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354 Morphological Changes in Livers of Rats Fed Polychlorinated Biphenyls Light Microscopy and Ultnisti ucture Utinale D- Kimbrough, MD; Jlelph E. Lindtr; and Thomas B. Gmntt, Chambht. Go Mat* and female Sherman train rata wara fad patyeMarinatad biphenyl* Areelor 13S0 and Are* Ctor ISM at 0, SO, 100, BOO and 1,000 ppm In thair dial. Rata raoatvad the dietary tavala tor alghl month*, tight mtaroaeoptc ehangn on* alatad of hypertrophy of tha Itvor caHa, Inclusion* In tha eytoptaam, brown pigment In Kuptlar cell*, lipid accumulation, and, at tha higher diatary levels, adonoflbroola, Ultraatructural changaa of tha liver* of aapoaad animal* consist** at : Incroaaa In smooth ondopiaamta ratlcuhim atypical mitochondria. Upld raeuolaa war* * eaalonally surrounded by eoncantrle membra** The eplthetle) component ef adeneObtoate co slated of gobtet call* *nd ecil* that tatrwa.. tha aplthaUum which line* the Mo duets, la gtr aral, the efteet of Aroolor ISM on the liver m mere pronounced than that t Aroolor it**. Polychlorinatnd biphenyl* (PCBs) widely distributed in tha environment.1 They ore marketed in tha United States under the trade name Aroolor followed by e four difit number with the lest two digits indicating the percent of chlorine. They were Amt marketed in the 1930*. Jones and Aldan8 reported a case of chloracne in a worker who had been heavily exposed to a chlorinated biphenyl. Miller1 reported pathological changes in animals ex* posed to a commercial chlorinated biphenyl. He studied rata, rabbits, and guinea pigs, and found liver damage in all aeries of ex* perJments, as well as skin changes in the animal* receiving subcutaneous Injections or applications of the material to the skin. Liver damage was most pronounced in the guinea pig. The rat livers had intercellular hyaline bodies in addition to the fatty de generation that was observed in all three species. Bennett and his oo-worker*4 also reported that Aroclors affected the liven of rats. Von OetUngen6 diecuese* these earlier findings in his book "The Habgenated Hy drocarbon*: Toxicity and Potential Dangen" After the Second World War, the PCBs wars increasingly used for moisture Submitted for puUte*Uce Jan 18. 1973; *ee*p*d April 28. From the QwraUee Toxicology Laboratory, Envi- raunootet Protection Afcoty, Cnombtoo, Go. R**d In port bofoto the 12th mount mtwting of the Society of TbxtooJoty, Wlllismobur*. Ve, March B', 1972. ' Reprint vequoftte to Chambte* Twicolofy Labor** lory. Environmantel Projection A|tmy, 4770 Bu- foi'd Hwy, Chambloo, Ga 30341 (Dr. Kimbrough). proofing, seeling, impragnstion, and vnp euppreneion in prolonging the raeMuel life r insecticides and as fire retardants. They a: be found in synthetic resins, synthetic an. natural robber, cellulose rosim, paint, vu nish, wax, asphalt, and ally) starch. The have also been used in printing inks, textildyes, and as hast transfer fluid. In 19fr> an outbreak of poisoning that involved least 600 people occurred in western Jspi: where rice bran oil wav contaminated wit) Kanechlor 400, a PCB.c The eonUminatint of the oil oocurred because PCBs used a heat exchangers in the manufacturing pro eas leaked Into the oil through pinhole* it the pipe*. This incident prompted Nishiiu miT to study the effect of PCBs on tbs liver* of mice and monkeys. He found a hr> amount of acidophilic material in the cyto plasm of hepatocytee and fatty vacuak* Using electron microscopy, he observed "my lin figures" in the cytoplasm, and an in crease in smooth endoplasmic reticulum atu! lipid droplets. More recently, PCBs leaked into fishmeal from a heat exchanger of a processing plnm in North Carolina. The contaminated fi*hmeal was fed to adult chickens and breeder* The contamination was discovered when th eggs from the breeders did not hatch. Sow* of the chickens also exhibited symptoms of chick edema.8 The fact that PCBs can pro dues chick edema has been described repeatedly.8-** Contaminant* may be at least partially responsible for some of tlieae toxic effects. *f+- ' ' A 'v .t`: -V.'rvV '* *?'