Document 8RM7e1eRgnbnxE5n4xrVJmg9Z

Report On Hlstopathologlcel re-evaluation of livers from rets treated with AROCLOR NEV 0111*6 710398 WATER PCB-SD0000034283 I -1- SUMHARY A rcvlev of slides from rats fed chronically with three doses of AROCLOR 1242, 1254, and 1260 for different time Intervals shoved a dose-dependent hopatotoxic effect, characterised by degenerative and regenerative processes. Ulth one exception, all lesions were considered non-neoplastlc. Structures similar to cholangiocarclnomas and hepatoses were found in one rat. Hovever, the possibility of metastaees of a carcinoma into the liver has been also considered. The results are discussed and suggestions for further studies have been stade. . NEV 011147 710399 WATER PCB-SD0000034284 INTRODUCTION A total of 549 slides, submitted fot consultation from Konsanto Company, were said to represent liver tissues from 540 albino rats continuously fed diets containing 1 (T-l), 10 (T-ll), or 100 (T-lll) ppm AROCLOR 1242 (A group-157 liver sections), 1254 (B group-176 liver sections) and 1260 (C group-211 liver sections), and sacrificed at Intervals of 3,8,14, and 24 months. A study with AROCLOR 1260 In albino rats revealed no carcinogenic effects. However, Investigators conducted another experiment with AROCLOR 1260 and reported induction of hepatocellular carcinoma in 26 of 184 experlmentals, while the ration in controls was 1 out of 173 In addition in the same study 146 of 184 experimental rats showed neoplastic nodules. Proa this study. Dr. Kimbrough and other NCI consultants (Dr. Robert Squire and Morton Levitt) concluded that AROCLOR 1260 had a hepatocarcinogenic effect when fed in the diet of female Sherman strain rats. Histopathologic evaluation of additional liver sections from rats of a 2-year chronic oral toxicity study of AROCLOR 1242, 1254 and 1260 by Dr. Cordon of Industrial BIO-TEST Laboratories Inc. indicated that all 3 lots of AROCLOR were slightly tumorlgcnlc at levels of 100 ppm, when fed continuously In the diet for 2 years. Additional material from the latter experiments has been submitted for re-evaluation as to whether there are apparent reasons for the varying rosults obtained by the two laboratories and auggestlons regarding possible additional animal testing. MATERIALS AND METHODS For the most part, one slide por rat was submitted, and there were 1-3 slices of liver tlssuos per slide. However, in the case of 4 rats, there were 2 slides each. Therefore in the final accounting, the number of liver slides exceeded the number of animals by four. Tlssuos wero stained with hematoxylin NEV 011146 710400 WATER PCB-SD0000034285 and in, pltccd in conventional plastic slide boxes for transport, end were of sufficient quality for evaluation. Some slides were not adequately identified, with regard to sex or treatment groups. In some cases, tissues other than of the liver (l.e., of the mammary glands or pancreas) were found in a few slides, and these were not subjected to histologic evaluation. Four of the liver slldea could not be evaluated because of: (1) advanced autolyals in 2 cases (A2230F and A^272H) and (2) severe infiltration by malignant lymphoma cells in 2 other tissues(CjS69M, C^S89M). The slides were evaluated in the same sequence as they were found in the plastic slide boxes. However, the final analysis was performed according to the submitted information with regard to the groups of rats per each dose level and the data wak susmarlzed in tables. The following criteria were used in the evaluation process: Vacuolization: Small or lsrge vacuolar changes in the hepatocytes (Fig, 1) indicative of fatty metaaiorphosls. Focal acidophilic alteration; Focal degeneration of the hepatocytes characterized by intense eoslnophilia of cytoplasm and pyknosla of nuclei (Fig. 2). Single acidophilic alteration: Scattered eosinophilic alteration of hepatocytes (Fig. 3). Focal granular alteration: Croup of hepatocytes with granular or vacuolar foamy appearance (Figs. A and 5). Single granular alteration: The same cell alteration as above, but in scattered areas rather than in groups. Forlnucloar halo: Vacuolar alteration of cytoplasm in areas naar the nuclei. This alteration was distinguishable from fatty metamor phosis, and seams to indicate the location of glycogen, which was extracted by processing (Fig. 6). Such a change ' was often associated with NEV 01HA9 710401 WATER PCB-SD0000034286 eosinophilic homogenisation of the cytoplasm around the nuclei of the hepato- cytes (Fig. 7) and seems to represent the cell-bounded glycogen. _______ Single cell necrosis: Necrosis snd degeneration of Individual cells found throughout the tissue or as group cell necrosis of a certain area. This alteration was found In 2 forms: a lytic font (Fig. 8), Indicative of acute toxic effect with or without minimal Inflammatory reaction and coagulatlve fora (coagulatlve necrosis) (Fig. 9) associated with epithelioid cell reaction (see below). Cell enlargement: Enlargement of the hepatocytes up to 8-fold of their normal size in localised form as a ao-called "hyperplsstlc nodule" (Fig. 10) or in a more or less diffuse form (Fig. 11; aee also A^* 31 IF, 287F, 291F, 982M, 983M, BjX: 59F, 60F, B3: 443F, 445F, 484M, 491M, 499H, 507F, 522F, 524F, 527F, S41F, Extra IF. Extra 4F, 329F, Extra IF, 2F, 3F). The enlarged cells showed usually eosinophilic, vacuolar or granular alterations (Figs. 12 and 13) and were often associated with bile duct formation (transformation) (Figs. 14 and 15), or with fibrosis (Fig. 16). Ductunl proliferation: Formation of new ducts or proliferation of