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EPL
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
MAX 2 0 1980 VC D ^ ^ -'<3 "
PATHOLOGY REPORT ON THE BRAINS FROM MICE, HAMSTERS, AND RATS
EXPOSED TO VINYL CHLORIDE IN IBT STUDY 663-03222
-
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Submitted to: Chemical Manufacturers Association
Washington, D. C. 20009
May 14, 1980
CMA 006718
EPL
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
PATHOLOGY REPORT ON THE BRAINS FROM MICE, HAMSTERS, AND RATS EXPOSED TO VINYL CHLORIDE IN IBT STUDY 663-03222
I. INTRODUCTION
At the request of the Chemical Manufacturers Association,
Experimental Pathology Laboratories, Inc. conducted a pathology evaluation
of the available brains from mice, hamsters, and rats either exposed to
vinyl chloride or used as controls in Industrial Bio-Test (IBT) Study
663-03222. This inhalation toxicology study was conducted in the IBT
facilities at Decatur, Illinois, and was initiated on September 10, 19^3.
The experimental design for this study is as follows:
H
Group
Control Tl* T2* T3* T4**
Number of Animals
MiceRatsHamsters
MF
MF
MF
100 100 100 100 100 100 100 100
--
100 100 100 100 100 100 100 100
100#
100 100 100 100 100 100 100 100
--
______ Exposure Levels
50 200 2500 2500
ppm Vi nyl ppm Vinyl ppm Vinyl ppm Vinyl
Chloride Chloride Chloride Chloride
*No food, water, or bedding in cages during exposure **Food, water, and bedding to remain in cages during exposure
#A11 rats of same sex, either sex permitted
The protocol as amended called for the inhalation exposure of the above groups six hours per day, five days per week. Mice were to be exposed for nine months; rats and hamsters for twelve months. These groups were originally scheduled to be held for equal additional periods of time (nine or twelve months); but, subsequently it was agreed that
CMl*i 006719
EPL
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
they would be kept for their lifetime or sacrificed if moribund. All
animals were to be necropsied either at the time of death or sacrifice,
and a relatively complete set of tissues was to be preserved in 10%
neutral buffered formalin. These tissues were to be examined from all
animals in the control, T2, and T3 groups. If exposure related lesions
were detected in the organs of the T2 or T3 groups, these same organs
from the T1 group were to be examined.
An EPL pathologist (Dr. William Busey) and four histology/
pathology technicians traveled to IBT at Northbrook, Illinois, where *
the material from the study is archived. At IBT, facilities were
**
provided for examination of the residual wet tissue, paraffin blocks,
and microscope slides. In addition, facilities were provided for the
histologic processing of brains recovered from the residual wet tissue.
II. MATERIALS AND METHODS A. Residual Wet Tissue All of the bags of residual fixed wet tissue from the mice,
hamsters, and rats were examined for brain material. If brain material was discovered in the bag, it was recovered, examined grossly for any alterations, and trimmed into three to five sections for histologic processing.
B. Paraffin Blocks All of the paraffin blocks from the mice, hamsters, and rats
were examined for the presence of embedded brain material. If brains were discovered, the blocks were set aside for microtoming and staining.
-2- CMA 006720
EPL
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
C. Microscope Slides (IBT Prepared) All of the microscope slides from the mice, hamsters, and
rats were examined for brains. All brain slides were examined microscopically at IBT by the EPL pathologist.
D. Pathology Sheets
The original pathology sheets from the mice, hamsters, and rats
were examined for gross descriptions of brain abnormalities. The
descriptions of any brain abnormalities were recorded along with the
date of death of any animal with a recorded gross or microscopic
^
brain lesion. In addition to the gross description of any brain ab
normality, the microscopic findings of the IBT pathologist were also
recorded.
In the animals for which brain material was recovered from either the residual wet tissue, paraffin blocks, or microscope slides, an attempt was made to verify the animal identification. This was done by comparing the animal number and date of death recorded on the pathology sheet with the animal numbers and date of death recorded on the bags of residual wet tissue and with the animal numbers embedded in the paraffin blocks or recorded on the microscope slides.
