Document mqoZj9eDReE2M2rBnEkggENKQ

Potential Health effects la the Human Proa Exposure to polychlorinated Biphenyls (PCBs) and Related Iapurltles January 23, 19B3 Prepared by: Drill. Frless. Hays. Loomis i Shaffer. Inc. ' Consultants in Toxicology 1901 M. Fort Myer Dr.. Suite 204 Arlington. VA 22209 HONS 015583 Victor *. Drill, M.D., Ph.D. sd%s*3=*ikc-jCSS^S* Sayiyfec L. Frlctt, Ph.D. ,^rtvv\A. Tad A. Doania, M.D., Ph.D. c, C. Boyd SharfFar, Ph.D. HONS 01S5* TABLE Of CONTENTS !! Executive Suaaary ..................................................................... 1 I. Introduction ................................................................... 9 II. Yusho Episode ............................................... 25 III. Body Burdens, Metabolism andKinetics .................... 31 IV. General Toxicity ................................... S3 v. Skin and Other CutaneousTissues ............................... <1 VI. Liver Effects ................................................................. VII. Gastric Lesions ............................................................. <3 95 VIII. Carcinogenesis Experiaentaland Clinical .......... 99 IX. heproductive Effects .................................................... 117 X. Mutagenesis ............................................................. 131 XI. Other Health Effects ............................. 137 XII. Epldealoloqy........ ........................................................... 1S9 XIII. References ............... 203 XIV. Glossary of Taras ......................................................... 223 HONS 015585 1 EXECUTIVE SUMMARY The present study on the potential health effects in Itiusan populations fros exposure to coaimercial polychlorinated biphenyl (PCS) sixtures under occupational or other envlronaental conditions was conducted by a teas of specialists in the medical, toxicological and epidemiological sciences designated as the Category I teas. Draft material for the study report was reviewed by a second group of specialists designated as the Category II teas, and other scientists, leading to consents and suggestions for Improvement whicb were incorporated into the draft report. The available body of scientific literature on health effects of KBs in humans and in test animal systems was reviewed and analysed with emphasis on the relationships linking exposure, dosage to the biological target, and occurrence of specific health effects in the animal or human. Both the toxicological and epidemiological data from acute and chronic animal and human exposures were considered in generating assessments of the prob ability of occurrence of any specific health effect in humans. The results of these assessments are summarized below, separately itemized under each major health effect. It should be noted that each assessment applies to the potential for development of that effect under the type and level of human exposures actually encountered in the 0.3. during the past decades, with the most intensive integrated exposures having occurred in manufacturing operations thst were terminated in this country in 1ST?. HONS 015586 Yuxho Dlaaaxa Separata conxlderatlon vaa devoted to tha Yusho aplaoda racopnizinp tha apaeial character of the huaan exposures to high concentration* of alitarat of PCha and thair tharaal dapradatlon products, polyehlorlnatad dibansofuranx (PCDPx) and polyehlorlnatad quatarphanyls (fCOa). Several conclusions raachad by tha Catepozy X taaa ara of loportanoai (a) It la lapeaalbls to atlpolata whether any of tha health affacta obaarrad la causally ralatad to KB axpatvra. aInca tha other halopenated ccapounds ara alae hlolopldaily aetlvai (b) tha doeapa pattaraa asparlanead by Yuabo patlaota aad O.J. Industrial workara (KB~aapoaad) ara not at all eoaparablai tha lattar proup axparlaocad low lsvel. loop tins parled exposures primarily via Inhalation aad akin contaot, with only nlolnal oral lopoxtioni (e) tha alailar haalth affaata aaan la Yusho patlaota froo tha Japaaaaa aad Talwaaaaa aplaodaa of axpoaura to control* natad cooklnp olla point to tha taaa typa of tosie nlrtoraa rasultinp froo tharaal heat axehanpar action In the two events; (d) bacauaa of polata (a)-(c) abora, and tha fact that at laaat tha rcora la tha Yuoho olla ara potantially oora torie than tha Pda on tha baalo of anlnal data,, it la not poaalbla to aatrapolata tha Tuaho azparlance to prodletloo of aeota aad ab-hranle affect* of eoooarcial PCI nlrtarca in eh# huan; (a) finally, with raapoct to pradietioaa of honan earcinopansale froo tha Yusho type of exposure tha data ara ae ineooplata that eeaalaalona rapardinp any typaa and aanunta of excess cancan attribu table to theaa axpoauraa have to await further definitive study. HONS 01557 -J- Body Burdana. Metabolism, and Kinetics some general observations derive iron considar- ation of tha data on the atorage, distribution, metabolism and aaeration of coamareial PCI mixtures (with aaaoclatad impurities such as tha PCSFa) in isaamslian systaau. Tha dynamics of tha pathways by which thasa procassas occur in test animal modala have baan azplorad lntansivaly and hava baan fairly wall worked out, Tha variability of PCS affacts with spaeiaa of tsst animal nodal has baan Investigated for a number of Important affacta, and soma general structure vs. activity rules have emerged from thaaa studies. There thus asiats a conceptual framework, but not experimental data, for describing such phenomena in humans. Further, important data on tha biochemical interactions of PCSa, score and metabolites with tissues hava baan obtained that beer directly on interpretation of tosic affects in these tissues. General Toxicity . From acuta, subchronic and chronic studios of PCS affects in test animal models, a general suaasary of health affects encountered included (a) a low order of acuta toxicity; (b) skin leoionst (c) effects on diver tissue that ara ganorally reversible at lower doses but that trand toward lrrevarsibility with increased dosing; (d) effects on the gastric mucosa; (a) affects on the Maatrual cycle and on rapreducticn; HONS 015588 4- (f) porphyriai (g) affect* on the kidnayr and (h) miacelleneeea change* ineluding hematologic alteration*, thymic atrophy and lymphatic change*. Thara la a eonaiderabla rang* of apaeiaa *u*eeptibility to biological activity of tha PCI*. with ana repreeemtatlv* eemperiaon of order of daeraaaing activity being mink, monkey, rat. It ia concluded that thara la no baala for datamining which apaeiaa aoat accurately aarvea aa a model for prediction of general aubchronic/ehronie toxleity in nant rather, the judg ment of the aoat auitable aurrogate for nan auat be eada indepen dently for each major health effect. Finally, it ia noted that although there is acme olnilarity between acute health effect phenomena produced by KI expoauxe In the nonkey and human Yueho diaaaaa, it would be incorrect to equate Yuaho dlaeaae with pa intoxication becauae of the nuch nore ecmplez mixture of compound* encountered in Yuaho oil than in a commercial pea mixture. kln and other Cutaaeoua Tlaauae Comereial PCSa are eapeble of producing akin la*Iona in the monkey model and in expoaed humane, chronic adminiatration of PCSa to the monkey produce* ehloracne. In humane occu pationally expoaed to PCSa akin diaordera including ehloracne have oeeaaionally been obaarved. The** akin diaordera have been ahown to be reveralble in same of the animal and human atudiee. HONS 015589 -5- Liver HfKti PCI nixturee are capable of generating important affacta oa livar tiaaua in anlawl nodela. Thaaa affacta Include (a) iaeraaaa in livar weight#: (b) histopathologic changes la livar including enlarged hepetocytea, dapoaition of fat droplata in tiaaua, and tiaaua nacroaia and call death) (c) anlargaaant of the liver) (d) the occurrence of adenofibroala. a benign leaIonr and (a) an incraaaa in proliferative lealona of the liver. Including increeeae la hyperplaatlc foci and nodular hyperplaaia. Thaaa incraaaaa in prolifaratlva lealona appear to incraaaa in aavarity vith incraaaing degree of chlorination of the PCI uixtura, aa aaan in the greeter potency of Xroclor 12*0 over Aroclor 1214. The affacta on liver tiaaua are gen erally reveraible at lower doeea but tread toward irreveralbility with increaaed doaing. However, la contraat with the poaitiva findinga of PCI effecta on liver tlaeue in anlawl nodala, no aigniflcant affacta on liver function teata have been obaerved froai clinical data on hunaa populationa axpoaed to PCIa in the occupational aettlng. Further, there haa been no epldaadologleal finding of liver dlaeaae in U.l. occupationally-ezpoaed paraonnel. Xiao, aa noted in the Yuaho diacuaaion about pereona ezpoeed to coataninated cooking oil with a PC* content of 1000 ppw, there waa no finding of liver dlaeaae in the categorlea of either jaundice or hepatocellular injury. MOKS 015590 gtrlc Loolona then taated in aonkaya and rodanta. Pda (how apedoa apecificity with raapoct to a toxic effect oa the gaatric epithelium, or atemach lining. la the aoakay, with hrodor 1242, ehara ia a aucoua eenvaraiea of tho gaatrlc epithelium that can hoot ho deaeribod aa a dyaplaatie growth pattara, ihia growth pattara doaa not eoaatituta a nooplaatie trasaformation. In rodanta. Pda do not avoka thia affact on tho gaatrio mocoae. In humane occupationally aspoaad to Pda thara ara no clinical findlnga to data of gaatrle laaioaa, and no evidence of atemach eancar duo to thia oxpoauro. carcinoconaalai Experimental and Clinieal K alnaablo volume of aninal experimental work haa boon diractad toward chronic atudiaa in aovernl apaciaai tho aouaa, tho rat and tha dog. Thara ara acm araaa of intarpratation that ara (till undo* dabata hy tha invaatigatora conearaad. hot in tha opinion of tha Category I team tha following raproaonta coneluaiona that eon bo drawn from praaontly available datai (a) tho evidence on carcinogenicity ia negative for gaatrointeetiaal cardnone and bladder carcinoma ia rata and hopatocallolar carcinoma in tho dog> (b) eema atudiaa have reported an ineraaao ia hapatocollular carcinoma ia mica and rata aapeaod to ceaaaarcial Pda chronically, whereae other atudiaa have afforded nagative raaulta. HONS 015591 -7- With respect Co the possibility of esncsr linked to sxposurs' of humans to PCBs, epidemiological studies show to does ssssntlally negative rssults for hepatocellular carcinoma, gastrointsstlnal carcinoma and all othar fonts of cancsr. Thors is a tingla preliminary study that purports to show an lneraasa In melanoma (skin cancar) in occupationally axposad people, but tha full data display and analysis have not boon aada for this study. In contrast. In two larger and aora datailad studies, this finding has not bean confirmedt no axceas incidence of salancaa in axposad personnel has bean observed. Retrospective aortallty studies of PCB-exposed huaan populations have not doaonstrated a consistent relationship between extent of exposure and the developaent of any par ticular type of cancer. The huaan studies in bepaeocellular earcinoaa are not comprehensive, but to the extent that they have been developed the results do not confirm the projection of a risk for liver cancer based on the anlaal studies. Soaa findings of increases in lymphatic and heaatopoletlc malignancies were below tha level of statistical significance, and were refuted by observations of changes in the opposite direction in other epidemiological studies, even findings of statistically signi ficant differences between expoeed and control populations with respect to the incidence of rectal cancar in women at one plant have not been confirmed by observations in other studies. The variance in these findings points up the important principle that the Standard Mortality Batlo (SMB) aay vary widely in different HONS 0155S2 -I- studies, and that undue emphasis should not ha placed on the SMt found in one study unless it has been confined by siailar findings in repeat oc parallel studies. Unproductive Effects Experimental work with coesMreial PCS aixtures and aniaal eodels has been directed to the reproductive process itself, to taratogeneais in the offspring, and to possible fetotoxlelty. In aoat teat species,PCBs produce deleterious effects on reproduction at high dosages. In the feaale conker at relatively high dosages, difficulties are encountered in con ception, in implantation of the fertilised ovum, and in carrying the fetus to ten. similarly dosed, the sale sonkey does not transmit these difficulties to the reproductive process. In the bawn, exposed occupationally or otherwise to Ids, then is in general no evidence for adverse effects on the reproductive process, although there are little data free which to draw con clusions. In the very special case of Yusbo exposure to high levels of PCSs and other polychlorinated hydrocarbons, the new born in significant proportion wen pigeented, seall, and showed a retarded rate of growth. Sowever, this plgeentation disap peared and the infants caught up with control population infanta in total growth. The potential for PCb-induced teratogenesis, or produc tion of defects in the eabryo or fetus, has been investigated in several species of test anlaels. Host aniaal tests have yielded negative results when PCM were administered to pregnant feaales during the critical periods for organogenesis. HONS 015593 Several possible exceptions to this statement might bm nottd. In mica, a alnqle congener, 3,4,3',4'-tetrachlorobiphenyl, in duced a bahavloral da fact (*valtaing ayndroiaa') that may ba ralatad to an anatomical dafact in the inner aar. PCBs in mica may produea soma daisy in implantation, in rata, no gross taratological changas wars obsarvad, but soma alterations in thyroid structure or function produced by PCI administration might fall under the definition of terata. In dogs and in swine, no taratological offsets wars noted at lower PCS doses> however at the highest doses of PCS in the feed, at which the dam suffers marked reduction in food consumption and' is therefore nutritionally deficient, there are dosa-ralated taratological effects in the offspring. In monkeys dosad with PCSs, there are no dose-related abnormalities in the offspring, but they are smaller in sisa. Baaed on tnose observations, it is the Cate gory I team's conclusion that commercial PCBs present no appreci able risk of teratogenicity in offspring of human females exposed under occupational conditions. in test animals, l.a. rats, dogs and rabbits, PCBs are fetotoxlc when administered at relatively high doses to the pregnant female. In the human, the only reported epidemiological evidence for fetotosicity in exposed populations stems from the unique lusho event, in whieh causation nay not be linked to PCBS. HONS 015594 xo Mutaatnaala Inveetigatione of poeaible mtaganeeia !rn acuta or chronic axpoeuree to caianorcial tea* Hava ahown nagatlva raanlta la a aarlaa of In vitro aad tj vivo taat ayataaa. laolatad bacterial taat ayitau (Aaea taat) and Honan lyphocytaa la eul- taro ahowed ao avldanca for PCS-iaducad autatloa or tranafonetloa. With is. vivo yrtaoa la lataet aalaalai (a) cytoganatio taata for altaratioaa of call atracturaa or for ladoetlon of iiHrranmnaa abnotMlitiaa ylaldad nagatlva raanlta; aad (b) both tha acmao aieroauclaua taat aad tha doadaant lathal taat deaenatratad negative raanlta. Incubation of hones lywpbocytoa la anltnra with PCIa canned aa altaratioa la gluooea tranaport through tha call aaabraaaa. ' Thara la ae algnifleaat evidence that PCIa ara mutagenic la taat ayataau, aad oo raporta of auch activity la huaan populatloaa. Xt la quite naXlkaly that coanarelal PCS airturaa would aaart antagaale activity in huaana. fhla eonclu- aioa la cooalataat with tha lack of aaeaaa caacar iacidaaea obaarvad la PCS-aapoaad hunts populatloaa. Othar Health Sffacta Thla grouping iaelodaa aaayaa ladnetloa. Iimuiio competence aad porphyria. PCIa laduea alxad function oxidaaaa (HPO) In tha livar of taat animate. Tha important laaua la whathar or not thia proeaaa lacludaa tha apadfle ladoetlon of eytochreaw P-add aa a ganaral proparty of tha PCSa. with tha addad implication that town ealdaaa ayataa la baiag iadnead that HOMS 015595 - 11 - could be involved In cheaical carcinogenesis. Several concluslona war* raachad with rsspect to this laauai (a) tha pradoainant effect of coaaarcial PCBa ia eytochroaa p-450 induction, not P-448 j (b) coaaarcial PCBa in tha O.S. can contain up to about 2 ppa of PCOPat and (c) tha PCDFa can induca eytochroaa P-448. Proa thaaa obaarvationa in aniaal nodal ayataaa and our judgment, it la concludad that undar conditiona of U.S. occu pational exposure to PCBa, nona of tha HPO inducing action* of tha coaaarcial mixtures will ba of toxicological aigniflcanca over tha lifatiaa of a pCB-axpoaad paraon. With raapact to potential PCS affacta on laaunocoapotanca in teat aniaal ayataaa, aoaa obaarvationa ara pertinent to tha aaaaaaaant of probable haaard in tha huaan. it haa bean ob served in chicka that if tha PCI doaagaa are high enough, atrophy of tha aplanic pulp and necroala of tha lymphoid ayatea can be daaonatratad. Siailar indicators of change in lsssunocoapatanca can also ba produced in ducklings, aica, and aonkeys aa a conse quence of aavara change in nutritional status. High doaas of PCBa leading to aarkad reduction of food intake and utilisation can lead to such changes in nutritional status. Those considera tions lead to two general conclusions relative to the PCB-axpoaad huxMnsi (a) aa projected from aniaal studies, if tha PCS dosage is high enough to lead to general toxicity in tha huaan (a.g., decreased food intake, fall in body weight, fall in weight gain). HONS 015596 u- iaaunoauppresalon aay ba demonstrable aaeendary to aalnutrition> and (b) e lower doaa levels, there is no likelihood of signifi cant laaninosuppreasion. Porphyria, or dapoaltion of porphyrin-derived pigments in liver and urine, haa baan obaarvad in aapariaaneal anlaala auch aa tha rat and rabbit doaad with pcia. Tha affaet haa a dalayad onset, and especially in tha rat, eases to taka placa by aachanlaaa diffarant free tboaa employed by known chaaieal porphyria-producara in tha human. It ia concluded that, aaida fro* tha unique eaaa of Toaho diaaaaa, no awidanco haa accrued tor tha occurranca of porphyria in populations exposed to PCM even under high laval occupational exposure eonditiona. Epidemiology Thia aoction (XII) of tha atudy prasanta a aaparata, indapandant aasesammnt af tha racordad apldaalologleal lltaratura and data baaaa on hnaan exposures to ceaaareial PCBa, and on tha aignificanco of tha health affacta attributed to theaa exposures. Suaaary points in thia aasasaaont includa tha following (a) aortality data, based on vary saall nuabara of deaths, do not confirm a carcinogenic affaet of PCM ia mam (b) data on huaan akin lesions in relation to PCS exposures have shown variability in lnddenea of this affaet with geographical locus and with in creasing blood level indieatora of exposure! (c) data free studies of llvar anxyeea and liver function suggest changes in one or acre enaymea related to PCS axpoaura that are not associated HONS 015597 - 13 with liver disease and that occur at lavali balow thoaa at whleh chloracna occur*: (d) thara la frequently a positive corralatlon batwaan PCB lavala and triglyceride lavala In bloodi and (a) epidemiological data on reproductive affaeta. hematology and immunology In human* exposed to PCBs do not suggest abnormalltlaa In thaao systems or procaaaaa. Human Occupational Exposure Lavala Of tha varloua affaeta notad In anliaal taat systems, only dermatological affaeta. Including ecme chloracna, haw* boon elaarly demonstrated in human populations at the doaaga lavala aaaoclatad with occupational axpoauraa. Tabla 10 su--arlaea tha natura and lntanalty of aoaio axpoauraa that hava occurrad to paraonnal involved occupationally with PCBa and tha blologleal indices that have accoaipanied thaaa axpoauraa, moaaured aa PCI content in blood and adipose tissue. Since the risk to huaan health fro* even high level occu pational exposures has bean shown by tha studies available to be low, it any bo concluded that much lower human exposure levels do not proaant significant risks. HONS 015598 aferenoe jociralU (1954) mgMB (1972) Plant MVUaran (1972) Itaun inchbain (1973) (1979) (1979) liff D 21/i cown o to/l kith (1991) (1991) 11991a) TW 1 BBUanuAL ODCUWTKWtt. HtPOBMC CP W0W9B TO KB (Capacitor plant tartan wlM oUkvIk noted)Onto npi(M In huaan aplibwlnlogy nfsaion PCD Concentration in Air , Dame uqAr Dnnaal Contact Noted? PCB LMl in llfnnri PlAflH Parts per billion** No. (MtiacS* {teari Ranqe 5200-6000 A (PCB Mg.) B 0 B r SO- 200 100- SOO SOO- 700 200-1700 99 370 60- 920 < 1000 12 13 320-2220 YM 34 U> expos. 70- 410 159 Med. * 410- COO 62 Hi * COO-1100 43 Aa Nnw 24- 393 170-12M N.O.- 2S4 Yas " 14 440 110-1900 920 320-2100 ---- 400 TT.-1200 V- 73 H- 41 I/-171 H- 25 6-2C6 It- 92 1^ S3 2-1412 H- 19 1-CO lr502 210-3330 B- 44 20- 150 1-237 34-2400 N- 51 10- 250 n? ra PCB level in Mipoar* Tissue Farts per nillice** tt>. Si9>.* ifean hna 3 SCO 160-635 L-24 2-271 II- 6 .2-19 l--1 * 1i/I forms ith (1961b) utility worker ransfonser repair groups) TTMUB 11 PCI) Concentration In Air , HW uq/W1 (rout'-mod) KB Iswl in Ocsanl Blood Plan contact Parts per billion** Motad? tto. Sidriects* Hun 37- 21S 14 L~ 23 H- 24 8 V~ 16 H- 7 tenge 5- 52 7- 74 1- 52 4- 19 PCB Level i,, Adipose Tissue Parts per Million** Ud. Sub.* Maan tenje 4 I/- 36 23- 59 H- 10 7- 17 13 Lr- 24 12- 35 H- 6 1- 10 7 hr- 11 1- 30 H- 6 4- 10 3- 62 Tea IS L- 22 9=~ti----H- 31 11-140 * 10 lr- 22 12- 48 #- 26 7-250 13 lr- 23 13- 52 *- 8 5- 25 Lr- 19 12- 42 H- 6 3- 11 rani (1961) 46-275 Has a 12 377 86-1319 200 41-470 ae (1911) xmntlva repair) Tas HR-------------- 13.4 UP3I5------ 34 5.6 1.0-21.6------ 15 14.2 lO- 30 5 1.4 l.b- 1.6 oanUoU------------------------------------------------------------------------------------------------------------ HONS 015600 Hotel KB pi in analyses ut miniwii in part! par billion (incluling mwm ng/Wl), ehila adipose tlana analyaaa an espnsaad In parts par dlltoa. *!>* KBb (kur homlcga) and "IT HBi IMflar MbIobI an defined as ^aclaa having, respectively, Mortar and Unger gaa chnnatagraphlc retention tlaaute tm the EOT naUteUte p,p -a*. "L* PCBs Incladu 2-KBs through 4'KBs, plus warn S-KBsi H* KBs include 5-KBa ml higher, plus aoae 4-PCBs. 19 I. INTRODUCTION A. Origin* and Methodology of the Study In August. 1991. tbs firm of consultants In toxicology. Drill, fries*, Bsys, Looals and Shaffer. Inc., Arlington. Virginia (DfHL8) entered into a contract with the Edison Electric Institute (EBI) and the National Electrical Manufacturers' Association (NEHA) whereby DrHLS agreed to exaalne the toxicological and epidemiological literature on polychlorinated biphenyls (KBs) and provide EEI and NEHA with DrHLS' Independent, professional opinion on the human health effects of KBs at varying dosages or sxpoaure lsvels. To this end, the principal scientific studies and data compilations available on toxicological and epidemiological effects of PCBs, as commercial mixtures and as purified single congeners, have been reviewed by a team of scientists designated as the Category I team. Members of the Catsgory I team are Drs. V.A. Drill, S.L. Tries*, H.M. Hays, T.A. Loomis, and C.B. Shaffer from DrHLS. Additionally, Dr. G. Natanoskl of the Johns Hopkins University has acted as an independent member of the Category I team charged with study of the pertinent epidemiological literature on PCBs and thair human health effects, leading to an Independent assessment and evalu ation of the probability, causality and reality of these effects. Catagory I team review of the animal and human data resulted in draft material on the relationships between KB exposure and specific health effects In test animals and in HONS 015601 20 - exposed huaun populations. rurthar, where huaan data were lackinp or ineoaplete, eha Catapory I taaa aeabers developed pacific projaeelona or oplnlona aa to the probability of ooeurranea of eartaln baalth offsets In exposed human*, baaad on tha exlstinp aniaal/huaan data baaaa. Health affaet araaa acrutinizad in cluded; panes*! toxicity; affaeta on akin and otbar cutanaoua tlaauaa; affaeta on livar; affaeta on paatrie tlaauoa; carciaopaneals (axpariaantal and ellnleal observations); reproductive affaeta ineludinp fatotoxleity and taratopenlcity; autapenesis; Yusho dlaaaaa and ooeurranea of eaneart and otbar haaltb affaeta ineludinp ansyae induction, ehanqoa in laaunocaapatanee, and porphyria. Or. Matanoaki'a troataant of epldoaiolopleal obaaryationa conatitutad an indopandant aaetion of tha draft report. Draft aeetione frea tha Category I taaa were than reviewed for eontant. conclusions and oplnlona by tha aaabara of a aeiantifie taaa of pharaacolopists and toxlcolopists doalpnated aa tha Catapory XI taaa; Dr. r.S. Standaart (Georpetown univer sity), Or. A. Alvaros (Uniformed Services University of tha Health Seianeaa), Or. J.A. Thoaaa (Hast Vlrpinia University) and Or. P.l. Interline (University of Plttsburph). Or. Interline was the prlae reviewer of the epldeaiolopleal contribution node by Or. Hataneaki. Ceaaants and erltipua froa Catapory II taaa aaabara, slnply and as a proup, wara then tranaaltted to tno Catapory X taaa for consideration, leadlnp to revisions and aaplifieatlona that HONS 015602 21 are in place in eh* final draft of ehia ttudy. Comanta and uggeationa fro* aeianeiata repraeantlng th* aponaora of thia atody, EEX and NEKA, ara alao eonaidarad. In th* final veraton of th* atudy, to th* *xt*nt poaaibl*. a Motion on auavaary and opinion la appended to aaeh dlaeuaalon of a potential humn health affect attributable to PCE axpoaur*. Th* primary reaponalbility for *acli of th*a action* la aaauaod by th* Category z t*aa, even though th* con tent may hav* ban*fitt*d tram uaaful oontributlona by Category II p*raonnl. >. Co--*rclal PCB mature* Polychlorinated biphenyl* (Pea*) are **ab*ra of a claaa of non-polar chlorinated hydrocarbon* baaed on th* biphenyl nucleue, In which aultlpl* chlorine atom are aubatituted on nans 015603 12 - either or both the prlaad and unpriaed aromatic ring*. Certain individual mashera ot tit* PCI family have boon praparad in a relatively pura state, with substitution of ring poaieiona by eblorina ranging from dichloro lsoaera (symbolised as 2 - CS) up to the nonoebloro (9 - CS) and dacachloro (10 - CB) derivatives. Commercially, PCSa vara aarkatad in tha United Stataa undar tha trada naaa of Mraclora. may vara alao aanufacturad abroad undar eha tradanaaaa *fhanoclor* and *pyralene* (franca), 'Clophen* (Germany), and Kanachlor (Japan), may ara comprised of aixturaa of chlorinated blphanyla. Tha laat too digits ot tha O.S. commercial nano donate tha percentage of chlorine in aach mixture, a.g., hroclor 1242 containa 424 by weight of Cl correaponding to an average of approalaately throe chlorinaa par blphanyl aolacula. Ukawlao, Aroclor 1254, Clophan A30 and Kanachlor 500 all contain 544 chlorine eorraapondlng to five chlorine atoaa par aolacula on the average. Coaaerelally uaeful airturna of VCBa have been widely dlatrlbutad over the world in the paat few decadaa. uauaiiy in appllcationa that have precluded aaceaalve exposures of uaar populations, however, becauae of the graat ehaaieal stability of thane polychlorinated aolaeulaa, their persistence in the environment after accidental release can be lengehy leading to possible erpoauree of people and biota in the biosphere. The results of these espoeures, as well aa those of personnel occu pationally exposed to PCSa in the course of ehaaieal synthesis HONS 015604 23 and manufacturing operations, are of great importance from ttaa aeandpolnt of potentially harmful health effects that might occur on an acuta or chronic basia. C. PCB Impurities Commercial PCB mixtures ara truly complex, containing variable numbers and amount* of congeners within a given family of compounds, and traces of iapuritiaa, all of which are poten tially toxic to humans and animals. Impurities that have been identified in PCBs as manufactured ara polychlorinated derivatives of napthalane (PCNa), terphenyls (FCTs), methylblpbenyls, and dibenzofurans (PCOPs). The occurrence of PCOPs is particularly noteworthy in view of the higher toxicity for certain congeners, relative to KBs. It is iaiportant to note that there are theoretically 133 possible KOP congeners, a few of which are believed to be highly toxic. Mhile reviewing PCB toxicological or epidemiological data, a number of factors related to the actual material involved oust be considered. The FCDP content of commercial PCBs varies for aroclors the reported range is 0-2 ppm of total PCDP congeners. Por European and Japanese PCBs, the reported range for KSP con tent is 3-20 ppm. The impurity levels can also be affected by exposure to high temperatures and oxygen. For example, Aroclor 1234 is converted to 2-3% KDPa at SSO-COO degrees C. These same conditions result in the formation of polychlorinated quaterphenyla (PCQe). HONS 013605 25 IX. Yusho Episode In 196S a mass outbreak of food poisoning occurrad in japan, following ingoation of a cooking oil coneaainatad with ;CBS and other compounds, that aroused worldwide concern over the potential human health affects from exposure to PCBs. However, this poisoning, which became known as Yusho disease, differs sig nificantly in several ways from occupational exposure to PCBs in the United Stataa so that data from the Yusho incident cannot be extrapolated to indicate the effects of PCBs in industrial situations. ' Recent studies of the rice oil involved in the Yusho poisoning show that the oil contained relatively large amounts of other chlorinated hydrocarbons such as PCDPs and PCQs (see Kuratsune at al.. 19761 and Bayabuchl at al., 1979). The rice oil that caused the disease was found to contain about 1000 ppm of PCBs, 5 ppm of PCDPs, and 1000 ppm of PCQS; the amounts of the latter two classes of chlorinated hydrocarbons in the rice oil are higher than in the Aroclors used in the united States. Kayabuchl reanalyzed the intake data for the Yusho patient, and calculated that the average intake for the mean latent period was PCS 4M mg, PCDP 2.5 mg and PCO 4 39 mg> the smallest intake by a patient was estimated to be 111, 0.6 and 105 mg respectively. PCS concentrations In the tissues of Yusho patients were much lower than those of asymptomatic Individuals with body HONS 015606 - 26 burdens of PCI* resulting from occupational exposure. further, pea fractions of blood, tlaauaa, and braaae nllk of Tuaho patlanta yielded gaa chromatographic patterns showing a larger amount of late-elutlng peak* than do PCa fractions of tlaauaa of Individuals aubjact to othar typos of PCI axpoaura (Koda and naauda, 1?S). These pattarna hava navar boon obaarvad In Individuals (buaan or animal) exposed to PCI* in othar situations, thay ara unique to Yusbo dlaaaaa. Also, PCOPs hava baan found In tlaauaa of XUaho patlanta. Purtbar avldanca for tha uniqueness of tba ayndroaa In huoana axpoaad to tha Tuaho oil la fumlabod In two rooont studios. Rayabuchl at a^. (1991) In follow-up studios on thaao patlanta flvo or aero years after tha poisoning found alqnlfleant positive correlations for tha years 1973-1971 between blood concentrations of PCM and the total amount of rice oil consumed, but not with the dosage of rice oil consumed per unit of body weight per day. xaahimoto at al. (1911) found that Tuaho la quits different from ordinary PCI toxicity In tha sense that, even 12 years aftar the first outbreak, PCQs have been found In tha patients' blood and both PCOa and PCOPs have been found In their tissues and organa. It ia obvious from this brief review that Tuaho cannot be considered a nodal to reflect the possible effects of the PCS exposure in man. Although much can be learned from the Tuaho HONS 015607 27 - Incident, It would b aialeadlng to attempt to intarprat the obaervationa on Yuaho patlanta aa valid aigna and ayaptoaa of ovaraxpoaura to PCIa or to attaapt to quantify tha poaalbla affacta of PCS axpoaura baaad on Yuaho dlaaaaa. K. Yuaho Plaaaaa Yuaho dlaaaaa la eharactarixad by tha ingeation of a alxtura of chlorlnatad hydrocarbona contalnlnq PCIa in larqa aaounta ovar a ralatlvaly abort parlod of time (latant parlod fro* atart of Inqaatlon to onaat of tha dlaaaaa avaraqad 71 daya). In contraat. tha atudiaa of PCI axpoaura In workara In tha United Stataa hava baan eonearnad with tha poaalbla affacta of chronic axpoaura to aaall aanunta of PCIa through Inhalation or akin.contact. The principal algna of Yuaho dlaaaaa ara akin condltiona auch aa acnafora aruptlona, plqaantatlon of tha akin and nalle, and hyparaacration of tha Meibomian glanda. Chloracna and hyperaacratlon of tha Haibcmlan glanda ara baliavad now to ba cauaad pradonlnantly by PCDPe. Byparplgaantatlon of tha akin la obaarvad raraly, If ever, In human populatlona with baavy occupational axpoaura to prlaarlly PCIa. Tha actIona of PCOPa appear to differ In aavoral waya froa tboae of tha PCIa. luratauna at al. (1970 aboved, for axaaplo. that tha liver appeara to concentrate PCora aalactivaly relative to PCIa. It waa alao found that relative to PCIa, tha concentration of PCOPa waa about 250 tinea higher in the rice oil than in unuaad Kanacblor-400. Additionally, tha PCOPa appear to HONS 01560S - 28 - be highly toxic, at laaat in tha rahbltj a tingle oral doaa of 0.3*1 ng/kg of tho trl- and tetra- chlorodibenxofurana cauaad tavara and oftan lathal nacsoaia in tba rabbit (Rofaann, 19311 auor at al., 19*1). a. yuaho Diaaaaa and Llvar function In view of tha affact of Kla on tha liver of tba rat and tha highly toalc action of Kora on tha llvar of tha rabbit, it vaa antlclpatad that tba Yuaho patiant would have aavaro Uar daaaga. but auch haa not baan found. In thoir raviaw of yuaho diaaaaa, Kuratauno at al. (1*73) Hat *tha aubjactiva eyuptoae of Tuaho aa atatad by patlanta') lit report Jaundlca. Data to eonflra tha patlanta' 'aubjactiva ayaptoaa* ara not pro*idad, nor ia tha praaanea of tbla 'ayaptoa* conflraad by otbor atataaanta of clinical findlnga. Prof. grabe (Chief of tba Study Group) did not list jaundlca aa a algn or ayaptoa of Yuaho diaaaaa and tho dlagnoatle erltarla adoptad in 1972 do not aaka rafaranca to jaundlca or tha naad tor a llvar function taat in thaao patlanta (tea Kuratauna at al., 1979). Tha following two papura on yuaho diaaaaa and llvar function ara in Japaneae and tha brief auaaary given below la taken froa tha raport of Kuratauna at al. (1979). Okwrara and Katauki (1999) They exaalned 24 patlanta aoon after tba onaat of tba diaaaaa) HONS 015609 - 29 - (1) Thar* war* no objective signs of liver disorders; (U) Ho patiants war* jaundiced and only tbra* had palpabl* livers (in on* patiant examinations of a livar biopay ahowad marked hypertrophy of eha aaooth andoplaaaic reticulum). Okunara (H72) i Livar function taata war* performed in 3d Yuaho patiant* with varioua subjective symptoms, (i) hn ineraaa* in lactic dehydrogenase (Loa-5) and in thymol turbidity titar waa obaarvad in ton* of tb* aavara cases, 'but no dafinit* avldanc* for livar diaordara waa obtainad.