principal ducts (Figs. 1, 12-16), sometimes associated with pcrlductnl fthrow Is in the form of connective tissue manchettes around . the individual bile ducts. In contrast to cholannlofthroats. which was characterised by both bile duct proliferation and fibrosis (Fig. 17). Stern cell proliferation: Activation or proliferation of AtupWer cells in localised area. Extramedullary hcmopooltlc foci wars NEV 011I5U 710402 WATER PCB-SD0000034287 5- lncludcd In this category. Epithelioid cell granuloma: Focal Inflammation, often with coagulatlve cell necrosis (Fig. 19). These lesions were often found In areas close eo periportal triads or central veins (Figs. 18 - 20). In one case, this Inflammatory reaction was present around a foreign body (rig. 21), which probably represents a parasite. In another section, structures reminiscent of fungeal hyphen (asperglllus fumigatus?) were seen (Fig. 22). Periportal inflammation! This Inflammation occurred in varying degrees of severity, and often in cases wleh epithelioid cell granulomas (Fig. 18). Lymph congestion: A peculiar lesion, characterised by formation of spaces lined with endothelial cells and filled with amorphous or grsnular material or erythrocytes (Fig. 23-25). Theta occurred in livers, without marked alteration of hepatocytes (Fig. 23), In livers with fatty meeamorphosls (Fig. 24), or in areas wleh enlarged hepatocytes (Fig. 25). This alteration mlghe correspond to fatey cysts or pellosls, as described by other investigators. Crystal deposition? Light-polarising material in ehe sinusoids, which probably represent fatey crystals. Other lesions: In {.animals, marked proliferation and cyselc distention of tin ducts (adenomatous ductal proliferation; cystic proliferation of bile ducts) wars aaan (Fig. 26). Tha non-ncoplantic character of these lesions was evident by the uniform cytologic appearance of calls and identification of normal hepatocytes between the ducts, Indicating a NEV 011151 710403 WATER PCB-SD0000034288 glandular origin from cha principal bile ducea. in one allde (B^: 527F), atypical glanda Invading liver parenchyma were found. This lesion seems to represent a metastatic tumor (probably a mammary gland carcinoma of the same animal from which his tumor was submitted), rather than a cholangiocarcinoma. In the same animal localised cellular enlarge ments of hepntocytce were found; the cells showed a marked pleomorphlsm, and occasionally contained bile pigment (Fig. 30). There was no ductal proliferation and no periportal trald in this area, but there were hemopoietic foci. RESULTS; The hlstocytologlc findings for individual allde(s) are listed on pages 13-37 and the suosiary of lesions, according to doae levels on pages 38-41 The grouping and subgrouping ms based on che report of Kerch 24, 1975, by Industrial Bio-Teat Laboratories. DISCUSSION: The pathological changes in the livers of both experimental animals and controls varied in quontltstivc but not qualitative aspects. As the dose level Increased, the lesions progressed In severity, Indicating AROCLOR'S dose-dependent toxic effect. No marked differences could be found among rate treated with 3 dlfforent lots of AROCLOR. The epithelioid cell granulomas often associated with cosgulatlve cell necrosis nnd periportal round cell infiltration soon to reflect an endogenous disease, such as parasitic or fungcal infestation (as found in 2 animals) In this colony of rats. Tho same might be true for the focal bile duct proliferation, periductal fibrosis, nnd cholanglofibrosis. The apparently higher incidence of this inflasuntory condition in the experimental animals might be sought as an NV 011152 710404 WATER PCB-SD0000034289 7 enhancing effect of the coatpound in the development and course of the disease. However, since their incidence in 24-month-old control rsts was even higher \ thsn in corresponding experimentsis, such an iatrogenic effect of the compound should be ruled out. It should be also pointeJ out that much liver alteration in animals, aa veil as in man, is distributed unevenly in the parenchyma and therefore might not be detected in a single section. Examination and comparison of several different liver aectione from the same ret will verify this fact. Besides their inflammatory reaction, suny other liver lesions found seem unrelated to drugs, and represent, rather, spontaneous age-related alterations, since they appeared in a higher Incidence in rats kept for 24 months. However, the more pronounced character of vacuolicatlon and degenerative and regenerative changes is attributed to the toxic effect of the compound. The most frequent finding in rats treated with 100 ppm of compound was cell enlargement, mostly in localised areas which resembled ao-called "hyperplastic nodules". Ve prefer the term "cell enlargement" to cell hypertrophy, alnce the enlargement of the hepstocytea in the sumbltted material is obviously due to degenerative effect(s) resulting in vacuolization, granulation and hydropic changes. The term hypertrophy should be reserved for describing regenerating or activated cells. The focal response of liver parenchyma to infectious or toxic agents la a known characteristic of this organ, and is in most cases, unspecific. Therefore, focal cell alterations do not always represent a "hyperplastic nodule" or premalignant and malignant lesions. The presence of many necrotic cells, sometime in form of piecemeal necrosis in areas of "hyperplastic nodules" definitely indicates their degenerative changes, associated with acme regenerative process. The compression of surrounding tissue, due to