl chloride.
-------
IX-4
of carcinogenic Risk
Animal studies and epidemiologies studies collectively confirm
vinyl chloride is carcinogenic. Numerous noncarcinogenic
Affects have also been noted. The NAS and EPA's GAG have calcu-
lated projected incremental excess cancer risks associated
with the consumption of a specific chemical via drinking water by
^thematical extrapolation from high-dose animal studies. The
tesults of these.'.calculations aite shown in Table IX-1. Using the
estimates generated by the NAS where the linear non-threshold
-stage model was utilized, it was estimated at the 95% confi-
dence limit that consuming two liters of water per day over a
^fetime having a vinyl chloride concentration of 100 ug/1, 10 ug/1
°r 1 ug/1 would increase the risk of one excess cancer per 10,000,
lQ0,000 or 1,000,000 people exposed, respectively. Using the
r«viaed GAG approach and the linear multi-stage model, it can be
*8timated at the 95% /confidence limit that consuming two liters
&e* day over a lifetime having a vinyl choride concentration of
2°° ug/1, 20' ug/1 or 2 ug/1 would increase the risk of one excess
c*ncer per 10,000, 100,000 or 1,000,000 people exposed, respec-
^ively. 7^ selection of the data for use in the model resulted
il1 the difference in the GAG and NAS risk estimates, since the NAS
b*sed ita calculations on an ingestion study in which rats were
**Posed to vinyl chloride by gavage, while the GAG used an inhala-
a study.
-------
DC-5
TABLE IX-1
Drinking Water Concentrations and Associated Cancer Risks
Range of Concentrations (ug/1)*
GAG HAS NAS
Cancer Risk
lO-4
10-5
10-6
limit)
200
20
2
limit)
100 170
10 17
1 1.7
*Assume 2 liters of water are consumed per day by a 70 kg adult for a
70 year lifetime.
-------
X-l
Quantification of Toxicological Effects for Vinyl Chloride
The quantification of toxicological effects of a chemical
consists of an assessment of the non-carcinogenic and carcino-
genic effects. In the quantification of non-carcinogenic
effects, an Adjusted Acceptable Daily Intake (AADI) for the
chemical is determined. For ingestion data, this approach
is illustrated as follows:
Adjusted ADI = (NOAEL or MEL in mg/kq)(70 kg)
(Uncertainty factor)(2 liters/day)
The 70 kg adult consuming 2 liters of water per day is used
as the basis for the calculations. A "no-observed-adverse-effect-
•
level" or a "minimal-effect-level" is determined from animal
toxicity data or human effects data. This level is divided
by an uncertainty factor because, for these numbers which are
derived from animal studies, there is no universally acceptable
quantitative method to extrapolate from animals to humans,
and the possibility must be considered that humans are more
sensitive to the toxic effects of chemicals than are animals.
For human toxicity data, an uncertainty factor is used to
account for the heterogeneity of the human population in
which persons exhibit differing sensitivity to toxins. The
guidelines set forth by the National Academy of Sciences
(Drinking Water and Health, Vol. 1, 1977) are used in estab-
lishing uncertainty factors. These guidelines are as follows:
an uncertainty factor of 10 is used if there exist valid
experimental results on ingestion by humans, an uncertainty
factor of 100 is used if there exist valid results on long-
term feeding studies on experimental animals, and an uncertainty
factor of 1000 is used if only limited data are' available.
-------
X-2
In the quantification of carcinogenic effects, mathematical
models are used to calculate the estimated excess cancer
risks associated with the consumption of a chemical through
the drinking water. EPA's Carcinogen Assessment Group has
used the multistage model, which is linear at low doses and
does not exhibit a threshold, to extrapolate from high dose
animal studies to low doses of the chemical expected in the
environment. This model estimates the upper bound (95%
confidence limit) of the incremental excess cancer rate that
\
would be projected at a specific exposure level for a 70 kg
adult, consuming 2 liters of water per day, over a 70 year
lifespan. Excess cancer risk rates also can be estimated
using other models such as the one-hit model, the Weibull
model, the logit model and the probit model. Current
understanding of the biological mechanisms involved in cancer
do not allow for choosing among the models. The estimates
of incremental risks associated with exposure to low doses
of potential carcinogens can differ by several orders of
magnitude when these models are applied. The linear, non-
threshold multi-stage model often gives one of the highest
risk estimates per dose and thus would usually be the one
most consistent with a regulatory philosophy which would
avoid underestimating potential risk.
