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1 I EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. 1 1 i 4 PATHOLOGY REPORT ON THE BRAINS FROM m MICE, HAMSTERS, AND RATS EXPOSED TO VINYL CHLORIDE IN IBT STUDY 663-03222 4 4 i 4 4 Submitted to: 4 Chemical Manufacturers Association Washington, D. C. 20009 4 4 May 14, 1980 4 4 4 DTH 00011816 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, 1973. The experimental design for this study is as follows: Group Control Tl* T2* T3* T4** Mice MF 100 100 100 100 100 100 100 100 -- Number of Animals Rats Hams ters MF MF 100 100 100 100 100 100 100 100 100?? 100 100 100 100 100 100 100 100 -- Exposure Levels 50 ppm Vinyl Chloride 200 ppm Vinyl Chloride 2500 ppm Vinyl Chloride 2500 ppm Vinyl Chioride *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 DTH 000118163 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. 11. 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- DTH 000118164  E PL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. i 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. 1 D. Pathology Sheets The original pathology sheets from the mice, hamsters, and rats m were examined for gross descriptions of brain abnormalities. The descriptions of any brain abnormalities were recorded along with the m date of death of any animal with a recorded gross or microscopic m brain lesion. In addition to the gross description of any brain ab normality, the microscopic findings of the IBT pathologist were also m 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. -3DTH 000118165 EXPERIMENTAL PATHOLOGY LABORATORIES, INC. I The brains recovered from the residual wet tissue were 1 processed, embedded, microtomed, and mounted on microscope slides at 1 IBT. The paraffin blocks containing brain material, previously embedded by IBT, were microtomed and mounted on microscope slides. Duplicate I 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, I stained with hematoxylin and eosin, and evaluated by an EPL pathologist. 1 HI. RESULTS 4 A. Number of Recovered Brains The following table details the number of brains recovered 1 from either the residual wet tissue or paraffin blocks previously 1 prepared by IBT: 1 Number of Brains Recovered from Residual Wet Tissue or IBT Paraffin Embedded Blocks 1 Group Mi ce Hamsters Rats MF MF MF 1 Untreated Control 54 43 18 20 T1 13 8 84 15 13 a T2 37 14 10 23 11 T3 12 14 13 6 23 17 a T4 12 a -4- DTH 000118166 EPL 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: Animal No. 641 664 667 672 Gross Observation 1 cm. mass located in front of brain in skull leaving a compression in brain. 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. 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. Front portion of brain was gelatinous and very soft. In addition to the above four gross brain abnormalities, the following brain with a gross abnormality was detected by EPL personnel: DTH 000118167 -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 Tab!e I. Microscopic evaluation of the brains from the control and vinyl chloride exposed male and female rats revealed olfactory neuro blastomas (esthesioneurobla stoma, 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 glioblastoma 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 proliteration 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. DTH 000118168 -6-  I EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. 