focal enlargement of cells (which were sometimes 8 times larger than normal liver cells), is self-explanatory apd is in no way indicative of malignant growth. A special staining would be of help in distinguishing non-neoplnstic from neoplastic lesions, which usually destroy the normal struc tures, such as the reticular network. In our opinion, liver lesions should be NEV 011153 710405 WATER PCB-SD0000034290 -8- consldered non-neoplastic, unless otherwise proven. Cytologic criteria, such ss cellular pleomorphlsm and nuclear atypla, are uncharacteristic features and could be seen in any damaged cell, particular in those of organs with s tendency to rapidly regenerate. The criteria of the non-neoplaatlc lesions in the submitted slides can be summarized as follows: 1. No evidence of destruction 2. In several cases, cell enlargement was not limited to a certain area, but had largely or completely involved the entire liver lobe. 3. In many of the lesions, regular liver structures were found, such as periportal triads, central vlens, stlnusoids as well as bile ducts often showing a tendency to proliferate. These criteria are in favor of the benign character of these lesions (see Farber: Methods in cshcer Research 7, 345, 1973). Since, as mentioned before, the liver lesions might show highly lrregulsr distribution patters, the absence of some regular structurea within the pathologic ares* is anticipated, and the examination of step section(s) of such tissues pertinent. 4. The cells in an area encompassing enlarged cella (the so-called "hyperplastic nodules") show the same cytologic alteration, as In surrounding tissue or In areas remote from It. This is in contrsst to the effect of well-known hepatogenic carcinogens, such as aflatoxln and ethlonln in which following treatment, the tissue surrounding the hyperplastic nodules is little different from that of normal liver (Fnrber, Ibid.). In only one of the present cases were there cytologic alterations which could Justify a diagnosia of malignancy. However, even In that lesion regular sinusoids with hempoeltlc f$ci (which arc very unusual features for a hepatoma) were present, so that the malignant character of the lesion is questionable. It seems possible that the atypical cytologic alteration of this lesion Is due to a response to a tumor metastasis, which was found In its borderline. The latter liver lesion could bo. interpreted as a cholangiocarclnoma. However, on comparing the 710406 histologic pattern of this tumor with the mammary carcinoma from the eame **EV 01115 WATER PCB-SD0000034291 rat, It becomes obvious that the liver leaion is a aerostatic lesion, rather than a primary neoplasm. Nevertheless, interpretation of these particular lesions is difficult and further study Is required. Other bile duct lesions, which we called adenomatous lesions, have been described and observed In many species and were considered cystic hyperplsia of the bile duct. The non-neoplastic character of these alterations is evident by their uniform histocytologlc patterns and by Che presence of normal liver cells between the ducts, indicating alteration of prs-existing ducts. - The question as to whether or not these lesions represent a prenalignant alteration cannot be answered, using the present material, and further discussion could only be speculative. Since most liver carcinogens induce tumors during the 8-12 months from the beginning of the experiment, it seams doubtful that AROCLOR will cause neoplasms at a time later than 24 months, which ia virtually the terminal age of suny rat atrains. However, additional study is needed to clarify the problem, particularly because different opinions exist about the nature of the liver lesions induced by AROCLOR. We might recommend the following: 1. Step-sectioning of tha present material and special straining of some of the tissues. If this procedure would not clarify the situation, a new experiment should be started (aee below). 2. The new set of experiments should compare findings in the same colony with those of other rat colonies, since apparently some strains of rats are unusually sensitive to certain compounds (Farber, Ibid.). For example the rats used in this study seemed to have an endogenous liver disease, which might influence the effect of the AROCI.OR. The experiment should also include additional groups with different feeding periods - - (l.e.. Including rest periods), as proposed by Tccbor and Becker. (Cancer Res. 31,, 1, 1971). 3. The use of special stains under certain experimental conditions might also deliver additional information (Epstein cjt el: Cancer Res. 27, 1702, 1967). NEV 011155 710407 WATER PCB-SD0000034292 Legend: 10- Fig. 1: Vacuolization of hapatocytae and focal bila duct prolIforation: A3-275M, 250x. Fig. 2: Focal eoalnophlllc alteration characterized by denae, loselnophlllc cytoplasm and pyknotic nuclei: B1-938F, 230x. Fig. 3: Scattered, ioelnophilic alteration of hcpatocytes: B3-68F, 250x. Fig. 4i Focal granular alteration, aaaoclatod with cell-enlargeoent. Two hepatocytes shoving eosinophilic alteration are seen within the granulated cello. Note atrophy of surrounding liver-tissue, probably due to compression of enlarge cells: Blx-43M, 250x. Fig. 3: Different types of granular alteration of hepatocytes, interspersed with eosinophilic alteration. Tho granulated cells ara often 8 times larger than noreal hepatocytes: A3-271M, 230x. Fig. 6: Perinuclear halo in hepatocytes: Blx-43M, SOOx. Fig. 7: Eosinophilic homogenization of cytoplasm. Use eosinophilic Material probably represents cell-bounded glycogen, which