* In a follow-up study of 131 Yuaho patiants tha naan a*run bilirubin waa 0.41 mg/100 al coaiparad with 0.47 mg/100 ni in control patiants (Hirayama at al., 1974). Tha dlffaranca waa atatistically significant and th* author* suggest that thar* nay b* accalaratad bilirubin diapoaal froa th* blood. It aay b* concluded that th* Japanese findings do not provide avldanc* for th* development of hepatocellular injury or jaundice in patiants with Yusho disease. C. Yuaho Piseas* and Carcinogenicity Drab* and co-workers (1979) report that SI of 737 Yuaho patiants in th* Fukuoka district had died and they list th* causa of death for 31 of th* patients. Thar* war* 11 deaths (3S.4t) from neoplasms which they stats is substantially higher than tha 21.lt rat* that is *tha aortality rat* from neoplasms in tha HONS 015610 - 30 - aaaa prefecture thta year.* A further analya la la not pro*idad. Tha following malignant neoplaama were Hated aa the eauaa o( death for the 11 petlenta with cancar. Anatoaleal Site Stomach Cancar No, of Caaaa 2 Stoaaeh Cancar t Liver Cancar Livar Cancar a Clrar Clrrhoala Lung Cancar Lung Tuaor 2* 2* 1 Braaat Cancar 1 Malignant Lymphoma TOTAL Autopeled _2 11 Information on ago and othar relevant aptdaalologlcal data ara not given, and avon a tantatlvo conclualon ragardlng Yueho dlaaaaa and any malignancy auat await further analyala. HONS 015611 31 III. Body Burdens, Metabolism, and Kinetics A. Introduction The degree of chlorination ( 2 to 10 atoms of Cl par PCS molecule) and tha poaltiona of tha chlorlna aubatltuanta on tha biphenyl rings both exert a profound Influence on how mammallan systems handle any given PCB aolacule. Tha degree and poeltion of chlorination play a major role in determining the' pathvaya for aetaboliaa and elimination of the parent moledelea and thalr aetabolitne by animal modele and the human. Tbeee etructural factora alao bear on lipid aolubility of the moleculee. and therefore Influence to aoaM extent the kinetlea of PCS tlaeme dietrlbution and atorage. The following aectiona deal with the preaent etate of knowlege on thee# PCS handling aechaniaaa em ployed by animal modela and the human, recognising that there la a strong linkage in the dynamic proceaaea beginning with expoeure and ending in excretion. Theae toplca will be treated In three groupingsi (1) distribution and storaqe of PCS metabolites in tissuesi (2) metabolism and excretions and (3) kinetics or the dynamics of PCS turnover in animal models and the human. Presently, some generalisations emerge with regard to PCS struc ture vs. reactivity relationships and mechanisms for handling FCSs in test animal systems that maka reasonable extrapolation to potential events in the lunsan organism possible, even when direct evidence for actions of a given compound or PCS mixture in human populations is not available. HONS 015612 - 32 - Additional attention ha* been diraetad to available Information on the aetiona of PCDPs In aniaal aodala and the human, and to a variety of biochemical atfacta racordad for PCS* and thair aatabolitaa in aaaaalian aystaaa. PCDPs aay ba con taminant* of soa* coa*aardally uaad Kla. Although 10-20 ppm of tbaaa eontaainanta have baan found in PCI* aanufacturad in Europe and Japan, only traca amount* on tha ordar of on* or two up of total PCDP congeners par p of PCS baa* baan raportad in tha Aaarican aanufacturad alrtura Aroclor 1254 (Iowa* at al., 1575). 0. PCI Platrlbutlon and Btoraoc in Tlaauaa A conaidarabl* body of litaratura oalata on atudla* of tha tiaa dapandanca of tha distribution, aoaaaant and atorap* of PCla and tbair aatabolitaa in tha tiasuas of aapariaantal aniaal aodala and of huaana, following aspoauraa to cblorinatad biphenyls as pur* compounds or aisturas. In tast aniaal aodala ualnp unlabalad or radiolabalad (1/2 C or 1/2 HI PCI*, controlled aspoauraa war* ganarally by tha oral rout* (atoaach tuba, or in tha faad) or by intravenous injection, followed by study of tb* cnanpinp distribution of tb* ap*nt and its metabolites in tba eirculatinp blood, in tissues, in bll* fluid and in axcrata as a function of elapsed tiaa attar doainp. In tb* huaan, aspoauraa with rasultinp body burdens of PCS* were panarally of tb* aubebronie type staoalnp either froa aasalv* poisoning events, as in tha Tuslto events, free chronic occupational exposures in air and via akin contact, and via PCS eontaainanta in air, water, food and surface contacts in tb* aabiant. Busan* aay also have been HONS 015bl3 - 33 - expoeed to PCBa occupationally In the chaaical aanufacturlng procaaa, in the aanufacture of capacltora and In the aanufactura and repair of tranaforaera. Until, racantly, aavaral aicroacopa laaaralon oils contained 30-40% PCBa aa Aroclor 12S4, cauaing potential eapoaurea of atudante, pathologlata, alcroacoplata, etci tha degree of expoaure la low and the penetration through akin froa thaae produeta aay not be aa extenalve aa in large acale aanufacturlng procaaaea. In huaan atudiea, PCS diatrlbutlon and atorage in readily obtained tieauea waa generally followed epldealologlcally in expoaed populationa by aonltoring levala in blood, aoaatlaaa in aother'a allk aa a function of tlae and aoaatlaea by aeaaurlng PCBa in adlpoae and other tlaaue aaaplea obtained clinically and poet aartea. Anlaal Model Baaulta The picture of diatrlbutlon and atorage of PCBa and their aetabolltea in tlaauea over tlae haa been developed aoet coapletaly froa controlled doae experlaanta in aniaal aodela. Generally, rata and alee were the aniaala of choice for thia work (Burae at al., 1974; Gayer at al., 1980; Cuiney at al 1978; Hattewe and Anderaon, 197S; Horalea and Matthewa, 1979; Albro and Plahbein, 1972; Burae at a^,, 1974), but the dog, aa well aa the aonkey, baa alao been uaed (Hau at al., 1975a; Hilling at al., 1979; Sipea at al., 1910). The dynaaica of tlaaue diatrlbutlon vary with different iaoaera and congenera, and depend In large aeaaure on whether or not the apeclfle PCB HONS 015614 - 34 - aolecular structure allow* rapid metabolise and excretion of polar aetabolites via bile, facaa and urlno (Hilling at al., 1)7*; Safa ej, a^., 1)71; lipaa jj, a,., 1)10; Hatthawa at *1., 1)7(: Gulney e l.. 1)71; Ouxalian. 1)7)) or alower aatabollaa with ratantion of parant eoapoonda and aatabolieaa In tlaauaa. Aa will be diacuaaad In the following aaetton, aatabolic txana- foraatlon in tha liver ia particularly faclla for those VCBa with lower chlorine content (2-0 through 4 - Cl, l.a. 2-4 ehlorlnaa par to molecule) and with adjacent ring carbon atone unaubatltuted by chlorine atone (Hatthews and Tuey, l)(0; Sundatron at al.. 1)7(; fato aj al., i)(0; Janacn and fuadatreat * a^., l)74b; Qhlaauddln e a^., 1)7; Hatthawa 1*7(). Tor aany PCI aolaculaa la which mtabollc tranaforaatloo and ascratlon ia not aseaaaivaly rapid, tha dynamic dlatrlbutloo of parant compounds and aotabolitaa in tlaauaa following doalag baa boan studied carefully (Mitutanl at al., 1)10; Safa at al., 1)71; Sipaa at al,, 1)10). Tha following generallaatIona appear valid in anlaal aodele for structures ranging from 1-0 to 4-0 and higher. flrat, tha tCU are readily abeorbed from tha gut following oral administration and appear rapidly in tha blood- atraan (Albro and Plabbain, 1)72; larlin at a^., 1)71; Chan and Hatthawa, 1)74). within alnutaa to hours, tha aatcrlala largely clear from the blood and aceuaulate in the liver and in auaele tissue (larlin at al., 1)71; lurae. at al., 1)74; Chan and Hatthawa, 1)74). however, traces of FOs have been found in tha HONS 015615 blood of humane, probably by redistribution from other tlssuaa, yaara aftar exposure. Tha livar la the primary locua for meta bolism of tha PCBs, aapaelally for raacelva spaeiaa, leading to lxturaa of parane molecules and aatabolitaa that than aithar tranaloeata to othar tlaauaa or ara excreted by both bile/gut, lusen/feces and urinary pathways. As translocation from livar and auscla occurs - in tha rodant modal and othar spacias ovar tlma parlods ranging from hours to many days, tha ultimata dapots for major amounts of tha non-polar PCBs and thalr polar aatabolitaa appear to ba adipose tissue and skin (Berlin at al., 197Si Hanson, 1979) Guinoy at al., 1979) Bursa at al., 1974). The general distribution pathway in rodents may therefore be characterised aa sequential migration from gut and bloodstream entry points to liver and muscle tissues, in a rapid process, and thence to depot storage in body fat and skin. whan tha PCS structure is such as to permit ready metabolism to polar hydroxy, dihydroxy or dlol derivatives, tha metabolic process say be closely linked in time with excretion of tha metabolites (Jensen and Sundstrom, 1974; Lay at al., 1979i Matthews and Tuey, 1990) Matthews at al., 1979; Matthews and Anderson, 197S). Animal studies on urinary and facal ox eration of PCBa (Gusollan, 1979) Matthews and Anderson, 197J> Berlin at al., 197S) Lay at al., 1979) Chan at al., 1974i van Millar at al., 197S), and rates of elimination of PCBs from liver into bile and then into gut/faces, show that tha larger MOMS 015616 - ]< - proportion of Mention in rodents 1* by focal eliainatlon (Kato at al.. IMOi Lay at al., l*7; Own at el., 17> van Millar at al., 1975; Chan and Matthews, 1*74) of polar aatabolltaa, noatly glucuronldes, alinlnatad via the blla. Tha dynaalca of dlatrlbution and elinlnatlon of KBa in two aonkay apaclas havo baan studied (Bsu, at al.. l*73a> Slpaa e e^., 1**01 Baa at al., l*7Sb), and an found to follow a aiallarly eoaplaa pathway, but with wldar tiaaua distribution ultlmtaly than that saan In tha rat. In our opinion, thla difference My relate In part to tha ability to analyse non tissues in larger aniMls. With fat tlaauas present la only snail proportions in the Infant Ihasua aonkay, the ultlaste depots Included bone marrow and tha adrenal glands. In addition to akin (Bsu jt 197Sa). ' Long-tern studies Involving chronic adninlstratloo of KBa at low dosage levels to anlnal models for significant tractions of their lifetlnes, with detarainatlona of total bur dens and tissue distributions achieved over tine periods at one to two years of ingestion, are lacking. Biwan Body Barden Moults fren tpldenloloelcal Studies tsperinental data on body burdens and tiaaua distribu tions of KBa In hunana as a result of praelaely-Masured In takes are net available. Bowever, there are aeveral population sectors far wblcb exposures to KBs can be at least roughly eetlMted, and fron which tissue aaaples (blood, subcutaneous and other fatty tissue, etc.) have been taken to obtain Indices of HONS 015617 - 37 - body burdan. The** aactocs include (1) human* occupationally axpoaad to PCBa durlnq yaars In which thay war* attployad In aanufacturlng procaaaas (Karppan*n tt ti,, 1972) Haaagawa at al., 1972) Kltaaura at al., 1973; Ouw at al., 1979) rischbain at al., 1979* Wolff at al., 1991) Haronl at al., 1991a, bj Salth at al., 1991a, bi Chaaa at al., 1991)) (2) huaana accidentally poiaonad by PCBa Inga*tad In contaminated fooda, aa In tha Yuaho axparlanca In 1999 and In corresponding ingestions of contaalnatad rica oil In Taiwan (Chan, 1990t EFA auaaary, 1990)i and (3) huaana living in araaa In which PCBa have aoaahow antarad th* food chain or water supply In aaaaurabla aaounta, loading to longtana, low-level body burdana In adulta that aay alao ba praaant In th* huaan allk aupply for tranaalaalon to infant* (Buaphray, 197S, 1990) Kuwabara at al., 1979a> Kuwabara at al., 1979b; Ha* and Oavlaa, 1979; watanaba at al., 1990). An additional aourc* of expoaura that 1* aore difficult to characterise quantitatively ataaa froa th* exposure of faailiaa to contaalnatad clothing of PCB worker*. Survey work baa bean done In all of these popula tion sector* worldwide. The results are sketchy, but tentative qualitative generalisations can be drawn. Blood or plaaaa levels of PCBa are most readily followed in potentially exposed population data using highly sensitive analytical techniques such a* gas chrenatography and aass spactroaatry. Por occupationally axpoaad paople (NIOSB, 1977) Salth at al., 1990a) values ranging froa 10 ppb up to a aaxlaua of 3330 ppb have bean observed, with th* additional HONS 015618 - 34 - qualitative finding from Japaneae referencea that tha half-life for disappearance of PCBa froa blood following eaaaatlon of axpoaura ranges froa ) to 30 aontha. PCB blood levala vara higher with lneraaaad duration of aapoaure. Tor ruaho vletlaa In Japan, with blood aaaplea taken 3-7 year* following axpoaura to PCBa, In the 1973-1973 tine fraaa (mods, 1977) valuaa In tha range 3-33 ppb were obaarved. Enhanceaent factora over control group levala (naan, 3 ppb) aa great aa 10 were calculated, but tha obaarved blood lavela vara atlll auch lower than levala found in japaneee capacitor vorkara. It la of Interact to note the obaervatlon of Hunphrey (1973) on the very alow clearance of PCM fron tha tioeuae of huaana eapoaed by eating flab. In general populattone, blood plaana or aerun levala of PCM in the range 3-19 ppb have been found (BXOM, auanary p. 30). A currant and well docuaMntad atody of body burdena of PCM in peraona aaployed tor aany yaara In capacitor aanufacturlng (Wolff e a^., 1901) la of apodal value froa the atandpolnt of lta correlatlona of tlaauc concantratlona with aatant of aapocurea. With highly chlorinated PCM (B-PCM), plaaaa concan tratlona of 1-344 ppb in aapoaad paraonnal correlated with total accuaulatad axpoaura tlaw. for tha laaa highly chlorinated PCM (L-PCM), plaaaa lavela In the range 4-2330 ppb oorrelated batter with apeciflc taaka of lndlvlduala working with thaae 2-CB to 4-Cl aolaculaa. Alao obaarved In thla atudy waa a correlation of lavela in plaaaa with levala In adlpoae tlsaue for each elaaa H0N1 013619 - 39 of PCBa, with B-PCB* and I.-PCBa taken aa separate classes, and an overall adlpose/plaaaa partition eoafficlant of 190. The levels of PCBs and aatabolitea in subcutaneous fat in humans have alao baan surveyed in general populatlona (NIOSH, 1977), in groups such aa Yuaho patianta with high exposures, and in aoaia occupationally exposed indlalduala. For tha general population, lavala in fat range froa laaa than 1 ppa to greater than 2 ppa. For Yuaho indlvlduala, elevated fat PCS lavala in tha range 13-7S ppa have been obaerved, correepondlng to peak anhanceaant factora as high aa 30 over the population at large. It should alao be noted that the apectrua of compounds in buaan tiaauaa la not neeaaaarily identical with tha apectrua in tha alature to which a given population was axpoaad (Kuwebera at el.. 1971a). Ranges of adipose tissue PCB lavala in occupationally exposed individuals have been reported aa 160-635 ppa (larppanen at al., 1972), 1-12.6 ppa (Chase at al., 1961), and 2-271 ppa (Wolff at al., 19*1). special surveys have been aade of PCa levels in the allk of lactatlng buaan aothera (Has and Davies, 1979t Natanabe at al., 19IOi HZOM auaaary) and of lavala in huaan eabryonic and fetal tissues resulting froa in utero transfer froa Yuaho feaalaa (HIOSH, 19771. Ruaan allk saaples with values of PCBa in the range 0.000-0.1 ppa have been observed. Claarly, con centrations in allk are higher than those in blood prlaarlly because allk la rich in fat. Organa froa the eabryonic and fatal tissue displayed PCB levels in tha range 0.002-0.750 ppa HONS 015620 - 40 Cor whole tiaauea, with Cat derived Croa thaaa organa yielding level* In tha range 0.04-1.14 ppc. C. PCI Hotabcllaa and excretion Aniaal axparlaanta involving axpoaura By Evading, in tubation or injection of puriflad PCI taoaars in taat aniaal nodala havo ylaldod aoaa iaportant generalixatlone on tha , aaehanlaaa aaployad by aaaaalian apoelaa to aatabollzo PCBe to ore polar derivative*, and to axerata both parant cocpound* and aotabolltaa. lagInning with raady abaorptlon Croa tha gut and tranatar to circulating blood, or with direct Injection into tha bloodatraaa, a given PCI aolacula ultlaataly raachaa tha llvor where aajor aetabolic actlona are initiated. Tha proceaaea of aetaboliaa and excretion aa a raault of theae actlona axe ecaplax, and dependant on the aolaeular atructura of the PCI. General Caaturaa of theaa proceaaea include tha following pointai (1) Variable aaounta of PCI aotabolltaa are axcratad via tha facaa after delivery to tha gut luaen via tha bile flow pathway. Unchanged PCIa can occur and be diacharged in ailk. Relatively laaaar aaounta are excreted aa polar aotabolltaa in ' urine than in facaa in aoat aniaal aodela (Rato at al., 1M0> Lay s&aj^., 1171 Chan at al., 1974i van Hillar a^a^., If75i Chan and Natthewa, 1174). (2) Metabolltea are Coned in patterna that differ quantitatively or qualitatively aaong aaaaalian apeclea. Thay are generally feraed by oxidative proceaaea that are thought HONS 0156*1 - 41 - to involve n arena oxida formation that raaults In nonohydroxylation, dihydroxylatlon, hydroxylation and nathylatlon, or dlol formation accompanied by partial reduction of an aromatic ring (Berlin et al.. 1975; Lay at al., 1979; Lucier at al., 197*; Hilling et al., 1979; Sundatrom at al., 1974; Gardner at al., 197J) Chen at al., 1976; Matthave at al., 1979; Van Hiller at al., 1975; Hau at al.. 1975a; Hsu at al., 1975b; Burse at al., 1970. Evidence also exists for dechlorination of a PCB in the process of metabolism (Kato et al., 1910; Hutsinger at al., 1974b). for some PCB structures, the procese of oxidative meta bolism nay be closely followed by excretion via the liver-bllefeces pathway (Chen and Hatthews, 1974). (3) Compounds with lower levels of chlorination (2 CB to 1 or 4 - CB) generally undergo metabolism more readily, and faster than the more highly chlorinated PCBs. The more highly chlorinated PCBs may persist in tissues for years because they are not metabolised. Indeed, 10 CB la virtually inert. (4) In the case of metabolism by oxidative pathways, the most facile process Involving formation of hydroxylated products occurs when one or both aromatic rings contains adjacent pairs of ring carbon atoms (called vicinal ring atoms) that are unaubatltutad by chlorine atome. In the absence of unsubstituted vicinal positions, direct hydroxylation can occur in the ring, but with greater difficulty (Gayer at al., 19B0; Hatthews and Tuay, 1910). HONS 015622 - 42 - The importance of vicinal unaubatituted poaltlona on KB ringa in facilitating oxidative natabollsa in the Unr ia explained by a aechaniaa that involvaa an arena oxida interne* diata (Daly at al., 1972). Khan aithar or both of tha vicinal poaltlona contain chlorlna, reaction rataa will ba lower, but tha mechaniaa la not antiraly ruled out. Additional aolecular rearrangeaenta, including tha ao-callad nib (National Inatltutaa of Health) ahift of a ring aubatltuent (Daly at al.. 1972), nay be involved. Laaa la known about aecbaniaaa of direct enaynatlc hydroxylation that do not procaod through an arena oxide inter* mediate. Arana oxide (S) Nydroxylatad aaeabolieea of tha PCBa and chair eonjugatea will generally dlaplay different ordara of toxicity than thoae ahown by tha parent noleculea. (<) A general point of lntacaat with ceepect to KB aetabolltee Ilea in tha obaervatlon that they are uaually more polar than their parent coapounda. Conjugation of tha hydroxy and dlhydroxy eetabolltea aa glucuronidaa or aulfataa can occur, leading to polar eonjugataa that can readily ba axeratad. Tha polar eharactar of eetabolltea, in eontraat with the non-polar HONS 015623 - 43 characteristics of tbs starting PCBs, can lead to differing dis tribution, storage and excretion patterns for the two classes of cheaical compounds. polar metabolites are not readily par titioned into fat or reabsorbed from the urinary or gastrointes tinal tracts. Therefore they are excreted relatively rapidly. D. FCB Kinetics Profiles of the dynamic growth and decay of PCS/ meta bolite concentrations in each key tissue can be drawn from controlled toxicological experiments. The distribution of a given PCS and its metabolites in the blood, tissues and excreta of test animals is followed as a function of tims after administration. Tissues are viewed as body compartmsnts into which materials are delivered from the arterial blood aupply, in which some metabolic processes say occur, and from which materials are delivered into the venous drainage systems, A collection of such compartments communicating with the blood supply and controlled by rates of flow through the comportments, with postulated equilibration of any given chemical in a compartment with its venous blood flow, constitutes an appropriate modeling' system for correlating PCI distribution, storage, metabolism and excretion kinetics in an animal over time. This multi-compartment aodel has been employed by Matthews and co-workers and others (Anderson et at., 1977; Bungay it tl., 1979; Tuey and Matthews, 1977j Luts et al., 1977), to sort out the kinetics of specific PCB isomers in rodent models. The PCB administration can be either direct MONS 0156/4 - 44 inaction of a PC* Into the blood circulation, or It* abaorptlon Into blood (ran tho put atear (coding or intubation ot tha coapound. fact*tory pathway* art ala tho liver/blla/gut routa or tha bloodAldney/urlnary allalnation ayataaa. Tho auccaaa o( a nodal aquation ayataa in fitting analytical data for a given PC* and predicting tba abapo of tea concentration va. tin* curve (or each organ or coapartaent dapanda In largo aaaaura on aavoral factor*, includingi (11 tha aaaignaont of aultabl* value* for diatrlbutlon coafficlanta of PC* coapounda in each coapartaent (2) tho differential blood flow to aarloua organa* and (3) tho claaranca froa organa and tba body. Tbla fitting procaaa haa now boon carried out for a nuabar of PCla for which binotic data are available (underaon at al., 1977* Chakraborty, 1971). Tha goodnaaa of fit of tha aodal to each aat of PC* klnatle data available attaata to tha validity of tha aaauaptlon that aatariala partition at aquilibrlua between blood and tiaaua according to purely phyaleal propartlaa Involving aolubillty paraaatera of the choaicala. t. Hlaoellanaoua loch*alcal Effect* of POa Studiaa of tha actiona of PCla in anlaal aodala and buaana caponed to thaao chahlcal agent* accldantally or la tha occupational aottlng have ravaalad a variety of biocbanlcal affect* on nahaallan organlaaa. Son*, auch aa alteration of drug aatabollaa by virtu* of PC* induction of alcroaeaal aixad function osldaaaa (HPO), are treated elaewher* in thla docuaent. HONS 015625 - 45 Other affects appear to ba unrelated eo HFO actions, and have baan datactad in the couraa of acuta or chronic toxicological experiments with laboratory aniaal oodals or epidemiological urvays of axpoaad human populations. In an animal study (Bastomsky at al., 1)75) aiaad at probing tha previous evidence on reduced serum bilirubin levels In Yusho patients, it was found that hroelor 1234-treated cats showed increased liver microsomal protein, as expected, but with no significant elevation in liver bilirubin UDP-glueuronyl transfa rase activity that could have accounted for reduced serum levels. Other studies (Grots et al., 1975) Lake et al., 1979) have shown enhanced levels of this trsnsferase activity. At present therefore, the mechanism underlying the hypoblllrublnemia In Yusho patients remains speculative. from epidemiological studies of Yusho patients (Strlk, 1979), a rather general biochemical finding has been the obser vation of porphyrins In urine and porphyrin accumulation in liver, as a result of exposure to chlorinated hydrocarbons including PCBs. Chronic hepatic porphyria is the designated condition, which increases with exposure and can therafore be taken as an indicator of the extent of PCB exposure. Porphyria is discussed elsewhere In this text (section XI). A biochemical factor that may bear on the toxicity of PCBs in certain sensitive human populations, e.g., fetuses, neo nates, ensyme deficient adults, ate., is related to the ability to excreta tha toxic phenolic metabolites rapidly and efficiently. HONS 015626 Sine* conann rout* of deration involves preliminary conjuga tion of th* phenolic hydroayl group* with glucuronic acid in eh* body, or aulfae* conjugation, it haa boon polntad out (Calabraaa, 1977b) that huaan group* that ar* biochemically daficlant in th* ability to conjugate could b* pradlapoaad to accuaulat* pea* and aatabollta* bacauaa of thi* daficiancy. A aor* aarloua conaeguanca of altarad liver capability would b* a raducad capacity to deal with arena oald* Intermediate* effectively. An lntaraatlng biochaaical defect in huaan lyapbocytaa haa been atudied (La* and park, 1910) that can be attributed to direct action of PCI* on theae whit* blood call*, for both huaan lyapbocytaa and aonocytaa, it ha* been found that intubation of the cell* with Aroclor 1294 la culture aadlua cauaea a decraaae in their ability to taka up gluooa* frea the aadlua. A non-aotaboliaabl* analog of glucoaa, 2-daoxyglucoa*, waa uaad to detect the biochaaical defect, which waa attributed to PCI expoaur* but which aay well be aor* general for any organic chaaieal that concentrate* in th* fat of the call wall, it aay entail direct action of PCBa on an active tranapore procaaa in cell aaabranaa. In thia regard, liver glueoae-4-phoaphataa* baa been found to be inhibited in rata fad varioua Aroclor aiatureo (Littaraat at 1., 1972). The proceaaea by vhieh PC* pretreetaent influanca* rata* of protaln and nuolelc acid (JUIA) ayntheala and turnover in rat liver tiaauea have been lnveatlgatad ayatanatleally HONS 015627 47 (Narbonne, 1979a* b, c, a), using radiolabeled substrata*, it la elsar that livsr tissue, In vivo and In vitro, rssponda to PCS treatment (Phanochlor DPO by inersasing tha protein synthaala in llvar sieroaoaal fractions In a procass that Is both aga and sax dependant. Concoaitant Incraaaaa In llvar fat are also saan vivo, as vail as changes In levels of SNA synthesis In various liver fractions and Increases In liver veights. Proa tha turnover experiments In rats. It la also observed that alcro- sosmI attsferane protein aetabollaa la enhanced by ingestion of Phanochlor DPS. . Seas further biocheaical effects of PCI exposures on the huswn are seen in workers occupationally exposed to these cheaicals for extended periods of tiaM (Salth at al., 1979), The findings, as yet unexplained in tens of requisite doeagee or underlying aeehanisaa, are thati (1) the circulating tri glyceride levels in blood plasaa are elevated for expoaed workers over controls, but are still within noraal levels) and (2) the circulating levels of high density lipoprotein are lowered in expoaed groups of workers. Another biocheaical effect seen in PCS-treated rats is worthy of note, since it relates to an lapalnsent of excretion of an laportant drug and its metabolites (Schaoldt at al., 1979). In the Nlstar rat pretreated with Aroclor 1249, the drug digl- toxln and its metabolites were blocked to a significant degree froa excretion via the bile. The results suggest that tha HONS 015628 - 41 - Block*** la due ae laaat in part to a pca-lnducad iapalraant of tha cleavage of on* of tha augara fro* digltoxin. rlnally, tha action of PCla leading to induction of ixad function oxldaaaa (MPO*) In tha livar, with elevation of aaaodatad cytochroaM* P-450 or P-44(, Baa potential conaequancaa. Thaaa ara dlacuaaad alaawhar* (auction XI). P. Sea* OOaarvatlon* on Polvchlorlnatad Olbaniofarana Tha PCDT*. ar* of apodal intaraat aInc* ebay ara known to b* highly toxic in tBair own right, and the dagra* to which, aa contaainanta, thay add to the potancla* of PCI alxturaa in production of adwara* baalth *ffacta in anlaal aodala and huaana haa not boon fully evaluated. Sovavwr, toxicological atudlaa in anlaala with PCDPa containing 1-4 or aora Cl ateaa par aolacul* (Norlta and Oiahi, 1*77 Ooldataln at *1.. 