** ' -jx, -**...J.. BIPHENYLS--KIMBJiOVGH ET AL 355 ( Qi(urinated dibenzofuron and chlorinated nflphthalanas have been found aa contominiinti in two European commercial PCBo.,J it i* po*lbl* that other PCB* are also conmtninated with these or other highly toxic lubiitncea.1* The effect of two PCBo, Aro cior 1254 and Arocior 1260, on 8herman 1 ditto rate, waa studied in our laboratory to pin batter insight into the toxicity of these V coimnereial products. The Arocior 1260 waa c. from the same lot as that studied by Vos i and Koeman.11 * Materials and Methods v Shtrmnn strain rats were used in these ex11 psrimenta The animals were caged individually and weighed weekly. To determine the single Jus oral LDfllH Arocior 1264 and 1260 were , flwn in peanut oil to groups of tan rata/dosage level by stomach tube as described by Guinea,** Survivor* were observed for a minimum of 16 days after treatment. The method of Lichtfleld and Wilcoxon'B was used to calculate the LDH value*. When the Aroclors wero fed in tliu diet they were dissolved in ether and mixed with corn* starch. The ether was allowed to evo|rate and the Aroclor-cometarch mixture wee mixed into increasing amounts of ground chow. Tn the feeding studies, S to 4-week-old male and fe male rats were distributed in groups of ten rats of each sex according to a table of random numbers. Their food consumption was mea sured during the second, fifth, 11th, 22nd, and 30th week of exposure to the dietary ievale of 0, 100, 600, and 1,000 ppm, and at similar inter* vela in tha groups fed 20 ppm and their con* trols. The rats fed 20 ppm were set up at a later data than the other dietary levels. For Tsble 1.--N'san Body Weight Gain and Uvar Weights of Rats Fed Arocior 1260* Relative Liver Welghta Blelsnr Level Oeeage Level Weight Oela Uvar Weights lee <*pm> (ms/kg/dey) fame) (gms) M 00 481 14.96 M 100 6.9 463 ia.i7 M SOO 11.1 sea 22.01 M 1,000 71.4 191 22.40 t0 100 0 296 11.23 7.2 283 12.20 9 800 31.2 189 12.07 l.OOOt 72.4 148 19.06 M 00 439 12.77 M 20 1.4 489 16.63 00 226 11.94 20 1.6 239 12.00 4 tn diet far eight msnthe; ten rate/group. tOnly two animats survived. freeUen ef edy WsifM Difference Prem (%) Centrals 2.8* 3.23 PC.001 4.29 P<.001 4.91 P<.001 3.12 3.40 P>.10 4.92 PC.OOlt 6.36 2.39 3.02 P<.001 3.74 3.90 P>.80 | Per the setusi ttver weight P>.09. Tibia 2.--Mesn Body Weight Gain and Uvar Weights of Rsta Fed Arocior 1254* Oelative Uver Weights Prsctlen ef Dietary Level Oeeage Level Weight tain Liver Weights edy Weight Dttlerense Prem lee (asm) (ms/bf/dey) lie*) ions) <%> Centrals M 0 0 404 14.14 2.44 M 100 6.0 49* 10.01 2.92 PC.02S M SOO r0 36.4 319 24.40 8.99 P<.001 0 244 10.89 3.19 9 100 7.6 236 11.90 3.62 P>.0St 800 37.S 198 10.90 7.47 P<.001 M0 M 20 0 483 13.90 2.93 1.4 439 19.30 2.90 PC.029 . 9 0 0 236 11.21 3.34 9 20 1.6 249 12.49 3.72 P<.02S 1* <* eiet for slg ht months; ten rete/greup. t Ceusi numbers of rets fed 100 ppm end 20 ppm. respectively, lor seme length ef lime did net show eignlflcant nereees in actual liver weight (A<. 