usually will be extracted during histologic procaeslng, giving rise to structures shown in Fig. 6: B3-Extra 2F, 250x. Fig. 8: Lyric form of group cell necrosis. No lnflamiaatory reaction le seen: B1-338M, 2S0x. Fig. 9s Coagulativo group cell necrosis associated with inflammatory reaction: B3-70F, 25Ox. ' Fig. 10: Focal cell enlargement of hcpotocytcs. The slnusoldae structure is still present. Note pale nuclei with enlarged, but uniform nuclei: B1-343H, lOOx. Fig. 11: Diffuse enlargement of hepatocytus with characteristic nuclei and nuclool A portal triad is seen in middle of photo: A3-314F,.lOOx. NEV 011156 710408 WATER PCB-SD0000034293 Fig. 12j Focal cell enlargement with tendency toward bile-duct formation, A3-314F, 250x. Fig. 13: Focal cell enlargement with vacuolic and granular alteration, aa well as bile-duct formation: A3-275M, 250x. Fig. 14: Focal cell enlargement showing proliferation of bile-duct epithelium: B2-60F, 250x. Fig. 13: Glandular aturcturea of hepatocytea within areas of enlarged hepatocytes. Mote apparent pleomorphiaum of the cells; however no atypia is present: B3-Ext.F, 250x. Fig. 16: Fibrosis and proliferation of bile-duct epithelium within area of regenerating and degenerating liver cells: A3-314F, lOOx. Fig. 17: Cholangiofibroaia surrounded by enlarged liver cells showing group cell necrosis (upper left corner): B3-541F, lOOx. Fig. 18: Eplthiellold cell granuloma with cosgulative cell necrosis, adjacent to a periportal tried, showing marked round cell infiltration: B3-70F, 250x. Fig. 19: Epithelioid cell granuloma with a multi-nucleated giant cell. Vascuolar degeneration, cell necrosis and call enlargement are seen in the surrounding tissue. B3-339F, 250x. Fig. 20: Epithelioid cell granuloma with multiple giant-cells in area cloae to central vein ( left lower corner): C2-707F, 250x. Fig. 21: Foreign body probably representing a section of a parasite of the liver associated with cell necrosis and few Inflammatory cells: C2-707F, 230x. Fig. 22: Cysttc degeneration containing structures similar to aapcrglllua fumientus. B3-Extrn 3P, 250x. NEV OlHs7 710409 WATER PCB-SD0000034294 Fig. 23: Cystic degeneration. The cystic spaces are lined endothelial-like cells and are filled with homogenous eosinophilic or granular material. Minimal enlargement of the aourroundlng liver cells: B3-489M. 250x. Fig. 24: Cystic alteration resembling lymphangiectasia in a liver showing severe vacuollsatlon: B3-459H, 250*. Fig. 25: Cystic alteration in area of focal cell enlargement giving rise to papillary structures of the hapatoeytes. Some of these spaces contain erythrocytes: A3-275M, 250*. Fig. 26: Cystic proliferation of bile-ducts (adenomatous bile-duct proliferation) A3-243M, 100*. Fig. 27: High magnification of the same lesion in Fig. 26 showing liver cell groups between proliferated ducts. Mote completely benign appearance of the cells. 250*. Fig. 28: Adenocarcinoma of the liver composed of tall columnar cells, inter spersed with mucous-producing cells. Morphologically similar tumor was found In the masaury glands of the same rat: B3-S27F, 250x. Fig. 29: Area of focal cell enlargement displaying pleomorphlsm of the nuclei. B3-S27, 500*. Fig. 30: Another area of the same lesion showing lntracytoplasmle bile-pigment . (arrow). 500*. * 710410 WATER PCB-SD0000034295 13- Code Sex No acoolisatlon r ir MMMFP FFFr Mm MMMMFF F F F 596 398 399 636 637 638 639 640 676 677 678 679 680 716 717 m. 711 720 .. _+ +, _+ _ + . * _ + . * -------- 3------------, MNT t 736 757 75fl753L Focal acidophilic alteration . Single acidophilic alteration 4 Focal granular alteration 44444 444 Single granular alteration Perinuclear holo Eoalnoph.honogenlzation Single cell necroaia 4. 44 .4 4 ^ 444 4 .44 4 4 4 4_ 44 4 4 44 4 44 4 Croup cell necroaia Cell enlargnent Ductal proliferation Periductal fibroaia Cholangiofibroaia Stern cell proliferation Epithliod.cell granuli < Periportal laflaaution c Lynph congestion +4 44 4 444 4 V<6 710411 WATER PCB-SD0000034296 Code nr Ko ______________________________ 760 Vacuolization '_ Focal acidophilic alteration Single acidophilic alteration + Focal granular alteration Single granular alteration + Perinuclear tolo + Eosinoph.homogenization + Single cell necrosis Group cell necrosis Cell enlargnent _ Ductal proliferation + Periductal fibrosis Cholanglofibrosls Stern cell proliferation Cplthllodocell granulona Periportal inflamation Lymph congestion . 14 C3 FF 796 797 798 F || M M M M M F F F F j|| M IT" M ffl 800 36 37 38 39 40 76 77 78 79 80 1011 1012 1013 1014 101S + + + ++ + + + + + + + + + + + + + + + + + + + + + + ++ + + + ++ ++ 4 + + ++ + + + OOTTTO A3N WATER PCB-SD0000034297 Code Sex Ro -15- rr "i FFF FFllFMMHH F 3 FFFllNMMM MF 1026 1027 1028 1029 1030 1041 1042 1041^045 1056 1057 1058 10*1 1Q71 107? 1073 1Q7S 1086 Vacuol lzat Ion __ _____ .+ _ Focal acidophilic alteration Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear holo + + .+ Eosinoph Jionogenizatlon Single cell necrosis + ++ + ++ + ++ ++ +___ ++ +++ +++ +++ + + ++ ++ + + + + + ++ + + + Croup cell necrosis Cell enlargnent _ Ductal proliferation Periductal fibrosis Cholangiofibrosls Stern cell proliferation Cpithllod .cell granul* Periportal lnflanatlon 4- + + + +++ ++ ++ 4- + + + + k Lymph congestion 710413 WATER PCB-SD0000034298 Code Sex No ' 16* 1' , c3 Pr c0 II F M M M M M F F F F ' C1 n c2. MHMMMF F F F FM . 1087 1088 1089 1090 801 802 803 804 803 816 817 818 819 820 71 72 73 74 75 76 77 78 79 80 81 Vacuolization . .