-3- CMA 006721
EPL
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
The brains recovered from the residual wet tissue were processed, embedded, microtomed, and mounted on microscope slides at IBT. The paraffin blocks containing brain material, previously embedded by IBT, were microtomed and mounted on microscope slides. Duplicate slides were prepared from each paraffin block containing brain. One set of slides was left at IBT and the other set was returned to EPL, stained with hematoxylin and eosin, and evaluated by an EPL pathologist.
III. RESULTS
*4
A. Number of Recovered Brains
-H
The following table details the number of brains recovered
from either the residual wet tissue or paraffin blocks previously
prepared by IBT:
Number of Brains Recovered from Residual Wet Tissue or IBT Paraffin Embedded Blocks
Group
Untreated Control T1 T2 T3 T4
Mice MF
54 13 8
37 12 14
_
Hamsters MF
43 84 14 10 13 6
__
Rats MF
18 20 15 13 23 11 23 17
- 12
-4-
CMA 006722
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
B. Pathology 1. Mice and Hamsters With the exception of focal encephalitis in Group T3
male hamster No. 2208, no gross or microscopic alterations were seen in any of the brains examined from the mice and hamsters.
2. Rats
Grossly detected changes in the brain were described at
* the time of necropsy by IBT in four male rats from,the T3 group. These
gross observations are as follows:
>4
Animal No.
Gross Observation
641 1 cm. mass located in front of brain in skull leaving a compression in brain-
664 A gelatinous-like focus beginning on the anterior frontal half of the brain beneath the meninges compressing the adjacent brain tissue. Mid sagittal section of the brain reveals an 8 mm white firm focus involving olfactory region and compression of adjacent cerebrum.
667 A soft tan mass was found in the right frontal region in the skull cap compressing the front quarter of the brain. Mass located between the meninges and the skull cap 1 cm. in diameter.
672 Front portion of brain was gelatinous and very soft.
In addition to the above four gross brain abnormalities,
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the following brain with a gross abnormality was detected by EPl personnel <c uir
-5-
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
Animal No. ___________Gross Observation 649 0.2 x 0.5 tan mass attached to the left olfactory bulb.
The detailed histologic findings for the microscopic evaluation of the brains are presented in Table II. A summary of the findings is presented in Table I.
Microscopic evaluation of the brains from the control and vinyl chloride exposed male and female rats revealed olfactory neuro blastomas (esthesioneuroblastoma, esthesioneuroepithelioma, medulloepithelioma) in five T3 males (641, 649, 664, 667, and 672), one T3 female rat (761), and one T4 female rat (2413). A single glioblastomti multi forme was detected in the brain from T2 male rat No. 412, and a single astrocytoma was detected in the brain of T2 female rat No. 566.
The histological features of the seven olfactory neuroblastomas were remarkably similar. They were characterized by a proliferation of deeply basophilic cylindrical cells with abundant cytoplasm supported by small blood vessels. Characteristic pseudo-rosettes were present along with numerous mitotic figures. In most instances these neoplasms compressed the anterior portion of the cerebrum; and, in some cases, infiltration under the meninges was evident. The glioblastoma multiforme was characterized by a proliferation of a mixture of highly pleomorphic cells containing large nuclei. Numerous giant cells and mitotic figures were also evident. The astrocytoma was characterized by a proliferation of well differentiated astrocytes infiltrating the neuropile, forming no particular structural pattern. A few mitotic figures were eivdent.
00^724 -6-
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
Scattered instances of meningoencephalitis, suppurative meningitis, encephalomalacia, and focal encephalitis were detected in a few rats from both the control and vinyl chloride exposed groups. The incidence of these inflammatory lesions was low and not related to any treatment group.