1 Scattered instances of meningoencephalitis, suppurative meningitis, encephalomalacia, and focal encephalitis were detected in I a few rats from both the control and vinyl chloride exposed groups. The incidence of these inflammatory lesions was low and not related 4 to any treatment group. i IV DISCUSSION AND CONCLUSION The presence of seven olfactory neuroblastomas in the brains 4 from vinyl chloride exposed rats indicates a causal relationship between the exposure and the development of these neoplasms. Olfactory neuro I blastomas rarely, if ever, occur spontaneously in the rat. Three of these I neoplasms were initially diagnosed by IBT as neuroepitheliomas. Subsequent review of the slides indicates the classification of olfactory neuroblastoma 1 to be appropriate for these neoplasms. The glioblastoma multi forme detected in T2 male rat No. 412 was also initially diagnosed as a neuroepithelioma 1 by IBT. Subsequent evaluation of this neoplasm indicates that this lesion J is more properly classified as a mixed glioma or glioblastoma multiforme. The olfactory neuroblastomas detected in these vinyl chloride I exposed rats are apparently identical to the neuroblastomas reported by Maltoni in 1975,'*' and again in 1977.^ In 1975, Maltoni reported at the 1 New York Academy of Sciences Symposium on the toxicity of vinyl chloride- 1 *Tarcinogenicity Bioassays of Vinyl Chloride: Current Results, Maltoni, I C. and Lefemine, G., Annual New York Academy of Science, Vol . 246 ( 1975), 195-218. 2 Vinyl Chloride Carcinogenicity: An Experimental Model for Carcinogenesis 1 Studies, Maltoni, C., Origins of Human Cancer, Cold Spring Harbor Conferences on Cell Proliferation, Vol 4, 1977. DTH 000118169 I -7- 1 EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. 1 poly vinyl chloride. The results of his BT1 experiment revealed seven 1 neuroblastomas in rats exposed to 10,000 ppm of vinyl chloride, three 1 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 1 Spring Harbor Conference on Cell Proliferation, he again reported the results of his BT1 experiment in addition to the results of his BT3 and 1 BT7 experiments where neuroblastomas were induced in rats exposed to i 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 female 1 rat confirms the findings of Maltoni of an oncogenic effect on the rat brain from vinyl chloride exposure. 1 The shortcomings of this study have been previously documented. I Regardless of these, the rarity of this neurological neoplasm coupled with the fact that it has only been reported in rats exposed to known I carcinogens indicates a relationship between their presence in this study and exposure to vinyl chloride. As mentioned previously, the finding of I these neoplasms confirms previously reported results from vinyl chloride I exposures by Maltoni. Since the exposure conditions in this study have not been confirmed, the levels of vinyl chloride inducing these neoplasms 1 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 J these neoplasms in IBT Study 663-03222,resulting from vinyl chloride I exposure, cannot be determined. I ! WMB/sfh Pathologist -8- DTH 000118170 E PL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. IBT STUDY 663-03222 TABLE I SUMMARY INCIDENCE TABLES DTH 000118171 fl IBT Study 663-03222 Vinyl Chloride I Male Mice I BRAINS (NO. EXAMINED) a SUMMARY INCIDENCE TABLE Untreated Control (5) T1 (13) ... --....... T2 (3). T3 (12) a .............