+ Focal acidophilic alteration Single acidophilic alteration 4 4 4 4 4 4 4 4 4 + + 4 4 4 4 4 4 Focal .granular alteration 4 4 4 Single granular alteration Perinuclear holo Eosinoph.homogenization Single cell necrosis 4. 4 . 4 4 + 4. . +. + . 4_ ++4 4 4 4 4 4' 4 4 4 +___4_ 4 _ 4 _+_ 4 _4 _4. 4 4 4 4 4 4 444 444+4 4 + +44++ 44 +44 4 444 Croup cell necrosis Cell enlargment Ductal proliferation Periductal fibrosis +4 Cholangloflbrosis Stern cell proliferation 444 Jpithllod.cell granule Periportal inflanatlon Lymph congestion 4 44 44 4 +. + 4 4 444 44 4 4 + 4 ?9T TTO A3N WATER PCB-SD0000034299 1TOTTT0 A3N MTLCNANT LYMPHOMA Code Sex No -17- "2 II * I MMMMFF F F F FFHM HM M MM F F F FMMHMMFFFFM M M M H ' 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 I 2 3 4 5 6 7 8 9 566 566 591 567 569 Vacuolization ____ + ^ + __ +++ ++++++ I Focal acidophilic alteration Single acidophilic alteration + + + + + + + + + + + + + + + + + + + + + + + + + + + Focal granular alteration Single granular alteration + ++ + + + + + + + ++ ++ + + + + + + + + + + + ++ + + + + + + + + + + + + Perinuclear holo Eosinoph .homogenization Single cell necrosis + + + + + + + + + + + + + + + + + + +*+ + + + + + + . + -* ++ + + + + + + ++ ++ + + + + + + + + + + + + + + + + + ++++ + + + Croup cell necrosis Cell enlargnent Ductal proliferation Periductal fibrosis .Cholangiofibrosls +++ ++ ++ ++ + ++ + + + + + ++ +++ + ++ ++ Stern cell proliferation Epithliod'cell granuloma Periportal inflamation Lymph congestion + > + ' + + + + + + + + + + + + + + + ++++ + +' + +* ++ + + + + +++ + +++ ++ + +++++ ++ + WATER PCB-SD0000034300 -18- Code Sex Vo -1 ,1M M H M H F F F F H F F F F F F F F F F F 572 576 580 588 589 595 601 04 605 582 583 607 608 609 613 621 627 628 631 634 635 606 610 Vacuolization ....... . ! Focal acidophilic alteration |1 + + +Single acidophilic alteration + 1 Focal granular alteration 111 Single granular alteration Perinuclear holo i+ + + + + + ii Eoslnoptv homogenization + ii Single cell necrosis Group cell necrosis + + iiiiiii + + + f + + + ++ + + H- ++ ++ + AA ++ + + ++ + ++ ++ + ++ ++ + + + + + + Cell enlargment _ Ductal proliferation ++ + ++ ++ ++ + + Periductal fibrosis + +H + + + + + Cholangiofibrosls + Stern cell proliferation _Epithllod> cell granuloma Periportal inflanatlon + + + s111 + 11 1 + + + + +* Lymph congestion NEV 011164 WATER PCB-SD0000034301 -19- Code Sex y. 2 MMHMMMMH HM M M M M1 F F P P F pl No______________________________ 620 626 633 655 657 662 667 (.40 641 643 644 645 646 649 651 673 775 Ext.733 765 776 773 780 Vacuolization . _. _ +++++ ++ + + <6 Focal acidophilic alteration Single acidophilic alteration ++ + + Focal granular alteration + Single granular alteration Perinuclear, holo ++ Eosinoph. houogeniration Single cell necrosis + + +++ Group cell necrosis Cell enlargnent + + ++ ++ Ductal proliferation + + + Periductal fibrosis + + + Cholangiofibrosls Stern cell proliferation + + * Jpithliod. cell granulosa < Periportal lnflanatlon o * *-* Lyvph congestion w ++ 710417 WATER PCB-SD0000034302 NEV 011166 k. Code Sex Vo_______________________________ Vacuolization ____________ Focal acidophilic alteration Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear holo ' _______ Eosinoph. hoiogen 1ration_____ SIngle cell necrosis Croup cell necrosis Cell enlargaent '_____________ Ductal proliferation Periductal fibrosis _____ Cholanglofibrosls Stern cell proliferation _ Eplthliod.cell granuloma Periportal inflamatlon Lymph congestion Fibrosis cholanglomatous lesion M F F FF 72 766 767 771 789 + + + ______________________4_ _+ 4 4_4_ 4- 4 4 4 _4_4 4 _4 _4 ________ 4 4. ______________ 4_ 4 4 4 44 44 ______4__4 4 4 4 4 44 4 __ 4 44 44 4 WATER PCB-SD0000034303 Code Sex No -21- rt \H V' MM M M M M 793 Ext. 8 8 11 12 21 23 33 686 L-- F F ' F F F F F F F F F F F F F^ 687 689 685 690 695 697 700 703 707 708 711 712 682 683 691 Vacuolization _ --+ + + _ . . .. + Focal acidophilic alteration . + .+ + + + Single acidophilic alteration ++ + + + + + + Focal granular alteration ++ +++ + Single granular alteration ++ + .+ Perinuclear holo ++ + + +++ - Eoslnoph.homogenization + + Single cell necrosis + + Group cell necrosis Cell enlargaent _ + ++++ ++ + + + + + + + + + + + + + + ++ + + + .+ + + + + + + + Ductal proliferation Periductal fibrosis CholangiofibrosIs + + ++++ + + +++ ++ + + ++ + Stern cell proliferation ++ + + ++ ++ JEplthllod.cell granuloma Periportal Inflaaatlon + + ++ + ++ + + 4- + ++ + - Lymph conges don o 710419 WATER PCB-SD0000034304 -22- Code Sex No Vacuolization r F MM FFFFFFFFFFFFFF HMMMMNFF 702 34 35 Ext. 46 47 49 51 52 56 59 62 63 64 66 70 71 Ext. 116 117 118 119 120 147 156 157 + + ++ ++ Focal acidophilic alteration + Single acidophilic alteration + + + ++ + ++ + ++ ++ + + + + +++ Focal granular alteration + + ++ + Single granular alteration + + ++++ +**'+ + +++ + + + ++ + + Perinuclear holo Eosinoph hoaogenization Single cell necrosis ++ ++ ++ + ++ + + + ++ ++ + + + + + ++ + + + ++++ + + ++ + + + + + ++ + + + ++ ++ Group cell necrosis Cell enlargaent Ductal proliferation Periductal fibrosis Cholangiofibrosis Stern cell proliferation Trr < _Epithliod cell granule Periportal inflaaatlon + + + + + ++ ++++ ++ ++ + + + + + ++ + + + ++ ++++ + ++ + +* + + ++ ++ ++ o Lymph congestion CD 710420 WATER PCB-SD0000034305 Code ' Sex Mo______________________________ Vacuollxat ion _ __ Focal acidophilic alteration Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear holo Eoslnoph.honogenizatlon Single cell necroele Croup cell necroaia Cell enlargnent * Ductal proliferation Periductal fibroaia Cholanglofibrosla Stern cell proliferation Epithliod*cell granulona z Periportal lnflanatlon <n Lymph congestion -23- _____________________ A____ FFPMMMMM 138 159 160 195 196 198 200 Ext --V P P F P P H M H` PFF FF FP 236 237 238 239)260 276 277 279 280 315 317 318 319 320 + ++++ + + + +.