IV. DISCUSSION AND CONCLUSION The presence of seven olfactory neuroblastomas in the brains
from vinyl chloride exposed rats indicates a causal relationship between the exposure and the development of these neoplasms. Olfactory neuro-^ blastomas rarely, if ever, occur spontaneously in the rat. Three of $lese neoplasms were initially diagnosed by IBT as neuroepitheliomas. Subsequent review of the slides indicates the classification of olfactory neuroblastoma to be appropriate for these neoplasms. The glioblastoma multiforme detected in T2 male rat No. 412 was also initially diagnosed as a neuroepithelioma by IBT. Subsequent evaluation of this neoplasm indicates that this lesion is more properly classified as a mixed glioma or glioblastoma multiforme.
The olfactory neuroblastomas detected in these vinyl chloride exposed rats are apparently identical to the neuroblastomas reported by Maltoni in 1975, and again in 1977. In 1975, Maltoni reported at the New York Academy of Sciences Symposium on the toxicity of vinyl chloride-
^Carcinogenicity Bioassays of Vinyl Chloride: Current Results, Maltoni, C. and Lefemine, G., Annual New York Academy of Science, Vol. 246 (1975), 195-218.
2Vinyl Chloride Carcinogenicity: An Experimental Model for Carcinogenesis Studies, Maltoni, C., Origins of Human Cancer, Cold Spring Harbor Conferences on Cell Proliferation, Vol 4, 1977. -7- CMA 006725
EPL
EXPERIMENTAL PATHOLOGY LABORATORIES, INd
poly vinyl chloride. The results of his BT1 experiment revealed seven neuroblastomas in rats exposed to 10,000 ppm of vinyl chloride, three neuroblastomas in rats exposed to 6,000 ppm, and five neuroblastomas in rats exposed to 2,500 ppm of vinyl chloride. In 1977, at the Cold Spring Harbor Conference on Cell Proliferation, he again reported the results of his BT1 experiment in addition to the results of his BT3 and BT7 experiments where neuroblastomas were induced in rats exposed to vinyl chloride at 10,000, 6,000, and 2,500 ppm. The findings of olfactory neuroblastomas in the T3 male and female rats and a T4 femaT?
* rat confirms tne findings of Maltoni of an oncogenic effect on the rat^ brain from vinyl chloride exposure.
The shortcomings of this study have been previously documented. Regardless of these, the rarity of this neurological neoplasm coupled with the fact that it has only been reported in rats exposed to known carcinogens indicates a relationship between their presence in this study and exposure to vinyl chloride. As mentioned previously, the finding of these neoplasms confirms previously reported results from vinyl chloride exposures by Maltoni. Since the exposure conditions in this study have not been confirmed, the levels of vinyl chloride inducing these neoplasms cannot be stated at this time. Similarly, because of the large number of missing brains from the control and exposed rats, the true incidence of these neoplasms in IBT Study 663-03222,resulting from vinyl chloride exposure, cannot be determined.
