4 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
| WASHINGTON. D.C. 20460
f January 6, 1984
OFFICE OF
RESEARCH AND DEVELOPMENT
SUBJECT: Review of a Card nogenl city Study on Vinyl Chloride
FROM:- Larry Anderson
lexicologist
Carcinogen Assessment Group (RD-689)
t'-r # n
Steven Bayard .yi^^ - &"•'-&. \s^
Statistician ' / "
Carcinogen Assessment Group (RD-689)
TO: Joseph Cotruvo
Director
Office of Drinking Water (WH-550)
THRU: Robert E. McGaughy .
Acting Technical Director
Carcinogen Assessment Group (RD-689 }
At the request of Dr. Marcus of your staff, the Carcinogen Assessment
Group (CAG) has reviewed the Feron et al. (1981) dietary administrative study
of vinyl chloride in rats. Dr. Larry Anderson has written the qualitative
analysis of the study and Dr. Steven Bayard has prepared the unit risk estimate.
This review is attached.
Attachment
-------
REVIEW OF A CARCINOGENICITY STUDY ON VINYL CHLORIDE BY FERON et al. (1981)
(Prepared by Drs. Larry Anderson and Steven Bayard, 1983)
The review of the subject study presented herein shows a clear dose-
related induction of hepatocellular carcinomas in male and female Wistar
rats given chronic doses of vinyl chloride monomer in the diet as well as
induction of hepatic angiosarcomas in male and female Wistar rats given a
chronic dose of vinyl chloride monomer in soya oil by gavageTT
MATERIALS AND METHODS
Vinyl chloride monomer (VCM) used in this study was obtained with the
high purity and composition described in Table 1. Polyvinyl chloride (PVC)
powder, with a particle size distribution (by weight) of: max 0.1% > 300 urn,
4% > 200 urn, max 90% > 88 urn, max 95% > 40 urn, was mixed with liquid VCM
before addition of PVC/VCM mixture into the diet. The diet of each dose group
contained 10% PVC powder with the desired dose level of VCM. A control group
was given a diet containing 10% PVC powder alone; the VCM content of PVC given
to the control group was < 0.3 ppm.
Albino Wistar rats (Cpb: WU: Wistar random), initially five weeks old,
were randomly allotted to dose groups according to body weight. In the dietary
study, the control group (restricted feeding) and the high-dose group each
consisted of 80 males and 80 females, and the remaining dose groups, including
controls given diet ad Ijbvtum, were composed of 60 males and 60 females.
-------
TABLE 1. CHEMICAL COMPOSITION OF VCM
(Feron et al. 1981)
Ingredient mg ingredientAg VCM
Vinyl chloride monomer > 99.97%, W/W)
Acetylene < 2
Monovinyl acetylene < 15
1,3-Butadiene < 10
Methyl chloride < 75
Ethyl chloride < 50
Chloroprene . < 1
1,1-Oichloroethane < 1
1,2-Oichloroethane < 20 ul/I (gas)
Acetaldehyde < 5
Hydrochloric acid ., . < 1
Iron < 0.5
Water < 100
Evaporation residue < 10
-------
These groups were fed a diet containing PVC alone 4 to 6 hours/day for five
days before treatment with VCM began. Diets were prepared daily, and'diet was
available to each group only between 0900 and 1500 hours each day throughout
the study. A second control group was offered a diet containing 10% PVC ad_
libitum. Animals were maintained on control or treatment diets until
termination of the study at 135 weeks for males and 144 weeks for females.
Actual doses of VCM ingested from diet were estimated by measuring, by
gas-liquid chromatography, the VCM content in the diet during the 4-hour feeding
period, the rate of diet consumption during the 4-hour feeding period, and the
amount of VCM excreted in feces at the end of feeding and at 4 and 9 hours
after termination of feeding. Fecal samples obtained 1 hour before the start
of feeding were also analysed. These measurements produced estimates of dietary
VCM levels and oral intake of VCM described in Table 2. Intake of VCM was
approximately 1.7, 5.0, and 14.1 mgAg/day in low-, mid-, and high-dose groups,
respectively.
A separate treatment group consisting of 80 male and 80 female Wistar rats
was given a 10% solution of VCM in soya bean oil by gavage at a dose of 300 mg
VCM Ag/day, five days/Week, until cessation of treatment at 83 weeks. The VCM
solution was prepared by injecting liquid VCM into the oil, and the VCM
concentration in oil was checked by gas-liquid chromatography. The group
treated with VCM by gavage was offered diet ad libitum. A control group given
soya oil alone was not included in this study.