+ + + + + ++++++ + ++++++ + + + + .+ + + ++++++ +++ ++++ + ++++++ + *> + + + + + + .+ + +++ ++++ + +++ + + t + +++ + + ++ + . + 4: + + +++ +++ + + ++ + + + ++ ++ + + ++++ + 710421 o WATER PCB-SD0000034306 Code v Sex No Vacuolization _^ Focal acidophilic alteration Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear holo Eosinoph homogenization Single cell necrosis Croup cell necrosis Cell enlargpent ............ Ductal proliferation Periductal fibrosis. Cholangiofibrosis Stern cell proliferation Jpithliod. cell granuloma Periportal inflanation Lymph congestion * Crystal deposition -24- I----? J ? ? ? ? T t t T t MMMM ? F F ---F-- 11 1 1" F 'H M M 832 835 834 846 848 849 864 865 873 878 879 891 893 894 895 906 907 908 909 910 11 12 13- _ 4 _4 4 4 4 4 4 4 .4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 44 4 4 44 4 4 4 4 4 4 4 _4 4 4 4 4 4 4 4 4 4 4 + 4 4 .+ 4 + 4 4 4 4 4 4 4 4 4 444 4_ 4 4 4 444444 4 4 44 44 4 4 4 444 4 4 4 44 44 4 4 4 4 4 44 4 4 .4 4 4 4 4444 + 4 +44 444+ 4 44 4 4 44 44 4 NEV 011170 WATER PCB-SD0000034307 Code ' Sex No_________________________ Vacuolization _ Focal acidophilic alteration Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear holo Eoslnoph* hoaogenizatlon Single cell necrosis Croup cell necrosis Cell enlargnent _ Ductal proliferation Periductal fibrosis Cholangioflbrosls Stern cell proliferation Epithliod. cell granuloaa Periportal inflanation Lynph congestion Crystal deposition -25- ? A. r 1_i ? A. *i-------------- :-- f_____________I_I___ _ a^, ---------------]-a'l. -- r - MMFFFFMMHMM FFFFF?TlMFFFFF??t? 14 IS 16 17 18 19 21 22 23 24 25 26 27 28 29 30 31 32 33 34 36 37 3S 39 *0 85 86 87 101 - + + + + + + + + + + + + + + + + + + -f + + + + +++++ +++ + ++ + + ++ + ++ + + + + + + + + + + + + + ++ ++ ++ + + + + + ++ + +++++ +++ + + + + + + +++++++ + + + + + ++ + ++++ ++ + + + + + + + -f + + + *+ + + *+ + ++ f ++ f ++ ++ + NfcV 0 1 U 7 1 WATER PCB-SD0000034308 26- Code ' Sex No Vacuolization ' _ __ 7 ?t A1 ?. Al . A, 1 t 71 ? 7 P' ? 7 ? ?FFFFFFFF ? 106 112 114 10S 107 109 122 125 127 129 130 138 141 147 151 155 144 131 132 135 139 16! + 4- + Focal acidophilic alteration __ +_ ++ Single acidophilic alteration * _ + + + _+ .. _+ + ' + . -f + + + + + + f + + + Focal granular alteration . + .+.., . . + ++ Single granular alteration . + .. + . -6.. +++ Perinuclear holo __ ___ + + + + . . 'f + + + + + + + + + + f + + + + f + + + f Eosinoph. honogenlzatlon +++++ + f + +++ + Single cell necrosis + ++ + + Croup cell necrosis Cell enlargnent Ductal proliferation Periductal fibrosis Cholangiofibrosls Stern cell proliferation Epithliod.cell granuloma Periportal inflaaation .-- ++ _ . . .. + . + + + + f ++ + ++ + + ++ + f ++ + f . . . ... . _ f + _+ + ++ + +++ + f ++ + + f + t- Lymph conges Cion N * Crystal deposition 710424 WATER PCB-SD0000034309 27- Code Sex No. ` "71 rA2- rr ? I^2 -- ? l II A, 2 7 * A-2 ? T ? ? T ? ?M ? t T F F F F F 1 F F F1 F F F F 168 179 182 184 187 Ext. 205 208 210 212 213 220 221 224 233 234 219 230 203 204 206 207 Vacuolization 4. 4 4 Focal acidophilic alteration 4 Single acidophilic alteration 4 4 4 4 4 Focal granular alteration ' 44444 Single granular alteration 44444 Perinuclear holo _ _ 4 4 Eoslnoph. homogenization 44 4 4 Single cell necrosis .` Croup cell necrosis 444 44 Cell enlargnenc 444 4 4 _ 4 _4 4 4 1 1 4 4 4 11 1 44 4444 444 41 1 44 44 4 4 1 4 4 11 4 4 4 4 4 4 4 4 4 4 4 Mhi O 44 4444 4 4 4 4 '4 4 444444 4 44 4 4 4444 44 * " *~ 4 . 4 - ... 4 4 * 4 o 4 OM 4 _i o ' ` . 44 44 44 4 44 4 Ductal proliferation Periductal fibrosis 4 4 4 4 4' 4 4 4 4 4 4 4 4 4 4 444444 4 4 44 4 4 44 Cholanglofibrosls Stern cell proliferation Eplthliod.cell granuloma <m Periportal inflamation 4 + o Lymph congestion u 710425 WATER PCB-SD0000034310 9 -28- Code Sex No v. nr J r' *3 ? ' M2M?M L J nrA3M MM M ? M ? ?? A3- FFFFFF 241 2S3 261 264 270 271 272 275 243 244 312 231 274 275 29* 297 302 306 308 311 31* 240 241 Vacuolization . 44 4 4 44 44 4 4 444 44 Focal acidophilic alteration + ..._____ 1ii . iSingle acidophilic alteration 4 4 4 4 4 +44 44444 4 4 4 44 4 4 Focal granular alteration 4 4 4 4 ! i 44 444444444 4 4 44 Single granular alteration^ 44444 4 4 4 4 4 4- 4 4 4 4 4 4 4 4 ' 4 4 Perinuclear holo __ _ _ 4 ... 44 MUo 4 4 4 4 4 44 44 Eoslnoph. honogenlration 4 44 4 44 44 444 44 Single cell necrosis Group cell necrosis 4 4. + 4 4 *1 44+ 4 4- 4 4 44 444 444 44 ` " ** - .. 4 4 4 4 44 44 Cell enlargnenc Ductal proliferation _ Periductal fibrosis Cholangioflbrosls Stem cell proliferation * m Eplthllod.cell granulona <. Periportal inflanation o 1-- - Lymph congestion ** 44 4. 4 , 4 444444444 444 44 1 4 444 ii4 4 4 4 4 444444444444 44 44 4 4 '4 4 4 4 4 4 444 44 4 .. . 4 i4 111 111 -+ 4 4 444 4 I1111 4 4 4 4 4 4 4 ! 44 4 1 4 4 11 4 4 710426 t WATER PCB-SD0000034311 NEV 011175 Code Sex No v, A3 A3 ? 7 A3 FFT 7 F 281 287 291 291 309 Vacuolization Focal acidophilic alteration + + 4- + + + Single acidophilic alteration + + 4- Focal granular alteration +++++ Single granular alteration + .+. + + + Perinuclear holo __ _ . + 4- 4- Eosinoph. homogenization + 4- + + Single cell necrosis + _ + 4- + + Croup cell necrosis + _ + _+ Cell enlargnent + + + 4- * Ductal proliferation + + 4- 4- 4- _Periductal fibrosis Cholanglofibrosis _ ++ ++ . +. 