Pathologist
WMB/sfh
-8-
EPL
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
IBT STUDY 663-03222 TABLE I
SUMMARY INCIDENCE TABLES
CMA 006727
IBT Study 663-03222 Vinyl Chloride Male Mice
BRAINS (NO. EXAMINED)
SUMMARY INCIDENCE TABLE
Untreated Control
(5)
T1 (13)
T2 T3 (3) (12)
-------------*4
EPL
Experimental Patholo^\ Laboratories 1 nc
CMA 006728
IBT Study 663-03222 Vinyl Chloride Female Mice
BRAINS (NO. EXAMINED)
SUMMARY INCIDENCE TABLE
Untreated Control
(4)_
T1 (8)
T2 T3 (7) (14)
"
*1
EpL | Experimental Patholoyv Laboratories, ln<
-10-
--
CMA 006729
IBT Study 663-03222 Vinyl Chloride Male Hamsters
BRAINS (NO. EXAMINED) Focal Encephalitis
SUMMARY INCIDENCE TABLE
1 Untreated Control
(4)
T1 (8)
T2 (14)
T3
(13) 1
Li
EPl
Experimental Pathology laboratories Inc
-- CMA 006730
IBT Study 663-03222 Vinyl Chloride Female Hamsters
BRAINS (NO. EXAMINED)
SUMMARY INCIDENCE TABLE
Untreated Control
T1
(3) ____ (4)
T2 (10)
T3 (6)
EPL
Experimental Patholoyv Laboratories Int
--
1 006731
IBT Study 663-03222 Vinyl Chloride Male Rats
SUMMARY INCIDENCE TABLE
BRAINS (NO. EXAMINED) Meningoencephalitis Suppurative Meningitis Encephalomalacia Focal Encephalitis Olfactory Neuroblastoma Glioblastoma Multi forme
Untreated Control
(18) 1 1
T1 (15)
1
T2 (23)
1
1
13 (23)
1 5
--
EPL
Experimental Patholo^v Laboratories Iru
-13-
CMA 006732
IBT Study 663-03222 Vinyl Chloride Female Rats
SUMMARY INCIDENCE TABLE
BRAINS (NO. EXAMINED) Meningoencephalitis Astrocytoma Olfactory Neuroblastoma Pituitary Carcinoma
Untreated Control
T1
(30)
(13)
1
T2
(ID 1 1
T3 (17)
1
T4 (12)
1
EPL
Experimental Pathology Laboratories, Int
-14-
CMA 006733
EXPERIMENTAL PATHOLOGY LABORATORIES, INC.
IBT STUDY 663-03222 TABLE II
HIST0PATH0L0GY INCIDENCE TABLES
CMA 006734
IBT Study 663-03222 Vinyl Chloride Male Mice
BRAIN
HISTOPATHOLOGY INCIDENCE TABLE
Untreated Control
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Key P
1
5
= Present
= Minimal
= Severei'High
N = No Section 2 = Slight I = Incomplete Section
A = Aulolysis 3 = Moderate
X " Not Remarkable 4 *> Moderately Severe'High
IBT Study 663-03222 Vinyl Chloride Male Mice
BRAIN
ANIMAL
NUMBER
1009 1013 1024 1025 1030 1031 1049 1052 1065 1066 1082
HISTOPATHOLOGY INCIDENCE TABLE
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N = No Section 2 = Slight I = Incomplete Section
A *= Aulotysis 3 * Moderate
X = Not Remarkable 4 " Moderately Severe/Higb
IBT Study 663-03222 Vinyl Chloride Male Mice
HISTOPATHOLOGY INCIDENCE TABLE
CMA 0 0 6 7 3 7
EPL
1 xpi-nmi'nlal I'nlholofjy Laboratories, Inc
-17/ " -t
Key
P 1 5
= Present = Minimal = Severe/High
N = No Section 2 = Slight I = Incomplete Section
A = Autoiysis 3 " Moderate
X *= Not Remarkable 4 Moderately Seuere High
IBT Study 663-03222 Vinyl Chloride Male Mice
BRAIN
ANIMAL
NUMBER
1407 1412 1414 1433 1435 1439 1443 1465
1477* 1488 1496
HISTOPATHOLOGY INCIDENCE TABLE
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I \[)iTimcntnl I'.itlinloKY Libor.itorii'S, Inc
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Key. P = Presenl 1 -- Minimal 5 = Severe/High
N = No Section 2 = Slight I = Incomplete Section
A = Autolysis 3 = Moderate
X " Not Remarkable 4 " Moderately Severe''High
IBT Study 663-03222 Vinyl Chloride Female Mice
HISTOPATHOLOGY INCIDENCE TABLE
Cm 006739
*Missexed
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-19* <* t
Key P = Present
1 = Minimal 5 = Severe^High
N = No Section
2 = Slight 1 = Incomplete Section
A = Autolysis
3 Moderate
X *= Not Remarkable
*4 Moderately Severe'High