1 end >.0S); however, the Increeee In relative Kver weight woe eignMieam A<.Ol. Arch Environ Health--Vol 25, Nov 1972 356 BIPHENYLS--KIMBROUGH F.T AL this reason, a second group of controls for etch ex was oddad to the experiments (Tables 1 end 2). AU animals that were fed PCB as well as their controls war# used in reproduction studies. The results of the reproduction studies will be reported separately. At autopsy, the tissues were Axed in a buffeted 4% solution of formaldehyde (formalin). They ware stained with hematoxylin-eoein for light microscopic study. Selected liver sections were cut on the cryostat and stained with Oil red O. Peris' stain for iron and a PAS stain were also performed on e few selected livers. Tissue from the Uvers of two male and two female rats at each dietary level except 20 ppm were minced and fixed in chilled 6% buffered glutaratdebyde for two hour#, postfixed for two hours in 1% oemie acid (omnium tstroiide), dehydrated through changes of alcohol end propylene ox ide, and embedded in resin. Sections were cut with a glass knife, stained with lead citrate and urany) acetate, and examined with the electron microscope. In a preliminary experiment, Azodor 1254 at the dietary level of 1,000 ppm for three months killed moet of the tats. Tissue from this preliminary experiment wee examined only under the light microscope. Result* There was considerable variation, in both sexes, In the acuta, oral, toxic effects of Aroclor 1260 and 1254 at various dotuge levels. It was impossible to calculate LD-^ values. The data indicated that tha LD,, values were about 4,000 to 10,000 mg/kg (or both mixtures. Autopsies of rata killed by either mixture revealed hemorrhage into the lung, stomach, and pancreas. Foci of ulcera tion surrounded by a severe inflammatory reaction were observed primarily in tha <iu dernun and occasionally in the glandular part of the stomach. When tha material was fed in the diet over a period of time, porphyria was observed in a number of animals poisoned with either mix ture. The liver fluoresced most consktently under tha UV light Occasionally, fluores cence of bones, serum, and urine was ob served. A more detailed study of this phe nomenon will be reported later. When Aroclor 1260 was fed dully to groups of ten male and ten female rats etch In their diet lor eight month*; ten rate/group, t Only nine tested since one ret that died showed too much autelyels- Arrlt Entfren Health--Vol 25, Nov }f>72 , Jty ; ^.psnAakr iSM'tf'iimSlu A rU A*"i STc" fci jt*- 'if* * *;.,. * y*9J'# to^fcb1 ir?-*' .V2*..jpev4T . "* *nA\ . - *;' *v' ` ..v.* fc5Ui^^^dlt |>l* <.. v...-. . .'*. >.*.% *, n 1,--liver MeUan of mil* nt fid 900 ppm vr 12*0 for light month*. Net* foamy cytoplasm d msny of hapatocyta* (hamatonNn>aotin x 129). ng 2.--Section of llvarfrom matt rat fad 1.000 ppm Aroe<^ 1294 for aight month* lllustrottng tdtnoflbte*'* Not* *r*a of fibrosis which surround* ductulaa of glandular call*. Csllular dtbrfa. polymorphonuclear Isukoeytai. or mucus can b* obaarvad In tuman of duetufa* (hamatoxyiin-aoaln xl2S). at dietary laval* of 0, 20,100, 500, and 1,000 ppm for tight month*, norm of tha control rata and non# of the malt rata fad tha mixture died. Qua female fed 100 ppm died after six month* exposure and two females fad 500 ppm died after one and two months flcposura. Eight females fad 1,000 ppm died riihin two experiment Araelor 1200 (ten the control*. li mala rats bicantly more trol* (Table sere larger dllfarenoa was 800 ppm tha . __ Kma waa increased as a result of the re* ducad weight gain of tliree anlmale (Table 1). Groimly, the livers of the exposed Animals "'fra soft and often yellowish brown or dark diva. Qmyiah-whlte, firm, glistening areas, naaiuring up to 0.5 cm in diameter, were **en on cross section in a number of livers. Tire dark livers ihowed pink-orange fluoreen* nee under the UV tight Fig 3.