The scientific data base, which is used to support the
estimating of risk rate levels as well as other scientific
-------
X-3
endeavors, has an inherent uncertainty. In addition, in
oany areas, there exists only limited knowledge concerning
the health effects of contaminants at levels found in drinking
water. Thus, the dose-response data gathered at high levels of
exposure are used for extrapolation to estimate responses at
levels of exposure nearer to the range in which a standard
Bight be set* In most cases, data exist only for animals; thus,
uncertainty exists when the data are extrapolated to humans.
When estimating risk rate levels, several other areas of
\
uncertainty exist such as the effect of age, sex, species
and target organ of the test animals used in the experiment,
as well as the exposure mode and dosing rates. Additional
uncertainty exists when there is exposure to more than one
contaminant due to the lack of information about possible
additive, synergistic or antagonistic interactions.
A« Non-carcinogenic Effects
Vinyl chloride has been shown to have non-carcinogenic
effects in animals and humans. Acute and chronic toxicity
studies have shown the major effects to be congestion and
edema of the lungs and hyperemia of the kidneys and liver.
Other non-carcinogenic effects have been noted, including
disturbances of the central nervous system, pulmonary
insufficiency, cardiovascular manifestations, gastrointes-
tinal symptoms and acroosteolysis.
Acute toxicity tests with vinyl chloride were carried
out by Patty e_t al. (1930). Single exposure of guinea pigs
-------
X-4
to vinyl chloride gas, 10 percent in air (100,000 ppra),
resulted in narcosis and death within 30 to 60 minutes.
Inhalation of lower concentrations resulted in ataxia
and narcosis. Pathological findings at necropsy were
congestion and edema of the lungs and hyperemia of the
kidneys and liver. Mastrometto et al. (1960) exposed
mice, rats and guinea pigs in an inhalation chamber to
10, 20 or 30 per cent vinyl chloride in air for 1-30 minutes.
The principal pathological changes observed were pulmonary
\
edema and hemorrhages, and congestion of the liver and kidneys.
In a chronic inhalation exposure study (Torkelsen
e_t al^., 1961), rats, rabbits, guinea pigs and dogs were
exposed repeatedly for up to six months to 50, 100, 200
or 500 ppm vinyl chloride in air. Detectable changes
occurred at all but the lowest concentration. Rats
exposed to 100 ppm (7 hours/day for 6 months) were judged
normal on the basis of appearance, mortality, growth, hemato-
logical examination and other factors. However, slight
increases were found in the average weights of the livers of
male and female rats. Rats, guinea pigs, rabbits and dogs
exposed to 50 ppm (7 hours/day for 6 months) appeared to be
normal in appearance, mortality and growth, and the increase
in Weight of the rat livers did not occur at this concentration.
At higher doses, pathological changes were increasingly more
pronounced. Basalaev et al. (1972) administered gaseous vinyl
chloride to rats and rabbits at a concentration of 0.03 - 0.04
mg/1 for 4 hours/day for 6 months. Cardiovascular disorders,
-------
X-5
changes in the bioelectric activity of the hypothalaraus,
nyperadrenalinemia, osteoporosis and resorption of bone
tissue were observed.
Feron ejt aiU (1981) carried out-a lifespan oral
toxicity study of vinyl chloride in rats. Vinyl chloride
Monomer was incorporated into the diet, or gastric intubation
°f a 10% vinyl chloride monomer solution in soya-bean oil
was used. Groups of 60-80 male and 60-80 female Wistar rats
w®re exposed to 0, 1.7, 5.0 and 14.1 mg/kg bw vinyl chloride
in the diet, or 300 mg/kg bw by gastric intubation. A variety
°f carcinogenic and noncarcinogenic effects were observed
at all dose levels. At the 14.1 and 300 mg/kg doses, shortened
blood-clotting times, slightly increased -foetoprotein levels
in the blood serum, liver enlargement and an increased haemato-
poietic activity in the spleen were observed. Non-neoplastic
liver lesions consisting of pronounced swelling, discolora-
tion and altered consistency of the lobes as well as nodules
and nodule-like processes were observed. At the lower dose
Bevels of 1.7 and 5.0 mg/kg bw, histopathological changes
in the liver were observed including clear-cell foci,
extensive necrosis, cysts, and liver-cell polymorphism.