IBT Study 663-03222 Vinyl Chloride Female Mice
BRAIN
ANIMAL
NUMBER
1105 1110 1112 1118 1139 1151 1156 1167
HISTOPATHOLOGY INCIDENCE TABLE T1
XX XXXXXA
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Key P = Present i = Minimal 5 = Severe/High
N = No Section 2 = Slight I = Incomplete Section
A = Autolysis 3 = Moderate
X = Not Remarkable 4 Moderately Severe'High
IBT Study 663-03222 Vinyl Chloride Female Mice
HISTOPATHOLOGV INCIDENCE TABLE T2
EPL
1 xpenmrntal Pathology Laboratories, Inc
-21-i' * t
Key P = Present
1 -- Minimal
5 35 Severe/High
N = No Section 2 = Slight 1 = Incomplete Section
A = AutolySJS 3 *= Moderate
X * Not Remarkable
4 * Moderately Severe'High
IBT Study 663-03222 Vinyl Chloride Female Mice
BRAIN
H1STOPATHOLOGY INCIDENCE TABLE
T3
CO ir>
XX XX XX XX XX XX XX
ANIMAL
NUMBER
1508 1516 1519 1522 1525 1526 1534 1545 1556 1573A 1578 1592 1599
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N = No Section
Minimal
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A = Autolysis 3 = Moderate
X = Not Remarkable 4 Moderately Severe/High
IBT Study 663-03222 Vinyl Chloride Male Hamsters
BRAIN____________ Focal Encephalitis
ANIMAL
NUMBER
1608 1612 1621 1698
HISTOPATHOLOGY INCIDENCE TABLE Untreated Control
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N = No Section 2 = Slight I - Incomplete Section
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X * Not Remarkable 4 = Moderately Severe'High
IBT Study 663-03222 Vinyl Chloride Male Hamsters
HISTOPATHOLOGY INCIDENCE TABLE T1
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P = Present
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5 = Severe/High
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I = Incomplete Section
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X *= Not Remarkable 4 " Moderately Severe/High
IBT Study 663-03222 Vinyl Chloride Hale Hamsters
HISTOPATHOLOGY INCIDENCE TABLE T2
i xporimentnl Pathology Laboratories, Inc
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Key
P = Present 1 = Minimal. 5 -- Severe/High
N = No Section 2 = Slight I = Incomplete Seclion
A = Aulolysis 3 *= Moderate
X = Not Remarkable 4 * Moderately Severe'High
IBT Study 663-03222 Vinyl Chloride Male Hamsters
BRAIN Focal Encephalitis
ANIMAL
NUMBER
2208 2226 2237 2244 2259 2260 2261 2275 2277 2295
HISTOP ATHOLOGY INCIDENCE TABLE
T3
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N = No Section 2 = Slight I = Incomplete Seclion
A = Aulolysis 3 = Moderate
X 4
Not Remarkable Moderalely Seveie'High
IBT Study 663-03222 Vinyl Chloride Female Hamsters
HISTOPATHOLOGY INCIDENCE TABLE
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X 4
Not Remarkable Moderately Severe^High
IBT Study 663-03222 Vinyl Chloride Female Hamsters
brain
ANIMAL
NUMBER
1948 1959 1961 1996
HISTOPATHOLOGV INCIDENCE TABLE XXXX
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Key
P = Present 1 = Minimal 5 = Severe/High
N = No Section 2 = Slight I = Incomplete Section
A = Autolysis 3 - Moderate
X = Not Remarkable 4 " Moderately Severe High
IBT Study 663-03222 Vinyl Chloride Female Hamsters
HISTOPATHOLOGY INCIDENCE TABLE T2
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Key
P = Presenl 1 -- Minimal 5 = Severe/High
N = No Section 2 = Slight J = Incomplete Section
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X ** Not Remarkable 4 * Moderalely Severe High
IBT Study 663-03222 Vinyl Chloride Female Hamsters
BRAIN
ANIMAL
NUMBER
2304 2310 2324 2326 2332 2356
HtSTOPATHOLOGY INCIDENCE TABLE XXXXXX