Body weights and food consumption were recorded periodically throughout
the study. Blood and urine samples from 10 rats/sex/group at week 13, 26, 52,
78, and 94 were analyzed for hematology, serum biochemistry, and urinalysis.
All animals were necropsied. Complete histopathologic examination of
tissues and organs from 20 males and 20 females from the control group
3
-------
TABLE 2. DESIGNED AND ACTUAL DOSAGE OF VCM IN RATS MAINTAINED ON DIETS CONTAINING PVC POWDER
(Feron et al. 1981)
Designed V(
Dietary
level
(ppm)
0
20
60
200
)M treatment
Intake
(mgAg body
weight /day)
0
1
3
10
Actual initial
dietary VCM
level (ppm)*
0
46
139
424
Oral intake
(mgAg body wj
Theoretical t
0
2.3
7.0
21.2
of VCM
;ight/day)
Actual
0
1.8
5.6
17.0
Actual oral exposure
level of VCM§
(mgAg body
weight /day)
0
1.7
5.0
14.1
*Average dietary VCM contents determined immediately after preparation of the diets.
^Assuming no loss of VCM by evaporation from the diets.
§0ral Intake of VCM diminished by the faecal VCM, which was found to be 8, 10, and 17%
of the actual oral VCM intake for the low-, mid-, and high-dose groups, respectively.
The VCM excreted in the faeces was considered to be still enclosed in the PVC granules
and thus not to have been in contact with the body.
-------
(restricted feeding), the high dose dietary group, and the gavage group was
done. Terminally sacrificed animals were supplemented with the longest
surviving decedents to yield the 20 rats per group. A limited number of
tissues and organs from the remaining rats, except interim sacrificed animals
and ad 1ibitum control animals, was histopathologically evaluated. All gross
lesions and tumors were microscopically examined.
Ten males and 10 females per group from the control (restricted feeding),
the high-dose dietary group, and the gavage group were sacrificed at 26 and
52 weeks. These animals were evaluated for gross pathology, histopathology
of the liver, kidney, and Zymbal gland, electron microscopic changes in
liver, liver and kidney weights, and liver and kidney function.
The control animals offered diet ad Ij bij:ujn were evaluated for body
weight, survival, and gross pathology.
RESULTS
A dose-related decrease in survival of treated rats in the dietary study.
was evident (Table 3). Death of treated animals was primarily attributed
to pulmonary or hepatic insufficiency due to neoplastic or nonneoplastic
lesions in these organs. By 80 weeks of gavage treatment with VCM, mortality
was becoming high (Table 3), and most of the decedents in this group has
lesions or tumors in liver and lung.
Body weights and food consumption were similar between control
(restricted feeding) and treated groups given VG4 in the diet. Animals
allowed diet ad libitum were heavier which appears to be a result of
greater food consumption by these animals (Figure 1).
Hematology, serum biochemistry, urinalysis, and organ function tests
were negative except for decreased blood clotting times and increased serum
a -fetoprotein levels in high-dose dietary- and gavage-treated groups.
5
-------
TABLE 3. CUMULATIVE MORTALITY OF RATS EXPOSED ORALLY TO VCM FOR UP TO 2.7 YEARS
(Feron et al. 1981)
Treatment group
(mg VCMAg body
wei ght /day )
0
1.7
5.0
14.1
30011
00
0
1.7
5.0
14.1
30011
o#
12
•
0
0
0
0
0
0
0
0
0
0
0
0
36
0
0
0
1
6
0
0
0
1
0
3
0
52
0
1
0
2
6
0
0
1
2
1
7
1
80
0
1
2
8**
23
1
1
2
7*
7*
24
4
\
f
92
Males
2
3
7
22***
47
3
Females
5
4
16** ;
43***
47
10
lumber c
105
6
6
12
40***
53
19
6
13
31***
60***
58
17
>f deaths t t
120
18
13
30*
. 56***
i 60
28
22
26
55***
60***
60
27
>y end of v
128
40
37
49
60***
60
46
27
32
60***
60***
60
42
/k:
134§
46
40
60**
60**
60.
46
32
34
60***
60***
60
43
143§
41
55**
60***
60***
60
52
^Initial number of rats: 60/sex/group.
§Surviving males were killed in wk 135 and surviving females in wk 144.
1lThe figures for this group were not evaluated statistically, because no corresponding control group was
included in the study.