197( vaarkaap at ai., 19(1) have ahown that the PCSf* ar* qualitativaly quite aiailar to thair atructural PCI analog* with reaped to propanla* of (. . tlaau* diatrlhution, aataholiaa and axeration. in eh* aouaa, tha heavily chlorinated iaoaaxa locallie In livar, aplaan and fat (Norlta and Oiahi, 1977), with a half-lit* for clearance fron the body of about two waaha. In the rat, aataholiaa occur* by oxidative pathway* leading to aono- and dlhydroxylatad derivative* (Vaarkaap at al., 19(1), with a wld* variation in ring poaltlon by tha hydroxy fund ion aaong the lower chlorinated PCDP*. The octacbloro darlvatlv* yield* no aatabollc produd* in tiaauaa or HOWS 015629 - 49 - excreta (Veerkaap at al., 19(1). in tha chick (coldateln at al.. 197*), tha 2,3,7,-tetrachlorodlbenxofuran (TCDP) haa baan shown to ba relatively poor in anxyaa induction. Bowavar, Goldatain at al. (197*, 1979a) hava ahewn that 2,3,7.S-TCor la a potant lnducar of eytochraaa P-450 and acyl hydrooaxbon hydroxylaaa. Soaa important data on pcor aatabollaa and axcratlon in tha huaan war# obtained (kappa at al., 1979) by analyala of livar tiaaua froo two daceaaad patianta in tha Tuabo dlaaaaa group in Japan. Proa tha differencaa in PCDF atructural relatlonahipa in tha contaainated rica oil and in tha PCSP tractiona isolated froa tha livera, infarancaa could ba drawn with reapect to PCDF atructura (all containing 4-C chlorine atoaa par aolacula) retained by the liver va. thoae that had diaappearad froa liver by procaaaaa of aetaboliaa/aliainatlon. In atrlklng parallallaa with PCI diepoaitlon in aaaaallan tiaauaa, it waa found that nona of tha PCOPa ratainad in liver had two vicinal unaubatltutad (by Cl) poaitiona in aithar aroaatlc ring, apparently, all such molecules had baan aufflclently auacaptlbla to oxidative aatab ollaa to ba hydroaylatad and axcratad froa liver in tha bile. Tha above obaervationa are not to ba taken aa alllnclualve with reapect to tha body of information that auat ba developed in tha toxicology of tha pcora. Thla claaa of com pounda , even at low contaalnant lavala, ia an iaportant contrib utor to tha total apactrua of toxic affacta froa coaaercial PCI lxturea. HONS 015630 - so - 2. duaaary and Opinion Sea* general reflections and opinions can reasonably be drawn troa tha pcawioua dlacuaalon regarding the use of anlaalderlved biocheaical and kinetic information to predict certain event* and basarde in huaan PCS Intoxications. (1) Pathways of absorption, distribution, aatabolisa and excretion have been explored fairly extensively in aniaal aodels. Proa the species variability seen, coupled with Halted observations in the huaan, educated guesses and predictions can be aade on the occurrence of certain toxic effects and processes in the huaan. (2) Hatbeastlcal analyses of kinetic data troa aniaal aodellng experlaenta lead to seae generalisations (butt at al.. 197?) that could apply to Kb turnover kinetics in the huaeni (1) kinetic rate constants for aatabolisa of KBs by the liver decrease as the degree of chlorination increases; (2) rat* con stants for biliary clearance of PCX aatabolites froa the liver are nearly the seae for all PCX*; (3) urinary clearance rates for TCSs decrease as the degree of chlorination of the parent aoleculaa increases; and, (4) for each PCS, the value of the distribution coefficient between fat and blood is greatsr than that in any other aajor tissue, indicating that tha fat eoapartaent of all tissues nay constitute the aajor PCS depot. (3) Kinetic aodels derived froa aniaal daea aay be use ful for prediction of tia* courses of action in tha huaan once MOMS 015631 - 51 - addition*! data on metabolism and claaranea rates Cor individual PCBa In human tlaauaa ara obtainad. (4) Soma general PCS atructura vs. activity relatlonahlpa hava emerged from animal atudias, particularly rodents, that can hava usaCul predictive power for the human. <S) Thera is soma relevance of the features of the absorptlon/dlatributlon/eetabollan/clearance processes discussed in this section to the toxicology of PCBs in animals and humans, ror examplei (a) The poesibility that an atene oxide intermedi ate can occur in PCI metabolism has apodal significance in terms of potential reactions with protein, rna or Dm to cause tlseue damage or damage to a cell's nuclear functions. (b) The retention of PCBs in adipose or other tissue can have major significance by creating reservoirs from which material can be leached over time for reaction at other tissue sites. (c) There is little evidence in humans for acute cytotoxicity of the kind usually associated with reactive metabolites. Rather, some of the adverse effects of PCBs, e.g., ehloracne, could stem from the physical presence of unreacted material in the cells along with oils and/or sebaceous materials of the skin. MOMS 015632 53 - IV- Oanaral Toxicity A. Oanaral ConaldTitlona Any attaapt to undartaka a ayataaatlc avaloation of tha toxicity of PCBa la confoundad by a nuabar and vaclaty of factora that coaplicata tha lntarpratatlon of tha flndinga and Halt thalr ganaralizatlon. Tharafora, thaaa factora ahould ba racognizad at tha outaat of conaldaration of tha avallabla body of toxicological litaratura. Tha aora iaportant of thaaa factora ara liatad aa followai (a) Tha aultlpliclty of caaaiarclal producta of both O.S. and foraign aanufactura; (b) Tha aultlpliclty of laoaarlc foraa of PCla in coaaMrcial producta; (c) Quailtativa and quantltatlva dltfarancaa in aatabollaa of dlffarant laoaara within tha aaaa apaclaa; td) Quailtativa and guantltatlva dltfarancaa In aatabollaa of tha aaa< laoaar batwaan apaclaa; (a) Oiffarancaa in rataa of aataboliaa of dlffarant laoaara within tha aaaa apaclaa; (f) oiffarancaa In rataa of aataboliaa of tha aaaa lacaar batwaan apaciaat <g) oiffarancaa in tha biological half>livaa of dlffarant laoaara within tha aaaa apaclaa; (h) oiffarancaa in tha biological half-llfa of tha aaaa laoaar batwaan apaelaa; HONS 015633 54 - (1) lb* praaanc* in ccamrcial product* of iapuritie* of aucb greater toxicity than that of PCBa> (j) Th* variability between coaaarcial products of tba as* typa (i.e.. aam degree of chlodnation) in th* concantration of iapuritia* of much greater toxicity than that of pea*; (k) 1b* variability between coamrelal products of tba diffarant typaa U.a., different degrees of chlorination) in tba concentrations of iapurltias of such graatar toxicity then that of fdii and (l) Oiffaroncas between apaclaa in auscaptibility to tba toxic action of (1) individual isomra and tbair mtabolltaa, and (11) th* iapuritia* that my b* praaant in coaaarcial product*. lb* preceding factors my underlie th* conclusion reached by the Fanal of lasardous Trsca substance* (1172) that "(tlhare la no consistent ralatlonshlp between tosielty and <5agree of chlorination which is valid for diffarant apaclaa and diffarant routes of exposure.* to this sight b* added the obser vation that thara is often no consistent relationship between the results of investigations on products of th* aam dagra* of chlorination fro* diffarant aanufacturars. Them observations const1tut* caveats that should b* born* in *lnd as individual toxicological axparlmnts and results ara avaluetad. >. Impurities in Comarclal Product* The work of Vo* and bis associate* (Vos and Koamn, 1970; Vo* at al., 1970; Vo* and Mam, 1971) lad to a recognition HONS oiSbSt - 55 - of eh* aignlficant rol* played by tree** of inpuritiaa in coaacel*l PCB* In influencing th* <pp*r*ne toxicity of th* letter. In atudie* Involving ehr* camerelal PCB* of th iu d*gr* of chlorination, th** lnveatlgator* found narked diffaraneaa in toxicity that w*r* traoed to tba pretence, in two of th* product*, of mail mount* of chlorinated dlbaniofuran* (PCOPa) and chlo rinated naphthalan**. Th* PCOra at* related eloaaly, both atmeturally and toxlcologlcally, to th* chlorinated dibnxodioxin*. Th* 2,3,7,t-t*trachlorodibanao-p-dloxin laoaar ia an *xtr*mly potent toxicant in aaaaala, *ap*clally for th* fetua. Th* chlo rinated naphthalan** ar* laa* toxic than tha chlorinated dloxlna, but n*v*rth*l*aa caua* chloraon* and other ayapton* in awn aiailar to thoaa produced by PCOPa. '* Th* extent of th* contribution aad* by contaalnanta to th* toxicity of coamrelal PCB* ia uncertain, but th* conaanaoa ia that it ia aubaeantlal. Tb*r* a*ma little doubt that th* akin la*ion*, including chloracn*, ar* caua*d by PCDPa. Th* Panel on aaaardoua Trace Subatanc** (1972) atat** that eh* pcora "ar* probably th* chief if not excluaiv* caua* of chloracn* in an." rlahboin (1974), in hia review of th* toxicity of chlo rinated biph*nyla, ob**rv*a that "(11 Ivor daaag* and akin laalona ar* b*ll*vd to b* cauaed priaarily by chlorinated dibenxofuran contminanta and to a alnor extant by PCB itaalf." furtharaor*, aInc* th* chlorinated dibenxodioxlna exhibit pronounced eabryotoxlclty, it ia not unreaaonabl* to *xp*ct that eh* PCOPa aher* thl* property and, h*nc, ar* largely reaponalbl* for th* f*tal HONS 015635 - St deaths and resorptions that have bean observed axperisentally with cosaardal PCM. An appreciation of tha role played by eontaalnanta In tha toxicity of coaaarclal PCM la iiaportant for two reasons. Plrat, It say axplain dlacrapanclas batwaan tha results of jtudiaa of apparantly similar commercial products. Saeond. It points up tha difficulty of attempting to use PCI tlsaua lavala to corralata tha rasulta of laboratory studios with observations of occupationally or environmentally axpoaad populations. Pov example, some animal populations In tha onvlronaant appoar to ba unaffactad by PCI tlssuo levels that ara equal to or graatar than thosa assoclatad with advarsa affacts on cosparabla spoolas in tha laboratory. C. General Toxicology 1. Acuta Toxicity Tha Aroclora of tha PCB class hava a low ordar of acuta toxicity. Tha acuta oral LDSOs for rats ranga frost l-io 9/kg. Tha USOs by alngla application to tha skin of rabbits ara approximately 1-3 g/kg. Oral and dorsal U3S0 data hava boon sussarlssd by Plsbbain (1174). Kimbrough at al. (1P7I), and tha panal on lasardous Tract Substancaa (1J72). 2. Subchronic and Chronic Toxicity (a) ganaral Subchronic and chronic toxicity ara groupod togathar for purposas of this discussion sinca tha affacts of ehronie MQNS 015636 - 57 - xpoaura to PCI* art aaaantially axtanalona of thoaa obaarvad fron rtpttttd axpoauraa of thorttr duration. Thtra art nuaaroua publltbtd studio# in which ecaaaerelal PCBa (Aroclora) have bttn adainitttrtd by varloua routta for varying ptrioda of tie* to aoat coaaon aaaaaiian aptciaa of laboratory aniaala. Out of tbia aaaa of obaarvationa. on* aay idtntify two principal citato* of biological tffacta of that* aubatancaa. Tbaaa claaaaa ar* (a) altarationa in th* livar, and (b) akin laaiona. <b) altarationa in th* Livar Enlargement of th* liver, both in abaolut* tana and aa a percentage of body weight, baa bean obaarvad conalatently in noat apacloa conaequant to repeated expoeur* to PCM, altbougb It 1* nora pronounced in rodanta than in other*. Tbia phanoaanoa haa boon reported for aica (Xiabrough and Linder, 1974), rata (Bruckner at al., 1973, 1974a, b), guinea piga (Voa and Van Drial-Grootanhula, 1972), rabbit* dollar and Zinkl, 1973), doga (Calandra, 1976), and eonkaya (Allan at al., 1973). Early onlargaaont of th* liver la priMXily th* raault of an increaa* in th* aia* of th* hapatocyta aaaoclatad with an incraaae in th* aaount of th* aaooth andoplaaeic ratlculue (SEh). Thoaa davelopaonta ar* aaaoclatad alao with Ineraaaad onxyeatlc activity of tb* livar (Bruckner at al., 1973). A detailed dlaeuaalon of tha effect* of PCBa on livar in teat aniMl syataea ia given in (action vx. HONS Q15637 - 5* (c) sign Lealon* Cutanaoua effect* Croat repeated expoaure to eoaaarclal rCBs can ba elicited by feeding to aonkaya or akin application to rabbi ta, although tha raaulta ara aoaavhat aora dramatic In tha Coraar. Tha raaulta oC thaaa anlaal atudiaa ara diacuaaad In aaetlon V. (4) macallanaoua Effect* ypatplaaia and dyaplaaia of tha gaatrlc aucoaa haaa baan obaarvad in aonkaya Cad a dlat containing 100 ppa of Aroclor 1141 Cor tbraa aontha (Allan and (tocback, 1973). Oaatrolntaatlnal laaiona do not appear to occur in rodanta, areapt at vary large ingle doaaa by aoutb (Kiabrough, 1979). A dietary concentration of 2.S ppa of Aroolor 1240 produced altarationa in the aanatrual eyelea of adult, fenala rhaaua aonkaya (Allan at *1., 1979). Menaaa vara prolonged, and there war an lncreaee In aanatrual blaading. Hepatic porphyria baa bean deaonatratad In alca after Caading Aroclor 12S4 (Xlabrough and Linder, 1974), in rata after feeding Aroclora 12S4 or 12(0 (Kiabrough, at al., 1972), and in rabbit* after repeated akin application of Aroclor 12(0 (Vba and Baaaa, 1971). Urinary ercretlon of coproporphyrin vaa lncraaaad in rata fad Aroclor 1242 (Bruckner at al., 1974), and both urinary and focal excretion of perphyrlna vaa lncraaaad in rabbit* re ceiving rapaatad akin application* of Aroclor 12(0 <voo and Baaaa, 1971). other effect* reported Cor one apaciaa or another include atruetural ehangaa in tha kidney (Voa and Baaaa, 1971* Bruckner at al., 1974a, b) haaatologlc altarationa (Brueknar at HONS 015638 - 59 - al., 1974a. b) and thymic atrophy together with a reduction In tha nuabar of germinal cantara In tha aplaan and Lymph nodas (Voa and Baaaa, 1971). D. Suamary and Opinion Voluainoua lltaratura oatabllahaa that commercial PCBa art capabla of producing a variety of biological affacta whan adalnlatarad in largo quantitiaa to experimental aniaala. Tha majority of thaaa affacta can be grouped into two catagorlaa, namely, tboaa Involving tha akin and tboaa Involving tha liver. A nuabar of aiacellanaoua affacta that have bean obaerved in one apaclaa or another can be conal.derod aacondary to tha action of the aubatancea on tha liver. In general, tboaa affacta are only elicited by relatively high doaagaa of tha PCBa, reflecting tha low order of acute toxicity of the o.S. commercial mlxturee. Thera ia a coneiderable range of apaclaa auaceptlblllty to the biological activity of KBa aa aoaaured by the alia of the doaaga, tha duration of tha expoaure, and the aevorlty of tha effect. Mink appear to be the moat auaceptlble, aonkaya aoaevhat laaa ao, and rodenta the aoet raaiatant. Thera ia no baaia for a judgment aa to which apaclaa aoat accurately aervaa aa a model for aan. A comparlaon of tha obaarvatlona on humane in tha Yuaho incident with thoae on monkeya fad relatively email aaounta of PCBa haa lad eome lnvaatigatora to conclude that the latter apaclaa la an appropriate eurrogate for aan. Although there are aone aiailarltlaa between Yuaho dlaeaaa and the flndinga in aonkaya, they are not aufflciant to juatify auch a conclusion. HONS 015639 - SO - There la evidence throughout tha litaratura that soae of tha biological atfacti obaerved experlaentally with ccaaereial PCI aixturaa ara cauaed not by PCla theaaelvea but by othar chlorinated arooatic coapounda praaant aa lapurltlaa, auch aa tha PCOPa. Tha eigniflcanee ot thia finding la that po lawala reaulting froa occupational or anwlronaaneal expoaurea cannot ba interpreted in tha aaaa way aa theaa obaarvad in aaparlaantal anlaala. A broadar iaplieatlon of thia clrcuaatanea la that tha raaulta of laboratory atudlaa ara not nacaaaarlly predictive of what aay bo axpactad froa lneidantal axpoauraa aInca tha natura of tha axpoaura aay hawa differed in tha two lnatancaa. Aa la alwaya tha caaa In aaparlaantal toxicology, tha validity of taat raaulta aa pradlctora of baxard to aan auat await eonfiraation or danial by obaorvationa of axpeaad buaan populationa. Fortunately, tha raporta of actual Injury to aan froa PC* axpoaura ara few, although axtanaiva aptdeaiologleal aurvaya bava baan conducted and othera ara In pro?raaa. An evaluation of tha apidaaiology of axpoaura to PCaa la tha aubject of aaetion XXX of thia report. Still othar aectlona of the re port deal with apeelflc potential health affacta in greater detail. HONS 015640 - 61 V. Skin and Other Cutaneous Tissues Epithelial and follicular hyperplasia and hyperkaratoala hava baan raportad to occur following tha application of PCBa on tha skin of rabbits (Vos and Baaas, 1971). Skin laslona hava also boon obsarvad In rata and guinea pigs free tha application of peas. Repeated application of Aroclor 1260 to the skin of rabbits caused thickening of tha skin as a result of hyperplasia and hyperkeratosis of tha apithaliua (Vos and Baaas, 1971). Cutaneous affects hava baan elicited in aala rhesus aonkeys fad a diet containing 300 ppa Aroclor 1240. within one aonth tha aniaals lost conaidarsbla hair froa the head, neck and back (Allan at al.. 1973, 1973). Siailar affects hava bean obsarvad in faaala rhesus aonkaya fed a diat containing 23 ppa Aroclor 1240 for two aontha (Allan at al., 1974). within six weeks tha aniaals began to lose hair and davalopad obvious signs of edaaa of tha lips and eyelids. Saall pustules involving hair follicles appeared about the aouth, cheeks and neck. Abrahaa and Allan (1973) showed that the infant aonkey was able to tolerata doses of PCBa that produce extreae morbidity in adult aonkeya. they suggested that there aay be variations in absorp tion, distribution, aetabolisa, storage and axeratlon in adult and infant aonkaya that aay account for these differences. Follicular hyperkaratoala is an laportant feature of the occupational dlsaasa known as acne, which is charactarlsed by tha appearance of papules, ecsMdones and cysts. Industrial HONS 015641 - (2 - dexaatoais of th* aenafora typa has baan observed *mong workers axpoaad to eblerlnatad hydrocarbon* (Jonaa and Aldan, 1934, Hayara and Silvarbarg, 19M> Maroni at al.. 19*1). Savon caaaa of chloracn* of th* faca and baad hava baan reported aaong 14 chaaical operator* axpoaad frea 9-19 aontha lntaraittantly to lew coneantcatlona of chlorinated biphenyls (Maiga and XIbaa, 1994). Pueelnalli (1994) and Bofaan at al. (19<2) report cblocacna la several capacitor workara, wbaraaa Saith at al. (1911) noted that none of the capacitor workara exaained in thla recant aarray war* found to bar* acaefoca laalona suggastiv* of chloraca*. Th* aenafora aruptiona that occur in tba akin of both aonkaya and rabblfea aay b* cauaad by a aquaaoua aataplaatle chaag* in tb* apitballua lining tba aabacaoua 9landa, which raault in a change in tb* character of th* aaeration froa noraal oily to karatlnacaoua. This condition frequently raaulta in plogglag and ruptura of tb* gland* with conaaquant inflaaaatory reaction* (aena). The question of whether a alailar condition can occur In aan froa oxpoaur* to 9C*a will b* dealt with in another auction of thia report. It baa baan auggaatad tbat tb* cutaneous eruptions that occur in both anlaala and nan froa exposure to coanarelal preparations of PCls aay b* duo to certain lapuritias. Chaaical analysis of tb* PCls tbat contaalnatad th* rice oil that caused th* xusho dlsaaaa in Japan abound high levels of polychlorinated dibanxofurana (Kuratsun*. 1970. HONS 015642 1 - VI. Effect of PCBa on liwr A. Experimental Oats 1. Liver Wight The administration of PCBa aay lnduca an increase In liver weight (Tabl* 1). The affact is nor* prealnant at the higher doaa levels; tha lower doaaa of PCBa do not Incrtaa* llvar waight. tha datallad data of Riabrough at al. (1972) art not included in tha tabla. They found that Aroelor 12(0. adainiatarad with tb* diat in doaaa of 500 and 1000 ppa for eight aontha. significantly ineraaaad llvar weight in aala and faaala rata; doaaa of 20 and 100 ppa war* affactlv* only in aala rata. Aroelor 1254 ineraaaaa llvar weight in both aala and faaala rata at doaaa of 20, 100 and 500 ppa. Although tha data in Tabl* 1 llluatrat* tha affact obtalnad In aubchronlc and chronle atudiaa, it abould b* notad that llvar waight aay also b* ineraaaad in acuta toxicity atudiaa. PCB conganara (panta-, haxa-, and haptachloroblphanyls) given in a high single dose of 50 ag/kg, can increase liver weight In eh* rat; in aeat but not all tests, liver triglycerides, cholesterol and phospholipids wars ineraaaad (Yoahlhara at al., 1979). in tha aonkay a single oral dose of 1.5 g or 3.0 9/kg of Aroelor 1254 produced slight anlargaaane of the liver in 4 days (Allen, Norbaek and Bsu, 1974). Tha increase in liver waight is correlated with hepatic call hypertrophy and an increase in saooth andoplaaalc reticulum HONS 015643 - 45 Table 1 tffact ef K3i on Liver Weight and Morphology lt41a in Mice Weight Chaagea +-iacroaae 0-no change Major liatolog ical flndtnga Xlabrough Linder, 1974, Aroelor 1254 Stadioa la Data fleoaorphlaa, aaeroaia Bennett. at al., 9CB, <S~C1 Keplin^ar at al. _ 300 ay 250 ag 100 p$B ( daya B to 100 daya 11 aoatha Calla awollaa, hyallaa grmaelae Arr-lor 1254, 12(0 10 ppa 1 ppa Aroelor 1242 100, 10, 1 pia It aoatha IS aoatha 1( aoatha' 0 0 0 Uttantt at al., 1972 Aroelor 1242, 1241 1254, 12(0 500 ag SO ag 5K 0.5 ag 4 weeha 4 waaka 4 weaka 4 waaka - 0 0 Alloa t Abrghaaaen, 1973, . 0.1 la. dint Aroelor 124(, 1254, 12(2 Srocknar at al., 1197J)__ 'l00 ag/k 1 every 2ad Aroelor 1242 day 5r\ -ier et al. ~)l974 25 ppi 5 ppa ( waaka 3 waaka 2,4,4 aoatha rat droplata, araaa of aaeroaia acoolation 0 Mo change with HU ataia, inert* lipid with Sedan IV ataia HONS 0156'.'. COIfflMUtP - 7 tabic l umrrxHczo) Iffact ot FOa on IAyr Maleht and Morphology lursa at al., ' Aroclor 12*2, 1014 Wes at al.. Aroclor 12(0 harachloroblphanyl KoUar ( Slnkl, 1973 Aroclor 1294 Aroclor 1242 Aroclor 1221 Allan at al., 1973 ' Aroclor 1241 Aroclor 9440 Waighs Changes +iacraase 0*oo change Stadias la Rats (Continued) Major U*toU leal findings 100 ppa op to 10 Booths 1 Studios la Rabbits 0 telarged hapa- tocytas, tecoolatad cytoplasn charaetarlsad as mild -tianjaa 120 dacBol 4 aaafcs 9 a weak Rydropic ii|a ration, nacres 300 ag oae M 14 aaaks ' m Stadias in tbs Monkey ... 0 tnlarged bapato cytaa, aacrosis Enlarged bapato cytaa, sons aacrosis Mo histological change 300 ppa 9000 ppa 90.days ** ' Enlarged bapato cytaa, no aaero * ) MOWS 015645 Table 1A Liver Lesions in Albino Rets Treated with Aroclors for 2 Veers* (Data frost Levinskas, 1981) Diet lavol, ppe Control 0 No. eninels examined Vacuolar change Focal necrosis Focal lyapliold infiltration Focal hypertrophy hepatocytea Nodular hyperplasia Ductal hyperplasia llepatcma Cholangiohepatona Hepatocellular carclnoaia 23 1 1 1 0 1 5 0 0 0 Aroclor 1242 1 10 100 32 29 7 11 00 23 ii 33 00 00 00 It 9 0 0 3 3 1 0 Aroclor 1254 1 10 100 30 2t 79 31 20 34 03 63 00 00 00 2f 13 1 1 14 14 14 4 2 0 *The results of this study were presented in a si-- srisisd tons by Calandra (197S) and were later reanalysed and tabulated by Lavlnskas (19*1). Aroclor 1260 1 10 100 26 25 57 43 0i 3 13 07 <7 01 00 00 25 9 6 0 9 6 12 7 4 0 9999TO SNOW - 71 - In the rat, rabbit and aonkey (Voa at al., 1972; Allan and Abrahaaaon, 1973; Bruckner at al., 1974a; Allan, tiorback and Bsu, 1974; Allan, Carstana and Baraottl, 1974). Bcoblchon and Ccaeau (1974a, b) found that tha affaet of PCBs adainiatarad intraparleonaally on llvar weight and on hopatle anayaaa aaaoclatad with hepatic endoplasaic raticulua waa ralatad to tha poaitlon of tba chlorlna aubatltutlon on tha blphanyl nucltua. However, all of tha congeners and laoaara adainiatarad at a doaa of 50 ag/kg intraparltonaally for tbraa daya produead an incraaaa in aaooth andoplaaaie, lipid droplata and aierobodlaa, although tha quanti> tatlva raaponaa varied (Banaell and Eeoblchon, 1974). 2. general Histology Tha adainlatration of PCBa to axpariaantal aniaala will product hiatopatbologlcal changaa in tha llvar. Tha aaln affacta obtained ara the production of enlarged hepatocytea, fat droplata and alight degree of nacroaia; the occurrence of thaaa changaa depend particularly on the doaa of tha PCB and to aoae extant on tha particular Aroclor (Tables 1 and 1a). Nacroaia aeeaa to be ora severe in the rabbit than In the rat. In general, tha Morphological changes observed in the liver of PCB-treatad aniaala are alallar to those found after treataent with other chlorinated hydrocarbons. In a detailed study, Uabrough at al. (1972) found that Aroclor 1240 (20, 100, 500 and 1000 ppa) and Aroclor 1294 (20, 100 and 900 ppa), given in the diet of rata for eight aontbs, produead HOAS 01564 7 - 72 - enlarged Liver calls and cytoplasmic Inclusions. at the higher doses, thara was evidence of lipid accumulation, which was asso ciated with a foaay cytoplasm, and pigment aceuaulation In tba Kupffer calls. the pigment gave a positive Prussian-blue reaction, indicating the presence of baaoaiderln. Studies of rats four eo six aonths after exposure to different doses of aroclocs 1014 and 1242 Indicated that the morphological changes are reversible and disappear gradually after dosing is stopped the bepatoeytss were still larger than controls, but the frequency of vacuolated cytoplasm or Inclusions within the cytoplasm had decreased (aurae 2i si.. 1*74). Aroclor 1254 was evaluated by the national Cancer Institute (17). Fischer rata receiving ,25 ppm in the diet for J eight weeks had enlarged livers, but without evidence of hlstologleal abnormality. The administrations of doses of 25, SO and 100 ppm for 104-105 weeks did not Increase the frequency of liver lesions such as congestion, inflaamatlon, necrosis or anglectasis. ]. Menofibrosls Menofibrosls (synonyms: bile duct proliferation, blla duet adenomatosis, cbolangloflbrosls, fibroadenoma) has been observsd In some rats receiving peas. Menofibrosls Is gansrally regarded aa a benign lesion. In their review of experimental tumors, Stewart and Snell (1557) stated that there Is no con vincing evidence that adanofibrosla Is a precancerous lesion. HOhS 015048 73 It should b noted, however, that xeuber (1944), studying 2acataaidofluorana and 2-dlacetaaidofluorane, suggested that adsnoflbrosis is a pcseancsrous isslon for ths developeent of cholanglocarcinoaa. (1) Studios in ales. Xiabrougb and Lindor (1974) obaarvad foci of adanofibrosit in tha livsr of sons aiea with 300 ppa of Aroolor 1234 in tha diat for 11 aontha. Ito at al. (1974) coaaent that thay did not observe oholangioflbroaia in iea receiving xsnaohlor. (ii) studlaa in rata. Klabrough at al. (1972) obaarvad adanofibroala in rata traatad with Aroolor 12(0 and 1234> tha affact was obaarvad at tha higher doss lavala and particularly in aniaaln receiving Aroolor 1234. Khan tha feeding of 300 ppa of Aroolor 1234 was diacontinuad and tha aniaala atudlad up to 10 additional nontha, tha fat and livar eontant of PCS raaainad high and tha adanofibroaia parslstad (Xiabrougb at al., 1973). In a latar papar involving traataant with Aroolor 1240 at 100 ppm for 21 aontha, aantion is only aado that a few rata showad areas of adanofibroaia, indicating a low dagraa of reaponao, but data are not tabulated (Kiabrough at al., 1973). in further studies by tha saaa group adanofibroaia was not ob served in rata fad Aroolor 1014 or 1242 (100 ppa) for up to 10 oaths (Bursa at al., 1974). In a study with three Aroclors, adalnistration of 100 ppn in tha diet for 24 aontha produced a low incidence of HONS 015649 - 74 - cholaoglobepatCM (Table iA), bat concentrations of 1 pp or la ppm nn without effect (Calandra, 137<i tavinsksa, 1341), Treatment did not significantly i!!ict ductal byperplssi*. The study of tho National Cancar Institute (137) did not observe adonofibrosla in tats receiving Aroclor 1234 at dosos of 23. 30 and 100 ppa for 104-103 woska. In studiss with various Kanocblors. Ito at al. (1374) administered Ianaeblor 300, 400 and 300 in tba dlat at eoneontratlona of 1000. 300 and 100 ppe. at tba eoneantration of 1000 ppe of tba lanechlors, tba ineidanca of cholangiofibroaie ranged from 13 to 304 in tba rata> cholangiof ibroelt did not occur at laaals of 300 or 100 ppm. Klaura at al. (1170 also taportad cholangiofibroeis in rata traatad with Ianaeblor 400. 4. Byperplaatic fool and Nodular Syperplasla in tba Llaar yperplaatic fool or hyperplastic araab rapraaant ainiaal changes in tba hapatocytaa. Such foci or araaa of hyparplaatlo changes aro uncaaaon in untraatad young rats, but lacrsaaa witb aga. The hyperplastic araaa or fool aay coexist with nodular hyperplasia and/or hepatocellular carelnoaa. The significance of hyperplastic foci is that they say be part of a spectrum capable of progressing to a nodule (Squire and Levitt, 1373). The hyperplastic nodule (nodular hyperplasia, neoplastic nodule, hepatotal is generally as large or larger than tha area of eeeeral lobules, and the lealon la sometime elevated above HONS 0l5b* 75 - tha aurface et CM livar. Tha laalon la frequently raCarrad to aa a naoplaatlc nodule and aoaa eonaidar It to ba a aanlCaatatlon of a carcinogenic procaaa, the aarliar atagea of which nay ba repreaented by tha hyparplaatic foci dlacuaaad abova. Tha uaa of thaaa tana in tba llearatura la confuting, aa acne who uaa tha word 'hyparplaatic nodula* regard tha laalon to ba part of tha naoplaatlc procaaa whoreaa othara eonaidar it to ba unrelated to naoplaala. Soae invaatigatora uaa tha tana adaneaa or hopetone to dealgnata tha laalon, iaplylng that it la a benign neoplaea. oeaplte the differing tanlnology, it aay ba eonaidered that tha hyparplaatic foci and nodular hyperplaaia (naoplaatlc nodulea) occurring in the liver an benign lealona rather than carclnoaaa. However, aueh nodulea aay be pact of a aaqueoca of neoplaatio changaa that eventually progreaa on to hapatoeallular carclnoaaa. Although tha data on hyparplaatic foci and nodular hyperplaaia are dlacuaaad in thla auction and bapatocarcinoganaaia are dlacuaaad in auction VIII, tha espariaantal data on tba inci dence of benign and aallgnant lealona are given in the tana table ao that tha overall biological affect of tha treataent can be obaerved aa a unit. (i) Studlaa in nice. Xto at al. (1573) obaerved nodular hyperplaaia in alee only at tha highaat doae level of Kanechlor 500. (Nagaaakl at al., 1572, reported tha eaae data.) Nharaaa Kanechlor 500 produced nodular hyperplaaia at 500 ppa, leaner doaaa ware not active and Kanechlor 400 or Kanechlor 300 HONS 015651 - 7* - was inactive at all doses studied (Tails 2). Thara was soaa evi dence that the administration of Kanaeblor 300 lneraasad eha nodular hyparplaatic rssponsa lnduead by 9-or p 1seasre of bsnssno hexachlorlde. Klabrougb and Lindar (1974) observed adoneflbroala and hspatoaas In 9 of 24 ales fad Aroelor 1234 (300 ppa In tba dlat) for 11 soothsi in aniaals fad kroelor tor only si* aontbs followod by a five nontb recovery tbors was no adanoflbroala and tba Isol ds new of bepetoaui was only 1/24 nlew. (it) Studlaa in rata. Keplloger at al. (1971) did not obawrrw bapatle lsslona in rata rsealsing dlffarant Aroclora for 1( aontbsi bowavar, re-evaluation of tba alldaa indieatad a significant laeraaaa of nodular byparplaala In tba treated aniaals (aaa National Canear Inst1tots, 1971). Ito at al. (1974) observed nodular byparplaala la rata receiving 100, 300 or 1000 ppa of Kanaeblor 300r a laaaar effect was obaarrad with Kanaeblor 400 and there was no significant affaet of Kanaeblor 100. Klabrougb aj a. (1973) reported a aignifleant laeraaaa in tba incidence of hyparplaatlc fool or areas and neoplastic nod ules in faaala rats given 100 ppa of Aroelor 12*0 alsad with tba dlat for 21 aoatha (Table 3). In another study, tba dietary administration of 100 ppa of Aroelor 1242. 