-- c -- -- a ........ ......... ------------ -- ---- -- ------- -- -- a-- a ------ ------------------------------------------------ ------- ---- - -------- --- -- ------ ,-------- a-- -- m ------- ------ -- m-- -- a E P I. I x|)crimtMiUil l\illiol<>ny I .\bnr.Moi lev Int 9 >TH 0liai72 IBT Study 663-03222 Vinyl Chloride Female Mice BRAINS (NO. EXAMINED) SUMMARY INCIDENCE TABLE Untreated Control (4) T1 (8) T2 T3 (7) , (14) ----- ---------- -- ---- -- -- , -- ---- -- -- ---- ---------- -.... ----------... -- -- __ . . . -- ' -- - ---------- ... ------------- EPl Experimental Pathology I ahoi atones, Im 10 DTH 000118173 I IBT Study 663-03222 Vinyl Chloride Male Hamsters BRAINS (NO. EXAMINED) Focal Encephalitis < SUMMARY INCIDENCE TABLE Untreated Control (4) T1 (8) -- T2 (14) T3 (13) 1 ------- ----------- ------ ----------- -------- --- -- _________ -- -...... ......... .......... ........ -- -------- -- ------ -- -- ------ ---------- ------------ --- -- -- --------------------- ------------------- -------------- --- __ _________ -- --------- -------- --.....- - -... ( xpprimental Palliolo^v I <ibor,iloi ii'\ ln< DTH 000118174 I IBT Study 663-03222 Vinyl Chloride I Female Hamsters I BRAINS (NO. EXAMINED) I 1 i I I I I 1 I I J SUMMARY INCIDENCE TABLE Untreated Control (31 T1 (4) T2 (10) T3 (6) ----------- --- ------------------ ----- ---------- -- -- -------------- -- -- -- -- -- -- -------------- -- -- -- -- -------- -------- -- ----- --------- -- -- i .Ii Txiwrimenlat I'.Hholo^y I abor.itoi ics, 111< DTH 000118175 IBT Study 663-03222 Vinyl Chloride Male Rats SUMMARY INCIDENCE TABLE V 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 -- --------- __----- ------------- T3 (23) 1 5 "1 EPL F xpcrimcntcil Palhoi -- -- -- ---------------- ............ -- -- -- -- - -.......... .. --- --------------- -- -- DTH 000118176 X 0-->f 0 "0 >H 1 o rO O < z o o m z o m --i > ro r-m [ l I I I I I CO no no ro n>Q. COi o ro --*s ccnn -- o 2 =r o. n> o <-c+ Q)--j *<C--j co c-o--li < 3 o f**3Dn -- DTH 0 1301 1308 1368 1382 1386 1390 1396 ANIMAL NUMBER X X X X X X X -- BRAIN ---- -- -- -- ---- -- -- -- -- 1' ---- -- -- -- --- -- -- -- -- -- I no ----------------------------------------------------------------------- :------------- Experimental Pathology Laboratories, Inc. Key: P = Present 1 = Minimal 5 = Severe'H ign N = No Section 2 = Slight I = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High I IBT Study 663-03222 Vinyl Chloride 1 Female Rats I- BRAINS (NO. EXAMINED) I Meningoencephalitis Astrocytoma * Olfactory Neuroblastoma Pituitary Carcinoma I I I I 1 k k SUMMARY INCIDENCE TABLE Untreated Control T1 T2 (30) (13) ----------------- (IDl l ------------- --- 1____ -- -------------- T3 (17) 1 T4 (12) 1 ---- -- -- ------------- --- -- ----------- ---- --............ - -- ---------- ------ -- .. ------------- ----------------- -- -- ---------------- -- -- k k k ---- -- --------- --- - -- --------------- I xpcrimcnt.il PdtholoHV I .iboraloru's, In< DTH 000118178 EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. IBT STUDY 663-03222 TABLE II HIST0PATH0L0GY INCIDENCE TABLES DTH 000118179 m -o 9 * * * I I C/--oI3 I T3 > --X( I r~O O -<O I z g om I z o m >H I rC~mD 9 i i I R I V -------------------------- !