^Additional control group housed in a separate room and having constant access to the diet containing
10% PVC without VCM.
Values marked with asterisks differ significantly from those of the controls according to the chi-square
test: *P < 0.05; **P < 0.01; ***P < 0.001.
-------
60O
900
400
300
e
o
200
Mol«3
Females
20 40 SO 80 100 120 l«0 I6O
Duration of experiment, wk
Figure 1. Average body weights of the extra controls fed the 10%-PVC diet
ad libitum (-) and of the rats given 300 mg VCM/kg body weight in oil by
gavage f~). The weight curves of the rats receiving 0, 1.7, 5.0, or
14.1 mg VGM/kg body weight/day from the 10%-PVC diets fed for 4 hr each
day all lie within the shaded area. (Feron et al. 1981)
-------
Liver/body weight ratios were higher in high dose dietary- and gavage-
treated rats compared to dietary (restricted feeding) controls at 26 and 52
weeks; however, the evaluation of these results might have been strengthened
if liver weights themselves had been reported and if organ weight data had
been obtained at other times during the entire study.
Gross lesions in livers of treated rats were described as pronounced
swelling, discoloration, varying numbers of cysts, and nodules and nodule-
like processes up to 4 cm in diameter. Larger firm and pale nodules with
central necrosis, found mainly in completely distorted livers, were diagnosed
as carcinomas. Angiosarcomas were mainly multiple soft dark cystic nodules
containing blood and granular necrotic material. Neoplastic nodules were
small, firm, and compact with no signs of necros.is.. Small hemorrhagic or
gray nodules were located in pulmonary lobes of treated animals. Nodules in
the peritoneum were found in slightly higher incidence in animals given VCM
in the diet compared to "other groups.
Histopathologic diagnoses of hepatic tumors and lesions are presented
in Table 4. A dose-related increase in the incidences of hepatic neoplastic
nodules, hepatocellular carcinomas, and hepatic angiosarcomas in both male
and female rats given VCM in the diet is clearly evident. Females appear to
have been more sensitive to the induction of hepatocellular carcinomas by
VCM treatment; however, males were evidently more sensitive to the induction
of angiosarcomas. Gavage treatment with 300 mgAg of VCM effectively induced
angiosarcomas but not hepatocellular carcinomas in males and females.
Nonneoplastic lesions common in liver of treated rats were necrosis,
cysts, and polymorphism (Table 4). Ultrastructural examination of liver
specimens from high dose dietary- and gavage-treated rats sacrificed at 26
and 52 weeks revealed hepatocytes with foci or vacuolated cytoplasm.
8
-------
TABLE 4. TYPE AND INCIDENCE OF TREATMENT-RELATED HISTOPATHOLOGICAL CHANGES IN THE LIVER
OF RATS EXPOSED ORALLY TO VCM
(Feron et al. 1981)
Incidence of change
Type of Treatment group
change t (mg VCMAg/day)...
0
Males
1.7 5.0
Animals killed after
f Mo. of rats examined...
Clear-cell foci
10
0
— 11
—
Animals killed after
No. of rats examined...
Clear-cell foci
Basophi lie foci
Eoslnophilic foci
Neoplastic nodule
Hepatocellular carcinoma
Cystic proliferation of
bile ducts
9
1
0
0
0
0
0
«— v_
__
_-
—
—
; __
—
14.1
26 wk
10
1
52 wk
10
8**
0
2
1
1
0
300§
9
1
9
0
0
0
0
0
0
0 1.7
.
10
0
9
0
0
0
0
0
0
Females
5.0 14.1
10
5**
10
8**
4
5**
2
1
4*
300§
10
2
8
0
1
0
0
0
0
Animals found dead or killed in extremis or teminally
No. of rats examined...! 55
58
56
59
55
57
58
59
57
54
Clear-cell foci
Basophi lie foci
Eosinophilic foci
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
0
8
3
0
0
0
9**
18
23***
1
1
0
16***
21*
27***
7**
2
6*
21***
22**
33***
23***
8**
27***
9
12
11
3
1
27
4
0
8
2
0
0
24***
33***
35***
26**
4
0
22***
17
20*
39***
19***
2
36***
28***
29***
44***
29***
9**
10
19
6
2
0
29
fc~o"ntTnue~d""oh~"the~ foTTdwTng pag~e~7
-------
TABLE 4. (continued)
Ijicjdjince j)f_-Change
Males
Females
Type of Treatment group
change t (mg VCMAg/day )...