--Area of adanoflbroais aa In Fig 3 from famolo rat fed 300 ppm Aroetor 1284 for sight months. Area was mnlmd undar electron mlerasespa (Pig B- 10> tolwldlne Wv# xooo). Arch Environ Health--~Vol 25, Hou 1972 MQNS 08175 7 BIPHENYLS--KIMBROUGH ET AL The incidence of the various light micro* seopic findings of the liven an given In Table 3. They consisted of hypertrophy of the individual Uvsr cells. Often the nuclei were hyperdnomatic and showed pteo* morphism, end occasional mitotic figures were observed. The cytoplasm had either large vacuoles or appeared foamy (Fig 1). Eosinophil inclusions idsntical to those de scribed in the liver of rate that have been exposed to DDT,*0 mirax,tf or dieldrin1* wen also obssrvsd. The Kupffer ceils and perivascular macrophagss of some liven con tained a brown pigment Froaen sections of liven containing the brown pigment fluoieased pink under UV light which is consis tent with the presence cf porphyrin. Some of the pigment showed a positive staining reac tion for iron with Peris' stain as well. In addition to these findings, some liven also exhibited focal areas of fibrosis which con tained glandular structures (Fig 2 and 3) that either formed strands or dilated cystic ducts that were filled with cellular debris (polymorphonuclear leukocytes) or a mucus like PAS-poeitive substance. The glandular calls had a pale, scanty, basophilic cyto plasm and usually a hypochromatlc nucleus. The areas of adenofibrosis corresponded to the grayish-white, glistening areas described grossly. The glandular epithelium appeared stratified in some areas. Electron micracoptc study revealed (Fig 4 to 10) an inerts* in smooth endoplasmic reticulum (Fig 5) in the hepatocytes of all but the control rats (Fig 4). Many large and small Upid vac uoles and occasional atypical mitochondria were alto seen. At the dietary level of 100 ppm, dark and light cells, dilated bile ducts, and granular cytoplasmic inclusions additional findings (Fig 6). At the distary level of 500 and 1,000 ppm, concentrically arranged membranes which surrounded lipid vacuoles were also observed. They have been previously described in livers of rats 1*4 DDT and dieldrin.1 * The cytoplasm nf many cells hod a loosened-up, "moth attn' appearance (Fig 7), with occasional vneuolee containing a few strands of electrondense material. These ceils corresponded tn the hepatocytes with foamy cytoplasm ob served under the light microscope. Widening of intarceliulur spaces, ocossional phsgocytixed red blood ceils, and an increase in collagen were observed. The nodular, gray, ish-white areas (Fig 8) that represented fjfl 4.--Svetlan from norms! mete ret liver. N. nucleus; M, mitochondria; HER, rough andoplaarme reticulum; SEft, ameoth endoplasmic reticulum (lead eitrete. uranyt acetate x 13.490). Arch Environ Health--Vol 25, Nov 1972 mons oaivsa fa . -* FI# 8.--(aetlon from mil* fit Mvar foci 100 ppm Aroetor 12(0 for aipht month*. Not* larp* Amount of omootn onpoptatmle ratleulum. SCR, amooth andopfasmic ratleulum; M, mitochondria; n, mieloua (load eltroto, uranyl acotato x 34,200). Flf (action from llvor of fomola rat fad 800 ppm Arocior 12(0 for *I(M month*. Not* tmafl and iaro* voauataa rrfthln eytapiaam, *om* filled with RpM ana advert with tlrandt of doth granular malarial (arrow*). V, vacuolaa; M. mitochondria; Cl. *ll border; BC, bil* eanalteiriua; REIf, rough andopiatmte ratlcu* him; SCR, amooth ondopiaamie rotteulum (load citrate, uranyl acatata x 13,490). _ .te * .. IP SgUiJ^e! -V'-v -T.'l * - r *-r r'Z; 1-{r-. . no 7.--*eeMon from liver of mala rat fed 1,000 ppm Aroelor 1200 tor eight monthe. Nolo "matheaten" appearance of the cytoptaam (lead eltrata, uranyt acetate x 13,490). Pig t. --lactton from IIvor of famala rat fad Aroelor 1294 for eight monthe. Note large amount of eollagan, ffbroMaatc, and epttfteftel eefta lifting a ductule. C. ceUagan; Ft, Itbrobteet N. nectaoet CC. apltftallal eatt (arrow): CL, lumen of ductule (lead citrate, uranyt aeoteta X9.320). in dii *11 ONS 0 8 1 7 6 0 Arch nctron Health---Vol 25, .