Suciu ejt al. (1975) examined exposure of workers to
v*nyl chloride at high concentrations. Air concentrations
r*nging from 100 mg/ra3 (40 ppm) to 2,298 mg/m3 (900 ppm)
Produced euphoria, intoxication and narcosis, in a dose-
relationship. In an epidemiological investigation,
-------
X-6
Spirtas et al. (1975) conducted a survey of 200 vinyl chloride
workers and 89 rubber plant workers (controls). The vinyl
chloride workers were categorized into low and high exposure
Sroups. The high exposure group consisted of workers who
"ere exposed to concentrations ranging from 20-200 ppra
and the low exposure group consisted of workers exposed to
°-50 ppm vinyl chloride. Information was sought on the
frequency of eight symptoms, including dizziness, nausea,
headache and weakness. The results showed a statistically
8ignificant dose-response relationship for 5 of the 8 symp-
toms when comparing vinyl chloride workers with rubber
workers, and between high and low exposure vinyl chloride
vorkers. A similar but non-significant trend in the remaining
syn»ptoras categories was also noted.
8» Quantification of Non-Carcinogenic Effects
In the calculation of an adjusted ADI, a chronic study
ln which animals or humans are exposed to the chemical at
arious dose levels with a no-observed-effect-level or a
minimal-effect-level being identified is used. Ideally, the
study should use the oral route of exposure. For vinyl
cMoride, the toxicological studies which fit some of the
above criteria are the Feron et a_l. (1981) and Torkelson e_t
^i» (1961) studies. The Torkelson et al_. (1961) study examined
vinyl chloride inhalation exposure in rats, rabbits, guinea
and dogs at various dose levels. At 100 ppra, the only
rsa effect noted was the slight increase in the weight
the livers in the rat, and not in the other species.
-------
X-7
Thus, a rainimal-effeet-level of 100 ppm could be used for
the derivation of the an adjusted ADI. However, a major,
limitation of this study is that inhalation exposure was
used, which presents problems in terms of conversion factors
needed to convert from inhalation to ingestion exposure.
In the Feron et. a^L. (1981) study, carcinogenic and
non-carcinogenic effects were observed at all dose levels.
At the lowest dose of 1.7 rag/kg bw, a variety of effects
were reported, including narcosis of the liver, liver cysts
and nodules. It is not possible to identify a no-observed-
adverse-effect-level from this study, as effects were seen
at every dose level. However, 1.7 mg/kg/day may be used as
a minimal-effect-level for the purpose of calculating an
adjusted ADI, using an appropriate safety factor to account
for the fact that the no-observed-adverse-effect-level is
below this value. Using this study, the calculations are as
follows:
(1.7 mg/kg/dav)(70 kg) = Q.06 mg/1
{1000X2 I/day)
Where: 1.7 mg/kg = Miniraal-effeet-level from Feron et al..
(1981) study
70 kg * Average body weight of adult human
1000 = Uncertainty factor; animal study where
no-observed-adverse-effect-level was not
identified
2 liter « water consumption per day for an adult human
Thus, the adjusted ADI for vinyl chloride using non-carcinogenic
data and 100 percent exposure from drinking water would be
0.06 mg/1. This number should be appropriately reduced if
-------
X-8
there is shown to be significant vinyl chloride exposure
from other sources, such as food and air.
c» Carcinogenic Effects
Vinyl chloride has been shown to have carcinogenic
effects in animals and humans. Viola et al. (1971)
reported the carcinogenic response of male rats (AR/IRE
Wistar strain) exposed to vinyl chloride by inhalation.
Rats exposed to 30,000 ppm vinyl chloride for 4 hours/
day, 5 days/week for 12 months, demonstrated an increased
incidence of skin carcinomas, lung adenocarcinomas and
bone osteochondroma over controls.