1234 and 12*0 for 24 months lneraasad tba incidence of nodular hyperplasia (table 1A)> a lesser affect was obtained with 10 ppa, and 1 ppa did not produce HONS 013632 -77- table 2 Incidanea of Liver Laaiona In Mala Hlea Treated with PCIa for 34 Week* (Data of Ite at al, 1973) Incidence PF in diat Hodular Hyperplaaia Hepatocellular Carclnoaa Xanachlor S00 Xanachlor 400 Xanachlor 300 Control* S00 250 100 500 250 100 500 250 100 - 7/12 0 0 0/12 0 0 0/12 0 0 0/6 5/12 0 0 0/12 0 0 0/12 0 0 0/4 ) HONS 015653 -79- TMU 3 Xncidanea of Livar Laiiom in Fuit Juts Traatad with Aroclor 1260 (Data froa Kimbrough at al., 19751 Lasion Hyperplastic foci or asaas :ieoplaatlc Nodules Bapatoeallular Carcinoma Xncidanea Controls Expaxlmantal 21/173 0/173 1/173 112/1*4 144/1*4 24/1*4 ) HONS 015654 -81 TABLE 4 Incidence of Liver Laaions la Mala and Female Rata Treated with Aroelor 12*2, 125* and 1260 100 ppa la Oiat far 2* month* (Data from Calawdra, 1975) Modular hyparplaaia Hepatemaa ' Hapatoealiular carcinoma 1242* 8/20 2/20 0/20 Aroelor 1254** 13/27 4/27 0/27 1260 7/27 S/27 0/27 *10 malas and 10 famalea **13 mala* and 14 famalaa MOMS 015655 -83- IMU S Xneidanc* of Livar laiion* la Mala and Famala Riti Traatad with Aroelor 1254 . (Data iron National Cancar Institute, 1971) Number of animal* nacropsiad * gyparplaatio foci or araaa Adanoaa, NOS+ Hapatocallular carcinoma Mala* Low Mid High Do** Ooaa poa 24 24 24 fwala* Low Mid High Ooaa Do** Do** 24 22 24 S 8 12 00 1 01 2 C 9 17 0 12 00 0 * Hvp*rplt*tie foci, hapatocallular adanoaa* or carcinomas vara not diagnosad in tha control*. + Not oth*rwi*a spaeifiad ** a* dafinad in raport ) HONS 015656 85 positive response (Calandra, 1974; Lavinakas, 1981). All three Aroclora produced an lneraaaad nuabar of hapatoaaa at tha high dona (Tabla 4). There was no avldanea of aataataala or invaalveneea, and tha laalona warn regarded by tha pathologists aa benign tuaora. Tha results of a bloaaaay of Aroolor list for carcino genicity, using doaaa of 25, 50 and 100 ppa In tha dlat, ara auaaarlxad in Tabla 5 (National Canear Inatltuta, 1978). Thalr uaa of terms la confusing, for although thay uaa tha worda 'nodular hyparplaala* in thalr tabla. thay atata In tha tast that *tha araaa of nodular hyparplaala appaarad to ba alcroscoplcally siailar to what la currantly taraad 'focal araaa of callular alteration.' Thus, wo have uaad tha ton 'hyparplaatle foci or araaa* in Tabla S to daacrlba thalr raaulta. it la evident froa tha data In Tabla 5 that tha hyparplaatle foci warn praaant In a doae-relatad frequency. Although tha lncidanca of tha hypar plaatle foci did not differ significantly froa tha controla, tbla lncidanca appaarad to ba related to traataent. Tha biological significance of tha Increase in 'focal araaa of cellular altera tion* la not claar aa relatively few adoncaaa were found. Both tha above studies (Kimbrough et el., 1975 > National Cancer institute, 1978) deaonstrate an Increase in proliferative laalona of tha liver; tha affect is greater with Aroclor llto than with Aroclor 1254. (ill) Studies In does. Hepatic nodular hyparplaala did not occur In tha dogs receiving dietary levels of 1, 10 or 100 HONS 015657 - 86 ppm of hroclor 1262, 1236 or 1260, respectively, for two yeera (Calandra, 1376). tech treatment group consisted of eight dogs (four fsaal* and four sale). 3. Susmary and Coassnt The adalnistratlon of high doses of PCBs to eniaals can produce hepatic enlargement and an increase in liver weights, which is associated with an increase in smooth endoplasmic reticulum. Other effects include a slight degree of necrosis and the presence of fat droplets and a vacuolated cytoplasm. These changes, which are similar to those found after treatment with other chlorinated hydrocarbons, ars readily Induced by high doses of rcis, but arc absent when lower doses of peas are given. Tbs response appears to be greater with increased chlorination of the biphenyl nucleus but, depending on dose, even the high chlorinated derivatives may not produce a positive response. Treatment with PCBs usually increases the occurrence of hyperplastic foci. The nodular hyperplasia, neoplastic nodules or hepatomas have been reported to be increased in sosm studies, but other evaluations have not confirmed these effects. The effects of PCas on the occurrence of nodular hyperplasia, neo plastic nodules, hepatomas, or adanofibrosia is highly variable* acme studies bsve reported a positive effect whereas others failed to shew an effect of treatment. Again the change in histological response or in frequency of benign hepatic tumors is related to both the dose of PCS administered and the degree of chlorination of the PCS. MONS 015658 - 87 - Data on hepatocellular carcinoma in PCB-treated aniaaia ara discussed in section VIII. b. Clinical Data 1. Liver function in PCB-exposed Workers Based on results in aniaaia, it waa expected that i( PCBa produced a significant degree of injury in aan, it would ba to the liver. Such has not bean the ease, aa the clinical atudiaa auaaaarised below have provided little evidence for the occurrence of hepatic dysfunctions in rCB-exposed workers even though the blood level of PCS aay be relatively high. (i) ouw at al. (1170 studied liver functions in 14 workers espoaed to Arcelor 1242 for one aonth up to 21 yearsi 11 were exposed for sore than one year and It for five or aore years. Scattered individual abnoraal test results were obtained! serua bilirubin was noraal and in all 14 aubjecta, alkaline pheepbataae waa elevated in 1 of 14 subjects and serua transaminase (SOPT) y was Increased in five tests. There was no relationship of the results to the blood level of pcs and the mean of each hepatic function test for the whole group was within noraal Halts. BSP / The abbreviations used in this section are as follows: SOOT serua glutamic oxaloacetic tranaaalnase SGPT serua glutamic pyruvic transaminase SCOT - serua gaaaa glutaayltranspeptidase LOG - serua lactic dehydrogenase AST aspartate aainotranaferaae ALT serua alanine aainotranaferaae SOCT serua oralthln-carbanoyltransferase BSP - broaaulfonphthaleln HONS 015659 - 200 a correlation Oatwaan diastolic blood prassura and H-PCB but this disappaarsd whan corractad for ago. Othar investigators have not found this ralationabip, so the difference may be associated with an unrecognised Interrelated variable or a chance association related to the Multiplicity of factors chae have been e'xaained. Marsbaw at al. suggested that workers in capacitor Manufacturing plant (population of fischbein at al.) had de creased vital capacity and restrictive inpalraent of lung func tion in the absence of signs of radiographic change (Narshav at al., 1971). they have compared the rvc to that of other worker populations in previous haaardous exposure studies as well as to a non-saoking normal population. The reported percent abnor mality of PCI workers is lit coopered to S.Ct cited for nonsaoking populations. The comparisons do not indicate that they have been controlled for aaoklng habits and sax. Most studies have reported no clinical dlseaae in pcaaxposed populations with the exception of Tusho disease and chloracne (Xarppanen at al.> Humphrey, Saith at al.j Chase at al.,; eralas ae al.). Some have reported symptoms that are difficult to evaluate since aost are subjective and could be related to worker bias. Fischbein at al. suggested that neurologlcsl ayaptaaa ware increased but there is no stallar group with which to compart workers and thus aake this aaseasaent. Smith at al. MQNS 015756 201 (1981) in tli* study of th* combined work sites found that cough ing at work and irritated ayes were related to both L-PCB and H-PCB. Lot* of appetite and peripheral "tingling" were associated only with L-PCB. History of skin rash was associated only with H-PCB Many of theta differences ware not observed when individual work Site data were analyzed separately. Th* lack of a difference in each site may result because jobs were included as a confounder variable. Mott studies have not even reported any symptoms or history of disease (Baker et al. and Kreiss et *1.) In all studies reviewed there was little evidence of clinical disease with th* exception of chloracn* and this condi tion seened to be most frequent under specific conditions of exposure. Th* ocher common but not consistent findings were abnormalities of lipid metabolism, especially blood triglyceride levels, and abnormalities of liver enzymes, especially SCOT and CCTP. which were related to levels of PCBs. Th* lipid and liver changes appeared to occur at lower levels than the skin manifescations and were not associated with clinical disease or symptoms. HONS 015759 -203- XIII RlftRCNCIS ALLEN, J.R. and ABRAHAnSON, L.J. (1979). Responses o rata exposed to polychlorinated biphenyls for fifty-tvo weeks, II coapositlonal and ensyaatic changes In the liver. Arch. Environ. Contaa. Toxicol. I, 191*200. ALLEN, J.R.. AttRASAtlSOH, L.J. and NOABACK, O.H. (1973). Biological at facta of polychlorinated biphenyl* and triphenyla on the subhunan prlaate.. Environ. Re*, 6, 144-154. ABRAHAJISON, L.J. and ALLEN, J.R. (1971). The biological raapona* of infant northunan prlaate* to a polychlorinated biphenyl. Environ. Health Perspcct.. Experiaental I*au* no. 4, tl-ir ALBAO, f.U. and riSHBEIN, L. (1972). Intestinal absorption ot polychlorinated biphenyl* in rats. Bull. Environ. Contaa. TokicoI. 8, 26*11. ALLEN, J.R. (1975). Response of the nonhuoan priaate to poly chlorinated biphenyl exposure, fed. Prop. 14, 1679-1679. ALLEN, J.R. and ABRAMAMSON, L.J. (1971). Morphological and biocheaieal change* in the liver of rata fed polychlorinated biphenyl*. Arch. Environ. Contaa. Toxicol. 1, 265-210. ALLEN, J.R. and NORBACK, D.H. (1971). Polychlorinated biphenyl- and triphenyl-induced gastric aucosal hyperplasia in priaate*. Science 179, 49B-499. ALLEN, J.R.. CARSTENS, L.A. and BARSOTT1, O.A. (1974). Residual cttccts of ahort-tera low-level exposure of nonhuaan priaate* to polychlorinated biphenyl*. Toxicol. Appl. Pharaacol. 10, 440-451. ai.i.en, J.K., NORBACK, O.H. and HSU, I.C. (19741. Tissue aodificulions in aonkeys as rolated to absorption, distribution and excretion of polychlorinated biphenyls. Arch. Environ. Contaa. Toxicol. 2, 66. ALLEN, J.R., BARSOTTI, O.A. and CARSTENS, L.A. (1980). Residual affects of polychlorinated biphenyls on adult nonhuaan prlaate* and their offspring. J. Toxicol. Environ. Health 6, 55-66. ALLEN, J.R. at si. (1979). Reproductive effects of halogenated aroaatlc hydrocarbons on nonhuaan priaate*. Ann. H.Y. Acad. Sciences 320, 419-425. MOMS 015760 204' ALVARES. A.P. and KAPPAS, A. (177). The Inducing properties of polychlorinated biphenyls on hapatle aonooxygenasea. Clin. Pharmacol. Thorap. 11. OOP-11*. ALVAACJ. A.P., RICKERS. O.R. and KAPPAS, a. (1071). Poly chlorinated Biphenylsi a new typo-of Inducer of cytochroaa p-441 la tho liver. Proc. hat. Acad. Science USA 70, 1121-1129. alvares, a.p. et al. (1977). Alterations In drug metab- oliaa in workers exposed to polychlorinated biphenyls. Clin. Pharmacol. Thorap. 22. 140-140. anderson, n.m. et *1. (1977). The construction of a pharma cokinetic model~?or the disposition of polychlorinated biphenyls In the rat. Clin. Pharmacol. Thorap. 21, 70S-773. 0ASM, A.x. (1970). Report on Psulsboro, N.J. Robll Oil Plant Study. Dept, of Coma, nod., Onlv. of Pena. School of Medicine. IAND. A.X., GROVER, p., ROOEMNAIKE. I.. O'LEART. K. and STELLMAM, J. (1977). PCM and melanoma. New tog. J. Hod. 190, 101. (Letter to Editor.) ~ BAHN, A.K., SOSEMNAISE. I.. MRRMAMN, N., GROVES, 9., STILLMAN, J. and O'LEAST. I. (1970). nalanoma after exposure to peso, sew tog. J. Nad. 199. 4S4. (Utter to Editor.) SARER. E.L.. LAN0R1GAN, P.J., GLOtCI, C.J.. (ACS, H.H., LIDOLE. J.A.. SOME, V.W.. EOOSWETR, N.J. and MEDIAN, L.L. (19*0). Metabolic consequences of exposure to polychlorinated biphenyls (PCI) in sewage sludge. Am. J. Epidemiol. 111. 991-901. OARSOTTI, O.A. and ALLEN, J.R. (1979). Effects of polychlorina ted biphenyl* on reproduction In the prlaate. fed. Proc. 14. lit. OARSOTTI, D.A., MARLAS, R.J. and ALLEN, J.R. (1970). Reproduc tive dysfunction In rhesus nonkays exposed to low levels of polychlorinated biphenyls (Aroelor 1140). fd. Count. Toxicol. 14. 99-101. ASTONSIT, C.l. at al. (1979). On the aechanism of polychlori nated blpheayl-lnSueed hypoblllrubinaemla. Clinics Chisles Act* *1, 171-174. SAUER, I., SCSULTS. E.l. and APXECELSCRG, U. 119*1). Mrufliche vergiftuagen ble der herstellung von chlorphenol-verbindungon. Arch. Cewerpath. Gewerbehyg. 10, 910-999. HONS 015761 205- SECKER, G.H. et l. (1979). Polychlorinated biphenyl-induced morphologic cKanges in the gastric mucosa o the rhesus monkey. Laboratory Investigation 40. 373-383. BENNETT, G.A. et al. (1938). Morphological changes in the livers of rats result!ng~from exposure to certain chlorinated hydrocarbons. J. Indus. Hyq. Toxicol. 20, 97-123. BERLIN, M., GAGE, J. and HOLM, S. (1975). Distribution and metabolism of 2,4,5,2',5'-Pentachlorobiphenyl. Arch. Environ. Health 30, 141-147. ------- ------------- BERTA22I, P.A., ZOCCHETTI, C., GUERCILENA, S., FOGLIA, M.S., PESATORI, A. and RIBOLOI, L. (1981). Mortality study of oals and tamale workers exposed to KBs. Paper presented at the Inter national Symposium on Prevention of Occupational Cancer, April 21-24, 1981, Helsinki, Finland. (IS pages including cover page.) BICKERS, O.R. (197S). Microscope Imersion Ollsi Effects of skin application on cutaneous and hepatic drug-metabolising enzymes. Biochan. Pharmacol. 24, 779-183. BONES, G.u. et al. (1975). Identification of Chlorinated dibensoturana in Xaerxcan polychlorinated biphenyls. Nature 256, 305-307. BROWN, d.p. and JONES, M. (1981). Mortality and industrial hygiene study of workers exposed to polychlorinated biphenyls. Arch. Environ. Health 36, 120-129. BROWN, J.F., Jr., COE, J.T., and POCOCK, H.D., Jr. (1981). Human health effects of electrical-grads pCBa. Unpublished. BRUCKNER, J.V., KHANNA, K.L. and CORNISH, H.H. (1973). Biological responses of the rat to polychlorinated biphenyls. Toxicol. Appl. Pharmacol. 24, 434-448. BRUCKNER, J.V., KHANNA, K.L. and CORNISH, H.H. (1974a). Effect of prolonged ingestion of polychlorinated biphenyls on the rat. Fd. Cosmet. Toxicol. 12, 323-330. BRUCKNER, J.V., KHANNA, K.L. and CORNISH, H.H. (1974b). Poly chlorinated biphenyl-induced alteration of biologic parameters in the rat. Toxicol. Appl. Pharmacol. 28, 189-199. BUMGARNER, J.E., HAMMER, O.I., COLUCC1, A.V., CREASON, J.P. and FINKLEA, J.r. (1973). Polychlorinated biphenyl residues in refuse workers. Report from the National Institute of Environmental Health Sciences, Research Triangle Park, NC. (As reported in NIOSH Criteria Document.) HONS 015762 -206- BUNGAY, P.H. et al. (1979). Pharmacokinetic* of halogon*cod hydrocarbon*. Ann. N.Y. Acad. Science* 320, 257-270. BURSE, V.U.. KIMBROUGH. R.O., VlllAHECVE, E.C., JENNINCS. R.W., (.INDEX, R.E. and SOVOCOOC., G.H. (1974). Polyenlorinated biphenyl*. Storage, distribution, excretion, and recovery! liver oorphology after prolonged dietary lngeation. Arch. Environ. Health 301-307. BURSE, v.w. *t *1. (1976). PCS netabolisa in rata following prolonged oxpoeur* to Aroclor 1342 and Aroelor 1016. Bull. Environ. Contaw. Toxicol. 12 122-128. BUSCR, a.x. and BOSSHAXDT, B. (1978). forawtlon of polychlorinated dlbenzofurana (PCDfe) froo the pyrolysle of PCI*, Chaaosehere 1. 109-119. (CBI ------- --------------- CALABRESE, E.J. (1977a). lnsufficiont conjugate glucuronldation activityi A pooetbl* factor in polycblorlnated biphenyl (PCI) toxicity. PCI Wdleal Hypothetea, 3(4), 182-163. CALABRESE, E.J. (1977b). nethodologlcal approachea to deriving environmental and occupational health atandarda. A Wiley Intecacience Publication. CALANDRA, j.c. (1975). Summary of toxicological atudiea on. coexaarclal PCI*. Proc. of the national Conference on Polychlor inated Biphenyl*. Sovember 19-21. Chicago, til. CALAIIDRA, J.C. (1976). Summary of toxicological atudiea on coaaaercial PCIa. Proc. of the National Conference on Polychlorinated llphenyla. tKpA-J4o/i-7S-flo4, pp. 77-42.) CUAXRABORTY. D. (1971). lioeheaical atudia* on polychlorinated biphenyl toxicity in rata: Manipulation by vitanin C. Internet. J. Vit. Nutr. lea. 41, 22-31. CHASE, X.H., HOMO, 0., THOMAS, 0., BERNEY, B.W. and SXHOM, R.E. (1961), Clinical and oeeabollc abnoraalitiea in occupational xpoaure to polychlorinated biphenyls. (Preaented at the American Occupational Health Conference, Atlanta, Georgia. May 1, ifai. 2a pagea.) CHEN, p.R. (1980). levels and gaa chromatographic pattern* of polychlorinated biphenyl* in the blood of patients after PCI poisoning in Taiwan, lull. Environ. Centam. Toxicol. 25. 325-329. ------------- -- HONS 015763 -207- CHEN, P.R. and HATTHEVIS, H.B. ( 1974). Hetabolism and excretion ot 2,4.5,2', S'-pentachlorobiphenyl (PCS) in the male rat. Toxicol. Appl. Pharmacol. 29. 88. CHEN, P.R. at al. (1978). Metabolism of 2,4,5,2',5'-pentachloro- biphanyl in the rat. Drug Hetab. Dlap. 362-367. CHENG, K-J, HSEIH, K-H, LEE, T-P, TANC, S-y, TUNC, T-C, (1981). Immunologic evaluation of patienta with polychlorinated biphenyl poisoning; Oeteraination oC lymphocyte sub-populations, Toxicol. Appl. Pharmacol. 61^ S8-63. CLEHENT ASSOC., INC. (1981). Chemical hasards to human reproduction. COLLINS, W.T., Jr. and CAPEN, C.C. (1980). Fine structural lesions and hormonal alterationa in thyroid glands of perinatal rats exposed in utero and by the milk to polychlorinated biphenyls. Am. J. Pathol. 99, 125-142. COUVILLION, J.L., EARL, r.L. and VAN LOON, E.J. (1974). Toxi- codynamics of KB 12S4 in the beagle dog and miniature seine. Toxicol. Appl. Pharmacol. 29, 104. (Abstract.) CURLEY, A., BURSE, V.W. and GRIN, H.E. (1973). Polychlorinated biphenyls; Evidence of transplacental passage in the Sherman rat. Fd. Coamet. Toxicol. 12, 63-67. DALY, J.w. at al. (1972). Arena oxides and the NIH shift. The metabolism,ToxTeity and carcinogenicity of aromatic compounds. Experimentla 28, 1129. DAVIS, C.J., HeLACHLAN, J. and LUCIER, C. (1979). Waltzing syn drome in mice following prenatal exposure to 3,4,3',3'-tetrachloro- biphenyl. Teratology, in press. DIKSH1TH, T.S.S., ROCKMOOD, W.. ABRAHAM, R. and COULSTOK, F. (1975). Effects of a polychlorinated biphenyl (Aroclor 1254) on rat testis. Exp. Hoi. Pathol. 22. 376-385. EARL, r.L., COUVILLION, J.L. and VAN LOON, E.J. (1974). The reproductive effects of K1 1254 in beagle dogs and miniature swine. Toxicol. Appl. Pharmacol. 29, 104. (Abstract.) ECOBICHON, D.J. and COHEAU, A.H. (1974a). Comparative effects of commercial Aroclors on rat liver enzyme activities. Cham. Biol. interac. 9, 341-350. HONS 015764 -208- ECOBICHON, D.J. and COMEAU, A.tl. (1974b). Isoaencally pur* chlorobiphenyl congener* and hepatic function In tha rat: influence of poaition and degree of chlorination. Toxicol. Appl. Phacaacal. 33. 94. ---------------- EPA. (1977). Potential lnduatrlal carcinogen* and mutagens. EPA. (1980). Ambient Hatar Quality Criteria for Polychlorinated iphenyla. CPA 440/9-80-0(8. FAITH. R.E., LUSTER, M.I. and VOS, J.C. (1980). Effacta on imaunocoopetence by cbaaicala of onvironnental concern. Reviews in Biochemical Toxicolocv, ad. Hodcaon. Band ( Philoot. LETC.on. I73-!1T. Elsevier*PuEIXan. FISHBEIN, L. (1974). Toxicity of chlorinated biphenyla. Ann. Rev. Pharmacol. 14, 139-198. FISCHBCIM, A., HOLfr, H.S., LILIS, R., THORNTON, J. and SEL1ROPP, I.J. (1979). Clinical finding among PCB-axpoaad capacitor aanu- facturlng workers. Ann. H.Y. Acad. Sclancaa 330, 703-719. FUNATSU, I., YAttASHlTA, r., ITO, ., TSUGAMA, S., FUNAT3U, T., YOSNIRANE, T,, HAtASHI, (1., RATO, T., tARUSHIJI, (1., ORAHOTO, C., YAflASAEI, S.. A*IMA, t., RUMO, T., IDE, H. and IDE, I. (1972). Polychloroblphanyla (PCBa)-induced fetopathy. I. Clinical obaa tion. Kuruas Had. J. 19, 43-91. .- CARONER, A.n. at al. (1973). Polychlorinated blphenylsi Rydroxyiatad urinary metaboTiees of 2.9,2',S'-tetrachloroblphenyl Identified in rabbita. Biochea. Blophva. Rea. Co--un. 99. 1377-1384. CELLERT, R.J. and WILSON, C. (1979). Reproductive function in rata axpoaad pranatally to paatlcldea and polychlorinatad Biphenyl* (PCBa). Environ. Rea. 18. 437-443. CEYER, H., RRAUS, A.C. and RLEIN, W. (1980). Ralationahip between solubility and bioaccumulatlon potential of organic chcaieala in rate Cheaoaphere i, 277-291. GHIASUOOIN, s.n. at al. (1978). Metabolism of 2.9.2'-trichloro- 2.9,2' ,S'-tetrachIaro-, and 2,4,9,2' ,S'-pentachlorobiphenyl in r*'; hepatic microsomal system. Toxicol. Appl. Pharmacol. 38, 187. COLOSTEIN, J.A. (1979a). The structure-activity relationships of halooenated biphenyls as Smyrna inducers. Ann. N.y. Acad. Sciences 320, 184. HONS 015765 -209 GOLDSTEIN, J.A. et al. (1970. Experimental hepatic porphyria . ,induced by polycKTortnated biphenyle. Toxicol. Appl. Pharmacol 27 437-448. ~ GOLDSTEIN, J.A. et al. (1978). Toxicological aiieaament of hexachlorobiphenyl laomera and 2,3,7,8-tetrachlorodiDenzofuran in chicks. II. Effects on drug metabolism and porphyrin accumulation. Toxicol. Appl. Pharmacol. 36. 81-92. GOLDSTEIN, J.A. et al. (1978). 2,3,7,8-tetrachlorodlbensofuran in a commercially available 99% pure polychlorinated biphenyl isomer identified as the inducer of hepatic cytochrome P-448 and aryl hydro carbon hydroxylase in the rat. Drug. Hetab. 01sp. S, 2S8-264. GOOD, C.K. and PENSKY, n. (1943). Halowax acne ('cable rash*). A cutaneous eruption in marine electricians due to certain chlorinated naphthalenes and diphenyls. Arch. Dermatol. Syphllol. 48, 2S1-2S7. GRANT, D.L., VILLZNEUVE, D.C., HCCULLY, K.A. and PHILLIPS, W.E.J. (1971). Placental transfer of polychlorinated biphenyls in the rabbit. Environ. Physiol. 1, 61-66. GREEN, S., SAURO, F.H. and FRIEDMAN, L. (1975b). Lack of dominant lethality in rats treated with polychlorinated biphenyls (Aroclors 1242 and 1254). Fd. Coamet. Toxicol. 13. 507-510. GREEN, S., CARR, J.V., PALMER, K.A. and OSWALD, E.J. (1975a). Lack of cytogenetic effects in bone narrow and spernatogonial cells in rats treated with polychlorinated biphenyls (Aroclors 1242 and 1254). Bull. Environ. Contam. Toxicol. 13_, 14-22. GRQTE, w. et al. (1975). Blochen. Pharmacol. 24, 1121-1125. GUINEY, p.o. at al. (1978). Effects of 2,3,7,8-tetrachlorodlbeniop-dloxin on tBe JTatribution and biliary excretion of polychlorinated biphenyls in rats. Toxicol. Appl. Pharmacol. 45, 403-414. GUZELIAN, P.S. (1979). Body clearance of halogenated hydrocarbons: Workshop summary. Ann. N.Y. Acad. Sciences 271-272. HANSELL, n.M. and ECOBICHON, D.J. (1974). Effects of chemically pure chioroblphenyls on the morphology of rat liver. Toxicol. Appl. Pharmacol. 28, 418-427. HANSEN, L.G. (1979). Selective accumulation and depletion of poly chlorinated biphenyl components: Food animal implications. Ann. N.Y. Acad. Sciences 238-248. HONS 015766 210- HANSEM, I.C., BYEBLY, C.S.. METCAtr, B.t. and BEVIU, B.F. (I9y1). Effect o a polychlorinated biphenyl mixture on swine reproduction and Claaua raalduaa. Aa J. Vac. Bee. 34(1), 13-16. HAM, l., HAHAOA, A., KltlUM, 3., EWOO, T., and KAHAdO, X. (1974). Follow-up atudy of eondanaar factory after uaa of FCB dlacontlnuad. Fart I. Jjn. J. End. Health 16, 345-386. (Aa raporead in dIOSR Critarla Document.) HAM, I. at al. (1975). Follow-up atudy of eondanaar factory atear uaa of FCrdiacontinued. Fart III. Jn. J. Ind. Haalth 271-372. (Aa raportad In NIOSH Critarla Oocuaent.) ~ HASEGAWA, H., SATO, n. and TSUBUTA, a. (1972). 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Baalth Paraoact. 109-117. VOS, J.G. and lOtnAM, J.H. (1*70). Cooperative toxicologic study vita polychlorlnatad biphenyls in chlekana with special referones . to porphyria, adaea formation, liver necrosis, and tissua residues. Toxicol. appI. Pharmacol. 17, 696-44S. VOS, J.G. and BUMS, S.B. (1971). Dermal toxicity studies of tech nical polychlorlnatad biphenyls and tractions thereof in rabbits. Toxicol. appI. Pharmacol. If, 417-633. VOS, J.G. and VAX DJUEL-CJtOOTEMTOIS, L. (1972). PCB-inducad suppres sion of tha humoral and cell-mediated Immunity in guinaa pigs. Sci. Total fnvlron. 1, 269-342. VOS, J.G. and HOTEHBOOn-RAM, E. (1972). Coaparativs toxicity study of 2,4,5,2*,4',9*-bexachlorobiphanyl and a polychlorlnatad biphenyl aixtura in rabbits. Toxicol. AppI. Pharmacol. 23, 963. HONS 015777 -221- VOS, J.C., KOENAN, .1.11., VAN OCR HAAS, II. L. , TEN NOEVER OC (IRAUW, II.C. and UE VON, R.H. (1970). 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Glossary of Terms or Abbreviations AX BSP GGTP H-PCBa L-PCBs LOB PCBa PCDFs PCNa PCQe PCTs SCOT SGPT SOCT Yusho ro Fla, Fib alkaline phosphatase broaaulfonphthalein liver function taat gaaaa glutamyl tranapaptidaaa PCBa with high dagraaa of chlorination PCBa with lowar dagraaa of chlorination lactic dehydrogenase polychlorinated biphanyls polychlorinated dibenaofurana polychlorinated naphthalenes polychlorinated quaterphenyls polychlorinated tarphenyls aerua glutaaic oxalic transaainaae aerua glutaaic pyruvic transaainaae serum ornithine earbaaoyltransferase the disease.noted in Japan following human ingestion of cooking oil contaminated with PCBa, PCDFs and PCQe. parental test aniaals litters derived from first generation animals at their first (a) and second (b) matings MOMS 015779 88 - teats war* also perfoned on seven workers with relatively high blood PCI) four of eha seven easta were slightly above the norail Halt of St but, aa tha authors atata, alnea othar eondltlona aueh aa fever nay loeraaaa BSP retention, thaaa results by thenselves could not bo takan aa proof of hapatle danage. Tha up taat raaulta did not ahow a significant correlation with blood PCI levels or tha length of axpoaura (5 to 23 yaara) to PCI. (11) Plachboln at al. (1P7S) atudied liver func tion taata In 321 workara axpoaad to PCBa In an electrical nanufacturlng plant for laaa than five yaara to aore than 23 yaara. The pereont of testa that gave an abnoraal test result was SOOT 2.2%, 3OPT 7.2%, LM 2.S%. alkaline phosphatase 1.2, and aerua bilirubin $.3%, and Indicated a "vary low prevalence of abnoraal liver findings.* Thera was no consent or analysis to state that a certain nuaber of the subjects showed a pattern of abnoraal liver function tests Indicative of hepatic dysfunction. These data can be taken to represent a serlas of randon teat raaulta that night be aspectad In a population of 321 Individuals ranging in age from lass than 30 years to over 70 years. Control subjects or non-eaposed workers were not Included for conparIson. There was perhaps sons Indication of a relationship of SOOT levels to plaasM levels of POs, but the two exposure categories of PCS levels are too broad and require a finer analysis. (Ill) laker et al. (1910) studied liver function In 141 Individuals with various degrees of exposure to PClai tha HOMS 015660 - 88 - an PC* aarua level* for the four taat group* varied froa 17.4 ppb to 73.1 ppb. Thara waa no chang* In llvar function taata (SOOT. SOFT, LOR, alltalin* phosphataa* or aarua bilirubin) In ralation to PCS blood lavala in althar drinJcara or nondrlnkara of alcohol. Sarua GGTP (gaaaa glutaayl tranapaptldaaa) corralatad with aarua PCS. but a eorralation did not exist whan alcohol drinkara war* raaovad froa tha analysis. <iv) Haroni at *1. (1881a, b) atudiad liver function in 10 worker* axpoaad to pCBa for an avaraga of 12 years and reported that 1C individual* had an abnoraal livar finding aa judgad by clinical asaalnatlon or by laboratory taata. Inapactlon of tha data ahows ralatlvaly fav inatanca* of abnoraal livar function taata. Tha aoat fraguantly altered laboratory taata war* aa followst 8 of 80 subjects with increase of SOCT activity 7 of 80 subjects with increased aarua aaino- transfarasa activity (Mt or ALT) C of *0 aubjacta with incraasa of SOCT activity. It is evident froa thalr data that aany of the change* ar* slight, and as test results froa control subjects war* not included, v* do not know what the normal test variations aay b* for 80 control aubjacta of a similar ag*. Further, examination of the data for tha 14 subjects with clinical hapatcaagaly shows only one subject with an abnormal test in thra* types of testa ( scot, ast/ ul and SOCT)1 only two of the aubjacta gave a positive response in two of HONS 013601 - 90 - the teat typeat eight aubjacta had an abnormality in only one cast I thraa aubjacta had normal coat raaulea. Sorum bilirubin and alkallno phosphateae activity wars within tho normal range In all aubjacta. laaod on the above review, it ia evident that only one of the to subjects ahowad a pattern of teat reaulta indicative of abnormal liver function* the other teat reaulta reflect only random varlatlona from normal. Haronl at al. also reported that the mean level of blood PCM in the It workera with abnormal liver findings waa slgnificantly higher than that of ft workers without abnormal liver flndlnga. but the ranged for the two groupa ahow conaiderabla overlapping and the two aubjacta with the higbeet blood pea lavela bad normal liver function taata. The only control we can uae to evaluate tbe auggeated relationahip between pea blood level and liver function are the 10 aubjacta with chloracnei theae 10 individuala bad normal liver teat reaulta deaplta the fact that their aaan blood PCX concentration waa high and not algnlficantly different from the dean blood PCX level found in the Id workera dlaeuaaed above. Thua, it cannot be aald that this atudy demonatrataa a relationahip between a high blood PCX level and abnormal liver function taata, atteating further to the randoaneaa of the liver function teat reaulta in the atudy. (v) Mith_et_iU. (1911a, b, c) evaluated liver function taata in PCX-expoaed employeaa from an electrical aanufacturing plant, a municipal electric utility company and a privately-owned HONS 019662 - 91 electric utility company. The data on SCOT and GGPT are difficult to evaluate aa tha results of the measurements ara not 9Ivan, and therefore may ba aaauaad to ba within normal population levels; rathar. tha authora sought eorralatlona batwaan tha I09 of SGOT and GGTP with tha I09 of tha lowar aarua pCBa and tha log of high sarua PCBa. Calculations includa siapla eorralatlona, aaparata ragrasalona with tha confoundara aa pradletora, and aquarad par tial corralatlon, plua othar ceaputatlons to aaa if aaaociatlona existed. Thair tablaa 6, 7 and I auaaariza aany of tbair calcu lations , and data for transaalnaaas from tabla 7 ara suaaurisad balow. Corralatlon With Serum log L-PCB Sarua log B-PCB Electric eoulpswnt Coapany log BOOT log GCTP Municipal alactrle utility coapany log SOOT log oan Privately-owned utility coapany log SGOT log GGTP Slg statistically significant NS not significant NS Sig Sig Sig NS NS NS NS Sig NS NS NS L-PCB * lowar chlorlnatad biphanyls H-PCB higher chlorlnatad biphenyls MONS 015603 - 92 - Comlatlona (aaaoelationa) war* found ae eha agulpsant ccopany but tba data cannot b# axaainad to datarain* tf tha calculated value baa any aadleal significance. Correlations at tb* publialy-ovnad utility coapany war* not significant. At tb* privataly-ovnad utility coapany, tb* only positive finding waa a positive aaaoelatlon of SOOT wltb aarua L-PCB. it la not elaar wbat tb* ebang* In tbla on* taat raault aaana aa tb* sarua L-rCM war* not significantly dlffarant batwaan tb* axpoaad and nonxpoaad group*. Tb* taat raault* for total bilirubin, alkalia* phoapbaataa* and lactie dabydroganaa* ara not diacuaaad. and it la praauaad that than* aaaauraaanta of livar function war* not abnocaal. 2. 11tar plaaaaa in PCt-txooaad Sorters Hadical axaalnation of PCB-axpoaad workara baa not ahewn tb* praaane* of liwar dlaaaa*. In th* atudy of Plaehbain at *1. (1979). physical axaalnation of 326 Individual* (ag* laaa than 30 to ovar 70 yaara) ravaalad 4 individual* wltb abnocaal llvar alx*. two of wbaa bad a hiatory of baavy aleobol intakes on* of tba four bad a alight alavatlon of on* livar function taat (SCOT of 5S). In another atudy of 14S individual* wltb varying dagrnaa of K1 axpoaura, tbar* wa* no avidanca of livar dlaaaa* aa datarainnd by aadleal hiatory and physical axaalnation* (taker at al.. 1914). Saith at al. (1961) did not find avidanca for liva- MQHS 015664 - 93 disease in their subjects, there being no significant finding* on physical examination of worker* at an alactrical equipment manufaeturing plant who war* heavily exposed to PCSa, or worker* at a municipal utility company or a private utility company who vara leas heavily exposed. Deaths from cirrhosis of the liver were not increased by exposure to PCI (Brown and Jones, 1981)r six deaths ware observed (three of the six consumed alcohol regularly) versus S.f expected. 