\'oi> J972 T\* -~ *'**- .ai*L^^^XA.3ai^lJLaa^ fl/PW^NV/^S--/f/A/fl/?Or/(7H JTT yl 3CX xleniive foci of adenoAbroeia consisted of hepatocytes of all the other exposed rata fibroblasts and a great daal of ooUagon that ware enlarged, vacuolated often with hyper- ptirroundod rosettes of epithelial cell*. These chromatic--sometimes enlarged and some otila were cuboidal or columnar Jn ahapo. times pyknolio--nuclei which occasionally The free aurface was lined by microvilli, and displayed mitotic figures. Varying degrees of celts contained large, pale nuclei The cyto Abrosis around the bile ducts were observed. plasm was granular, with many ribosomes Hyperplasia and proliferation of glandular and a few endoplasmic membranes. Some of cells simulating bile ducts were also seen in these liver duct oelli contained a graat deal tlwee areas. In some areas, the sinusoids of mucus and resembled goblet cells similar were dilated and contained cellular debria, lo thoee observed in the intestinal tract (Fig lined by et II "compressed" hepatocytes. A 9) . The cytoplasm oontained tonoAlaments brown pi?.1 t wax seen within the macro and, particularly naar the duct lumen, the phages. A <- .v livers stained with Oil red O boundaries between adjacent cells were showed a large amount of red staining (Up- marked by prominent terminal bars (Fig id) material. Tha animals that died not only 10) . had liver lesions but also suffered from se In a preliminary study in which 1,000 vere pulmonary congestion and, in a few ppm Areolar 1254 was fed in the diet to ten instanoee, from maasiva hemorrhagaa Into mala and tan famalt rata, five of the males tha soft tissue or tha paritoneai cavity. and eight of the females died. At autopey of When 600, 100, 20, end 0 ppm Arodor iho aaposed animals, the livers wars pals 1264 ware fod to the rets for eight months, and enlarged and contained Ann, grayish' two melee end one female rat died at 600 white, glistening anas. One mala rat that ppm, but none died at tha lower dietary died after 49 days exposure showed only levels. The rata fed 600 ppm Arodor 1264 alight enlargement of the liver cells. The gained lees weight than the controls. The Arch Snviron Health--Vol if, Nov 1878 ms p(0 10--Hletiaf msgntfiesttoi of two spitheNsf Milt from Fig 9 ttorira T. tonoWormnte D. 6mmowne* N, metros; M. mltwhondrie; CB, etK terror (leed citrate, urenyl acatete *94.200). liver* of the exposed group* were larger than those of the oontrol* (Table 2). This was significant In all but the female rata fed 100 ppm. At autopsy, the livers of the expoeed animals, particularly at the higher dietary levels, were soft, yellowish-brown, or dark olive. Firm, grayish-white, glistening areas were seen, especially in those fed higher PCB levels. Occasionally, the liver surface was nodular. Them livers also fluoresced when expoeed to UV light The light microeooplc findings arc given in Table 4. The observed changes in tbs livers of exposed rata were quite similar to those described for Aroclor 1200, except that all male rets at 600 ppm and one mala rat at 100 ppm had areas of adenoflhroeia in thair liver, while none of the males demonstrated this at the respective dietary levels of Arodor 1280. In the females, the incidence of adenoflbroeia was mud) higher at the seme dietary levels of Arodor 1254 than in those fed Aroclor 1260. The electron microscopic examination of the different liver changes summarised in Table 4 corresponded to those already de scribed for Aroclor 1260. The mein difference between the two com pounds was the much higher incidenoe of adenofibnmis at a lower dietary level of Aro clor 1234. When fed over e period of time, Aroclor 1260 seemed to bo more toxic to female rata. Such a aex difference could not be established for Aroclor 1254. Comment Arodor 1260 and 1264 have a definite effect on the liver. This affect is mors pronounosd with Aroclor 1264 whan all mor phologic changes of equivatat dietary levs)* of Arodor 