Proliferation of atypical
sinusoidal cells only
/Extensive necrois
Cysts
Liver-cell polymorphism
Centrilobular degeneration
Focal haematopoiesis
0
2
4
2
4
0
0
1.7
0
4
3
16*
0
1
5.0
4
8
4
28***
0
0
14.1
7
23***
16***
42***
1
10**
300§
6
21
3
36
1
8
0
4
5
9
34
1
1
1.7
6
6
30***
51*
2
3
5.0
3
19***
41***
38
3
1
14.1
4
27***
49***
41
1
6
300§
7
24
3
41
18
12
tSpecific hepatocellular lesions were classified according to Squire and Levitt (1975).
§The figures of this group were not evaluated statistically, because no corresponding control group was included in
the study.
1INot examined.
#The initial number of animals was 60/sex/group. A number of rats could not be examined because of cannibalism or
advanced autolysis.
Values marked with asterisks differ significantly from those of controls according to the chi-square test:
*P < 0.05; **P < 0.01; ***P < 0.001.
10
-------
Vacuoles were identified as swollen mitochondria.
Lung angiosarcomas were found in treated rats (Table 5). Most of
these angiosarcomas were described as multiple foci of tumor cells with a
growth pattern suggestive of metastases, and pulmonary metastases of
hepatocellular carcinomas were frequently observed. Conversely, primary
neoplasms in the lung were also identified, and lung angiosarcomas were
found in seven rats with no liver angiosarcoma.
Although increased incidences of abdominal mesotheliomas in treated
rats were not significant (P > 0.05, Table 5), a dose-related decrease
in latency for development of this tumor type was reported, without pre-
sentation of data.
A possible treatment-related nonneoplastic lesion was "very marked"
hematopoietic activity in the spleen of 6/40 males and 10/40 females in the
high dose dietary- and the gavage-treated groups compared to slight to
moderate spleen hematopoiesis in controls.
11
-------
TABLE 5. SITE, TYPE, AND INCIDENCE OF TUMORS IN THE LUNG AND ABDOMEN IN RATS
EXPOSED ORALLY TO VCM FOR OVER 2.5 YEARS
(adapted from Feron et al. 1981)
Site and type
of tumor
Treatment group
(mg/VCMAg/day)
Males_
0 1.7 5.0 14.1 300t
JLp^J^jifAJLLJ-yinpj-5
Females
0 1.7 5.0 14.1 300t
Effective no. of
rats
55
58
56
59
55
57 58 59
57 54
Lungs
Ang1osarcoma
19** 19
5* 23
Abdomen
Mesothelioma
6* 3
tThe figures for this group were not evaluated statistically, because no corresponding control group was included
in this study
*S1gnificant difference from controls by chi-square test (P < 0.05).
**Significant difference from controls by chi-square test (P < 0.01).
12
-------
DISCUSSION
Results of this study indicate that limiting the animals to a daily 4-hour
feeding period did not compromise their health and survival; however, the
/
4-hour daily treatment with VCM was effective as an inducer of neoplastic and
nonneoplastic lesions in liver. Limiting the animals to a 4-hour feeding
period reduced the unavoidable exposure to VCM evaporating from diet; however,
the rats receiving PVC in the diet for 4 hours each day were housed in a
"well-ventilated" room. Rats given VCM in corn oil were separately housed in
a "well-ventilated" cabinet.
Ingestion of VCM as a VCM/PVC mixture in diet produced a dose-related
increase in the incidence of neoplastic nodules and carcinomas in liver in
all treated groups of male and female rats. In contrast, gavage
administration of VCM in soya oil produced a high incidence of hepatic
angiosarcomas but few hepatocellular carcinomas. Nonneoplastic liver lesions
common to treated rats were necrosis, centrilobular degeneration, and mitochondria!
damage. Slight increases in liver/body weight ratios and a -fetoprotein levels
in treated rats may also reflect liver damage. Most pulmonary angiosarcomas
were metastases from hepatic angiosarcomas.
Induction of hepatic angiosarcomas in male and female Wistar rats given
300 mg/kg of vinyl chloride in soya oil by gavage for 83 weeks'in the study by
Feron et al. (1981) is supportive of the similar finding in male and female
Sprague-Oawley rats given doses of 50 mg/
-------
The contrast between the effect of VCM administered by gavage in oil and
orally in diet on the spectrum of neoplastic and nonneoplastic liver lesions
induced in rats in this study is not clear and should be further investigated.