3. Summary and opinion The review of clinical data demonstrates that exposure to PCSs does not significantly affect liver function tests. Liver function remains normal in individuals with aeasurable, and freq uently high levels of serum PCB. Also, exposure to PCBa does not result in the production of clinically detectable liver disease. The induction of enxyme systems in the liver and the biological aignifleance of this process, as mediated by KBs, are discussed in section XI. HONS 015665 - 95 - Vli. Gastric Lesions The oral administration of PCBa to nonhuaan prlaataa haa baan shown by Ulan and co-workars to lnduea hypertrophy and hyperplasia of tha gastric aucosa. Hucoaal eysta aay ba praaant within tba aplthallua of tha stoaMCh, but In tha mucosal lining and tha subaucoaa, thaca aay ba adaaa of tha aubaueoaa of tha atoaaeh. In addition, thara is frequently invasion of tha under lying mucosa by lsolatad glandular alaaants of tha aucoaal aplthallua. General affacts of this nature hare baan produced in tha monkey byi 1) a single oral dose of l.S g or 1 g of Aroclor 1241 (Ulan, Norback and Hsu, 1974). li) Aroclor 1241. 300 ppa and Aroclor 5400 (a polychlorinated triphenyl), SQ00 ppa in tha diet for 90 days (Ulan, Abrahaason and Morbaek, 1973; Ulan and Norback, 1973). ill) Aroclor 124*, 25 ppa in tha diet for 2 months (Ulan, Cantons and Bersottl, 1974). iv) Aroclor 1240, 100 ppa in the diet for 2-3 aontha (Ulan, 1975). v) Aroclor 1245, 2.5 ppa and 5.0 ppa in tha . diet for up to one year (Barsotti and Ulan. 1975). (Gastric changes wars not listed for these doses in Ulan's review.) HONS 01566b - 94 - rt) The hyperplastic gastritis My persist for over om year following discontinuance of PCI exposure (Allen, 1975). A mixture of low chlorinated biphenyl (Clophen A-30) was not observed to produce gastric laslons In the aonkay (Xatropouloa at el.> 1977). Tha findings of Allan at al. wars racantly confined and axtandad by laekar at al. (1979). Tbair study involved sis monkeys, ona untreated and ona aaeb receiving a dlat containing 3, 30. or 300 ag/kg of PCS (Aroclor 1242); two asnkaya raoalaad a dlat eontaining 10 sg/kg. Monthly blopaias takan froa tha graatar curvature of tha stoaacb ahowad a draaatlo dacraasa la tba nuabar of parlatal calls with a concealtant laoraaaa In tha '' nuahar of mucous naek calls. Tha lyaoganio (chief) calls ware also reduced in nuabar. This was followed In all treated anlasls by a aucoua conversion of tba gastric epitbeliua. with downgrowth of the gastric glanda into tba subaucoaa and tba eventual tarnation of cysts. It is noteworthy that tba lesions wars confined to tha stoaaeh; no changes wars found in other regions of tha gastrointestinal trace. Tha gastric changes can be described as a dysplastlc growth pattern, but thara is no neoplastic transformation (Allan and Horbaek, 1973). however, tha authors speculate that they are suggestive* of an eventual neoplastic transformation. Analysis of tba resales obtained In tha aonkay Indicates that tha pca-lnducad aorphoiogle changes In tha gastric aucoaa HONS 015667 - 97 ay be pacific to this epeclea and not predictive of poaalbla affaeea In man. (i) Evan within tha aonkey a apacificity of action la preeent, aa tha laalon lnducad by pCBa la found only alon9 tha greater curvatura of tha atoaachi nalthar tha cardiac nor pyloric portions wara affactad (Backar at al., 1979). (11) Hypertrophy and hyparplaala of tha 9aatrle aucoaa hava not boon reported In tha rodent (Allan and Abrahaaaon, 1979), rabbit (Voe, 1972) or In other apeciea (voa and roenaan, 1970). Clinical flndlnga to data hava not auqqeated or Indicated that eapoaure to PCBa incraaaaa tha occurrence of cancer of the atoaach In the huaan (aee alao aectlon VIII, relating to carcinogenicity). MONS 015668 - 99 - VIII. Carcinogenesisi Experimental and Clinical A. Eaparlm*Mi1 Studies All author* do not ua* tba word* tuaorlgonaal* and neoplasia to lndleat* tha mm typo of raapon**. Tuaorlganasl* i* a general term that rafar* to both benign growth* and Malig nant growth*i eoapounda My affect tha oocurronoa o bonlgn tuaora without inducing cancar. Maoplaaia aaana simply a naw growth. Tha tana `naoplaala* can rafar to a bonlgn or Mlignant growth. OftantlM* author* My eoablna data relative to bonlgn and aalignant growth* so that whan tha tarns tuaorlgonoala or naoplaala *r* used, they auat ba earofully daflnad. 1. Bapatocallular CarclnoM* (I) Studio* In Mica. Ito at *!.(173) ob- arvad bapatocallular carelnoM* in ale* only In tha high doaa group glvan Kanaehlor $00i lowar doss* of Kanaehlor S00 or tha other Kanaehlor* did not produce a carcinogenic response (Table 2). Tha administration of 100 ppa of Aroclor 12S4 In tha diet for 11 aonth* did not Indue* hepatocellular carcinomas in ale* (Kimbrough a Linder, 1974). (II) Studla* In rata. The adalnistration of Kanaehlor 400 ter 400 day* did not Indue* bapatocallular carcinoma (Klaura a Baba, 1973), but the period of traatMnt My haw* boon too brief to detect a carcinogenic affect. In a further study Klaura at *1. (1970 administered Kanaehlor to rats for sis months but due to body weight change* a variable dosage schedule mi employed. Following the casMtion of traatMnt, the rata were HONS 0156b1* - 100 fad oa a normal diet for 270-410 day*t autopsy, aftar a total axparlnantal period of 430-990 days, did not reveal hepatocellular carcinoma In any of 12 rats. Ito .at al. (1974) traatad rata tilth dlffarant do*** of Xanechlor 900, 400, and 300 for period* up to 32 V**k*> hapato eallular carcinoma* war* not observed, but tha duration of treataent was probably too abort to rula out tha possibility of a positive rasponss. Tha thras aajor studlaa pertaining to 90* and hepatic earelnoaa In the rat are those of Klabrough at al. (1979), Calandra (1979) and tha National Canear Xnatltuta (1979). Klabrough and eo-vorkars, using tha Itanaan strain of rat, found that 100 ppa of Aroelor 1290 in tha diet for 21 aontbs produesd a signlfleant inereaso in the incidence of hepatocellular earelncaa la feaale rats (Section VT, Table 3). Hals rata were not studied. The administration of thrae dlffarant Aroelors at a dose of 100 ppa to rata for 24 months (Table 4) did not Induce hepato cellular earelnoaa (Calandra, 1979). Tha author states that this negative finding was baaed on evaluation of tha liver Mo tions by 3 pathologist*, who read the slides independently and separately. Be states further that Professor 9. 9our re-evaluatod the Klabrough slides and did not agree with tha reported findings (sea also section VI, Table 1A). The results of the National Cancer Institute (1979) bioaasay of Aroelor 1294 for possible eareinogenlclty are shown in section VI, Table 3. riachar 344 rata were used and the 90 HONS 015670 101 nixcura waa adalnlatered at three doea levela US. 50 and 100 ppa) in tht diet for 104-103 week#. Tha affaet of the traataant on body weight and aortality at tha higher doaa lavala deaonatrated that aaxlaua tolaratad doaaa were need, thua providing a aatlafactory taat of earelnoganle potaneial. K aufficiant nuabar of rata of both aaxaa waa available for aaaningful atatlatieal analyaaa of tha incldanca of late-developing tuaora. traataant waa aaaociatad with only thraa hapatoeallular carcinoaaa In aala rata, which waa not aignlficantly diffarant treat tha controla, and it waa concluded that Xroclor 1234 waa not earelnoganle In tha bloaaaay. (Ill) Studlaa In doca. Hapatoeallular cardneaa did not occur in doga (four aala and four faaala par group) receiving 1, 10 or 100 ppa of JUraclor 1242. 1254, and 120, roapactlvaly, in thalr diata for two yuan (Calandra, 1973). (iv) Dlacuaalon. Data frea tha aouaa provide only llaitad and raatrictad avidanca for a carcinogenic affect of tha japanaaa eoapound Kanacblor 300 (Table 2). Studlaa on the rat give conflicting raaulta on hepatic carclneaa. (Section VI deala with tha benign hepatle proliferative leelona found in tha treated rata, which aay or aay not indicate carcinogenic potential.) Kiabrougb at al. (197S) reported an lneraaaa of hapatoeallular carcinoaaa in faaala rata receiving Aroclor 12(0, wbaraaa the atudlea of Calandra (1973) and the National Cancer.xnatitute (197S) did not obaarva a aignifleant lneraaaa in hapatoeallular carcinoaaa in rata raeeiving different Aroclora. Whether the HONS 015671 102 - divariant results ara ralatad to th* different attain* of rats that vara used, represent diffaraneaa in tha affaet of th* two Aroclora, or ara dua to oehar factors ia not known, it is obvious, hovavar. that in viaw of tha differing rasulta obtained it is not possible to astrapolata or project posalble effects in sen. Sapetoeellular carcinomas did not develop in dope treated with Aroclor for two years. 2. Bladder Cancer Klabrougb (1272) observed bladder cancan ia two rata fad 100 ppa of Aroclor 12(0 for sight aontbs. in a later study with 200 rats receiving 100 ppa of Aroclor 12(0 for 21 aontbs tbs only bladder tuaor observed (a transitional cell papillose) was in a control anlaal, and It was concluded that 'the occurrence of the bladder tuaor in tbs previous esperlaant was apparently un related to the Ingestion of Aroclor 12*0* (xlabrough at *1., l79). This type of variation deaonstratea tba unreliability of attaching . significance to aaall changes in tuaor incidence in a given ex periment , particularly when the incidence does not show a statistically significant difference from a control group. Benign or aalignant bladder tuaora did not occur in rats trsated with Aroclora lIS* (IS, S4 and 100 ppa) for 104-10S weeks (national Cancer institute, 1771). Th* above studies do not. demonstrate that adainlatration of Aroclor 12S4 or Aroclor 12(0 Induces bladder cancer In the rat. HONS 015672 103 3. Stomach, Interntlnal Tract Cancer Treatment of female rats with Aroclor 1260 (100 ppm in dlat) for 21 months did not Induea tuaora In tha gastrointestinal tract (Kimbrough at al., 1973). Traataant of rats with Aroclor 1234 (23, 50 and loo ppm in tha dlat) for 104-105 weeks did not lnduca gastrointestinal carclnoaas (national Cancar Instituta, 1976). Tumors occurrad In randoa sannar as llluatratad In Table 6. 4. Carcinogenesis - othar Organs Studlas with FCBs in relation to cancar of tha Hear, gastrointestinal tract, and urinary bladder have bean discussed separately above. In tha studies with PCBs other organs have bean evaluated in detail without finding any affect of chronic administration of Aroclors on the incidence of benign or aalignant neoplasms. The following appraisals refer to tuaors of these other organs. Kimbrough at al. (1973) found that the chronic administration of Aroclor 1269 to rats did not affect the incidence of benign tumors or carcinomas of the thyroid gland, adrenal gland, uterus, lung and other organs. Frequently investigators look only for Increases in tumor Incidence, when in fact decreases are often obtained. It is worth noting that mammary adenocarcinoma occurred in 3/173 control animals versus an incidence of 1/164 in treated animals. If the incidence had been reversed, some authors may have commented or suggested that FCBs may increase the occurrence of mammary cancer, but such would noe have been HONS 013673 -1U5- Tahla 6 Incidenca of Gastrointestinal Carcinomas in Kats Traatad with Aroclor 1254 - (Data frees National Cancar Institute, 1971) Number of Carcinoma* Wales Control low Doaa Had. Doaa Blah Do-- Stomach, adenocarcinoma Jajumm, carcinoma Cacum, adenocarcinoma ramalea 0 0 0 0 0 0 10 01 10 Stouch, adanocarcinoeui 0 1 10 ) HONS 015074 - 107 the oaae as the number of naaaary adenocarcinomas In control groups can vary significantly from study to study, if tha lncidanca of spontaneous tuaort can vary, than tha nuabar of malignancies in tha traatad group will vary with each experiment independent of the treatment given. An additional illustration of tumor variability is the incidence of ovarian granulosa theca cell tumors which was S/149 in controls versus 0/1(3 in the treated animals. In the national Cancer Institute (1970 study, the chronic administrations of Aroclor 13S4 was without affect on the development of benign or malignant neoplasms in the various body organs of tha rat (the liver, gastrointestinal tract and urinary bladder were discussed separately above). In the atudy, interstitial cell tumors of the testes were present in nearly all control and treated animals, there being no effect of treatment. Leukemias, which were the second most common neo plasms, were found in 1st of control males and 17% of control females. A statistically significant dose-rslatad trend for leukemia was present in the treated males but not in the female rats. However, direct dose comparisons between each treatment group (male or female) and tha control group were not statisti cally significant, so that an affaet in males could not be clearly related to the administration of Aroclor 12S4. Adding the few lymphomas to tha leukemias for the analysis did not change the HONS 015675 10 - conclusion. Kimbrough at al. (197!) also did not find a sig nificant lifict of hroclor 1240 on leukemia Incidence (1/173 in controls va. 0/114 in treated anlsala). It any 6a concluded from tbaaa atudiaa that the chronic oral adalniatration of high doaaa of kroclors 12(0 or 12S4 doaa not induce benign or malignant tuaora of tha thyroid gland, adrenal gland, uterus, lung, beaatopoietic ayaeea, pituitary gland, thyaua, kidney and other organs in raes. J. Suaaary and Opinion Animal atudiaa do not provide convincing evidence that PCM induce liver cancer. Of the major studies in the rat, one baa been judged positive and 2 have been negative. Sepatlc car* clnoaa was not produced in the dog. Chronic administration of aroclora in the rat did not induce bladder cancer, gastro intestinal carcinoaaa or cancer of the thyroid gland, pituitary gland, adrenal gland, uterus, lung, hematopoietic syitea or other organs. B. Clinical Studies the studies of >rown and Jonas (19(1) and Mrtasal and co-workers (11) have evaluated the relationship between ex posure to PCM and the subeequant development of cancer. Both analyses are retrospective mortality studies of workers to deter mine the cause of ebe death and, for malignancies, tha specific type of cancer causing the daaehi the deaths are designated as 'observed eases.* the person-years of exposure of the workers to ' HONS 0i5<>?<> - 109 - PCS MCI determined and combined into calendar time periods and five-year age groups to calculata fro* mortality statistics tha number of "expected" deaths. Tha number of obsarvad varaus expected daatha was than comparad. Background data ralatlva to thasa studias ara summarised brlafly. as followst (i) Brown and Jonas (1991). Tha authors analysad 163 known daaths occurring among 2,587 workers sxposad to pels for 39,018 person-years. Cxpoaura to FCBs rangad from thraa months to ovar 20 yaars. Tha typa of FCBs usad at tha plants wara Aroclor 1254, 1242, and 1018. (ii> Battassl at si. (1981). Tha authors analysed 27 daaths occurring m 1,310 workers sxposad to FCBs for 20,585 parson-yaars, determining 'observed* versus 'expected* rates for malignancies, mortality was studied for a 25-year period (1954-1978). Exposure up to 1984 was mainly to Aroclor 1254 and Fyrallne 1478; starting in 1985 mixtures with 428 chlorine wara usad (mainly pyralina 3010 and 3011). (iii) Batin at al. (1978. 1977). These authors report 2 cases of malignant melanoma in 31 man exposed to Aroclor 1254. It is not elear from their studias if they ara discussing morbidity or mortality; Brown and Jones (1901) interpret tha report as mortality. pertinent data on tha mortality from malignancies ara summarised in Table 7 and ara discussed below. HONS 015677 - no Ml Wallcnanclea. Brown and Jonaa reported 39 0bzervad caaaa of cancer varaua 43.1 txpected caaaa, whereaa Bartazxl at al. found a atatlatlcally algnlfleant tneraaaa in aalaa, but not In female workera (Tabla 7). There waa no tncreaae In tha riak of Mortality fro* all malignanelaa wits length of aapoaura or wltb tha number of yaara of employment (Brown and Jenna, 1BB1). Bectu*. Tha only atatlatlcally significant dltfaranca obaarvad in tha atudy of Brown and Jonaa waa for roetal canear In faaalaa froa Plant 2 (Tabla 7). Thera waa no significant finding for faaalaa In Plant 1, aalaa la Plant 1 or 2, or for tha coablnad data for aalaa and faaalaa. Tha lneldanaa of rectal cancar abowed a alight, but atatlatlcally lnalgnlfleant, Ineraaaa with Ineraaaa la Latency) no direct relationmhlp with lnereaaad length of aapoaura la apparent. Bertaiii at el. (19(1) did not report a caaa of roetal cancer in PCS eapooad Individuals. Stomach, Panoraaa. Tha atudlaa did not daaonatrata an incraaaad rlak tor atouch or pancreatic cancar (Table 7). Baoetocellular Carclnou. Three caaaa of liver cancer ware obaarvad In tha atudy of Brown and Jonaa (19(1), but the difference froa tha control rata waa nee reported to be atatlatl cally algnlfieant (Table 7). Bartazxl and eo-workara did not mention obaarvlng any caaa of hepatic cancer. Examination of tha data for latency effect or for length of aapoaura to PCBa did not show any relatlonahip to development of liver cancar (Brown and Jonaa, 19(1). HONS 01S67S Table 7 Peatha from Specific Types of Cancer Comparison of Obaarvad Daatha la PCS Workars with Expected Daatha Humber of Caaaa Reference HaXienaney Stx Obaarvad Expact X All H,r 39 43.79 3 H 9 3.33 3 r C 3.33 1 Rectos H 1 0.51 1 Ptplant X) 0 0.11 replant 3) 3 O.SO 1 m,r 4 1.X9 X Stomach H.T X l.M X Panorama h.t 1 1.90 3 Digestive Organa H (stomach, pancreas, r biliary tract) 3 0.11 0 1 Hapatie Carcinoma H.T 3 1.07 X Lymphatic t Hematopoietic 3 3 H.T H T 3 4.34 3 0.4C 3 0.45 3 Melanoma H 1 H.T 3 H.T i 0.04 00- SHE 19 341 351 33C <0 53 340 310 ) 4. 435 444 - Statiatical Significance as P-0.04 HI as MB K0.0S MS MS MS MS MS MS MS MS MS P>O.OOX MS MS Eat 1, ? ' 1, : 3, SMS, ::s, ' Brown and Jonas* 1911 Bartasrl at al., X9BX Bahn at al., 1970, X977 standardiaad mortality ratio (obaarvad daatba/axpactad daatha x 100) Hot significant HONS 015679 - 113 - Lymphatic and Hematopoietic Cancer The two atudlea hew diametrically oppoalte rlak valuta, although neither ia tatiatleally aignifleant (Table 7). Melanoma. Bahn et al. (1976, 1977) reported two caaes of malignant malanoea occurring among 31 men who had been xpoaed to Aroclor 1254. Baaed on the Third National Cancer Survey incidence ratee, Bahn at al. calculate for a peraon-year analyala that only 0.04 malignant melanomaa would be expected, the difference being atatiatlcally aigniflcant (P*0.001). The xtenelve atudlea of Brown and Jonea and of Bectaxai at al. fail to confirm the increased rlak of mortality for malignant melanoma reported by Bahn and co-workara (Table 7), raining doubta about the aigniflcance of the Bahn atudlea. Even an aaaociation with the low P value of 0.001 haa not bean con firmed . Summary. The clinical evaluation of PCBa relative to cancer ia currently beaed on a limited amount of data, and any concluaion regarding their effecta muat be regarded aa tentative. Nevertheleaa, aowe detailed analyaea are available and eonclualona baaed on them, aa Hated below, are of acme aigniflcance. 1. Retrospective mortality atudlea have not demonatrated a conalatent relationahlp between expoeure to PCBa and the development of a particular type of cancer. 2. The clinical findinga on hepatocellular carcinoma are of great intereat aa aome experimental atudlea report an HONS 015600 - 114 - Increase In liver cancer In rodene* receiving PCBa. although Brown and Jones (1911) observed three caaea veraua 1.07 expected caaea. the difference la not statistically significant. Their analytic of PCB exposure and rlak of aortality from liver cancer la elao noteworthy alnca it did not demonstrate an effect of latency (number of yeara froa data flrat employed) or a relationship to Increased duration of deployment In Jobs Involving PCB exposure. These latter observations are. how ever, baaed on aaall numbers. Bertassl at al. (1BB1) did not report any significant relationship between PCB exposure and liver cancer. Taken together these studies do not confirm the projection of a risk for liver cancer In huaans based on the aniaal studies. 3. The SMB (Standard Mortality Batlo) aay vary widely In different studies, and eaphaaia should not be placed on an Increase In the SMB found In one study unless a significant change In SMB can be confined in several repeat studlas. for exaaple. Brown and Jones found the SMB tor lymphatic and heaatopoletlc malignancy to be decreased while Bertassl at al. reported an Increase, although neither result was statistically significant (Table 7). 4. Brown and Jonas observed a statistically signi ficant increase In SMB for rectal cancer in woman at one plant, but not in a different plant, and no significant effect In male workers at either plant wee observed. Bertassl et al. MOMS 015681 115 did not report any ractal cancar (Table 7). Overall, therefore, a convincing daaonatsation of ractal cancar as a raault of extandad exposure to PCBa haa not baan aada. HONS 015682 117 IX. Reproductive 8ffct A. Reproduction Numerous reports have appeared In the literature on the effects of polychlorinated biphenyls on reproduction In animals. Gellart and Wilson (1979) showed that female SpragueDawley rats given 30 mg/kg Aroclor 1221, 1242 and 1260 by gavage during days 14 through 20 of pregnancy had no affect on the reproductive function of the offspring as judged by (a) normal estrus cycles, (b) normal appearance of ovaries and utsrl, and (c) fertility of males, reeding 5S0 ppm of Aroclor 12S4 for 17 days to Sherman rata resulted in fewer litters, smaller litter site and loot mortality by day three of the rla pups. At 100 ppm survival of both Fla and FI5 offspring was reduced. Tbe pups were smaller than controls but appeared normal at weaning. Aroclor 1260 fed at a dietary level of S00 ppm OS.4 mg/kg) for 67 days prior to mating marksdly raduced litter else and survivalto-weaning In the rla and fib generation. Dietary levels of S ppm Aroclor 1234 and 100 ppm Aroclor 1260 had no effect on reproduction In rats exposed through two generations (Linder at al., 1974). A dietary concentration of 2.3 ppm of Aroclor 1246 produced alteration In the menstrual cycle of adult female rhesus monkeys. Hanses were prolonged and menstrual bleeding was increased (Allen at al., 1979). Keplinger at al. (1971) fed rats and dogs Aroclor 1242, 1254 and 1260 at doses of 1.0, 10.0 and 100 ppm. Ho adverse HONS 015683 - ua - effect on coproduction vaa observed in rata given i.o and 10 ppa Aroclor 1242, but there vaa a dacraaao in aurvival o pupa at 100 ppa of Aroclor 1242, 1234 and 12<0 aa vail aa a dacraaao in Bating indicaa. The effect of FC>a on raproduetion in beagle doga and awlne Baa bean atudiad by Earl at al. (1974). Aroclor 1234 lntarfarad algnlficantly with coproduction in doga at doaea above 2.3 ag/kg/day while in swine 10.0 ag/kg/day lowered ferti lity and aurvlvabillty of neonatae. The reproductive effacta in doga are guaationabla bacauaa of unexplained changed in the repro duction pattern aaong controla. a. Teratogenicity 1. Introduction Teratogenicity la that property of an agent whereby It la capable of inducing congenital defecta in the developing aabryo. Such agenta that are chealcal aubatancea are known aa *toratogena* and the defecta they induce are known aa "terete*. Although teratogenicity ia conaldared generally to Involve only anatoalcal defecta, aoae authorit tee regard functional or Me chanical changea aa aanlfeatatlona of teratogenicity. A dlatinctlon aunt be aade between teratogenicity and fetotoxlclty, t.e., toxicity to the fetua. The finding of dead or raaorblng fatuaea in the uearua of an exparlaental aniaal la not evidence of a teratogenic action of the teat aubetance. Slatterly, a aaaller alxe of the newborn ia indicative of fetotoxlelty rather than teratogenicity. HONS 015681* - 119 K aubatanca nay appaar to ba teratogenic if It produeaa aavera toxic affacta on tha pregnant fanala. Maternal dlaeaaa and nalnutrltlon if fact tha nunbar and quality of tha offaprinq. Dafacta In tha offapring that arc aacondary to toxic affacta of tha aubatanca on tha aothar arc not conaldarad tarata. taratogana produce their haraful affacta during tha period of fornatlon of calla, tiaauaa, and organa. Banca, once davelopnant of tha fatua haa bean coapleted, a teratogenic event can no longer occur. Cheaical aubatanca* adnlnlatarad to the nothar can be trananittad, together with their natabolltee. via tha ailk to tha auckling young, and nay produce toxic affacta in tha lattar. However, auch affacta are not indlcationa of teratogenicity. Conventional tact* for tha detection of teratogenicity involve adalniatration of the teat aubatanca to pregnant faaalaa at repeated intervale throughout tha period of organogenesla, a.g., daya 6 through IS of tha gaatation in tha rat. Tha treated faaalaa are aacrlflced on the day prior to parturition, and the fatuaea reaoved Croa tha utarua aurgically for exaainatlon. Alternatively, the teat aubatanca aay ba adnlnlatarad over rela tively long parloda of tiaa, and the aniaala allowed to bread normally aa in the uaual one- to three-generation reproduction atudlaa. The appaaranca of aalforaed offaprlng aaong the auecaadlng generation* would ba evidence of teratogenicity. In order for a chemical aubatanca to which the aothar la axpoaad to axart a direct action on tha concaptua, it or one MOWS 015b85 - no or nar* of Its MttteUtM auat be able to crol eh* placental brri*r. Trnaplae*ntil passage of PCS* baa b*n deaonatrated in several animal apacita (Allan at al., naoi Curley at al., 19731 CouviUlon at al., 1974> Grant at al., 1971), and la known to occur in th* huaan (funatau at al., 1972). 2. Mica PCBa war* not taratoganic in aic* at dosages up to 900 agAg given on day* 1 through < or day* 7 through 11 of gsstation (Toaruk, 1972). However, a racant atudy (Marks at al., 1991) with th* haxachloroconganar 3,3*,4,4'3.3'-bexaeblosobipbanyl in ale* at doaagas in tha rang* of 0.1-10 ag/kg/day during day* 0 through IS of gustation producad a significant lncraas* in fatal aalfornatlon, a significant decrease In a**rag* fatal weight, and an lncraas* In tha percentage resorptions. Torok (1970) reported that oral adainistratlon of 379 ng/kg or 790 ng/kg of 2,2'-dlchloroblph*nyl to nice on days on* through three of gestation resulted in prolongation of th* Interval between breading and parturition, tie attributed this observation to delayed inplantaelon. Although th* treated anlaala had fewer litters and leaser lean litter sires, there was no indication of teratogenicity. Sana ale* exposed to 3,4,3'4'-tatracblorobipb*nyl ware reported to exhibit a *valtxing syndrom* (Davis at al., 1979i Tllson *t al., 1979). The dosage was 32 ng/kg adnlnisterad by gavag* to th* aethers on day* 10 through 14 of gestation. 1b* HONS 019606 121 ayndrone conaiatad of lncreaaad motor activity, hyperreflexia, and epiaodea of head bobbing and rotational movamanta that were praaant up to at laamt eight nontba of age. Not all axpomad aia wara affactad almilarly, but avan thoaa that did not exhibit tha ayndroma abowad dlsiniahad performance in varloua naurobahavloral taata. Tilaen at al. (1979) rafar to thaaa obaarvatlona aa tha "behavioral taratology* of 4-CB. 3. Bata Thara ara a plathora of atudlaa in which tha reproduc tive affecta of feeding varloua Aroclora to rata have boon lnvaatlgatad (Calandra, 197( Gellert and tfllaon, 1979) Kapilagar at al., 19711 KapUngar at al., 1972> Under at al., 197i villa* neuva at al., 1971a). Collectively, thaaa atudlaa reported fatotoaicity aa tha doeage waa incraaaad, but no teratogenicity waa damonatratad. It may be ueetul to note tha order of magnitude of tha doaagaa involved, villeneuve at al. (1971a) found no effect from tha adainiatratlon of doaagaa of up to 100 ng/kg per day orally to pregnant fanalaa fron tha aixth through tha flfteenth'day of gaatation. Oltraatructural laaiona in thyroid follicular calla and a reduction in aerua thyroid hornonaa have bean reported in neonatal and weanling rata whoae nothera had bean fad a diet containing SO ppat or 900 ppa of Broclor 1254 throughout the period of gaatation (Collina and Capan, 1900). The autbora auggaat that alterationa in thyroid atructura and function in tha fatua or neonate nay be related to aubaeguent dlaturbancee in growth or development. MOWS 015607 122 - 4. Mu In th* study conducted by Earl at al. (1974), pregnant bitches war* given doaagaa o 0.23, 1.0, or 5.0 ag/kg of Aroclor 1254 Cron tha day of breading to tha day on which thay wara nacropsied. At S.O ag/kg, thara waa an lncraaaa In tha pareantaga o raaorptlona, a dacraaaa In tha nuabar of live pupa par Uttar at birth, and a raductlon In tha pareantaga of thoaa surviving to two waaka. Tha tarata obaarvad conalatad of anlargad fontanallaa, claft palataa, and auparfluoua phalangaa. Thla doaaga waa aaid to Halt dlat conauaptlon aavaraly. Tha author* atata that ona llttar of tha control* *aay hav* had a ganatle dafact that cauaad an unuaually high ineldanea of tarata.* 5. Swlna Earl at al. (1974) lneludad ainlatura awlna (Bocae! atrain) in th* Invaatlgatlon daaerlbad lauaadiataly above. Pragnant aow* wara given daily oral doaagaa of 1 ag/kg, 10 ag/kg, or 30 ag/kg of Aroelor 12S4. Boalng bagan 21 daya bafora breed ing and waa continued until the day of nacropay. Tha author* concluded that doaa-ralatad effect* war* aaan at all traataent lavala a* avid*need by deer***** in th* nuabar of pragnanel**, nuabar of live pig* farrowed par litter, and pareantaga of lira offspring after two weak* of ag*. Syndactyly and claft palate* war* obaarvad in th* young of low* receiving 10 ag/kg, and patent fontanalla* and claft palates in th* offspring of thoa* receiving 30 ag/kg. A* in th* case of the dogs, tha higher dosage* caused a aarked reduction in food conauaptlon. MOMS 015688 123 6. Monkaya in a study raportad by Allan at al. (1974), six adult, feaale rhasus aonkays wars fad a diat containing 2S ppa of kroclor 1248 for two months. During this pariod, all aniaals davalopad characteristic signs of toxicity, although thay aalntainad a ragular menstrual cycla. One aniaal diad. At the beginning of the fifth aonth, or thraa months aftar discontinu ance of exposure to the tost substance, an attaapt was aada to bread the survivors. Thraa aniaals appeared to conceive, but only one succeeded in carrying her fotua to toxa. Although this infant was wall davalopad, its body weight was considerably lower than that of the average rhesus infsnt. Exaaination of the tissues showed no gross or aicroscopic lesions. in a second study by the Wisconsin group (Baraotti at al., 1976} Involving IS adult, feaale rhesus aonkays, nine were fed a diet containing 2.S ppa, and nine were fed a diet containing 5 ppa of Aroclor 1248. After seven months on these diets, the eight surviving animals from the 2.3 ppm group and eight from the S ppm group were mated with control sales. All aniaals in the 2.5 ppa group became pregnant, but three of these resorbed their embryos; the remaining five gave birth to live Infants, in the 5 ppa group six sniaals becaae pregnant. These impregnations resulted in three abortions, one resorption, one stillbirth (suffocation during difficult delivery), and one un complicated birth. At birth, the six infants were small? how ever, other than their small stature and focal areas of dermal HONS 015689 124 hyparpigmantatlon> thalr ganaral appaaranc*. haaograma, and oaaaoua davalopmant aa avaluatad radiographically wart normal. Tha adult, famala rhaaua monkays that vara tha original subjects In tha atudy diaeuaaad abova vara fad tha dlata contain ing 2.5 ppm or 1 ppm of Aroclor 1241 tor alx aontha prior to brooding, throughout gaatatlon, and for thraa aontha aftar dalIvory for a total of about IS aontha (Allan at al., 1SIQ). Only It faaalaa vara brad, lnaaaueh aa ono had dtad and anothor vaa droppad from tha atudy for aoaa raaaon not asplalnad. About ona yaar aftar dlaoontlnuanea of tha Aroelor-eontalnlng dlata, tha anlaala vara brad again to control aalaa. All of tha aaaaa survivor* In tha S ppm group conceived, but only four gaaa birth to lira Infanta. In tha 2.5 ppm group, ona anlaal had an abor tion and tha raaaining aaaan had uncompllcatad deliveries. Apart from thalr aoaavhat amallar also cemparad to tha young of tha control anlmala, tha Infanta appaarad normal. Analyaaa of adlpoaa tlaaua from tvo atlllborn infanta of mothara In tha S ppm group ahovad tha praaanca of PChs. but hlatologleal evaluatlon of adlpoaa and othar tiaauaa abovnad no abnormalltlaa. 