--------------------------------------- ------------------ Experimental Pathology Laboratories, Inc Key: P = Present 1 = Minimal, 5 = Severe/High N = No Section i2 = Slight = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High i * I I I C/--|5 ft O o > HI Xo r~ O O ft -< z o oI m z o m --i I > 05 rm~ t K * --* -3j. -CDH I m << --- on IS o rct o rr cl (V --L< OI -s cr> cr> cl to n> t o to no ro * no DTH 000118181 ANIMAL NUMBER X 1009 X 1012* X 1013 X 1024 X 1025 X 1030 X 1031 X .1049 X _1052_ X 1065 X 1066 X 1082 X 1084 BRAIN -- -- -- --- -- -- -- ' -- ----- ----T * 00 KA CD X ro CL I ICT) ------------------------------------------------------ -------------;---------------- Experimental Pathology Laboratories, Inc. Key: P = Present 1 = Minimal 5 = Severe/High N = No Section i2 = S light = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe.'High X m "O a3>: CD <3< CO -*2 --' O CcCtO O ZJ- Q. fO -- O n CTi CT> nC>L iCOO CO ro PO ro ----------------------------------------------------------------------------- -- -- Experimental Pathology Laboratories, Inc Key: P = Present 1 = Minimal. 5 = Severe/High N = No Section 2 = Slight I = incom plete Section A = Autolysis 3 = Moderate X = N ot Remarkable 4 = M oderately Severe/High n --Io "0 -->I oX r O Q i < z g o i m z 0118182o m H > m -0 1 * * x iHn TJO >H I X o r O oI -< o o1 m z O m H > 03 rm~ I I 1 1 t ------------ Experimental Pathology Laboratories, Inc Key: P = Present 1 = Minimal. 5 = Severe/High N = No Section 2 = Slight j = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High m -o i t t K K ft ft X GHOo I no -->I I Xo r OV -<o z o om I z o m --i I > 03 rm I I I I I I I ------------------------ E x p e r im e n ta l Pathology Laboratories, Inc. Key P *= P resent 1 = Minimal. 5 = Severe/High N = No Section 2 = Slight i = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High I r \ 1 1 1 1 -------------------------------------------------------------------- Experimental Pathology Laboratories, Inc. Key: P = Present 1 = Minimal 5 = Severe/High N = No Section 2 = Slight 1 = incom plete Section A = Autolysis 3 = Moderate X = N ot Remarkable 4 = M oderately Severe/High -- _ -----Experimental Pathology Laboratories. Inc. Key: P = Present 1 = Minimal 5 = Severe/High BRAIN n~>n <--o--o> O--3l< r=--<> -I 00 ro o cr-t- 3: 3--"-rC<l oo (D T Ol -I. Ol rCoL 0i0 onntnoooo I V i i ANIMAL NUMBER ---- X 1508 X 1516 -- -- -- ...... -- -- -- -- -- -- -- ---- X _1519_ X 15.22 X 1525 X 1526 lX 1527 i X 1534 to no ni o X 1545 X 1556 X 1573A -- X 1578 X 1592 X 1599 i i X iCO --I O i>H X O r~ O iQ -< z g iom oz m --i > 03 mr~ f i i f - N = No Section 2 = Slight i = incom plete section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High -- ---- -- -- -- ---- ---- -- DTH 000118186 r DTH I i I I I I ---- I I I x 0H)o I o -->i I X O r~ O QI < O mO I z o m HV > CD rm- f I CD -j. CD --' Z3 -H ro *<-- m I (znDO rCt i/>3 r--r *-o<. rt O ft) -s I l/ii (-o*D. IcOwn CO ro ro I ro t o r3t O 3o rl) CL Ct c3z "nrS>t CD 1698 1621 1608 1612 ANIMAL NUMBER X X X X BRAIN Focal E ncephalitis ---- -- -- ---- -- --- -- ---- ---- -- --- -- ---- ---- -- -- ------ -- -- ---- -- ---- -- -- --_ f IUNJ> ------ -- -- -- --------------------------------------------------------------------- Experimental Pathology Laboratories, Inc Key: P = Present 1 = Minimal 5 = SevereiHigh N = No Section 2 = Slight [ = incomplete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High I f 3 WH l T30 -->I r 1o r~ O <o j z o om i z o mr H > cn r~m i r i i i i R 3: =: -- Dl -> 03 n>--<3--1 re -- ir/*i (DOC 3 3-0. IS) --' nri>- -jO cn "S -- Oh cn Q. CO rb i O CO ro rroo - DTH I 1801 1839 1863 1870 1879 1881 1884 1895 ANIMAL NUMBER -- -- -- -- --- -- -- X X X X X X X X BRAIN Focal E ncephalitis -- ---- ---- ---- -- ---- ------ -- ---- -- ---- -- -- -- -- -- -- -- -- -- ---- -- ---- ---- ---- -- -- -- -iinP>o -- -- -- ------------------------------------------- -------------;---------------Experimental Pathology Laboratories, Inc. Key: P = Present 1 = Minimal. 5 = Severe/High N = No Section 2 = Slight I = incom plete Section . A = Autolysis 3 = Moderate X = Not Remarkable 4 = Moderately Severe'High I T. 0-I3 I 0 TJ ->H R 1o ro~ CD I -< Z O om I zo m HI > CD rm~ r i i i i i i m I * I co -- Z3 --I fO <<--' 00 3Z rt QJ O C 3 ja i/i --*<< rt O ro -ij* ccrn i/i n>a ico coo ro ro ro ANIMAL NUMBER X 2016 X 2033 X 2034 X 2037 X 2054 X 2068 X 2073 X 2076 ro X 2082 X 2084 X 2092 X .._2Q23_ X 2099 X 2100 DTH BRAIN Focal E ncephalitis -- ---- -- -- ---- -- .... -- ------ -- -- -- -- --- -- -- -- -- --- -- -- -- -- -- -- --_ -- -- ---- m 9 I ro i ----------- -- ---------------------------------------------------------------------Experimental Pathology Laboratories, Inc Key: P = Present i = Minimal. 5 = Severe/High N = No Section 2 = Slight i = incomplete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe,'High k DDTTIH 000118190 k --k k * * * X -COHo k 13 >H k Xo r O o z o om k zo m --i k > CD r~ m k k I k k PO ro ro fD icOo co Cl U) rO)f OT O) -5 cn 3 IT CL on -- rCciO -- o 0J -- CD fD--'3 --I frt*c 2208 2222 2226 2227 2237 2244 2259 2260 2261_ 2273 2275 2277 2295 ANIMAL NUMBER CO X X X > X X --X X X X X BRAIN Focal E ncephalitis ---- -- -- -- ---- -- ---- --- -- ---- -- -- -- -- -- I PO l ---------------------------------------------------------------- ;--------------- Experimental Pathology Laboratories, Inc Key: P = Present 1 = Minimal. 5 = Severe/High N = No Section 2j = Slight = incomplete Section A = Aulolysis 3 = Moderate X = Not Remarkable 4 = Moderately Severe/High H1STOPATHOLOGY INCIDENCE TABLE CM CM CM COO i/> I CD S- ro -o cd VO -r- +-> VO V- CO >> --o e03 U3 OI 4-> <D </) r-->C) r--0e3 CO (D -- > Lt- ft. UJ Key P = Present ------------------------------------------------------------------------------------------------------------------------------------- 1 = M inim al. Experimental Pathology Laboratories, In c 5 = Severe. High N = No Section i2 = Slight = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High m "C X C--1O "0O >H oX r O CD -< Zo mo z o m --I > CD r m -------------------------------------------------------------------- Experimental Pathology Laboratories, Inc -Key: P Present 1 = Minimal. 5 = Severe/High N = No Section 2 = Slight j = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe'H tgh I I I I I I I X C--IOo I *o >H I X ro O <a I z o mo I zo m H* > 03 rm n I I n n j -- -- ---------------------------------------------------------------------------- Experimental Pathology Laboratories, Inc. Key: P = Present 1 = Minimal 5 = Severe/High N = No Section 2 = Slight i incomplete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High I I I V I I V X cHno I 13 >H I Xo r O CD 1 -< z o o zmo m >I 03 rm R R I I R R I ' ----------- ----------------------------------------------------- ;---------------- Experimental Pathology Laboratories, Inc. Key: P = Present 1 = Minimal. 