Additionally, possible differences in the sensitivity of rats to the liver
toxicity of VCM when given in the diet during daily restricted 4-hour feedings
and when offered in the diet ad libitum could also be explored; however,
evaporation of VCM from diet should be considered in designing a study for
such a comparison. The evaluation of rats treated with VCM by gavage could
have been strengthened if a concurrent control group treated with soya oil
alone had been included in the study.
Feron et al. (1975) analyzed VCM solutions in soya oil and various
dietary preparations of VCM for stability and reactivity. These investi-
gators reported a slow evaporation of VCM from soya oil at room temperature,
e.g., a 5.6% solution lost 10%, 16%, and 29% of its VCM after 1, 4, and 8
hours, respectively, and no evidence of reaction products from storage of a
10% VCM solution in soya oil was noted. Feron et at. (1975) compared the
following diet?: a) diet mixed with a solution of 3% VCM in soya oil in an
open vessel; b) diet mixed with soya oil and liquid VCM, individually, in
a closed vessel; c) diet mixed with PVC containing 1,850 ppm or 4,400 ppm
VCM. Storage of these diets in open vials at' room temperature'revealed loss
of VCM from diets a and b to undetectable levels by 1 and 2 hours,
respectively, after mixing. The VCM in diet c evaporated more slowly, thus
indicating greater stability, with 1,850 ppm.reduced to 750 ppm by 6 hours
and 4,400 ppm decreased to approximately 2,600 ppm by 4 hours after mixing.
The rate of VCM evaporation from diet in the study by Feron et al. (1981)
discussed herein corresponds to the results by Feron et al. (1975) in that
14
-------
the initial 49, 139, and 424 ppm VCM levels in Table 2 decreased to
•
approximately 25, 75, and 225 ppm, respectively, by the end of the 4-hour
feeding period. Feron et al. (1981) and Feron et al. (1975) concluded
that VCM was released from PVC during transport in the gastrointestinal
tract, and the percentage of VCM eliminated in feces in rats fed VCM in
diet, as described in Table 2 herein, indicates an 83 to 92% absorption
of VCM which is close to the estimated 92% absorption of VCM in soya oil
given to rats in the study by Feron et al. (1975).
15
-------
UNIT RISK ASSESSMENT FOR VINYL CHLORIDE
The data used to estimate a unit risk for oral exposure to vinyl chloride
are based on the Feron et al. (1981) study. The statistically significant
increases reported for liver and lung tumors were considered biologically
significant. For the liver tumors, neoplastic nodules were considered a
progression toward hepatocellular carcinomas, and these are included in the
analysis in Tables 6 and 7. Extrapolations using the linearized multistage
* ?
model show values of q^ for the individual tumors ranging from 8.8 x 10"c
to 1.3 x 10"1 for the males and from 5.8 x 10~2 to 1.3 for the females. The
value of q£ based on males was 3.0 x 10"^ for liver tumors and 2.9 x 10~*
based on all tumors combined. For the females the value of q^ based on
liver tumors was 1.9 and for all tumors combined was 2.3. All units of q^
are per mg/kg/day.
Before proceeding with the unit risk estimates an explanation of the
total tumor counts in Tables 6 and 7 is necessary. For the liver all
animals with hepatocellular carcinomas were assumed to also have the neo-
plastic nodules. Thus, only the neoplastic nodules and liver angiosarcomas
were added to derive the total liver tumors. Otherwise, the totals would
have exceeded the number of animals examined. Also, in adding the lung and
liver tumors, the totals were not allowed to exceed one less than the
number examined. The result of this latter restriction was to raise the
value of q* slightly due to increased variance. In fitting the response
data in Tables 6 and 7 with the human equivalent dosages, the human equivalent
dosages were derived by dividing the corresponding animal dosages by
. The human weight (W^) was assumed to be 70 kg; the male rats
16
-------
TABLE 6. TYPE AND INCIDENCE OF STATISTICALLY SIGNIFICANT TREATMENT-RELATED CHANGES
IN THE LIVER AND LUNG OF MALE WISTAR RATS EXPOSED TO VCM IN THE DIET. VALUES OF q,
AND CONCENTRATION FROM MULTISTAGE EXTRAPOLATION MODEL INCLUDED
Treatment group (mg/kg/day)
0 1.7 5.0 14.1
Number of rats examined0
LIVER
Neoplastic nodules
Hepatocellular carcinomas
Angiosarcomas
TOTAL LIVER TUMORSd
LUNG
Angiosarcomas
TOTAL ANIMAL WITH TUMORS&
55
0
0
0
0
0
0
58 56
1 7
1 2
0 6
2 13
•
0 4
2 17
59
23
8
27
50
19
58
^d
(mgAg/day)'1
2.1 x
8.8 x
1.3 x
3.0 x
1.1 x
2.9 x
10-1
10-2
10-1
10-1
10-1
10-1
95% lower-limit concentration
ug/1 associated with risk"
10-4 jo-5 10-6
16.7
39.8
27.0
11.7
31.8
12.1
1.7
4.0
2.7
1.2
3.2
1.2
0.2
0.4
0.3
O.I
0.3
0.1
aHuman equivalent q\ = qi(a)(Wh/Wa)1/3 in (mgAg/day)"1.