1264 and 1260 are compered. AH dietary levels tasted so far showed an in crease in the size of the individual liver cell* and often an increase in the liver weights. Accumulation of fat was observed at 100 ppm, and it was very pronounced at the higher dietary levels. The incidence of cyto plasmic inclusions was higher at the lower dietary levels. This Is probably due to the fact that at the higher dietary levels moat o( tha cytoplasmic components have been re placed by lipida. The pigment obeerved in the Kupffer oells showed positive prussian blue reaction and repreeanted, at least in part, hemosiderin. The fluareecenoe of the liven under UV light wes caused by the presence of porphyrin, which resulted in the dark discoloration of the liver. An additional finding in the livers wes the presence of grayish-white, glistening area# which microscopically corresponded to eden* ofibroels. This lesion consisted of glondular. often mucus-producing, epithelial cells form ing ductules. They were surrounded by fi brosis. Synonyms for this lesion are chniagJofibroxis, bile duct proliferation, bile duct adenomatosis, and fibroadenoma. Stewart *ONS QaUt,t Arch Environ Health--Voi 25, Kov J972 RIPHENYLS-miBHOVCH ST AL 303 ind Rn*!!1" g*W. nn axcllvnt deacrlption of gitiKitibnMitt of the liver o( rata. The aulhura (enrluded tint "xdcnoAbroxtx ia a contractini Mon built up by the incorporation and ! liamforination ot nonnal (Irepatio cords) ud pathologic (paeudotubulw) components of tin surraundlnf livar. Thus far than is no convincing evidence that adenoflbroeia is a prscanceraus lesion.'* Adonofibroaia, tor innance, hn* been described in liven ot rats fad butter 'yellow (p-dimathylaminoasobennne).M Recently, Reuber11 ted liamsters 2aosUunidoAuorene or Z-diacetamidoAMOrene tod produced adenocercinomns. He thought thnt some ot these carcinomas originated loan bile ducts. The author interpreted adenofibrosis as dtolangioAbrosis, suggesting that sdsnoAbratis la the rat was a precancerous lesion and was identical to the lesions he obstved in hamsten which, in his opinion, also represented a prtcanderoua lesion. He postu lated that the observed cholangiocardnomaa developed from the adenoAbrosle. Glaser and his colleagueae* produced a highly malignant namplantablo tumor, derived from tha liver ot a hamster ted 2-ecetylaminoffuorene, that did not appear to be malignant in the donor but showed changes similar to the adanoAbrwis described in tills paper. It is possible that the malignant lesion was not simply de rived from tha adenoAbrosis-type lesion but from ceils that alrendy manifested irrevers ible preneoplastic changes that were not miaoacopically detectable. Miller1 found fatty livers, liver necrosis, snd inclusions In the cytoplasm ot the hepetocytes in rote that had been eapoeed to a Uphanyl with 42% chlorination. Ha did not mention edenoAbrotls in hie report How ever, he studied n different biphenyl end hie animals warn exposed to the chemical for much shorter periods of time. NishisumP studied tha effect of a biphenyl with 48% chlorinaiiotr In monkeys and mico. The lungrst exposure time was 26 weoks. Ha decribsd enlargement of the liver, fatly rhangee, gmnuler cytoplasm of the hepatorytes, Increase In site of Kupffer cells and lepalocytee, and a brown pigment in some 4 these cells, but did not observe adenoAiroslt At sonli stages ot exposure he obsrved, with tha electron microscope, an in crease In tha smooth endoplasmic reticulum, arlallon in tho nppeerance of mitochondria, and an Increase in tho number of microbod ies, a* well as "myelin figures" which seem to be simitar to the concentrically arranfed membranes tl>at have been described In rata after exposure to chlorinated hydrocarbon*.1" The increase Jn liver weights and tho obser vation of inclusions in the cytoplasm has been reported for several persistent insecti cides.1*1* To our knowledge adenoflbroeia has not been produced with chemicals such as DDT, dleldrin, pyrethrum, plpsronyl butoxide, and mires. Unlike Niahlzumi's find ings^ an increase in the number of micro bodies was not observed In the rats fed PCBs in this study. The increase in smooth endoplasmic retic ulum has also been observed with other chemicals, and It Is not surprising that chlor inated biphenyls induce microsomal enzymes.