7. Clinical Data Funatau at al. (1972) atudlad In datall four bablaa born to mothara vbo bad ingaatod rlca oil contaalnatad vita a haat-aschanga fluid containing peso, pcora and PCQa. Tha aothara vara among tha population axpoaad In tha "Yusho" aplaoda. Thraa of tha four bablaa exhibited aoaa avidanca of lntrautarlna mal nutrition or ratardatlon of grovtb, and all four had dark brown MONS 015690 - 125 pigmentation of the akin that was moat pronouncad at the geni talia, axillae, and near the fingernalla. The aame pigmentation was noted on the lipe, guma, and palate. While one or more of the Infanta diaplayad other clinical aigna, no neurological or cardiovascular abnormalltiea, nor any aalformationa were observed. The pigmentation of the akin and mucoua meabranaa diaappeared within two to five oontha of age in all eaaea. 8. Summery and Opinion (a) In a variety of teata, commercial PCS olxturae (Aroclors) ahowed no teratogenic activity in mice, rata, rabbits, and monkeys. (b) Earl at al. (1974) have not demonstrated convinc ingly a teratogenic action of Aroclor 1254 in dogs or swine. An evaluation of their work suffers from a paucity of information and the possible presence of e genetic defect in the dog colony. The published abstract tends to be misleading. Examination of the unpublished manuscript shows that the authors did not regard the two lower dosages as teratogenic for either species. The highest dose is said to limit food consumption severely in both species. Therefore, it is likely that the defects observed in the offspring were the result of severe asternal malnutrition. Hansen et al. (1975) failed to find teratogenic effects in swine when the mothers were fed a diet containing some 20 ppm of Aroclor 1242 throughout gestation and nursing. (c) The observations of Collins and Capen (1990) on ultrastructural alterations in the thyroid glands of perinatal HONS 015691 m rats whose mothers vara exposed to Aroclor 1254 ara indicative of functional changes rathar than of teratogenicity. (d) Tha occurrence of a "waltxing syndrome* in aiea exposed prenatally to 2,4,3' 4'-tatrachlorobiphanyl night raprecant a true teratogenic affect (Oavia at al.. 1979). This phenomenon uaually raaulta from a atructural or functional defect of tha middle ear. Tha dosage uaad to produce the ayndrome ia relatively high. Chile tha expoaed animala vara not uniformly effected lnaofar aa the overt signs ara concerned, Tllaon at al. (1979) praaented evidanca to show a wider pre valence of aore aubtla nauro-bahavioral affacta, rt la not known whether thia condition could be induced by a commercial 90 mixture. (a) Tha aclentlflc literature preaently euppoxte tha conclualon that fCBa praaent no appreciable riak of teratogenlclty for humana, in our opinion, in view of tha eaaanelally negative teat raaulta in four teat speciea and the guestionable poaitive findings in tha dog and in awlna. . C. ratatoxicity labblte given 1.0 mg/kg of Aroclor 1294 daily for 29 daya of gaataeion had no effact on the developing fetua but dcaaa of 12.9 to 90 ng/kg ware fatotoxic. Rata appear to be more realatent than rabbita, aa doaaa up to 100 mg/kg do not cauaa fetal daatha or malfomationa (villanauva at al., 1971a). Embryotoxlc affacta of Canecblor 900 and 900 ware produced ia HONS 019692 127 - Sprague-Dawley JCL rata whan (ad at lavala of 500 ppa In tha dlat throughout gaatatlon (Shiota, 1976b). olata containing S.O ppa at Aroclor 1246 wara fetotoxlc to rhaaus monkaya. Fatuaaa and naonatas of aothars with Yuaho dlaaaaa hava developed aoan of tha charactarlatlc aigna of dlaaaaa aa a raault of tranafar of PCBa to tha fatua and infant through tha placanta and braaat (ending (Yaaaahlta, 1977) Natauda, at al., 1978; Yakuahijji at al., 1978). Studiaa in aica on tha tranafar of PCBa to fatuaaa and offapring Indicate that tha aaount tranafarrad dapanda upon tha ehaalcal atruetura of tha individual coapounda and tha poaitlon of tha ehlorina atoms within tha ehaalcal atruetura (Natauda at al., 1978, 1979). Aroclora 1242 and 1234 are potent inducera of hepaticalcroaoaal enayaea. A alngle intraparltoneal injection of 100 ag/kg of Aroclor 1242 to rata incraaaad liver weight, total alcroaoaal activity, aa aaaaurad by hydroxylation of acetani lide and N-demethylation of aainopyrane, and hepatic cytochroaa P-4S0 (Bruckner at al., 1973). Tha breakdown of andoganoua aubatancaa auefa aa progaaterona, aatradlol and taatoatarona haa bean ahown to be incraaaad in aniaala pratraatad with chlori nated biphenyla (Orbarg, 1978). It la poaaible that altaratlona in tha aetaboliaa of the andoganoua aubatancaa by PCBa aay upaet tha normal balance that ia aaaantial for implantation of the fertllixed ova in tha utarua (Smith, 1968). Feeding a PCI mixture containing 60t chlorine aigniflcantly incraaaad tha uterine weight of guinea piga (Voa, 1972). HONS 015693 128 - Yaaashlta (1977) studied the clinical features at pci, pCOf and PCQ induead fetopathy in four babias barn from aetbara poisoned by eontaainaead rlca oil. There waa intrauterine ra tardacion of growth, dark brown pigsMntatlon on tha akin and aueoua aaabranaa, adaaatoua faea and axopthalaua. in aoaa caaaa tha ratardaelon paraiatad for aany aoneha but tha infanta eventu ally gained thalr weight for tha age group. although over 100 nuralng aothara raaldlng in Michigan during 1977-1978 had raaiduaa of PCBa In braaat ailk ranging tsea 1.0 ppa to over 1 ppa, thara hava baan no raporta of aarlooa adverse affacta on raproduetlon or Infant Mortality (Vlckiser, 1981). 8uaaatY and Opinion 1. It la apparant froa atudiaa on huaana and aniaala that cartain claaaaa of polychlorlnatad biphanyla ara aora toxic than others and that tha dagraa of chlorination ia one of tha determinant factors in their toxicity. But, aa atatad previously under eutanaoua toxicity, tha praaence of contaalnanta aay be responsible tor the adverse affects on reproduction. Olshl at al. (1978, 1980) ccaparad tha activltlaa of pCSa and dlbanaofurans in rata and found that dibensofurans aarkadly dapraasod body weight, decreased weights of tha thyaua, ventral proatrata and saalnal vasielaa and raducad heaoglobin and haaatocrit values, while pels bad little or no affect. HONS 015694 129 2. On the queatlon of fetotoxicity in pCB-expoaed feaalea, poeitiva raaulea ara aaan in certain teat anlaala (rata, doga, rabblta) whan tha pCBa ara adainiatered at relatively high doaaa (greater than 10 mg/kg) to pregnant anlaala. In tha huaan, the only reported evidence for fetotoxicity In expoeed populaeiona ateaa froa the unique Yuaho event. In which cauaation nay not be linked to PCBa. No auch reporta have been aade on other expoeed huaan populatlona, auggeating the abaence of thla effect in the huaan under occupational expoeure conditiona. HONS 015695 131 X. Mutagenesis A. General Th cam 'autagenesls* refers to any procaaa that Induces a permanent change (nutation) In tha ganatle coapoaitlon of a call, thereby causing that call to diffar in a conalatant way fron Its pacant. if a nutation occurs in a gain call, tha offspring resulting froa tha union of that call with another will have an altered genetic coapoaitlon that will persist in tha gain line unless tha alteration la lathal. Nutations ooeur spontaneously through unknown aachanIsas, but they also nay bo caused by radiation or cheaieal substances (autagena). Millie in a strict sense tha tera 'nutation* applies only to changes in tha DMA at tha molecular level, it is considered broadly to include alterations in tha nuaber and structure of chroaoaoaes. Mutagenicity is tha property of an agent, cheaieal or physical, to induce nutations. Chaaieal substances aay be tasted for autaganiclty by a variety of aathods. aaong which are those that eaploy (a) bacterial teat systeas, lb) cytogenetic analysis in vivo, (e) cytogenetic analysis in vitro and (d) doaInant lethality in a rodent. a. sacterial Teat Srateaa The *Aaes test* is the aost popular test of autagenasla eaploylng a bacterial test systea. It is a so-called 'backward* autation aystea that uses a series of autant strains of salaonella typhiaurlua that have lost the ability to synthesise the aaino HONS 015696 - 132 eld histidine. Hano#, they can grew only If exogenous histidine Is supplied. A mutation has occucced if, after exposure to tbs chemical substance, tbs organisms regain the ability to grow In tbs absence of histidine. ` Aroelors 1221, 1254, and 12(0 showed little eutagenic activity In the Ames test (Wyndham et al., 1970 with Indications that Aroelors with lower chlorine contents are weekly positive in the Salmonella test systems. However, these results must be discounted since they could not be replicated (McMahon et aJ^., 1979> Safe, 1910). As a general finding. Saddle and*Sauce (1977), McMahon at aJU (1979), Sehoeny et al. (1979), and Safe (19S0) were unable to find evidence of mutagenicity of KBs in bacterial test systems. C. Cytogenetic Analysis in Vivo In this procedure, the experimental animal is treated with the test substance and, after a suitable period of time, sacrificed for examination of rapidly dividing tissues, lone marrow and the seminiferous tubules are generally the most frequently used tissues for this purpose, it is euataanry to inject the animals with colchicine several hours before sacri fice in order to promote the accumulation of cells in the meta phase stage of division. In this stage, the chromosome can be examined sore readily for abnormalities. . In two investigations, KBs were judged not to have produced chromosomal abnonsalities. Dikstilth et al. (1975) HONS 015*97 133 examined sealniferous tubules of rats at different intervals after daily dosaqes of SO mg/kg of Aroclor 1354. Graan at al. (1975a) examined both bona narrow and spermatoqonlal calls of rats after aithar a single doss of 5000 ag/kg of Aroclor 1242. or four daily dosss of 500 aq/kq. in all caaas, it was concluded that no siqnifleant chroaosoaal daaaqs had occurred. The micronuclaus teat is a test for aqants that tend to break chroaoeomss (clastoqsna). A alcronuclaus is a fraqaant of chroaatin that has broken away froa a chroaoscaa during coll division and has failed to ba included in either of the daughter nuclei. The phenomenon can be observed best in newly formed erythrocytes since these stain differently froa the nature erythrocytes in that they exhibit polychromasia for a period of 24 hours or so. Furthermore, the nucleus has bean extruded at the last saturation division so that the alcronuclel, which reaain behind, are readily visible in an otherwise ehroaatlnfree cell, nicronuclei occur in a saall fraction of normal red cells, but their incidence is increased by the action of elaatoqens. The teet is carried out by administering the aqent to the test aniaal, and examining the polychromatic erythrocytes in bone marrow smears after soma interval of time has been allowed for nicronuclei to form. Huddle and Bruce (1977) reported Aroclor 1254 as nega tive in a micronucleus test. HONS 015698 134 D. Cytogenetic Analyala in Vitro Hooplngarner at *1. (1972) activated cultured huaan lyaphocytea with phytohenagglutlntn and treated thaa with 100 ppa of Aroclor 1234 at varioua atagea of a dlvlalon cyela. The call* than wara exaained for chroaoaoaal abarratlona for tba dlffarant atage treataenta. Aroclor 1234 had no apparant affaet on chroaoaoaal Integrity aa neaaured by cytologlcal evidence. E. Doalnant lethality In Kodanta A doalnant lathal natation la ona that ocean In a gera call. while It doaa not lapalr tha function of that eall. it tilla tha fart111tad ovua or tha developing aabryo. Mica and rata ara tha prafarrad asparlaantal apaclaa. In Ita alaplaat fora, tha taat conalata of treating aalaa with tha aoapactad autagan, aating thaa with norial faaalaa, and counting tha noabar of wlabla offapring. Tha taat could ba uaad to datact doalnant lathal autationa in faaalaa, but it would ba difficult to rula out adaana affacta on tha aabryo that aight ba aacondary to non-ganatic affacta on tba aothar. Graan at al. (1973b) concluded that Arodon 1242 and 1234 ware not autaganic ainca they failed to induce doalnant lathal autatlona in rata. In alailar atudiaa reported both by Kaplinger at al. (1972) and Calandra (1974), Aroelora 1242, 1234, and 1240 wara adalnlaterad to aala, albino aiea In a alngla intraparltoneal doaaga of either 300 eg/kg or 1000 ag/kg. Subaaquant aatlnga of theae anlaala to control faaalaa ahowad no affect ot HONS 015699 - 135 treatment on tb* number of implantation or resorption alt**, number of viable embryos, or praImplantation loaa. P. Salary and Opinion Thar* la no evidence from in vivo taat systems that any connareial PCS mixture la mutagenic. The aana obaarvatlon hold* trua for th* bulk of tb* Investigations employing in vitro techniques. In our opinion, therefore, it is quit* unlikely that th* PCS* as a class avok* autagenic activity in th* huaan, either acutely or chronically. Sine* ehaaical mutagenesis and carcinogens*la often correlate for a given active cheaical, this opinion Is reinforced by th* essentially negative findings on carcinogenesis in populations occupationally exposed to PCS* (sections VIII and XII). HONS 015700 137 XI. Othar Wealth Effects A. Enzyme Induction 1. Introduction Moat chaaicala that aro allowed to antar tha body ara converted by tha body to a varlaty of different chaaical antitiaa. In thla manner, food bacoiaaa trenaCorned into energy. Chaaicala, othar than food or thoaa that ara naturally praaant in tha body, that ara introducad into tha body ara generally called `xanoblotIca," and they alao ara frequently converted by the body to darlvatlvea of tha original coapounda. The convaraion procaaaaa ara regulated by tha enzymatic ayataaa generally taraed blotranaforaetion ayataaa. Although there am a Multitude of xenoblotlo eubatancaa to which huaana ara axpoaad, there are only a few different enzyme ayataaa involved. Tha body baaically biotranafocae cbeaicala by oxidizing, reducing, hydrolyalng or combining (conjugating) tha agent with othar chaaicala. Although each of thaaa ayataaa la important, of particular internet hare ara thoaa ayataaa that raault in convaraion of the original coapound to the oxidized derlvatlvee. It la not uncommon for tha body to react to aoaa xenobiotic coapounda that it normally biotranaforaa by increaalng lta ability to perform the biotraneforaatlon function by producing an lncraaae in tha aaount of anxyaaa available. Thla proceaa, which la called 'induction* of tha enzyme ayataa, affectively aakea tha body aore capable of blotranaforming not only the coa pound that initiated tha induction but alao all othar coapounda MOWS 015701 - 133 that an oxidized by tha taae enzymatic system. in this aannar It li feasible tor a given xenobiotie aqane to Induce a biotrans formation ayataa that affects tha ability of tha body to blotransfota not only tha original compound but alto a larga nuMiac of othac xanoblotlea aa wall aa aom* naturally existing cbaaleala within tha body. Shortly, it will ba ahown that tha Pda in general have baan daaerlbad aa being affactlva, that la, potant lnducara of sajor oxidative blotranafocaation systems In experiaantal animals and in tha human, via Induction of anayaas, tha eoneantration of various normally occurring chamlcala may bo altarad. Tha aoiantlflc avldanca associated with those subjects will ba evaluated In tanas of the available currant lltorstur*. The major oxidative blotranafotmatlon ayataa la the body, aa far as xenoblotics are conearned, is present In greatest activity In the liver and la present In lesser activity la meet other tissues. In experimental studies, the liver generally serves as a monitor of drug or cbaaical affect on tha oxidising enzymes. The ensysMS are located in the 'microsomal* fraction of tha liver calls. This la a fraction of tha cell that can be obtained by proper ultracentrifugation techniques. Tha biotraaafozmatioa ayataa of Interest la known aa tha 'aleroaosMl alxad function oxidase ayscm (NPO)*. functional ly this ayataa operates to Incorporate oxygen into the xenobiotle agent via a series of enzymatic actions. The system does this by asking an 'active* oxygen atom available via a hameprotein enzyme. This heneprotein Is in fact a family of proteins collaetively idantifiad aa MOWS 015702 - 139 - "cytochrome P-450." Tha ability of the enzyme to operate as an oxidative ayatan is dependent on tha existence of several naturally occurring tubatancas and, in particular, on tba axiatanea and quantity of availabla cytochrome P-450 in tha microeoaal fraction of tha liver. Microsomal P-4S0 can bo aoasurad diractly or indiractly using various substratas. Olract aaasuraaant of P-4S0 is based on aaasuraaant of tha protein systaa from which these enzymes obtained their naaa, that is, whan tha ensyaos are reduced and coabinad with carbon nonoxide they exhibit, in a apectropbotoaetar, naxiaal absorption of light energy at the wavelengths of 450 nanonetars, hanca the naaa cytochroaa p-430 systaa. Tha P-450 systaa can also be measured in tarns of its activity on specific substratas such ax ethylaorpblne and antlpyrlne. induction of this systaa is measured in tarns of an increase in P-450 and/or its activity (baaed on units of protein par saapla of nicrosoaes). Investigations of ansyna induction have aaparatad tha P-450 enzymes into two groups, identified as P-450 and P-44S groups, on tha basis that various components of tha P-4S0 group of enzymes are 'induced* to different degrees by different xano blot 1c agents. The P-450 ensyaes are those that are salnly induced by the barbiturates, whereas tha p-448 enzyaea era aainly induced by 3-aethyleholanthrene and show naxiaal absorption at 440 nanometers. Tha literature includes studies that suggest that the P-440 ensyaes as well as the P-450 enzyaea are Induced MOMS 015703 140 - by certain pels although there appears to ba iou spaeias and tlssua specificity In their Inductive propartlas. Investigations of the effects of PCBs on cytochrome P-4S0S have centered on two areas of Interest. One Involved the Induction aaehanlsm via the use of either a commercially available aaapla of a single PCS congener (such as 2.4,9.2',4',S'-hexacblorobiphenyl) that was synthetically prepared and could be tagged with a radioactive atom to facilitate analytical work. Generally, a group of eaperiaental anlaals (rats) was administered the PCS. Saaplaa vers then obtained at various levels. Livers were thee examined directly for the quantity of cytochrome P-490 or indi rectly for P-4S0 and P-440 activity via its emyaatlc action on various substrates, the liver say also be examined histologically and for evidence of the stats of protein synthesis. Induction of the p-490 enxymes in the human is estimated by aeasurlng the plasaa elimination rata (plasea half life) of antlpyrlne in controls as compared to exposed subjects, antlpyrlne is a drug that is completely absorbed when given orally and eoapletely aetabollted by the liver P-490 microsomal eyetee. the second area of interest concerned the ability of the liver microsomal system eo blotransfore PCS. of particular interest wee the nature of the Intermediate and final products of the biotransformation process. This subject is important in understanding the toxicology of the PChs because of the following hypothesesi HONS 015704 - 141 - (a) Certain PCBa Indue* the microsomal mixed funtion oxidation system* thereby influencing not only their own metabolism but alao the aetabollaa and time coura* of action of available endogenous hormones as well as other xenoblotlcs (including drug*) adainieterad to huaana. (b) Certain PCB* or contaainanta of eoasaerclal preparations of PCBa aay lead to tha formation of lnteraadiat* epoxide type derivatives, and thee* derivative* can covalently bind to aacronolecules in the liver thereby leading to hepatic toxicity. 2. induction of Liver Enzymes various studies have reported on the effect of short tens exposure of rats to mixtures of chlorinated biphenyl*. One such study by Ecoblchon at al. (1974) used the Aroclors identified as Aroclor 1019. 1221. 1242. and 1254, and another study by a rranch investigator, Barbonne (19(0), used a French preparation known as Phenoclor DP*. In both studies the sample material consisted of a mixture of congener* of the chlorinated biphenyls. These studies showed that when rats were administered 10 ppm of the PCBs In their diet for only one day. tha livers from the animals showed induction of P-450, aniline hydroxylase, and asinopytlne-M-damethylase. The induction of these enayaes was maximum in about five days. If the rata were given 10 ppm of the PCBs in the diet for t consecutive days. Induction occurred in three to five days and to a lesser extant over the remaining MOMS 015705 - 142 - a day interval. In tha Eeobichon study, intraperitoneal injection of the Aroclor* In doaaa of $0 agAg was nada for three consecutive days. Aniaals wara aaerlftcad 94 hours laear. Mixed function oxi dative anzyaaa wars found to ba Induced In tha liver. Tha greatest induction waa aaan with tha aora highly chlorinated Aroclors. Tha conjugation entyae Induction occurred rapidly on axpoaure to tha aroclors, and particularly to those Aroclors that are aora highly chlorinated. The PCBs used In theaa studies ware eoeoerclal grade. In order to batter understand which of tha P-430 cytochroaea are induead by tha PCBs, hyan at al. (1*73) treated groups of rats with Aroclor 1254, phanobarbltal or 3-aethyl- cholanthrana. The livers ware used to prspara thraa different P-4S0 fractlona on the basis of differing aolecular weights and they identified the three fractions as P-4J0*. P-430|j and P-430c. All three of tha P-430S ware'obtalnad froa the PCB traatad anlaals. P-450* and P-450b **n obtained froa tha phanobarbltal traatad rath and P-430* and P-4S0e ware isolated froa tha 3-aethyleholanthrene traatad rats. (P-450e is probably equivalent to P-44S). There fore, this study showed that the Aroclor induced at least three identified cytochroaea including tha type induced by phanobarbltal and the type Induced by 3-eethylcholanthrene. In 1910 Parkinson at al. Investigated tha validity of tha concepts that were currant at that tlae regarding tha structure- activity relationship between apedflc PCI congeners and hepatic MONS 015706 X43 enzyme Induction. The study was designed to yiaid tbs structure vs. activity data. Basically, they conducted experiments in rats using 8 synthetic PCB congeners plus phenobarbital and methylcholanthrene as enzyne inducers. They concluded that in order for a PCB to Induce a nethylcholanthrene-type or a mixedtype liver enzyme system, the PCB would have to contain chlorine substituted at specific positions on the phenyl rings, whereas the PCB inducers of the phenobarbital type had multiple diverse structures that could not readily be defined. whether peas are administered for as short a time as 1 to 3 days or whether they are administered daily for up to a year, various liver enzymes appear to be Induced, but the phenomenon of induction does not seen to be specifically very harmful to the animals. Mien and AbrahaaMon (1878) ted rats diets containing 100 ppb of Aroclor 1248, 12S4, and 1280 for 13, 28 and 52 weeks. The growth rate of these rats was comparable to the controls but the test animals did show liver hypertrophy, some focal cellular degeneration and an Increase in serum lipids. In general, the effects ware no greater in those animals that received the diet for a year than in those that received the diet for 13 weeks. Mvares at al. (1873) published results from experi ments that Involved treatment of rats with Aroclor 1254. Intraperltoneal administration of 25 ag/kg/day for 6 days HONS 015707  144 - produced a tripling of cytochrome p-448 coneane of tha livara and a 10-fold lneraaaa In tha anzyaa activity involving bento(a)pyrana hydroxylation (which ia a typical 3-oethylcholanthrene typa of induction), aa wall aa an lneraaaa in ethylaorphine-Kdaiaathylatlon (a typical pbanobarbltal typa of induction). Thay tharafora concludad that Aroclor 1254 induced a mixture of both 9-448 and ?-4S0. In 1977, A1varan and Xappaa daaerlbad aoae additional work that ahowod tha ability of Aroclor 1294 to croaa tha placental barrier of tha rat, to bo tranamitted to tha neonatal rat through tha Mother'a milk, and to cauae lncraaaaa in biotranafonaatlon anzynaa in the fetua and newborn. Goldeteln at al. (1971, 1979) attaapead to reaolve tha guoatlon of whether pure to conganera had anzyaa Inducing proportion that vara different froa tboee produced by coaaorclal preparatlona of tha alngla conganera or tha 90 commercial alaturaa (auch aa Aroclor 1294). Theaa authora aynthoalzad a 'pure* aaapla of 2,4,5,2',4*.S'-hexachlorobiphenyl and ahowad that it had different anzyaa Induction propertiaa than did tha aaaa coaaarcially obtainable, apeclally prepared, congener that waa reported to be *994 pure*, tha diffarance in the induction capability of the two proparatlona waa prlaarlly in regard to the induction of P-449 cytochroaee in which tha aynthetically pure laoaer, at doaaa of 290 mg/kg adalnlatarad to faaala rata, induced aryl hydrocarbon hydroaylaae (AIBi a P-44* anzyaa ayataa) only 9-foldi whereae the coaaercial laoaer at a doee of 50og/kg produced a 20-fold tncreaaa of AU. Alao, a SC-HS analyaia ONS 01570a - 145 - of the two preparations of hexachlorobiphenyl showad that the commercial preparation contained 4 contaminants that were not present in the purs congener, two of these contaalnants were Identified as a trl and a tetra chlorodlbenzofuran (TCOr). TCDF was then shown to be a potent inducer of AHH and cyto chrome P-448. The ED (effective dose, SOI of test aniaals) for TCDF re: enzyne Induction was found to be O.S aicrograas/kg for three days. Therefore, the conclusion was that even a 99% pure congener that was commercially obtainable can contain sufficient dibensofuran to alter the ensyae induction action. In one report, Alvares at al. (1977) had studied alterations in drug aetabolisa in both rats and hraans. In the rat study Aroclor 1014 elicited a barbiturate type of induction of hepatic enzyaes. That Aroclor did not Induce cytochroae P-448; however: Aroclor 1254 did Induce cytochroae P-448. The huaan study Involved S workers in a capacitor aanufacturing plant who handled prlaarlly Aroclor 1018. These exposed workers showed a low half-life (10.8 hrs) of antlpyrine as compared to control non-ezposed subjects (who showed a half-life of 13.8 hrs). The voluaa of distribution of the drug in the two qroups was not different, so the com parison of the half-lives of the drug In the two groups Is valid. Thus, enzyne Induction occurs in the huaan in response to occupational exposure to Aroclor 1018 and the induction HONS 015 709 - 146 - a aeasured by antipyrine aetabolisa Is a P-450 type of Induction. In 1976 flickers at al. raportad on tha effects on liver anzyaas aaaoclatad with topical adalnistration of laaaraton oils (as uaad in aicroscopy). These Inara Ion oils wara known to contain approximately 30t PCBs. Ona to tan aicrolitars of tha oils wara appliad dally for sis days to tha shaved backs of rata and tha animals wara sacrificed on tha 7tb day. Tha authors found that both skin and llvar anzyaas wara lnducad. In a second axparlaant 10 aicrolitars of tha oil was topically administered on ona occasion only, and tha aniaals wars sacri ficed at various intervals following application of tha oil. 9-460 and llvar aonooxygenases wara lnducad (including bensoa-pyrana hydroxylase, a 9-440 enzyae aystea) showing naving! affect in 2 days with a slow return to normal by 20 days. In this study there aust have bean vary large differences between individuals in tha control group because their data show vary large differences between groupa with only a 9St significance. The iaaarsion oils currently aarkatad in the (ISA do not contain 9C0a. 3. Metabolites of OCBa Shlaada and Sato (1900) studied tha reactive metabo lites of PCS aetabolisa. Their work involved tha use of isotopelabeled PC> congeners. This work suggests that PCI epoxides aay be the activated forms that covalently bind the aacroaolaculas in the llvar cells. A bexacblorobiphenyl congener MONS 016710 147 12,4,5,2*,4*,5'-hexachlorobiphenyl> that has no adjacant unchlariaatcd atonf in the biphenyl ring and that cannot be converted to the epoxide was found not to be covalently bound althouqh accumu lation of this PCB in the liver was found to occur. Other PCBa show covalent binding that is principally with microsomal proteins rather than the ribosomal RNA; a conclusion based on the finding that various proteases would solubilise the radioactivity of the labeled atom. Treatment of the animals with phenobarbital produced livers that showed good covalent binding to the PCB, but treatawnt of the animals with nethylcholanthcene produced livers with poor PCB binding capability. The authors concluded that PCB epoxides were formed by the monooxygonase system and these epoxides were responsible for the binding of the compound to microsomal proteins. Thoir conclusions are based on indirect findings. 