Concentration in ug/1 = (-35000/q]r)ln(l-R).
cFound dead or killed in extremis or terminally.
dSum of neoplastic nodules and liver angiosarcomas.
eTota1 must be at least less than total examined.
17
-------
TABLE 7. TYPE AND INCIDENCE OF STATISTICALLY SIGNIFICANT TREATMENT-RELATED CHANGES^
IN THE LIVER AND LUNG OF FEMALE WISTAR RATS EXPOSED TO VCM IN THE DIET. VALUES OF q?
AND CONCENTRATION FROM MULTISTAGE EXTRAPOLATION MODEL INCLUDED
Treatment group (mgA9/day) ^
0 1.7 5.0 14.1 (mg/lcg/day)-1
Number of rats examined0
LIVER
•'Neoplastic nodules
Hepatocellular carcinomas
Angiosarcomas
TOTAL LIVER TUMORSd
LUNG
Angiosarcomas
TOTAL ANIMAL WITH TUMORS6
57
2
0
0
2
0
2
58
26
4
0
26 .
' 0
26
59
39
19
2
41
1
42
57
44 1.3
29 5.0 x 10-1
9 8.8 x 10-2
53 1.9
•
5 5.8 x 10-2
56 2.3
95% lower-limit concentration
ug/1 associated with risk"
10-4 io-5 10-6
2.7
70.0
39.8
1.8
60.3
1.5
0.3
0.7
4.0
0.2
6.0
0.2
0.03
0.07
0.4
0.02
0.6
0.02
aHuman equivalent q = qi(a)(Wh A^) in
Concentration in ug/1 = (-35000/qi)ln(l-R).
cFound dead or killed in extremis or terminally.
dSum of neoplastic nodules and liver angiosarcomas.
eTotal must be at least less than total examined.
18
-------
were estimated to weigh 350 grams and the female rats were estimated to
weigh 200 grams (Figure 1). Thus, the corresponding human equivalent
dosages were 0, 0.29, 0.85, and 2.41 mg/kg/day based on the male rats,
and 0, 0.24, 0.71, and 2.00 mgAg/day based on the female rats.
When the response and human equivalent dose data were fit to the
linearized multistage model, the 95% upper limit on the largest linear
term (Table 7) was
qj = 2.3 (mgAg/day)'1
To derive an estimate of the 95% lower level of concentration, d,
corresponding to a 95% upper level of risk, R, the following equation
is used
R
where d is the lower limit on dose in mgAg/day. To solve for d in
ug/liter, we use the transformation
1 mgAg/day x (70 kg/2 liter) x 1000 ug/fog = 35000 ug/liter
If we set R = 10~5 then
d = (-35000/qi) In (1-10"5) (ug/liter).
For the highest value of q£ = 2.3 (mgAg/day)" (Table 7), setting
R = 10-5 yields a value of d = 0.15 ug/liter. Setting R = 10~4 or 10~6
yields values of d = 1.5 ug/liter and d = 0.015 ug/liter, respectively.
For comparison purposes only we compare the potency of vinyl chloride
by the diet versus the inhalation routes. A previous memo we sent you
19
-------
estimated the 95% upper limit of potency for VCM as qf » 1.7 x 10"2
(mg/kg/day)'1 based on an inhalation study showing angiosarcomas and
other tumors in rats. That potency estimate was derived for water quality
criterion purposes. In that document an inhalation to ingestion by gavage
relationship of 1 ppm inhaled = 2.28 mg/
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Feron, V.J., A.J. Speek, M.I. Willems, 0. van Battum, and A.P. de Groot. 1975.
Observations on the oral administration and toxicity of vinyl chloride
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Maltoni, C,, Lefemine, G., Ciliberti, A., Cotti, G., and Carretti, D. 1931.
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