5 = Severe/High N = No Section 2 = Slight I = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = M oderately Severe/High i I I C/H5 i 0 -0 >H 1o r~ O ot -< z g o m z o m4 H > CD rm~ 1 4 4 4 4 4 4 i I I I 4 Ol -> CO --' =5 --I ro <<--> co 73 rt-c CU o r+ 33" O.w o '*< -s cn -i. cn rcq. ico o CO ro ho no DTH 00 ____ L i (_o 97 X 84 X 80 X 73 X 69 X 64 X 57 -5O O c3+ O Q_ ro 55 X 54 X 51 r+ EU c+ -nJ> 43 X 41 c3: X 39 X 28 X 27 X 26 CO 19 X 15 ANIMAL NUMBER X X BRAIN M eningoencephalitis Suppurative M e n in g itis E n ce p h a lo m a la cia Focal E n ce p h a litis O lfa c to ry Neuroblastoma G lioblastom a M u lti forme m -o i CO --------------------------------------------------------------------- Experimental Pathology Laboratories, Inc -Key: P P resent 1 = Minimal. 5 = Severe/High N = No Section 2 = Slight j = incom plete Section A = Autolysis 3 = Moderate "X = N ot Rem arkable 4 M oderately SevererHigh k k Xk C--IO O v >H k r~Xo Ok o < z oI mo zo mR H > DO rm~ V I R R R R R k 9 K k k CO no no no nC>L iCO o cn cn --is. o 30 c+ iQ>nrtj--OIiC<a 0--3I l/> nOJ>--' *=_i<3--. 3: < -- ANIMAL NUMBER X 205 206 X 207 X 210 X 212 X 228 X 234 X 256 X 264 X 268 X 269 X 274 X 279 X 286 X 299 ~ DTH _______________1 CO BRAIN M eningoencephalitis Suppurative M eningitis E n ce p h a lo m a la cia Focal E ncephalitis O lfa c to ry Neuroblastoma G lioblastom a M ultiform e -- -- -- -- -- I CO no -------------------------------------------------------------------- Experimental Pathology Laboratories, Inc Key: P = Present 1 = Minimal. S = Severe/High N = No Section 2 = Slight I = Incomplete Section A = Autolysis 3 =* M oderate X = Not Remarkable 4 = M oderately Severe/High I * X C--IO * "0o >H X ro O* o -< z o mD I z o mI H > CD r mI I V i 1 .if I i I ro I ro o3--*xa I DJ--' -3j. C--ID I (V X--1 GO 20 rt DJ O C I co <rc>l 1coo ccnn -5 -i. rt 00 DTH C X 491 X 489 X 484 X 475 X 471 X 469 X 464 456 459* X 453 X 452 X 445 X 440 X 436 435 X 433 X 430 X 428 X 426 X 418 X 413 412 X 404 ANIMAL NUMBER X X CO BRAIN M eningoencephalitis Suppurative M e n in g itis E n ce p h a lo m a la cia Focal E ncephalitis O lfa c to ry Neuroblastoma G lioblastom a M u lti forme -O oono fPX (x> Q_ 1 CO CO -------------------------------------------------------------- -------------------- Experimental Pathology Laboratories, Inc. Key: P = Present 1 = Minimal 5 = Severe/High N = No Section ' 2 = Slight 1 = incom plete Section A = Autolysis 3 = Moderate X = N ot Remarkable 4 = M oderately Severe/High X V)oH *0 >H Xo r O G) -< zo o m z or m -1 > 0m3r r r i i i i i r o#--* -3J. C--ID CD *< --* CO TV ri ft* o c r+ 3" a to O--` *c -s cn - cn CL CO ro i o cnoo ro ro DTH 00C ANIMAL NUMBER 601 609 616 618 625 632 639 641 644 649 651 655 663 664 667 668 671 672 676 677 682 687 694 X X X X X X X X X X X X X X X X X --- -- -- brain M eningoencephalitis Suppurative M e n in g itis E n ce p h a lo m a la cia Focal E ncephalitis O lfa c to ry Neuroblastoma G lioblastom a M ultiform e ro TD "O "O ~o .-- -- ..... - ....... .... -- i CO ----------------------------------------------------- Experimental Pathology Laboratories. Inc. Key: P = Present 1 = Minimal. 