Caputo ejt al. (1974) exposed male and female rats
(A and IRE Wistar strain) by inhalation to 0, 50, 500,
2,000, 5,000, 10,000 and 20,000 ppm vinyl chloride.
Liver angiosarcomas, lung adenocarcinomas and skin
squamous cell carcinomas were observed in all groups
except those exposed to 50 ppm. Tumors appeared between
8 and 13 months from the beginning of the inhalation
treatment.
A series of inhalation and ingestion studies
examining the carcinogenic effects of vinyl chloride have
been conducted by Maltoni (Maltoni, 1981). Vinyl chloride
was shown to cause tumors in all the animal systems tested
twice, rats and hamsters) both through inhalation and ingestion
exposure. In one study, Sprague-Dawley rats were exposed by
-------
X-9
inhalation to vinyl chloride at concentrations ranging from
50 to 100,000 ppm for 52 weeks. Angiosarcoraa of liver,
zymbal gland carcinomas, skin carcinomas, mammary carcinomas
and other tumors were found to occur'. One ingest ion study
showed the occurrence of angiosarcoma of the liver, mammary
carcinomas and other tumors at 50.0 mg/kg.
As discussed in the "Non-Carcinogenic Effects"
section, Peron ejt al. (1981) carried out a lifespan oral
toxicity study of vinyl chloride in rats, wistar rats
were exposed to 0, 1.7, 5.0 and* 14.1 mg/kg bw vinyl
chloride in the diet, or 300 mg/kg bw vinyl chloride by
gastric intubation. The results showed that rats exposed
to vinyl chloride, monomer at levels of 5.0 mg/kg bw or
more demonstrated hepatic angiosarcomas, pulmonary
angiosarcomas, and at the higher levels, a few extra-
hepatic abdominal angiosarcomas. At the lowest exposure
level of 1.7 mg/kg vinyl chloride, liver-cell tumors and
an increased incidence of foci of cellular alteration
were noted. The author concluded that vinyl chloride is
a carcinogen when administered by the oral route, and
that the tumor response seems to shift from the exclusive
development of angiosarcomas at very high levels to the
exclusive induction of hepatocellular tumors at low levels
°f exposure.
Epidemiological studies examining the carcinogenic
effects of vinyl chloride have also been carried out.
The first study associating vinyl chloride exposure in
-------
X-10
humans with cancer was conducted by Creech and Johnson,
1974. This study described three cases of angiosarcoroa
of the liver in workers at a polymerization plant in
Louisville, Kentucky. Since that time, a number of
studies have also demonstrated this association.
Monson et_ a^. (1975) conducted a proportional mortality
study of workers from two vinyl chloride plants who died
between 1947 and 1973. Death certificates were obtained for
142 out of 161 workers (88%) who died within this time period.
\
Deaths attributable to cancer were 50 percent higher than
expected (a statistically significant difference). A 900
percent increase in cancers of the liver and biliary tract
vas noted (five angiosarcomas). Excluding angiosarcoma, a
275 percent excess in numbers of cancers was observed.
•
Nicholson et al. (1975) studied a group of 257 workers (of
whom 255 were traced) exposed to vinyl chloride for at least
5 years in a polymerization facility. Exposures were estimated
to often exceed 10,000 ppm. Their mortality status was evalua-
ted beginning 10 years after start of employment until 1974.
Among the 24 deaths were 3 cases of angiosarcoma of the
iiver. Preliminary findings indicated a 25 percent increase
in deaths over the expected number and a 131 percent increase
in all cancer deaths, although neither of these increases
was statistically significant.
The National Institute for Occupational Safety and
Health (NIOSH) conducted a study which involved 1,294
individuals who were exposed to vinyl chloride for at
-------
least 5 years, and for whom at least 10 years had elapsed
since initial employment. A total of 136 deaths were
reported versus 126.3 expected (not a significant differ-
ence). A 49 percent increase over the expected number of
cancer deaths was noted, a statistically significant factor.
A statistically significant excess number of deaths occurred
for brain and CNS cancer, respiratory cancer, and biliary and
liver cancer (Waxweiler et al, 1976).