4. Interactions Based on the Induction of Enzymes by PCDs; One report (Murphy et l., 1979) described atudles that tho authors claimed indicated the existence of a drug Interaction in the form of potentiated lethality of fluroxene in Aroclor pre treated animals. The authors did show that the Aroclors induced hepatic onsymes. Their method of neasuring enzyme induction was to measure the metabolism of warfarin by livers of the Aroclortreated animals according to a procedure that they had developed and that they claimed could differentiate between induction of P-450 as compared to P-448. They found that Aroclor 1254 in raes mainly induced cytochrome P-448 whereas Aroclor 1280 Induced mainly HONS 015211 - 148 eytochraae P-430. The authors than indicated that both Aroclors eauaad animal* to show increased lathality on subsequent adminlatratian of fluraxona. we hava difficulty Interpreting this article, tie do not baliave that the conclusions are aupparted by the data that are given. In one case involving Aroclor 12(0 the data are not given in the table and in the other case the data obtained following administratis of flurcsene do not appear to be different frs the control data. 3. Ensvmcs Other than Cvtochrqaes Affected by teas Two additional reports deal with an action of the Aroclors on ATPase activity. One of these reports (bee and Park, 1973) used cultured human lyaptaoeytes and showed a doee-reapenae relation for aroclor 1234 and inhibition of nitochondrlal respira tion. rroa this effect they indicated that there aay be a decrease in adenoelna triphosphate (ATP) concentration. We can see no way to avaluate what this report aeans since the concentrations of the Aroclor used are not correlated with concentrations that sight be involved in intact biological systeas. The other report (balocca and Carlson, 1979) indicated that the Aroclors produced in vitro inhibition of rat nagneslun ATPase activity at a concentration of 10 parts per elllion. A weak correlation was found between increas ing inhibition and Increasing chlorination. A strong correlation was found between PCI-induced inhibition of the ATPases and de creasing aqueous solubility. We don't know what these results signify other than that they seen seen to be incidental findings -- many oeher chlorinated hydrocarbons do the same thing. MONS 015712 - 149 4. Suweary and Opinion The available data from experimental studiaa on animals and nan indicat# that th conaarcially available praparationa of tha KBs (Aroclora) aa wall aa aoma highly purifiad PCS conganara act to induca some ot tha hapatic anxymaa. Conaidarabla effort haa baan davotad to determine which of tha nicroaonal enzymes ara inducad by tha Aroclora. Thara ara aoaa data that indicata that tha predominant induction occurs for tha P-450 typa of cytochromes (identified as a phenobarbital-type of induction). When experi ments ara conducted with tha *more pure* congeners thara is vary little evidence for induction of any enxyme systems other than tha P-4S0 cytochromes. In general, induction is greatest with tha most highly chlorinated darivatlvas, but tha least chlorinated deriv atives also Induca the P-450 cytochromes. Tha subject of whether tha "pure* conganara of tha PCBa have lass action on tha cytochrome aystems than tha coaaaercial materials may ba only of academic interest, since tha preparations that ara available to Industry and tha public ara tha commercial preparations such as the Aroclora. It should ba raeognixad that authors tend to describe effects due to PCBs whereas they ara usually referring to effacta of Aroclora (such as Aroclor 1254). which are mixtures of KBs plus various trace contaminants. The commercially available preparations of tha KBs are capable of inducing certain hepatic enzymes in tha rat and there is one report suggesting that occupational exposure to HONS 015713 - ISO commercial PCS* nay indue* an hepatic *nxyn*. Thar* *r no d*E* auggaating that th* ov*rU health of Eh* animal* or aan la lnflu*ne*d a* a con**gu*nc* of PCI-induced aicrotonal anijneea. Although it i* auggaatad by aom* people that changing th* mtibolic tranaformatlon capability ia inh*r*ntly d*tria*ntal to th* animal, thar* ia no r*al *vid*nc* to aupport auch an hypothaal*. whan anxynea ar* induced and thay ar* than involved in th* bio activation of xanobiotic agent*, auch anaya* induction could ba harmful depending on th* doaag* aaguanc* and th* inherent toxi cologic propertied of any apaclflc agent. On th* other hand, if th* anxyaaa that ar* induced ar* involved in biolnactlvatlon of xanobiotic compound*, then induction aay be beneficial to the aniaal again depending on the doaag* aequenc* and Inherent toxleologic propertlaa of any apeclfic agent. There la no good ex perimental or clinical evidence that PCha aay act through their anxyaa induction capability to affect 'hormone' level* and raault xn harmful affacta on th* body. a. PCI Effect* on Imaunocompatanc* A few r*porta appeared prior to 1970 that auggaatad indirectly that PCBa nay influence lamunoconpetanc*. in 1970, Voa and Koeaan *bowed that when chick* war* fad 400 ppm PCI for (0 day* they (homed atrophy of th* aplanle pulp and lymphoid nacroala. (Chick* at higher doaaa all died during th* eaat.) Th* chick* alao ahewed porphyria and llvar nacroala. in 1971, Voa and teem* reported that eoaatareial PCI aaaplaa applied to HONS 015719 - 151 the akin of rabbit* dally flva tine* weekly foe 38 week* (27 application* aach containing 188 ag PC8) produced hiatologlc atrophy of tha cortax of tha thyaua and a reduction in tha number of garainal canttra in tha aplaan. At thia tia* tha animala allowed marked chloracne of tha akin, incraaaad fecal coproporphyrin and protoporphyrin aa well aa liver and kidney daaage. Tha authora atated that thaaa affacta ware atrong in dicator* of an ianunoeuppreaaiva action of tha PCBa. In 1977, Looae and co-workara fad Aroclor 1242 to mica for alx waaka. Tha aniaala ware then imaunogenlcally atloulatad with ahaep cad blood call* a* an antigen and the antibody raaponaa waa aaaaurad. The method of aaaaurlng anti body activity involved plaque-cell eatlaation in tha aplaan and tha aaaauraaant of tha plaaaa iaaunoprotaina. Poaitiva finding* war* obtainad aa caaparad to control* and tha author* particularly remarked about tha reduced IgA level* found in tha PCB-traatad aniaala. It waa alao noted that clinically aubtoalc level* of Aroclor 1242 war* profoundly iaaunaauppraaaiv*. The** authora alao cite tha work of Hollar and Thigpen (iaaunoaupprea- t aion by a PCS to paaudarabiea virua in rabbita), Voa and van Oriel-Grootenhula <iaaunoaupreaaion by PCB in guinea piga) and Friend and Tralnar (incraaaad mortality in duckling* that had bean pravioualy axpoaad to Aroclor 1254 and than inoculated with duck hapatiti* virua). HONS 015715 152 - in 1978 , Loose and eo-workecs studied the affects of KBs on host resistance ayataaa. nice that ware tad dtata con taining 167 ppa Arodor 1242 for thraa weeks and for six weeks exhibited increased sensitivity to salmonella endotoxin and a decreased survival tiae to inoculation with malaria. Thus they concluded that host resistance was impaired by prior treat* aent with PCBs. Also in 1978, Thames and Rlndsdlll reported on studies in which they fed aonkeys 2.5 to 5.0 ppa KB (Araclor 1248). After six months the aonkeys developed chi oracne, alopecia and facial edema. After 11 aonths control and treated aonkeys were tested with antipens (sheep red blood cells and tetanus tosold). The only positive finding was In the 5.0 ppa aonkeys who showed significantly lower antisheep red cell antibodies as capered to controls. No effect was obtained regarding the antibody response to tetanus toxoid. These authors also fed alee up to 1000 ppa of the PCS for three to five weeks without evidence of evert toxicity, but these anlaals did show a higher mortality when challenged with the pathogen salmonella typhlavriua as coapared to the controls. In 1980, Olshi and Riraga reported on their studies in which they had given alee PCBs (caaaeerclal product) by oral intu bation once weekly for four weeks. Other groups of alee were fad Cor (chlorinated dibensofuran) or COO (chlorinated dlbenxo-p-dloxin). Only the groups of anlaals that had received 10 or 100 HOHS 015216 153 micrograms/kg CDF showed decreased thymus weights. All groups wtrs challenged with endotoxin and again only the CDF-pretreated animals showed increased lethality compared with the controls. It is noteworthy that the authors found no deaths in their con trol animals given endotoxin, a finding that raises doubt about their experimental design. In this study the PCS pretreeted animals did not show increased susceptibility to endotoxin. In the same year (1980) Imanishi et al. showed that mice fed PCBa for 21 days at 100, 200, or 400 micrograma/gm were significantly more susceptible to herpes simplex virus and alectromelta virus than were animals fed a PCB-free diet. In 1981, Cheng et al. reported on the immunologic evaluation of patients from Taiwan who developed an acne-like skin disease, termed Yu-Cheng disease, that was related to the consumption of rice-bran oil contaminated with PCBa, PCDFs and PCQs (in an accident very similar to Yusho). The authors had 30 such patients who showed average whole blood PCB levels of 45 ppb, with a range of IS to 98 ppb, plus an additional control group of 23 healthy persons matched according to age and sex who showed no detectable levels of PCB in their blood. The patients had decreased concentrations of IgA and tgn immune globulin but not IgG. Their study of subpopulations of lympho cytes showed that the percentage of B cells was not affected by the disease but the percentage of some species of T cells was decreased as compared to the controls. MONS 015717 1S4 - Environmental chemical affects on imaunoeompatanca have bean attentively reviewed by faith, luster and Vos (1980). A number of studies cited by than found PCBs to be immuno suppressive in various species (from ducklings and cRlcks to mica and monkeys), in soma eases at dose levels that produce little effect other than hepatocyte hypertrophy. Only one study (Street and Sharma, 1975), which involved feeding low levels (0,18 to 8.5 ag/kg/day) of Aroclor 1254 to rabbits, showed no significant effect on humoral or call mediated re sponse. Our review of the Street and Sharma report indicated that there was a dose-related trend toward Immunosuppression in their animals and at the higher doses (2.1 and 8.) mg/kg/day) for four to eight weeks the animals shotted significant increase in liver weight. The .raltb. Luster and Vos review lists several general factors (nutritional status, hormonal levels and amounts of immunoregulatory proteins such as alphs-fatoprotaln) that influence immune function. Therefore those studies in which immune function was studied following exposure to levels of the PCSs that resulted in overt toxicity are meaningless from an immunotoxlcologlc viewpoint. In contrast, immunosuppression at dosage levels that do not produce general toxicity would be significant. Sumsary and Opinion The overall conclusion that can be reached in regard to the studies on the effects of PCBs on immunocompetence lsi HONS 015718 - 155 (1) with exposure conditions that lead to general toxicity, immunosuppression nay be demonstrable, but it may be indirectly induced; (2) with experimental conditions wherein only subclinleal toxicity is observed, such as hapatocyte hypertrophy, there is the possibility that immunosuppression is also produced; and (3) under still lower Kl exposure conditions it is impossible that immuno suppression is involved. Perhaps the beat study to estimate a no effect dose for exposure to PCBs would be the Thomas and Hindsdlll (1978) study which suggests that six months' exposure to between 2.5 and 5 ppm of PCBs in the daily diet of monkeys is a threshold for effects on the immune system. Unfortunately, there are few data directly concerned with the dose-response relationship for effects of the PCBs on the immune system in animal models or the hwaan. C. Porphyria The administration of PCBs to cats will produce a delayed type of porphyria, i.e., deposition of porphyrins and their degra dation products in tissues and excreta. Although the mechanism of action of the PCBs is unknown, it apparently differs from that of other porphyrogenic compounds such as hexachlorobenzene or isopropylacetamide. It has been thought that the effect of PCBs in animals may indicate that these compounds can induce conditions suen as porphyria cutanea tarda in man, but clinical data have not shown this to occur in PCB-exposed workers. (i) Experimental Data. The fecal content of copropor phyrin and protoporphyrin of rabbits was increasad by Aroclor 12*0 HONS 015719 - 156 - and by hsxachlorobiphanyl, but the difference was statistically significant only Cor coproporphyrin (Voa at al. 1972b). Bruckner at al. (1974) obaacvad an increased excretion of urinary coproporphyrln In rata given Aroelor 1242, S or 23 ppm for two, four, and aix months. Goldstein al. (1974) aapbaalzad tha dalayad onsat of tha KB-induced porphyria; rata fad 100 ppa of Aroelor 1234 became porphyrlc aftar two or aavan aontha of treatment. Although tha axcratlon of coproporphyrin and other porphyrlna was incraasad, tha largest alavation was in tha uroporphyrin fraction. There was also a marked accumulation of uroporphyrin In tha liver. Tha studies of Coldstain at a^. suggest that PCBs aay affect uropor phyrin formation or utilisation. The induction of delta-aainolev linlc synthetase (ALA synthetase, a rate-limiting enzyme in heoe synthasla) does not appear to be the eechanlsa by which porphyria is induced by PCS, as it is for many porphyrogenic ehsaicals. In thair studies the Increase in ALA synthetase activity was probably secondary to the porphyria. Also, Aroelor acts to increase liver cytoehroee P-430 rather than to decrease it. Bexaehlorobensene Is known to induce a delayed type of hepatic porphyria slailar to that produced by Aroelor 1234. However, tha two responses apparently differ significantly as Goldstein at a^. reported that tha rats fad KBs did not exhibit tha nervous or cutaneous signs associated with haxaehlorobensane poisoning. HONS 015720 - 13? (11) Clinical Studies. Son* o{ th* Yusho patients investing rlc* oil contaminated with PCBS reported pigmentation of eh* akin and nail*, but thart war* no atudiaa to avaluae* a poaaibl* relationship of th* reported aymptons to any change In porphyrin natabollsn (Xuratsune, 1972). Smith at a^. (1981 a,b,c) determined urinary coproporphyrin, uroporphyrin and porphobilinogen in PCB-exposed workers; they did not find a correlation between th* urinary porphyrins and th* serum level of the lower chlorinated KBs or th* higher chlorinated PCBs. Th* subjecea did not have any recognizable dysfunction and there was no clinically apparent illness with high levels of PCB exposure or with high serua PCS. Other investigations evaluating th* health effects of PCB exposure have not reported cases of porphyrin>r*latad disease or cases of porphyria cutanea tarda (Fischbein *t al. 1979) tiaronl et al. 1981). Th* observation that PCBs increase ALA synthetase in animals raisas th* possibility that PCBs can cause an attack of porphyria in patients suffering frost acute, intermittent porphyria. However, a case of this type ha's not been reported in th* medical literature. As noted above in studies on the rat, th* action of PCBs appear* to differ from that of other porphyrie agents. HONS 015721 - 159 XXt. Epidemiology Although case raports of toxic effects, especially skin lesions related to expoaure to chlorinated organic chemicals, have been recorded almost from the beginning of their use (Jones and Alden, 1930, few epidemiological studies appeared until the accidental exposure of a large Japanese population to PCBs, peers and PCQs from the contamination of rice oil. Since that time, numerous studies have been undertaken to determine the health effects related to exposure to PCBs in the workplace and general environment. It muat be remembered that there were problems in these studies in assessing the effects because some of the environmental exposures may have Involved PCBS that bad been alterad by processing at high temperatures (Brown, J.P., Jr. et al., 1981). The numbers of individuals exposed occupationally are relatively small, although some may represent the heaviest and most protracted exposures of sny reported, and their added burden of PCBs from the workplace muat be compared to the back ground levels that are currently present in all populations. Many of the commonest changes noted in biochemical and other medical measurements obtained in screening surveys have not yet been associated with any subsequent development of disease. in order to evaluate the epidemiological studies that assessed the effects of PCBs, we will discuss the results of mortality data, morbidity data, and screening surveys separately even though many studies include data on several outcomes. HONS 01blli - 160 - k. Mortality Studiea In 1966. an unknown number of pereona in tha waatam part of Japan ingeatad rtea oil containing tanachi or 400 that vaa csntaalnatad with polychlorinated dibanzofurana (PCOra) in amounta 2S0 timaa aera than tha uaual lavala in Japanaaa PCBa (IA*C, 1970) and aora than 1000 tiaae tha uaual lavala in b.S. Aroclara. By 1977, 1663 caaaa of 'Yuabo* bad baan recognized baaad on ayaptoaa of ocular dlsturbaneaa, akin laalona, prlaarily aubjective neurological ayaptoaa and blood PCB lavala (Uraba, 1979). rifty-one daatba hava occurred In tbaaa patianta and tha eauaaa hava baan reported to Include liver caneara and lymphcaaa. However, tbara hava baan no raporta on tba numbara of aapactad daatba by apaclfic eauaaa baaad on tha uaual death rataa In aial' lar Japanaaa populatlena. tha dlatrlbutlcn of eauaaa aay aimply rapraaant the uaual dlatrlbutlcn of daatha found in the age groupa eharacterlatic of tuabo patianta, and ao it ia tapoaalbla to aaaaaa tba nortallty pattarna of thaaa eaaaa at tha praaant tiaa. Bartazzi at al. (1911) hava reported a aeudy of 1,310 workere, preeminently waxen, who, beginning in 1944, Initially were axpoaad to Aroolcr 1254 and Pyralana 1476 and aubaaguantly ware axpoaad to aixturaa with 429 chlorine content. Mortality data ware collected on all indlvlduala with aiz maitha cr acre of aaployaant over a 23-year period ending in 1976. xna total nuabar of daatba (27) waa email but there waa an ezeeaa of mortality in HONS 015723 161 - female worker* compared to the general population, which is un. uaual for any working group. This study demonstrates a signifi cant excess for all neoplasms for the combined sexes and an excess specifically of lymphomas. It is difficult to interpret these data since the type of cancer incriminated seems to differ from that of other studies. Further, the data of Brown and Jones (1911) (see below, and also the compilation in Table 7, section VIII) on workers in two manufacturing plants do not confirm a finding of excess malignancies in PCB-exposed personnel. The unusual two fold excess in mortality of female workers in the Bertassi at al. study deserves further attention. A retrospective cohort mortality study of 2,567 workers in two electrical capacitor manufacturing plants that had used FCBa for over 30 years, identified 163 deaths (Brown and Jones, 1981). The type of PCBs used over the years had varied and in clude Aroclors 1254, 1242 and 1016. The overall mortality and total cancer mortality ware low, but there were three-fold ex cesses of cancers of both the rectum and the liver (with a total of 7 deaths) although the results were not statistically signi ficant. The only significant excess wss that of the subset of rectal cancers in females in plant 2. The standardized mortality ratios (StMts) for rectal cancer, liver cancer or cirrhosis did not increase with increasing latency or duration of employment. Unless one can demonstrate that the risk of cancer increases in association with increasing duration of employment, which serves HONS 015724 - 162 aa a proxy noaaura of dose, it ia difficult to suggest chat cha agent la poaaibly causative toe tha dlaaasa. Although chit atudy haa davotad atrlcc attention to dataila auch aa tha completeness of Identification of workers and ascertainment of outcon* it haa not verified tha diagnosis of caaaa nor invaatlgatad the preaenca of confounding varlablea. Rectal cancara are often aiaclaaaifiad by location in the intes tinal tract. Tha claaaification 'liver cancara* aay include cancara of tha gall bladder and biliary system aa wall aa oetaatatic laaiona to tha liver troa cancara at other aitaa. There fore whan one haa an axcaaa of liver cancara. verification of apacific aiea within the livar ayataa aa wall aa identification of prloary livar laaiona la extreaely important, eapeclally ainca the nuaber of daatba troa tbia cauaa ia aaall. The lnveatigatora have not verified the dlagnoala of either liver or rectal cancara. Since alcohol la conaidered a frequent atiological agent for cirrhoaia of the livar and poaaibly for livar cancer, aoaa infor mation on conauaption would ba relevant aa a confounding virlable. :io data on poeaible confounding yariablaa have bean reported in the paper. The mortality data froe the occupational groupa and tba Yuaho patianta are baaed on vary aaall nuabera of deaths and at praaant do not confira a carcinogenic affect in aan. Tba obser vation of axcaaa livar cancer deaths in workers occupationally exposed to PCBa ia of aajor interest ainca tha liver was a target HONS 015 725 163 sit* lor change* in animals and sines man has demonstratsd svidsne* of subclinlcal alterations in livsr function. If liver cancers are to be evaluated, the diagnosis of primary cancers of the hepatic cells must be confirmed in the mortality studies since the number of cancers in the group will be very small. The available data demonstrate no consistency in the cancer mortality patterns in the studies and no data on a possible relstionshlp of cancers to dose of PCBs. 8. Morbidity or Incidence Oats shin Skin lesions have been reported in association with exposure to chlorinated aromatic compounds since the early 1900'e (Jones and Alden, 1930. Taylor has emphasised that acneform eruptions are more frequent with the chloronaphthalenea and the dibensofurana and that the variation in the quantity of these sub stances that may be present as contaminants in PCBs may account for differences in reporting of skin eruptions with exposures. Taylor has also reported that the acnegenic capacity of various compounds changed according to their form (fumes, liquid or solid) and the degree of chlorination (Taylor, 1979). These factors nay also influence the presence of reported skin disorders in studies. Not only the frequency but the characteristics of skin lesions have differed in the various studies. Jones and Alden's early description of the lesions they associated with chlorinated biphenyls included 'blackheads* or 'carbon-colored' comedones HONS 015726 164 sonatina* distributed in unusual araaa of tha body and oftan assoclatad with cystic areas and yallow pus (Jones and Aldan, 1936). Taylor noted that tha cystic swelling and hypersecretion of tha maibonlan glands ara lnportant characteristics of tha chloracnegenlc affect of PCIs compared to other similar chemicals. These ware tha typical lesions reported by Heiga at al. in 7 of 14 workers exposed to a KB vapor leak from a heat exchanger in a plant in Connecticut (Melga at al., 1954). The exposure to vapors was intermittent but of extended duration. Liver function testa were normal in most of these workers and no KB levels in individuals were obtained, although an air sample prior to tha 3 onset of skin disease was 100 ug per a , which was within the accepted standards - The patients who were initially described with Yusho disease had lesions similar to that described above in about 33 and a brownish pigmentation of tha skin and nails in 106 of patients. These freguancies were increased subsequently to in clude about 70 to BSt of patients because of new definitions of characteristics of disease or delayed development of the signs. The eyes were also involved, exhibiting swelling of the upper lids, hyperemia of the conjunctiva and eye discharge (Xuratsune, 1972). Pigmentation of the akin and eye discharges also occurred in newborns of affected mothers. Ho comparison groups have been included in these studies of Yusho patients, where the laaiona are pathognomic of KB-related disease this nay not be-necessary HONS 015722 - 165 but whan the lesions an more general, comparison groups are essential. There were histopathological changes In five patients autopsied that seem to be asaociated with contaminated rice oil ingestion. These changes Included hyperkeratosis of hair follicles and increased melanin pigment in the basal layer of the epidermis (IAJtC, 1978). Three out of the five cases also had proliferation of ductal epithelium of esophageal glands. It would have been helpful If these pathological assessments had been made blindly so that qualitative judgments such as 'increased melanin* could have been compared In exposed and non-exposed groups. Correlating these pathological findings with changing levels of PCBe. pcora and PCQs would also have been helpful but there are no reported data relating to these issues in the papers available. It is known that the amount of used Kanechlor in the rice oil consumed by the patients was between 0.5 and 2.0 g, which would indicate a PCS exposure similar to levels in occupational settings. Bars t 1. in two separate papers (1974, 197S) have described the skin lesions in workers in a capacitor factory where Kanechlor had been used. The serum PCBs of all workers ranged from 7 to 300 ppb but it is not known how these values correlated with the presence of skin lesions (Hara et al., 1974> Bara et al., 1975). Discontinuance of the exposure not only decreased the overall PCS level to 751 of the original value but the skin lesions disappeared to 'vestigial markings on a few individuals.* The summary of the report does not indicate HONS 015728 - 166 - th correlation of eh* blood PCB and akin laaiona although thar* ar* data In ehia paper on eh* half-life of PCBs in relation to duration of *xpo*ur*. tiasegawa has reviewed th* health of workers in fiv* plant* whom* industrial process included exposure to Kanechlar (Kasaqawa *t al., 1972). Th* industries included capacitor manufacture, PCS manufacture, and biphenyl recovery. Th* vapor concentrations ranged trot 11 to 9S ug/s . Skin lesions wore reported to be unrelated to blood PCB* but generally related to direct akin contact. Th* average blood PCB level was 170 ppb. Th* principal dermal finding* included bravn ehrasadermatosls of th* dcraal joints of hands, fingers and nail beds and acne. There were no further descriptions of th* latter lesions so that th* presence of chioracn* could net be confirmed, but th* brown akin discoloration certainly is typical of th* Japanese worker reports. Kltamura *t al. described 11 workers fraa an electrical capacitor aanufacturlng plant (Kltamura *t al., 1971). Th* lesions in 10 of the workers described in this group ar* even sore vague. They did not include the typical coloration of nails; ehloracn* was not directly diagnosed; and the follicular lesions did not occur at points of contact with PCBs. From the description of th* study it is not clear that th* author's conclusions that th* skin lesions w*r* due to PCBs was justified without further in formation on the usual frequency of similar types of skin lesions in normal papulations or a description of typical ehloracn*. Th* blood PCB level in this group was >20 ppb average. MONS 015729 - 167 lnou al. stud lad the health of workara who wars axpoaad to Kanechlor S00 In a thread-glossing factory (Inoua at al., 1975). The traquancy of skin lasiona waa low. Tha blood PCBs wars ovar 50 ppb in 7 out of 54 individuals studied. Ona parson had rapraaantativa ehloraena with blood PCBs of 190-210 ppb. Ouw at al. described ona casa of ehloraena aaong 34 workers axpoaad to Aroclor 1242 in capacitor aanufactura (Ouw at al., 1976). Tha avaraga blood PCB was 400 ppb. in addition five workers coaplalned of aesaaatoua rash but there was no de scription of lesions. Savon out of IS process workers and out of 19 impregnation room workers complained of burning and irritation of tha eyas, face and skin. It is difficult to recon cile these complaints with leval of exposure since it should have been higher in the latter group of workers than the former. Hov- 3 aver. Aroclor concentrations in air as high as 2220 ug/m ware measured. The investigators Indicated that the 'dermatological complaints* occur sore often aaong workers with higher 'blood Aroclor levels* but they also indicate there is no clear corre lation. It is difficult to be sure of the true meaning of dermatitis as elicited by history when the answers can be biased and the authors do not indicate which cases are related to physi cal findings only. As part of a health hazard evaluation at a facility that manufactured electrical distribution equipment, NIOSH studied the MQNS 015730 - 168 - health of tight worker* nd found no syoptoa* or physical ilgn* of chloracne (NIOSK, 1977). Thera were several subjects who reported skin rashes but not those typical of PCS exposure. The seen pea level in blood was 98 ppb with the highest value being 288 ppb. Another health hassrd evaluation waa done after an ac cidental spill of KBs (NIOSH, 1980). In this situation there were no signs of chloracne. However, the aean blood KB level of exposed workers was only 8.4 ppb> this waa below the aean for unexposed workers, fluaphrsy studied the KB level of indi viduals on the basis of fish consumption (Buaphrey. 1979). Re found that the KB level was correlated with fish consuaptlon with aean blood levels ranging froa 46 ppb to 82 ppb and a aaxiaua individual level of 188 ppb. There were no skin lesions or other health probleaa associated with KBs. A aedlcal and bioeheaical survey was aade of 120 sale workers exposed eo KBs in the aaintenance of railroad cars and locoaotives (Chase at al.. 1991). Among the exposed group of 88 workers the 'aedlcal hlseorlea and physical findings* revealed 'several cases of chloracne* -- "with none being found in the other groups.* No further details are given as to whether the conditions were currently active, nor waa there a description of the lesions. It would be of interest to eonfirn these case* as true chloracne since the current aean plasaa KB level in the exposed group is only 13.4 ppb (range 10-311 ppb), a very low level of KBs to be associated with chloracne. HONS 019731 - 149 - Flschbein et al. (1979) completed a medical survey at capacitor manufacturing workers who were self-selected for physi cal and bio-chemical examinations. A high proportion (45--55%> of both male and female workers complained of skin disorders with 111 giving a history of acne beginning after the onset of expo sure. "Dermatologic findings* were present on physical examina tion in 38 to 411 of female and male workers, respectively. However, these lesions included "erythema, swelling, dryness, and thickening,* which would not be lesions characteristic of KB exposure. Five percent of the study population had acnetorm eruptions. There is no mention of whether these were typical of chloracne or were the usual acne lesions found in any medical survey. Since skin lesions are common in the general population and since the population was self-selected initially it is diffi cult to evaluate these findings. The average lower KB homologuas in plasma were 124 ppb and of higher KBs, 48 ppb. The authors report that the skin findings were correlated with plasma H-KBs. Unfortunately, if the examinations were done with the observer knowing the job held by the participant, all results can be biased, since reporting might be related to the job held and the PCB levels were related to job. There was no note of skin hyper pigmentation but lit of workers had eye abnormalities Including "injected conjunctiva and palpebral hyperpigmentation and adeaa.* Again, it is not clear how frequently these lesions would have been reported in normal subjects had examinations been done without knowledge of exposure categories. KOhS 015732 170 - naronl it *1. (1981) recently reported on two groups of workers who were exposed to PCBs In the manufacture of capacitors. Ons group (A) had been exposed to both 54% end 428 chlorinated biphenyls. Although the levels of the trlchlorlnated chemical were similar in current enployees in the two plants (12S ppb (A) and 127 ppb (B>). the levels of pentachlorlnated agent differed (248 ppb (A) and SB ppb (B>). It is of intsrese that 10 eases of acne and folliculitis appeared in the two plants and at least four were entirely typical of the condition. All four typical cases occurred in nine employeee who had worked In a high power capacitor Impregnation area of plant A where levels of pentachlorlnated biphenyls were high. Their mean blood Kl was 4S0 ppb, a value not different from that of the five un affected workers but certainly higher than the overall levels in the two plants, naronl et 41. also noted two cases of bleeding hemangiomas, out one had existed from birth and the only difference in his condition was that bleeding had taken place after the job started and the lesion was excised. The other paeient had bleeding from the tongue and a cavernous hemangioma was discovered as well as chronic myelocyeic leukemia. Case repores such as this and particularly the unusual circum stances surrounding multiple conditions in one patient in the second case make such findings difficult to interpret. The re ports of chloracne appear valid and suggest a problem. Baker e al_. examined sludge users, workers in a ca pacitor plant, workers' families and community non-sludge users 0NS 015 233 - 171 (Baker at *i_.. 