5 = Severe/High N = No Section 2 = Slight i = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 M oderately Severe/High 196 (| 197 r DTH 000118199 184 9 194 159 160 i 166 174 9 176 178 9 180 n * in cnH o0 >H i 1 o r Oi o -< z o oi m z o mn H > CD r~m n i * n n * ro - co 3 3 -H << --' --'CO fD o rc:+ toio =--r*<c<l r+ O (/> "--5 0C^1h Cl Co fD IO rC\>O ro ro 146 OO 149 13 143 frQP+. "5 C0)D 154 142 138 137 136 130 125 124 117 116 113 106 102 101 ANIMAL NUMBER X X X X X X X X X X X X X X X X X X X X X X X X X X X BRAIN M eningoencephalitis A stro cyto m a O lfa c to ry Neuroblastoma P itu ita r y Carcinoma -- *o ---- ---- ---- -- ---- -- ------ m -g i co cni Key: P = Present ------------------------------------------------------------------------------------------------------------------------------------- 1 = M inim al. Experimental Pathology Laboratories, Inc 5 = Severe/High N = No Section 2 = Slight I = incom plete Section A = Autolysis 3 = Moderate X = Not Remarkable 4 = Moderately Severe/High n Xn 0H5 o TJ -->I X o r~ o -<o 1 z On mo z o m H1 > 05 r~m 1 1 * n n n * * * CO ro rroo COo 1 rDo. CO -S 0O'1! c* o --J --i CO <P o c+c 70 3" Q- <T> CO 3 3-4 c3o+o 3 c rp Cl fp CL oo 3 -co1+ CU 3 rp ~ DTH I 200 199 ANIMAL NUMBER X X BRAIN M eningoencephalitis A strocytom a O lfa c to ry Neuroblastoma P itu ita r y Carcinoma -- ---- ---- -- -- ---- "-- -- -- --- ---- ---- -- -- -- -- I U) cr\ I ------------------------------------ ;------------------------------------------------- E x p e rim e n ta l Pathology Laboratories. Inc Key: P = Present 1 = Minimal 5 = Severe/High N = No Section 2 = Slight 1 = incomplete Section A = Autolysis 3 = Moderate X = N ot Remarkable 4 = M oderately Severe/High ft ft ft ft ft ft ft ft ft ft ft --Iw ft ft ft i ft ft ft ft rm~ 03 H > m zo o m Zo Q < O r~ H X o > t) O i CO ro fr\\o> O- co fD IO Ch l/> -5 cr rf O po zr o_ oc rt> rt "H oo 0--3>- <<3-- a> -* 03 & DTH 00 302 303 326 331 335 342 349 363 369 376 381 382 397 ANIMAL NUMBER X X X X X X X X X X X X X BRAIN M eningoencephalitis A stro cyto m a O lfa c to ry Neuroblastoma P itu ita r y Carcinoma -- ICO X I -------------------------------------- ------------------------------ ;---------------- Experimental Pathology Laboratories, Inc. Key: P = Present 1 = Minimal 5 = Severe/High N = No Section 2 = Slight. I = incomplete Section -A = Autolysis 3 Moderate X = Not Remarkable 4 = M oderately Severe/High i I DTH 000118202 [ i_______________i___ i i i I V XI V> H o -o >I h Xo r Oi O -< z gi mo z o mI H > COr mi I I I k l ro no ro co o n> i Qu CO - cn cn rt O t/> -j "TJ < H-H n> -* co 3 3 --l & << --' -- co fD rt* OC TO ZT CL. 0> -- animal NUMBER 511 520 522 524 550 557 --( no 566 569 570 594 599 X X X X X X X X X "O BRAIN M e n in g o e n c e p h a litis Astrocytoma O lfa c to ry Neuroblastoma P itu ita ry Carcinoma ---- -- ---- -- -- T - ---------------------------- Experimental Pathology Laboratories, Inc. 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 ------------------------------------------------------------ -- :--------------- Experimental Pathology Laboratories, Inc. 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 ---------------------------------------------------------------- ;--------------- Experimental Pathology Laboratories, Inc. * I <ZH> 0 TJ > H 1 o r O a -< Z O o m zo m H > 0r3 m 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