4- Stern cell proliferation Eplthllod.ccll granulosa Periportal inflaaation Lymph congestion + WATER PCB-SD0000034312 -30\ Sex Vo Vacuolization f7 11 - .......................... || M M M M F F ' F FFHMMMMFFFFF1 MM 356 357 358 359 360 396 397 398 399 400 436 437 438 439 440 476 477 478 479 480 516 317 4 44 Focal acidophilic alteration .... ____ ... Single acidophilic alteration 4 4- _4 4_ 4- 4- 4- 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Focal granular alteration 4 . . .. 4 Single granular alteration 4- 4 4 .. 4 4. 4- 4- _4 -- 4 _ 4 4 4 4 4 4 4 4 4 4'. 4 Perinuclear holo * ____ .. _4 4 4 4- 4- . 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Eosinoph. homogenization Single cell necrosis + + a . _ 4_ 4- 4- 4 4 4 4 4 4 4 4 4 4 4 4 44 Group cell necrosis Cell enlargaent ' Ductal proliferation .. - . . 4 Periductal fibrosis Cholangioflbrosis Stern cell proliferation -.4_ .. 4 . 4 .. . 4. .... 4 444 44 444444 Epithllod.cell granuloma 4 44 Periportal inflanation 4 4 44 h Lymph congestion 710428 WATER PCB-SD0000034313 Code Sex No v 31- ' II--T----------------------- b3.3-------------- TIT ------ 1 ------- "11------------^ ~1 MMF FFF N M M M F F F F F M H M M> 518 519 520 5SS 557 558 559 5601 921 922 923 924 925 936 937 938 939 960 950 951 952 953 Vacuolization . Focal acidophilic alteration Single acidophilic alteration Focal granular alteration ' 4 44 4 4 4 4 4 4 4 4 4' 4 4 4 4 4 4 4 4 4 4 4 4 4 4 44 4 Single granular alteration 444 4 444 444 44 44444 4 4 4 4 4 Perinuclear holo Eosinoph. homogenization 4 4 4 4 4 4' 4 4 4 4 4 4 4 4 4 44 44 4 +44 4 444 44444444 444 4 Single cell necrosis Group cell necrosis 4 444 + 444 4 Cell enlargnent 444 Ductal proliferation Periductal fibrosis _ Cholangiofibrosis 9 Stern cell proliferation f<n Epithliod.cell granuloma o Periportal lnflamatlon .... ____ +4444 +4 4 4 4 4 44 4 -- 44 444 4 44 44 4 4 4 * 44 44 44 4 44 4 4 Lymph congest ion 710429 WATER PCB-SD0000034314 32- Code Sex No 2 Ih ,1 L . b3 "7'7 --B1x FFF r MHNMFFFF MM NMr r F 954 966 967 968 969 970 981 982 983 984 985 996 997 998 999 1000 41 42 43 44 45 46 47 48 Vacuolization Focal acidophilic alteration .4 4 .4. . .+ _4 .4 _ ,___ 44 Single acidophilic alteration 4- 4 . 4 4- j4 4 __4 4 4 4 4 4 4 . 4 4 Focal granular alteration ._ . 4 4 4 4 4 Single granular alteration__ ' _4._ + . . + .4 . + .4-. . 4. . 4 4 4 4 4 4 4 4 Perinuclear holo _____ __ 4 -- - 4 . 4- 4 4 4 T 4 4 ` 44 Eosinoph. homogenization 4 4 4- 4 4 4 4 4 4 Single cell necrosis + 4 . 4 4- 4 4 4 4 4 4 4 4 Group cell necrosis 4 Cell enlargment 444444 44 Ductal proliferation 4 4444 44 Periductal fibrosis Cholanglofibrosia _____ ___. _ . , ^ _ ^ .+ 4 4 4 4 4 4 444 4 4* 4 4 4444 4 4 4 4 4 4 4 4 4 4 4 4 44 44444 4 44444 44 4 44 44 4 4 44 4 Stem cell proliferation Epithliod.cell granulona Periportal inflaaation Lydiph congestion .. 4- ... t 4- _ 4 4 4 4 44 4+ 444444 4 4 4- 4- 4 4 4 4 4 4 4 4 4 fliTTTO A3N WATER PCB-SD0000034315 -33- Code Sex KO Vacuolization B.x r *ii-- -V- 1 z2 r --m FFMMMMMF F F F F M M H H M M F F F F M M N H H H 49 50 51 52 53 54 55 56 51 58 59 60 61 62 63 64 65 66 67 68 69 70 326 330 335 338 351 323 + ++++++ +++ + Focal acidophilic alteration + + Single acidophilic alteration + + + + + + + + + + + + + + + + + + + + 4- 4- 4- + + Focal granular alteration Single granular alteration _ + ++ +++ + + + + + 4- 4- + 4- 4- 4 4* 4- 4- + + 9 + + + + + + + + + + + + + + + + 4- 4- 4- + + + Perinuclear holo ______________ ++ + + + + + + + + + + + + 4- + + + 4-4- + + + Eosinoph. honogcnization________ Single cell necrosis + + + + + + + + 4- 4 4- 4 + ++ + ++++ + + + 4- + 4- 4- 4- + + + + + + Croup cell necrosis _____ + Cell enlargnent_________^________ Ductal proliferation Periductal fibrosls _ + ++ + + 4- + + +++ Cholangio fib rosIs Stern cell proliferation 2 Epithliod.cell granuloma m Periportal lnflamation Lymph congestion ++ ++ +++ +++ + +++ ++ + +++ ++ + ++ ++ + 710431 WATER PCB-SD0000034316 -34- Code Sex No 11 MMMFFF F F FF FFF FF FFF FF F 325 343 340 342 362 368 374 375 376 475 366 367 372 377 378 379 380 381 384 387 388 Vacuolization Focal acidophilic alteration . 4 ... . 4 4 Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear holo Eosinoph. homogenization Single cell necrosis Croup cell necrosis ______4 _ + + 4- 4 4 4 4 4 4 4 4 . 4 4 .4 4 4 4 4 4 4 4 4 4_ _ 4 __ 4 4 4 4 44 . ,~. . 4 _ 4 . .4 . + . + 4 . 4 _ 4. . 4 4 4 4 4 4 4 4 4 . 4 4. 4 4 4 4 4 4 4 4 4 4 4 4 444 44 4 444 444 444 444444 44 44 4 Cell enlargment 44 44 44 Ductal proliferation 44 4 444 44 4 4 Periductal fibrosis 444 444444 4 4 4 Cholangio fibrosis 44 4 444 4 4 Stern cell proliferation 4 44 Cpithliod.cell granuloma 4 4+ Periportal lnflanatlon + 44 Lymph congestion 09TTT0 A3M WATER PCB-SD0000034317 -35- 1---------- --ir -- Z-- Sex F F F F k n n H M M N N M N M N N F F F Ko 389 391 394 Ext. 415 417 418 419 423 426 427 491 402 403 40S 410 434 456 451 452 Vacuolization Focal acidophilic alteration Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear holo'______________ Cosinoph. homogenization Single cell necrosis Croup cell necrosis Cell enlargaent' Ductal proliferation Periductal fibrosis CholangiofIbrosis .Stern cell proliferation EpithLiod.cell granuloma Periportal inflamation ++ f 4- _ _+__+ 4- _+ . .+ __ . 4- 4 4-. ___ + + + +- 4 + + . _ - + ++ + .... + __ ++ .... 4- + -* + _+ 4 . . +. . 4 + + .... .. . . .. + + + i 111 | 11 11 +{ 111 + 1 +i 1 +- MM%n - +5 111 1 cMn + VI +> -) g a 1 .+ aa .4T.-. uu > i5111111 | !11111 - u . . .>a<as__ 11 + + iiitii iii i +J i ii iii +} ii + t iiii + + 4- 4- 4- 0 _ 4- 4- 4- 4- 4- 4- 4- + 4- 4 + 4- 4- 4- 4- 4- + 4 4- 4- 4- 4- + 4 4- 4 4- . . .... . 