1980). Sine* Che sludge contained PCBs, it was fait that its usa as fertilizer night seriously affect the PCS level in the blood. The level of Aroclor 1242 ranged from 7.2 to 48.6 ppb and for Aroclor 1254 from 10.1 to 26.5 ppb, with the lowest levels being found in sludge users and the highest levels in workers. No cases of chloracne or other symptoms of toxicity were noted but only two PCS values were above 200 ppb. Snith at al, examined workers involved in the maintenance, repair and overhaul of electrical transformers and measured levels of PCSs by job (Smith at al., 1981). The mean serum levels of L-PCBs in the municipal utility workers were 11 to 36 ppb with a maximum of 59 ppb, and of H-PCBs of 6 to 24 ppb with a maximum of 74 ppb. In the privately-owned facility work ers had similar values with L-PCB levels between 19 to 22 ppb with a maximum of 52 ppb, and H-PCB levels between 6 and 31 ppb with a maximum of 250 ppb. There was no significant difference in either place in the frequency of skin lesions between those with less than 10 ppb and those with greater than 10 ppb H-PCBs. There was a significant excess of symptoms of eye irritation in one and a history of bronchitis and loss of smell in the other among those with serum levels of H-PCBs greater than or equal to 10 ppb compared to less than 10 ppb. However, since these are subjective measures of disease and since workers may have been influenced to report subjective symptoms differently depending on job it is Impossible to evaluate the importance of these observations. HONS 015734 172 Saleh at el. reported on the physical findings and symptoms in 197 workers who manufactured alaetrleal equipment. The aarum lavala of L-PCBs in eha workara vanad by job, with the geometric means ranging from 89 to 502 ppb, tha hlghaat lavala (2400 to 3330 ppb) baing found In tha dapartaant where capacitors wars processed, finished, and tasted, and In a dapartaant that had asslgnad work throughout tha plant. Tha geometric mean laval of a-KBs rangad froa 22 to SI ppb, with tha hlghaat values (ISO to 250 ppb) In these dapartaanta. This plant had always used 42% chlorinated biphenyls, both Aroclor 1242 and 1014. Although thara ware soaa ayapeoas of skin and aya lesions (darkening of skin and nails, skin rash, and irri tated eyas) that appeared to be dlffarant between tha groups with L-PCB 200 ppb greater than or equal to 200 ppb eoaparad to those with lower values, these differences disappeared whan tha coaparlsons ware corrected for age and job. Thus one can conclude that symptoms wars primarily related to age and job with tha latter association baing either real or biased. Tha symptoms ware not related to the body burden of KBs indepen dent of job. No evidence of skin lesions suggestive of chloracne was found on physical exaslnaeion, in spite of some extraordi narily high KB blood levels. In a preliminary report, Bahn (1976) Indicated the incidence of cancer in (4 employees exposed to Aroclor 12S4 in a research and development laboratory and SS refinery workers HONS 015 735 173 - with a almilar expoeure Iren the aama art*. The investigator reported a significant axcaaa In the Incldanca of melanoma of the akin aa wall aa pancreatic cancar baaad an expected cancar rataa froa tba Third National Cancar Survey. in a subsequent lattar to tha Naw England Journal of Hadlclna, Bahn at al. have raportad only on tha axcaaa of Mlancna (Bahn at al., 1970. Whan Lawrence crltldxad tha atudy on tha baala of tha fact that Individual! could hava baan axpoaad to aultlpla chaalcala in tha laboratory environment (Lawrence, 1977), Bahn and col league! auggaatad that the raaaon for amphaalxlng tha aalanena riak waa tha biological plaualblllty of auch an aaacdatlon wharaaa an axcaaa riak of pancraatic cancera could have Indi cated an aaaociation with aultlpla chaalcala (Bahn at al., 1977). Tha invaatigatora theaaelvea hava diacuaaad aavaral of tha flawa of thia atudy. Information on true expeaura la liaitad and parhapa aore importantly one-fourth of tha axpoaad workera had to bo omitted. The author haa alao suggested that aha undareatlmated the death ratio by including individual! during their early yoara of employment whan there had not baan a auffldently long latency from tha time of firat expaeura of PCB to tha axpactad time of cancer development. There are other problema with thia atudy related to tha Identification of caaaa in the axpoaad population and tha coaparabillty of caaa ascertainment in the Third National cancer Survay data. Apparently tha Invaatigatora identified caaaa HONS 015736 174 - without attempting co validate the accuracy o dlagnoala. Pancraaelc cancer la vary difficult to recognize and dlagnoae. The dlagnoaea of the two caaea need to be validated fron hoapl- tal recorda in order to aake them comparable to data froa the aurvey. Skin cancera auch aa nelanonaa nay be dlagnoaed in doctora' officea. Thua, the lealona could be niaaed in the cancer aurvey data where recorda were obtained primarily fron hoapltala but identified in populaelona with routine nodical care. It would be neceaaary to validate the caaea in thle atudy through the uae of hoapltal and pathology recorda and then to coepare thaae caaea to a comparable group of employed individual! who have had active nedleal aurveillance by pfcyal- eiana. - In auaaary. the data on akin lealona in relation to PCI expoaurea have indicated a reaarkable conaletency. Individ ual! who have a body burden indicated by a blood level of 200 or aore ppb PCSa have an lncreaaed riak of ehloracno. There la little evidence of riak below thia level and thoae atudiaa that do auggeat a riak at lower levela uaually do not have a conparl- aon group or they have not collected the data in a Banner auch that biaa Bight be avoided. The data alao auggeat that typical akin lealona nay occur aore frequently in workara expoaed to PCIa that have been heated and to PCBa that have S4I or aore chlorination. Since the akin lealona occur more frequently after heating, it ia poeaible that chloracne ia actually due HONS 015737 175 - to some alteration or contamination of the PCBs with more acnegenic matariala auch aa dibenzofurana, as found in tha Yuaho incident. Symptoms of chloracna are reported frequently among those who use Kanechlor; this could be related to level of exposure or its hiqh level of PCDFs relative to PCBs. Such a possibility could not be evaluated with the information in these papers. The relationship to direct skin exposure could also not be evaluated. C. Biochemical Changes and Liver Function Extensive studies of liver function have been included among the recent papers on PCBs. Some of these are summarised In Table S. The early study of Meigs at al. involving a PCS leak from a heat exchanger indicated that there were no abnormalities in seven workers with chloracna except for some transient changes in liver function tests in one worker (Meigs et ajL.. 1954). These changes could not be definitely attributed to PCBs. The study of Hasegawa et aK of 99 workers in sis indus trial plants in Japan indicated that increases could occur in enzymes such as SCOT, SCPT and decreases in blood cholinesterase (Hasegawa et al., 1972). The authors regarded the changes in liver function as mild and not clinically significant. Kitamura et al. (1973) indicated that in tha 13 capacitor workers the hepatic function tests were normal. HONS 015738 TT SMir No. Satjacte INm at il.,M 1*72 Milan at aL ,11 1W Saw at al., 1*7* 7 NIOSN 1*11 7 flschbala at it J2I 1*W Tablt > . IlMl--lol StiMlw ml fnwn m4 llwr fooctloo Awri| Dot* CwnUtlw or tlmtlM with *u pph SCOT SCPT CSTP U LON llllruhl* Tat. ITS N.T. N.T. N.T. N.T. ___ Nous cholloaotaraaa Tat. >20 Tat. >S00 Tat. *0.4 La 124 N( 40 haptic faactlaa Ut* aanaal N.I. N.T. N.T. N.T. N.T. N.T. Nora. Nora. N.T. Nmv. N.T. Nora. OapartaN X afeawa aaraal 2.2* 7.2* I.** 1.21 2.U 01 ahaonail la *7 partial No coaaarlMo orm*. No correcMoa caarouadtat varlablat 1 | MOMS 015739 i i HONS 015740 181 ouv at al. tested eh* liver function of capacitor workers through tha uaa of biochaalcal markers and found tha ovarall taat data for tha group to b normal (Ouw at al., 1976). Tha BSP livar function taat vaa conductad only on indlviduala with blood PCBa above S00 ppbi four out of aavan workara wara abova normal levels, but it la not claar whathar thaaa valuaa wara above tha ranga of arror of tha taat or whathar thara wara other factors that might hava influancad tha rasults. it is indicatad that tha blood PCB laval and tha BSP taat do not corralata. NIOSH (1977) avaluatad tha livar function of aavan of sight workara axpoaad to PCBa in tha manufactura of slactrieal aquipmant. Tha lavala of SCOT, SGPT, alkalina phosphatase, and total bilirubin wara normal in a group of aavan workara with a naan PCB laval of 96 ppb. Fiachbain at a^. (1979) axaminad a group of 321 workara fran two capacitor manufacturing plants. Tha workara had maan lavala of 1,-PCBa of 124 ppb and H-PCBs of 48 ppb. A small proportion of tha workara had abnormalitias in tha biochamieal tasts. Two parcant had abnormally high lavala of SCOT, 7t high lavala of SGPT. 2t high lavala of GGTP. It high lavala of alka lina phaaphatasa and It high lavala of C.DH. However, thara wara no abnormally high lavala of bilirubin. Tha raaults of this study hava not baan corractad for important confounding variables such HONS 015241 as ags, alcohol tnealca and other dltsasss currently or In the past (a.j. hepatitis) chat nay influence these findings. There is no unesposed group Cor comparison. The investigators have not presented data correlating increasing ensyne levels to in creasing PCS levels, which would be an appropriate method of presenting the relationship between two variables that are con tinuous. The study does Include a comparison of the data di chotomised by two levels of SCOT, less than SO and greater than SO l.u. and two levels of both lower and higher boaologues of PCBs. These data indicated significant differences between the proportion of Individuals with high and normal SCOT levels for H-FCSs greater than ?S ppb compared to lower levels and for L-PCSs greater than 200 ppb compared to lower levels, it la not clear whether these PCS levels were selected afear esaainlng the data, in which case the conclusions would be questionable. The If individuals involved in a PCS spill (NI03R, 19801 had normal liver function teats that included total bili rubin, transaminase, alkaline phosphatase, and lactic dehydroge nase. The triglyceride changes could not be evaluated by the investigators because of inappropriate teat procedures. Choles terol levels were normal. This group had very low blood PCS levele of f.4 ppb as a mean value, a lavel lower than that of non-ospoaod group#. Baker et si. (19(0) studied PCS levels in ussrs of PCB-contsminstsd sludge ae a fertiliser compered to workers in HONS 015742 - 183 - PCB-ualng facility, their familias and non-aludge users in tha community. Tha PCB laval variad from 17.4 to 75.1 ppb in tha four groups with tha lowest laval baing found in tha aludga uaara. Thara vara no aigna of changing lavala of SCOT, scpt, allcalina phosphatase, LOH or bilirubin in ralation to blood PCBa in drinkara and non-drinkers of alcohol. Tha GGTP laval corralatad with PCB laval in tha total population but, vhan alcohol conaunari vara ramovad, tha corralatlon diaappaarad. naroni at al. (1981) atudiad livar abnoraalitlaa in 80 workara from a capacitor manufacturing and taating plant. Sixteen workara (20t) had aaymptomatic livar abnormalitiaa. Over 80% of thaaa had enlarged 11vara. Among thia group tha moat frequent enzyma alavatlona vara the gamma glutamyl tranapeptidaaa (GGTP) in half tha caaaa, the tranaaminaaea in 44% and the ornithin-carbamoyl-tranaferaaa (SOCT) in 38% of caaaa with enlarged livera. Tha mean L-PCB laval vaa significantly higher in workers with abnormal livar findings compared to con trols (215 to 92 ppb), mean H-PCB laval was significantly higher (308 to 178 ppb) and total mean PCB laval was significantly higher (524 to 298 ppb). Tha levels of PCBa in chase workers are high compared to values from many of tha exposures recently reported. It is intaraating that the authors report that al though there is an association between liver disease and PCBa thara was no such association for chloracna, but tha number of cases was smaller for the latter parameter. MONS 015743 134 Chase *t al. (1361) exanined eh* <*rua KB levels and eh* biochenieal markers of liver and lipid activity in 120 uintenanc* workers who had had varying exposure* to KB* in th*ir work. Plasna KB* war* correlated with SCOT and, after adjusting for age, eh* correlation between eh*** two variable* i* (till significant. There is no significant correlation between plas ma PCBa and GCTP or SGPT. If this correlation i* correct it has occurred with levels of KBa in the blood of exposed wor ker* (33.4 ppb) that are lower ehan those found in other studies relating aubcllnical changes in liver function with PCS* (NIOOH, 1977). However, without correction* for other potentially con founding variables such as alcohol intake and the history of other disease* such as hepatitis, it is difficult to assess the finding. Becently, H10SB has completed three studies repre senting cross-sectional nodical surveys in two groups, individ uals working in capacitor aanufacturing (Sitith it al., 1911a) and individuals working in aaintenanc* and repair of electrical tcansforaers (Snlth et al., 19tlb). The third study combined the data troo each study in an overall analysis. In the capacitor aanufacturing group there were 224 participants for whoa 1-KIs and B-KBs were datamined, as well as blocheaical studies. Several alnpl* correlations were cal culated and, for all those that were significant, aultlpl* regression aquations war* developed using all other predictor HONS 015744 185 variables Cor which information waa available. This included drug intake, smoking history, other biochemical markers, age, sex and others. Serum H-PCB was significantly correlated with SCOT and CGTP. There were, however, no clinical findings sug gestive of liver disease and no indication that the levels of these enzymes were abnormally high. Exposures in this plant were high with plasma PCS levels being 8 to 50 times the level found in the community. Smith et al. (1981b) have reported in the survey in formation on 9] individuals who were about equally distributed between a municipal electric system and a privately-owned elec tric utility company. The levels of H-PCBs and [,-PCBs are simi lar in the two facilities. There were very few enzyme tests related to liver function that were significantly correlated with PCS levels. The only significant correlation was a positive relationship between L-PCSs and SCOT for the private company. Smith et al. (1981) subsequently reanalyzed the data for the three sites presenting partial correlations for L-pCBs and H-PCBs Independently without correcting the level for alter nate homologues since they were closely interrelated. Under these circumstances, there is not only a positive correlation between H-PCBs and SCOT and GGTP at the manufacturing plant but also a correlation with L-PCS and GCTP. The positive correlation oetween L-PCB and SCOT still remained after corrections for the private utility company. Combining the data for all sites it is HONS 0157*15 186 noted that log SCOT and log GOT? damonaeraea both significant and haaogeneous tranda in relation to log L-PCB laval. Only log SCOT is ralatad to log H-PCB and in this case the trend for all sites is homogeneous but not significant. In these analyses, the only confounding variables considered were age and sex for one study site whereas the analyses in the previous papers con trolled multiple variables such as smoking and other diseases. Reducing the number of variables and increasing the number of subjects available for study may have accounted for the changes in the relationship with biochemical markers and symptoms to the levels of KBs. Becsuse of the many changes in relationship. It is difficult to lndlcste precisely the association between spe cific liver ensymes and specific homologues of KBs. It does . appear that in these studies one or more ensyme levels within normal ranges may be related to one or more types of KBs in the blood. In order to identify the enzyme system that is induced by the various chlorinated forms of biphenyls, Alvares at al. (1977) tested the Induction of liver cytochrome P-4S0 and P-441 by Aroeler 1014 in rata and in workers occupationally exposed to the agent. In rats, the lower chlorinated PCS elicited a barbi turate type of effece on the oxidative enzyme system inducing cytochreme P-450, ethylserphlne-N-demethylaae, and microsomal pro tein. Unlike Rroclor 1254, which induces both P-4S0 and P-44B, the rats with Aroclor 1014 showed little effect on benzol a)pyrene HONS 015746 - 187 hydroxylaae activity, which auggeate little induction of P-448 by tha chemical. Tha teata in axpoaed workara wara conducted by determining tha half-life of tha antipyrina whoaa mataboliam ia etimulated by tha barbltutata claaa of inducing aubatancaa. Tha workara had a aignificantly ahortar natabolic half-life of tha drug than tha controla auggaating that the Aroclor 1016 had induced cytochrome P-450. In a atudy of 4S6 community reaidenta in a town that had high levela of PCBe in fiah, Kreiaa at al. (1981) found a correlation between PCBa aa meaaured againat aroclor 1260 and GGTP. Thera were no correlationa with other liver enzyaea. Correctiona were made for aeveral other varleblea auch-aa ago, aax, fiah and alcohol conaumption, and obealty. In eummary, the data from the atudiea of liver enzymea and function auggeat that the populationa eapoeed to PCBa ueually do not have clinical liver diaeaae, although in one atudy there waa aaymptooatlc hepatomegaly (aee Table 8). Few of the early atudiea allow ua to aeparate the varioua homologuea of PCBa in order to correlate enzyme reaponae to level of chlorina tion of PCBa. Recent atudiea auggeat that SCOT and/or GGTP are the moat aenaltlve markera of change in the liver enzyme eyetema related to PCB expoaure. In the atudiea that included extenalve teating of all enzyme ayatema aa well aa characteri zation of the PCBa, the data have inconaistenciea that do not allow ua to judge clearly the level or the apecific type of HONS 015797 188 PC* that la ralatad to Incraaaad lavals of apaclflc livar anxynaa. (lany of tha atudlaa hava not eorractad for othar con founding varlablaa auch aa alcohol conauaptlon. Tha data ara auggaatlva that thara ara changaa In ona or aora llvar anxyaaa ralatad to PCS aapoaura that ara not aaaoclatad with dlaaaaa and say occur at lavala balow thoaa at which chloracna occur. 0. Lipid Hataboliaa Tha long-tara atudlaa of patlanta with Xuaho dlaaaaa hava ravaalad aavaral othar abnoraalltlaa. aaong which wara alavatad blood triglyearldaa (Uraba at al., 1978). In racanfc raporta of lndlvlduala axpeaad to PCBa. aaaaaaaant of lipid aatabollaa haa lndleatad aoaa abnoraalltlaa, but In ganaral no clinical aanlfaatatlona of thaaa abnoraalltlaa auch aa ineraaaad rlaka of cardlovaacular dlaaaaa have baan notad. Soaa of thaaa atudlaa ara auauurlxad In Tabla 9. HONS 015748 I Table UtM Stwdlat Surf? lhaher tan|i Cerrelatloa or alevatlaa of lipids SwbJecU Oaae Nt Triglycerides Chelestaral mil. l-Chol. ____________________________________________ ______________________________________ h-.- UH- Nasegawi at al., M )*n fat. 37tl Doer. Iter. I.T. Baer. Hera at )., 1*73 111 Tat. 7-300 leer. I.T. I.T. I.T. Nates * hauiMr at *1., 37 TwT Tat. 4 I.T. tanaa] I.T. I.T. Tlschhela at al. ,321 1*7* to 124 HI 4t agorted at ( above aoraal 10.5* 17.t* taker at al., 1M0 t* sledge user* It workers 19 worker faa. 22 coMaaal *y Tot. 17.4 75.1 33.5 24.4 HI (10.1 I2C.S jl4.t (12.0 fos. Noae Salt* at al.. 224 litla La 50-502 ag/al la*. HI 22-51 faa. Hdm Pm. ii ii tl. oaf. I.T. (S| la caanartsoo with eeatrel. Io correctloa Tar caaTouadlag variables Coopered for u-rct onli kulyiel ooly oo won- i alcohol drtakers la other variables caatrellad. [ Corrected for ether variables j HI I Study Subjects TMU (continued) Lipid Studies Average Correlation or elevatloo of llplda ppb Triglycerides Cholesterol N-Chol. L-Chol. Notes i li li HONS 015750 Sal lb at al-. IMIb 47 n*. Is HI 44 Prlv. Is HI Salih el al.. ISSIc (laaaalyses of Safari above) Capacttor lo HI Pub. ut. Prlv. ut. Is HI to HI (rain at al ., 4SS 11-16 ag/ul 4-24 Hass PM. IS-21 4-11 Pot. Nag. Non* Pm. Nona Pm. Him Hass 17.2 aicraaA. Nona (1.2-15).r Nose . . ** PM. Hass Naas foi. Hum Nt. Pm. Mom PM. mm b mm Nano Nose Nose Haas Nag. Naaa Naas Naaa pMltlva cerraUtioai corrected for other variables. Nose Haas Naaa Naaa Dom Naaa NMt Included fewer coafousdlag variables 1 ---------------------------------------- . i1 161 193 Hasaqawa t *1^. (197 2) had notd changes in lipid metabolism of Yusho patients as manifested by decreases in the blood levels of cholesterol, triglycerides, phospholipids and beta-lipproteins. Other studies such as that of Hera et al. (1973) on Yusho patients had noted elevated triglycerides in 554 of subjects who had blood PCBs above SO ppb. The latter data were not corrected for any risk factors such as age or weight. Bumgarner et al. (1973) indicated normal cholesterol levels in 37 refuse workers who had a mean PCB level of 4 ppb. Fischbein et al. (1979) has examined lipid metabolism in 321 capacitor workers. Cholesterol levels of 300 or mere mg/100 ml were found in 17.14 of workers and triglyceride levels of 200 or more mg/100 ml were reported in 10.54 of the papula tion. The total lipids were elevated (above 1 g/100 al) in 3.44 of the population. These metabolic parameters, however, are influenced by age, personal habits, and the presence of other diseases) it is therefore essential that the data be cospared to a population with similar age and sex distribution and that confounding variables be controlled before one can assess the role of PCBs in these observed changes. Since these compari sons were not made, no conclusions can be drawn from these observations. In the study of Baker et al. (1980) in which PCBcontaminated sludge users were compared to expoeed workers, their families and community controls, there was a highly significant HONS 015751 - 194 - positive correlation of piaaaa triglycerides and serum h-pcb. This correlation was strengthened whan alcohol consumer* wars removed. thaca was a negative cocralacion of HOC. eholascarol with H-PCBs chat waa noe statistically significant. The Investi gators suggested chat the oean level of aarua PCS In fasting subjects with hypartrlglycarldaala was only 29.0 ppb which la lower than tha levels at which this abnoraallty waa noted in previous studies (50-200 ppb. NIOSH docuaent). Xt is not clear, however, whether the other studies with higher levels have used total PCas. whereas this study used only B-PCBa in the correla tion analysaa. Tha B-fCBa constitute 35 to 99t of the total naan PCts in the groups. Personal characteristics aay influence triglyceride levels, and many factors were apparently considered by these investigators including age, set and drinking habits. These lipid abnoraalities aay be occurring at the lower PCS Halts, or even below those Halts reported previously. Chase at al. (1911) in their study of aalntanance workers exposed to PCBs found that levels of plasaa PCSs were significantly correlated with triglycerides but not with choles terol. Adjusting for age or lengch of employment does not change the significance of this correlation. The triglycerides are not significantly correlated with fat PCS levels. As aentioned pre viously the levels of plasaa KBs in this group of workers is low (33.4 ppb). HONS 015751 195 - Smith et al,. (1981a), in tha study of 224 workers from a capacitor manufacturing plant, found that serum PCBs were correlated with measures of lipid metabolism. Corrections were made foe relevant variables such as smoking, history of diabetes and heart disease, drug use, and others. The partial.correla tions indicated a significant correlation between serum H-PCB level and total cholesterol and triglycerides and a significant negative correlation of plasma triglycerides with serum l-PCB levels. When the levels of H-PCB and L-PCB were combined the correlation was positive as seen in other studies where total PCBs have been examined. There were no signs of cliniesl dis ease in relation to the elevated lipids. It was noted that eeveral of the lipid measurements were correlated with GGTP level. As the authors suggested, this may indicate that PCBs induce hepatic microsomal ensymes, as has been found in labo ratory animals and man, and these in turn nay increase synthesis of specific lipids. Smith et al. (1981b) in a health study of 93 workers divided between a public and private utility plant found corre lations of lipid metabolites with FCB levels that conflicted with data fraa tha previous study. Triglycerides were positively correlated with H-PCBs in one facility and negatively correlated with H-PCBs in the other. Both correlations were significant even after correction for multiple variables. Both triglycerides and cholesterol were positively associated with L-PCBs in only HONS 015753 196 on* facility *v*n though th* l*v*l* of eh* blphanyla in th* blood were similar In th* two population*. High density lipo protein* war* negatively correlated with R-PCBs in only on* stabllsha*nt. In this ca*e, th* othr facility also demon strated a similar negative relationship but th* lv*l of th* correlation was auch lower. Smith *t al. (19110 have combined th* data from ches* two studies and corrected th* results for only ago, s*s and study sit*. Under ths* circumstances there were les* con flicting data in th* correlations. Only on* significant corre lation with L-PC8 was noted and that was a positive correlation with cholesterol at th* private utility. Both cholesterol and log triglyceride were associated with B-PCBs at the equipment manufacturing sit*. Triglycerides and B-PCB were positively correlated and BCL-cholesterol and B-PCB negatively correlated at th* municipal utility Site. Combining th* data from all study sites indicated that log triglyceride was significantly associated with both L-PCB and B-PCB but the trend for all sites was homogeneous only with L-PCB. Log BDL-cholesterol was significantly and negatively associated with B-PCBs and this trend was consistent across all sites. There was no significant relationship of PCBs with total choleatarol. Kreiss at al. (1981) have studied a community where high levels of PCBs end DOT were founds in fish. Among the 4S8 participants, there was a positive correlation between cholesterol HONS 015754 - 197 - nd KBs Huund as Aroclor 1260. There was no additional contribution by ssrua triglyceride or HCL-cholesterol to tbs prediction ot serum PCB in multiple regression analysis. In summary, the studies in man suggest that there is frequently a positive correlation between PCBs in blood and triglyceride levels, although there are many studies that demonstrate no relationship. The correlation is often to the higher homoloques of PCBs and occurs in some cases with blood levels of H-PCB at 25 ppb or below. The data associating H0Lcholesterol and H-PCBs are not as often significantly correlated, but when they are, the relationship is negative. Lower levels of HDL-choleeterol may be an important risk factor for coronary heart disease but there is no evidence of a relationship of these lipid findings to clinical disease in these studies. The variation in the presence of lipid abnormalities in relation to PCBs in the studies and the variation in tho specific lipid changes observed would suggest that there may be a confounding variable that has been ignored and that is influencing these relationships, h positive correlation of blood lipids with plasma PCB levels could in part be a consequence of the ten dency of KBs to distribute equally among all lipid pools in the oody. E. Reproductive Effects Very few papers have addressed the problems of human reproductive effeots related to KB ingestion. The early paper HONS 015755 - 198 - by Kuratsune (1972) on the Yusho patients had indlcatad that out of 11 woman paelanta and two of tha wlvaa of patlanti who were axpoaad at any tima during pregnancy, thaca wara 19 liva born and two atlllborn Infanta and thraa of tha liva born wara amall for thair aga. Tha authora do not provide comparison figuras on reproductive outconas for that araa of Japan so that It la lmpossibla to assaaa tha maanlng of thasa flguraa. it la claar. however, that for all bablas whosa raeorda wara reviewed, akin staining and aya discharge wara usually peasant. Krelsa at al. <1911) simply indlcatad that thara was no association of miscarriage, still birth or Infant death rate independent of aga affects in a study of a community with high PCS levels. In gen eral, tha data on raproductiva affects from exposure to PCSs ara limited. r. Hematology and Immunology Host of tha studies of hematological affects have found no abnormalities and thasa observations have bean made in simple statements. Tha studies of Kitanura at al. (1973), Bumgarner at al. (1973), Karppanen and Kolho (1973). flschbein at al. (1979), aksr at al. (1910), and ttaronl at al. (1981) have not revealed any abnormalities of hemoglobin or leukocytes. Ouw e al. (1978) reported several protein and globulin tests on exposed workers that wara higher or lower than tha reported normal. However, tha overall levels of globulins ware not different in two groupa of workers with high and low exposures. In tha initial abstract HONS 015756 199 relating to the Baker et al. (1980) study, the authors reported increased hematocrit and hemoglobin in relation to PCB levels controlled Cor age. The second complete report corrects for several other variables that may account for the difference in results. In the three reported studies of Smith et al. (1981), the investigators looked at red cell count, white cell count, hemoglobin and hesMtocrlt and found no significant correlation with either L-PCB or H-PCB when corrected for confounding vari ables. In the latter studies they have also examined the corre lation of total protein, albumin and the various globulin frac tions and found no significant correlations after correcting for other factors. In general, there are no recent studies that suggest abnormalities of the heme system in man related to levels of PCBs. In addition, the Smith et al. (1981b) study of workers in electrical utilities showed no significant variation in PCBs related to urinary porphyrins, porphobilinogen or 17-ketosterolds or 17-hydroxysterolds. c. Other Factors Kraias et al. (1981) in the study of a PCB-expoaed com munity found increased diastolic blood pressure to be correlated with PCB levels even after the correction for other variables. No comparison data for a control group were given. The study of workers in the equipment manufacturing plant also demonstrated HONS 015757