According to the International Agency for Research on
Cancer (IARC, 1979), vinyl chloride is a human and animal
carcinogen. IARC'S evaluation^.of the chemical is as follows:
"Vinyl chloride was tested in rats by oral, subcutaneous and
intraperitoneal administration and in mice, rats and hamsters
by inhalation exposure. Following oral and inhalation
exposure, vinyl chloride was carcinogenic in all three species,
producing tumors at different sites, including angiosarcoma of
the liver. Vinyl chloride was carcinogenic in rats following
prenatal exposure. A dose-response has been demonstrated.
Vinyl chloride is a human carcinogen. Its target organs
are the liver, brain, lung and haerao-lymphopoietic system.
Similar carcinogenic effects were first demonstrated in rats
and were later confirmed in mice and hamsters. Although
evidence of a carcinogenic effect of vinyl chloride in humans
has come from groups occupationally exposed to high doses of
vinyl chloride, there is no evidence that there is an exposure
level below which no increased risk of cancer would occur in
humans".
-------
X-12
Vinyl chloride has been studied in a variety of short-
term test systems which evaluate the mutagenic potential of
the compound and/or its potential for interaction with DNA.
The results of these studies are summarized in Table 1.
Positive results in certain of these test systems are
considered to be predictive of carcinogenic potential.
When considering all of the data on vinyl chloride,
It is probable that vinyl chloride can exert its carcino-
Senicity through genotoxic mechanisms. It thus becomes
\
necessary to estimate the carcinogenic risk from exposure to
vinyl chloride.
-------
X-13
TABLE 1 - Results of Vinyl Chloride Mutagenicity Studies
A. Assay system Results References
In Vitro prokaryotic and eukaryotic systems
Metabolically activated
Salmonella typhimurium
system (Ames)
Escherichia coli K12
bioauxotrophic strain
Yeast
Germ cells of Drosophilj(a
Chinese hamster V79 cells
B. DNA Binding Studies
Mouse tissues (brain, lung,
liver, kidney, spleen,
pancreas and testes) in
vitro
Rat liver microsomes,
reconstituted cytochrorae
P-450 systems and isolated
hepatocytes
Rat liver microsomes with
NADPH
Bartsch e_t al., 1975
McCann et aT7, 1975
Elmore et al., 1976
Rannug ejt al., 1974
Garro et alT, 1976
Greim et al., 1975
Loprieno et al, 1976, 1977
Verburgt and Vogel, 1977
Huberman et al., 1975
Bergman, 1982
(Irreversible
binding to
RNA and DNA)
+ Guengerich et al.
(Irreversible
binding to
Protein and DNA)
1981
(Alkylation
of RNA)
Laib and Holt, 1977
C. Biochemical or biologic consequences of DNA damage
Bone marrow cells of
rats (in vivo)
Bone marrow cells of
Chinese hamsters (in vivo)
+ Anderson and Richardson,
(Chromosome 1976
damage)
+ Basler and Rohrborn, 1980
(Chromosome
aberrations and
sister-chromatid-
exchanges)
Cultured peripheral lympho- + Purchase e_t a_l., 1978
cytes in humans (vinyl (Chromosomal Purchase e_t a_l., 1975
chloride exposed workers) abnormalities) Ducatman et al., 1975
-------
X-14
D. Quantification of Carcinogenic Effects
EPA's Carcinogen Assessment Group (GAG) have used the
linear multistage model to calculate the projected excess
cancer risk resulting from lifetime exposure to vinyl chloride
-through the drinking water. The CAG numbers were calculated
assuming consumption of 2 liters of drinking water and 6.5
grams fish and shellfish per day, and were published in the
Ambient Water Quality Criteria Document for Vinyl Chloride,
U.S. EPA 440/5-80-078. For vinyl chloride, CAG used the
incidence of total tumors in rats exposed through inhalation
(Maltoni et al, 1975) to calculate the excess cancer risk.
They calculated that consuming 2 liters of water per day
having a vinyl chloride concentration of 200 ug/1, 20 ug/1
or 2 ug/1 would increase the risk of one excess cancer per
10,000 (10~4), 100,000 (10-5) or 1,000,000 (10~6) respectively,
per lifetime.