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Experimental Pathology Laboratories, Inc
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Key: P = Present 1 = Minimal 5 = Severe/High
N = No Section 2 = Slight I = tncomplete Section
A = Autolysis 3 = Moderate
X = Not Remarkable 4 " Moderately Severe/High
IBT Study 663-03222 Vinyl Chloride Male Rats
BRAIN Meningoencephalitis Suppurative Meningitis Encephalomalacia Focal Encephalitis Olfactory Neuroblastoma Glioblastoma Multi forme
ANIMAL
NUMBER
HISTOPATHOLOGY INCIDENCE TABLE
Untreated Control
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X = Not Remarkable
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IBT Study 663-03222 Vinyl Chloride Male Rats
BRAIN Meningoencephal itis Suppurative Meningitis Encephalomalacia Focal Encephalitis Olfactory Neuroblastoma Glioblastoma Multiforme
ANIMAL
NUMBER
HISTOPATHOLOGY INCIDENCE TABLE
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X = Not Remarkable 4 " Moderately Severe/High
IBT Study 663-03222 Vinyl Chloride
HISTOPATHOLOGY INCIDENCE TABLE
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N = No Section 2 = Slight I = Incomplete Section
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IBT Study 663-03222 Vinyl Chloride Male Rats
brain
Meningoencephalitis Suppurative Meningitis Encephalomalacia Focal Encephalitis Olfactory Neuroblastoma Glioblastoma Multi forme
ANIMAL
NUMBER
HISTOPATHOLOGY INCIDENCE TABLE
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X Not Remarkable 4 - Moderately Severe'High
IBT Study 663-03222 Vinyl Chloride
HI STOPAT H OLOG V INCIDENCE TABLE
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Key
P 1 5
= Presenl = Minimal = SeverelHigh
N = No Section 2 = Slight 1 = Incomplete Section
A = Aulolysis 3 = Moderate
X 4
Not Flemarkable Moderately Severe'High
IBT Study 663-03222 Vinyl Chloride Female Rats
BRAIN Meningoencephal i ti s Astrocytoma Olfactory Neuroblastoma Pituitary Carcinoma
ANIMAL
NUMBER
HISTOPATHOLOGY INCIDENCE TABLE
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A = Autolysis 3 = Moderate
X = Not Remarkable 4 = Moderately Severe/High
IBT Study 663-03222 Vinyl Chloride Female Rats
BRAIN Meningoencephal i ti s Astrocytoma Olfactory Neuroblastoma Pituitary Carcinoma
ANIMAL
NUMBER
HISTOPATHOLOGY INCIDENCE TABLE
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X 4
Not Remarkable Moderalely Severe'High
IBT Study 663-03222 Vinyl Chloride Female Rats
BRAIN Meningoencephalitis Astrocytoma Olfactory Neuroblastoma Pituitary Carcinoma
ANIMAL
NUMBER
HISTOPATHOLOGY INCIDENCE TABLE
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IBT Study 663-03222 Vinyl Chloride Female Rats
BRAIN Meningoencephalitis Astrocytoma Olfactory Neuroblastoma Pituitary Carcinoma
ANIMAL
NUMBER
HISTOPATHOLOGY INCIDENCE TABLE
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X XXXXXXXXXX
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p
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1__________________________________________
EPL
i
Pathology Laboratories. Inc
'
-39t
Key
P 1 5
= Present = Minimal = Severe/High
N = No Section 2 = Slight I = Incomplete Section
A = Autolysis 3 = Moderate
X 4
Not Remarkable Moderately Severe/High
IBT Study 663-03222 Vinyl Chloride
HISTOPATHOLOGV INCIDENCE TABLE
EPL
I xperimental Pathology Laboratories, Inc
-40-
Present Minimal Severe/High
N = No Section
2 = Slight I = Incomplete Section
A = Autolysis 3 = Moderate
X =* Not Remarkable 4 ** Moderately Severe/High