**-** Study of the adenofibrosia under the elec tron microscope shows the epithelial compo nent of the lesion consisting of two types of cell*--goblet cells and epithelial cells with granular cytoplasm, tonofllaments, and desmommas. The latter cells reeembl# tha epi thelial cells lining tha bile ducts rather than hepetocytes. The epithelial cells are reminis cent of "ovsl" oells which are thought to represent ductular cells. However, the oval cells are smaller and have a hyperchromatic nucleus.*" Whether thoy develop originally from bile duct epithelium or from other calls in the liver needs further investigation. The feet diet edenoflbroeie has not been observed in previous feeding studies with PCBs may have a variety of reasons such as the length of exposure, the animal species or rat strain, and the composition of PCB given to the rats. Contamination of PCBs with traces of other chemicals such as chlorinated dlbensodtadne, chlorinated dlbensofurans, or chlori nated naphthalenes may elm be responsible. Vos and Koeman11 checked Aroclor 1280 of the same lot and also did net demonstrate any contaminants. However, preliminary ehomiea! analyses of this lot of Aroclor 1254 suggest possible contamination with a chlori nated dibensofuran. This is still under Investigation." The significance of edenoflbroeie will be further investigated In order to establish whether it is an irreversible leelon snd whether it is transplantable. From expert- Arch Environ Health--Vol 25, Atav 19It 364 BIPHENYLS--KIMBROUGH ET A1 ence with DDT and other chlorinated hy drocarbons, it can ba deduced that the liver enlargement, as expressed by hypertrophy of the liver calls and the observation of inclu sions in the cytoplasm. Is reversible after cessation of exposure. The observed porphyria, which was also noted by Vos and Koemen,11 end the effect of PCBe on the liver, particularly the adeno- flbrosii, make it necessary to reevaluate our present concept of the toxicity of PCBs. Additional Information is alao needed on the interaction of PCBs with substances such as alcohol, chlorinated hydrocarbons, sex hor mones, lead, and, of oourat, the various con taminants that may or may not ba present In the PCBs. The quality of the diet may have an impact on the effect of PCBe. The findings described in this piper support the oonchiskn of Lichtenstein at al**--that the toxicity of the PCBs decreases as the level of chlorination increases. Htahard L. Moors assisted with the animal toots. Bstelte C. Grey did tho atetteUeal analysis. Undo W. Andaman end Ante R. Alterd puputd tbo Aroetor 1204 (lot No. AK-8S) ond Aroetor 1X80 (let No. AK-6) worn provided indie by Miassb ChomlMl Ob, Bt Loui%Mo Rafecenooa 1. Rteebrouh RW, Rtedw P, Peohell DB, *4 al: Polycbltenatsd biphenyls la toe flobel oaosyatem* Nature 290:1^771*1,102,16S6. 1 Jones JW, Amo HR As *__________ fete Arch Derm Syph 82:102*1484, 196ft S MHler JW: Pathoteste dean to espeeed to a oommarola] eateitMted dl tk Health Map 09:1,080-149*. 1044. 4. Bennett OA, Drinker CX, W i MP: pbeiofteal ohMBfoo In tbs liven of rots roanlrtag Iron exposure to oortolo nhtortatted bydioeertem. J /tetef Wyf Textol 2047-12ft HU. & Von Oettfecon WP: The Xehfnnl Hydro portent Tatkity and Fetentfcl Deneere, pubUoeten 4X4. 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