There are several problems with the data used by CAG
in risk estimation. The major problem is that inhalation
•
data were used, and the relationship between oral and
inhalation exposure toxicity is not well understood.
The National Academy of Sciences (NAS) have also
calculated excess cancer risk values using the multistage
model. The NAS have published these calculations in Drinking
Water and Health, Vol..l, 1977. For vinyl chloride, ingestion
data from the Maltoni e_t al. (1975) study was used, in this
study, rats were given vinyl chloride in olive oil by gavage,
four or five times per week for 52 weeks and held for their
-------
X-15
life span. This experiment was not completed at the time
HAS performed its computations, but the available data did
indicate the development of liver arigiosarcomas and other
tumors in rats exposed to 16.65 mg/kg. The HAS made the
decision to use this study because it was felt that the
limited gavage data were still superior to completed
inhalation studies for assessing risk by the oral route.
The NAS have calculated that consuming 2 liters of
water per day over a lifetime at a vinyl chloride concen-
tration of 100 ug/1, 10 ug/1 or 1 ug/1 would increase the
risk of one excess cancer per 10,000 (10"4), 100,000 (10~5),
°r 1,000,000 (10-6) people exposed, respectively.
The major problem with the NAS data is that the
Maltoni experiment was not completed at the time the risk
calculations were carried out, and thus the data cannot be
considered definitive. However, since that time the Maltoni
e*periment has been completed, and the NAS (Drinking Water and
leaTth, Vol. V, 1983) reexamined the data and decided to
continue using their 1977 risk estimates. Thus, the NAS
risk estimation uses ingestion exposure and represents the
best estimate of the carcinogenic risk from exposure to
vinyl chloride that is available at this time. Using the
NAS data, the excess cancer risk concentrations associated
with 10~4, 10"5, and 10~6 excess risk rates are 100 ug/1,
10 ug/1, and 1 ug/1, respectively.
-------
X-16
The World Health Organization has not calculated an
action level for vinyl chloride. An EPA Health Advisory
number for vinyl chloride also has not been calculated.
In the quantification of toxicological effects for a
chemical, consideration should be given to subgroups within
the general population which are at greater than average
risk upon exposure to the chemical. For vinyl chloride,
animal studies have indicated that older individuals, females,
newborns and alcohol consumers may be particularly sensitive
to the effects of vinyl chloride.
Vinyl chloride has also been demonstrated to have
interactions with other chemicals. Ingestion of ethanol was
shown to increase the incidence of liver tumors in rats
(Radike et al., 1977) and vinyl chloride was demonstrated to
have protective effects when administered with 1,1-dichloroethylene
(Jaeger, 1975) .
-------
EPA's Carcinogen Assessment Group (CAG) have recently
recalculated their excess carcinogenic risk estimates resulting
from lifetime exposure to vinyl chloride through the drinking
water. CAG based their preliminary revised risk estimates (1984)
on the Feron et al. (198.1) study. The .total number of tumors,
considering tumors of the lung and liver, in rats exposed through
the diet were used to calculate the excess cancer risk. They
calculated that consuming 2 liters of water per day having
a vinyl chloride concentration of 1.5 ug/1, 0.15 ug/1 and
0.015 ug/1 would increase the risk of one excess cancer per
10,000 (10~4), 100,000 (10~5) or 1,000,000 (1Q-6) people
exposed, respectively, per lifetime.
-------
X-17
REFERENCES
Anderson, D. and C.R. Richardson. 1976. Paradichlorobenzene:
Cytogenic study in the rat. ICI Report CTL/P1293. November,
1976 (unpublished).
Bartsch, H., C. Malaveille, and R. Montesano. 1975. Human,
rat and mouse liver-mediated mutagenicity of vinyl chloride
in £. typhimurium strains. Int. Jour. Cancer. 15:429-437.
Basalaev, A.V., A.N. Vazine, and A.6. Kochetkov. 1972. On
the pathogenesis of changes developing due to a long-term
exposure to the effects of vinyl chloride. Gig. Tr. Prof.
Zabol. 16:(2):24-27.
Basler, A. and G. Rohrborn. 1980. Vinyl chloride: An example
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