4- 44- 44- 4- + 4- 4 4- 4- 4 4- 4 4- + 4- 4 4- 4- + 4- Lymph congestion 4 NEV 011181 WATER PCB-SD0000034318 36 rr 71rrl-- 3- s.. FFFFFFF NHNM FH HMMM F F No 459 463 469 470 471 478 443 445 448 484 491 497 499 699 507 509 510 5.12 483 489 522 52 Vacuolization 4- 4- 4- ++4 444444 444 4 Focal acidophilic alteration 4- 44 Single acidophilic alteration 4 4- 4- 4- 4- 4- 4 4 444 44 44 4 4 Focal granular alteration Single granular alteration : + 4 4 4- 4- + 4- _ 4- + 4 4 4 4 4 4 4 4 4 4 4 4- 4- 4- + 4 4- 4 + 4 4 4 4 4 4 4 4 4 .4 4 Perinuclear holo 444 4- 4- 4- 4- 4 4- 444 4 Eosinoph. homogenization 44 4- 4 4- 4- 4 Single cell necrosis Croup cell necrosis Cell enlargment Ductal proliferation Periductal fibrosis Cholangiofibrosis. ' Stern cell proliferation Eplthllod.cell granuloma Periportal inflamation Lymph congestion 4 4- 4- 4 + 4 4 4 4 4 4 4 4 4 4 4 4- . .. 4 + _ . 44 .. 4 4- 4 4- 4- 4 4 4- 4 4 4 4 4 4 444 4 44 4- 4- 4- 4- 444 44 44 444 4- 4- ' 4 4 444 44 4- 4 '4 4 4 4 44 4 44 4- 44 4- 4 4 4 44 Advanced fibrosis 710434 WATER PCB-SD0000034319 Code Sex Wo , -37. 1F F F IF 2F 3F 4F - J-- 5F 5F F F F F IF 2F 3F 527 541 547 Ext. Ext. Ext. Ext. Ext. Ext. 536 537 539 441 Ext. Ext. Ext. Vacuolization Focal acidophilic alteration . + . +. Single acidophilic alteration _ + Focal granular alteration + Single granular alteration +_ + Perinuclear holo Eosinoph. homogenization ..... Single cell necrosis +_ + Croup cell necrosis Cell enlargment Ductal proliferation + + + _jfc_ f + + Periductal fibrosis ......... __ Cholangiofibrosis Stern cell proliferation + . .+ + Epithliod.cell granuloma .. + . .. .+ . . ..... . .. . . . ... . | .. - .* _ . + +_ + + . . .+ + e + . *. . ..+ _ + . .+. + + - . .. . - - + , L ... . + .. + +__ + + + +_ + . .*_ .... + ++ .. + +. - _ +_ + t + ++ + + + Periportal inflamation Lymph congestion Hepatoma(?) Cholangiocarcinoma (7) Cholangomatous lesion -1- + ......... NEV 011103 WATER PCB-SD0000034320 710436 Sacrifice Interval Dose Level Mo. of Aniaals Vacuolization ' Focal acidophilic alteration Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear holo Eoslnoph. honogenlzatlon Single cell necrosis Group cell necrosis Cell enlargnent Ductal proliferation Periductal fibrosis Cholangloflbrosls Stern cell proliferation Epithllod. cell granulosa Periportal inf lanatioi: o> Lymph congestion Crystal deposition -38A GROUP |--3 Month*--| p-8 Months--|1--14 Moothe-j j--24 Month*-! AI All AllI AI All All! AI All AUI AI All All! 11 10 9 6 3 .9 9 10 9 25 22(23)27( 6 3 1 0 0 3 2 3 1 4 12 20 00 000 000 0 35 2 11 8 10 9 4 3 9 9 10 3 1 3 `4 4 8 9 23 21 8 9 16 24 26 7 9 9 4 4 9 9 10 9 24 22 27 11 9 8 4 4 9 8 10 3 19 15 15 5 9 4 3 3 7 3 8 7 15 13 18 4 7 4 4 4 4 2 3 3 9 14 24 0 0 0 0 0 0 0 0 0 1 1 IS 0 0 4' 0 1 2 0 0 7 3 10 25 2 3 3 2 2 2 1 1 4 15 17 26 3 4 2 3 3 4 3 0 4 14 13 24 0 0 0 0 0 0 1 0 0 4 2 12 2 7 4 3 3 0 3 3 3 .3 0 2 23 042 04 3 1 52 2 01 00 00 153 000 00 1 234 000 01 2 085 011 010 9 6 0 WATER PCB-SD0000034321 -39B GROUP Sacrifice Interval Dose Level Mo. of AnInals 3 Months 8 Hontha 14 Months 24 Months ir ir lppn lOppe lOOppe Ippn lOppa lOOppa lppa lOppe lOOppe lppn lOppa lOOppe 10 10 10 10 10 10 10 10 10 31 26 29 Vacuolization 21 3 22 6 5 8 4 11 15 26 Focal acidophilic alteration 00 0 10 2 31 2 33 4 Single acidophilic alteration 10 10 10 10 10 10 10 10 10 30 19 28 Focal granular alteration 20 5 00 5 9 9 9 17 13 27 Single granular alteration 8 . 10 10 10 10 10 10 10 10 31 23 29 Perinuclear holo Eoslnoph. honogenlsatlon 10 10 89 10 7 97 10 7 9 6 9 10 9 25 20 12 6 9 6 20 16 2 Single cell necrosis ___ 01 3 55 8 0 7 9 19 10 26 Group cell necrosis 00 1 00 1 00 2 3 3 18 Cell enlargnent 00 4 00 9 02 1 7 8 24 Ductal proliferation 00 0 22 5 4 3 3 16 14 24 Periductal fibrosis 40 1 33 5 0 1 1 17 6 22 NEV O i l 185 Cholanglofibrosla 00 0 00 0 0 0 0 10 3 14 Stern cell proliferation 57 7 58 5 15 5 44 4 Eplthllod. cell granuloea co Periportal inflaratIon 12 31 3 2 4' 4 55 6 5 04 14 5 5 7S 66 2 6 Lyaph congestion Advanced fibrosis Hepatoea (? ) . Cholangiocarcinoea(?) 00 0 00 0 00 1 31 2 WATER PCB-SD0000034322 -40C GROUP Sacrifice Interval Dose Level No. of Aniasls ir 1r 3 Months II 8 Months . II 14 Months lppn lOppn lOOppu control lppn lOppn lOOppo control lppn lOppn lOOppn control 8 10 9 10 8 9 10 10 10 9 9 Vacuollration 76 1 2 50 0 1 12 8 2 Focal acidophilic alteration __ 00 0 0 00 0 0 00 0 0 Single acidophilic alteration 68 9 9 9 7 7 10 10 10 9 7 Focal granular alteration 00 2 i 1 8. 4 0 13 8 2 Single granular alteration I4 8 9 40 5 8 97 9 9 Perinuclear holo 2 7 8 10 5 7 3 10 10 7 9 9 Eoslooph. homogenisation 25 8 4 53 1 4 62 5 5 Single cell necrosis _ Croup cell necrosis Cell enlargnent Ductal proliferation Periductal fibrosis Cholangiofibrosis Stern cell proliferation Eplthliod. cell granulosa Periportal inflaration Lymph congestion 00 00 00 01 00 00 23 11 16 00 01 00 00 11 00 0 .0 54 01 21 00 34 00 00 00 22 00 22 76 10 6 00 5 0 2 1 2 0 2 1 0 0 6 0 0 0 0 0 3 2 6 0 79 00 00 03 01 00 04 45 74 00 9 0 7 3 S 0 9 7 7 1 5 0 0 1 a 0 7 2 6 0 OBTTT0 A3N WATER PCB-SD0000034323 r -41- C CROUP Sacrifice Interval Dose Laval Ho. of Anlaels --24 Months------------ 1 lppn lOppa lOOppn control 29(31) 30 14 24 VacoollxatIon Focal acidophilic alteration Single acidophilic alteration Focal granular alteration Single granular alteration Perinuclear hole Eoslnoph. hoaogenizatlon Single cell necrosis 16 25 41 22 16 79 9 11 12 15 35 14 10 14 1 10 9 6 4 1 10 9 4 24 8 18 20 12 11 Group cell nectosla Cell ealargpent 02 2 1 3 12 2 4 NfcV 011187 Ductal proliferation Periductal fibrosis Cholangioflbrosls Stern cell proliferation Epithllod. cell granulona (D Periportal inflaratlon Lyvph congestion Advanced fibrosis Cholanvloeafnttv lealrai 16 11 10 15 10 7 206 6 12 5 471 762 120 2 1 17 16 3 12 7 8 1 WATER PCB-SD0000034324