Document aDVDz1Y18M8vL0gv3no1obNJ9

ssso-so ENVIRONMENTAL PROTECTION AGENCY [40 CFR PART 761] [OPTS 62035;TSH FRL ] POLYCHLORINATED BIPHENYLS (PCBs) MANUFACTURE, PROCESSING, DISTRIBUTION IN COMMERCE AND USE PROHIBITIONS! USE IN ELECTRICAL TRANSFORMERS REFERENCE DOCUMENT VII. (13) HONS 017*34 I , , USE UF1S b^UJD FCo vrires/ o File Reports PCD 2 Report | EPA-450/3-77-045 i November 1977 g 6 o 11> [ *p 1 *s> ENVIRONMENTAL i . |i ASSESSMENT OF PCBs lii IN THE ATMOSPHERE n --j <~ ' N Mitre Corporation, "Environmental Aiiumnt of pcsa in - tha Atmoaphere' April 1976. Tablea 5-11 and 5-13. ' !. ! - HONS 017236 TA,LI coKMitmow or polychlobihated iranu in kakine and cannrarrAL ai n - Saapla Collection datee (1*73) Location** Volne of air (w3) FCB , (at/m3) 1 2/12-2/13 Barwuda 2 2/13-2/14 anode 1070 1320 0.59 0.30 3 4 3 6 7 8 9 10 11 2/15-2/16 2/16-2/1S 2/19-2/28 2/29-3/9 4/8-4/11 4/11-4/17 6/4-6/S */5-4/6 d/7-6/8 denude Serwuda Barwuda Berwuda Berwtada Berwuda 33*20*8, 63*14'W 34*39*8, 66*13'H 37*39*11, 68*12*H 918 1930 1740 732 1300 860 300 267 402 0.65 0.62 0.55 0.52 0.61 0.21 1.6 0.79 12 13 14 6/8 6/9 1/18-1/19 38*48*8, 69*14'H 40*32*8, 70*20*8 0.8.1. : 222 196 392 0.72 0.83 4.0 13 1/21-1/22 U.B.I. 1071 2.1 16 2/4-2/S 0.8.1. 744 5.6 17 3/8 Providence, 8.1. 76 9.4 *Th* "tel retained by the glnae-flber filter and Crapped on the polyurethane foae. Fllterreteinl eeluee for the Berwuda sawplaa were leae thee 2 perceet of the total--.not detereloed O.A.I., Qulweraity of Abode Ielnd. **Sawpl*a 9 throv|h 13 were collected free the l.f. Trident while the ehlp wee an route. The location eerke the eldpoint ef the collection track. . - Calculated aa Aroclor 12A2 or Aroclor 1248. -- ' Seercei Adopted free lldlawan, T. P., and C. E. Olney. 17A. Chlorinated Bydrocarbona In the Sargaoeo Sea. Ataoaphere and Surface Hater. Science 181i 316-318. TABLE 5.3 PCB COBCERTRATIOSS OPEB THE BESTEBB BOKTH ATLABTTC Station Data (1973) Sanpla voluna (n5) Vlad dlractlon PCB os n~3 (calc, as Aroclor 1254) Banmfa <32*20*B;64*40'B) (32*20'S;64*40'B) (32*20'B;64*40'H) Gaortaa Bank (41*40'N;67*30'V) (41*40'B;67*30'V) (41*40'B;67*30'H) (41*40*S;67*30'B) (41*40'M;67*30'H) Vlaayard Sound (41*20*N;70*50'V) Grand Banka (45*16*B;52*08'V) (45*16*H;S2*08'H) (4S*16'B;52-*0a'B) <45*16*B;52*08*B) 12 Pabrnary 13 Pabrnary 14 Pabrnary 15 Pabrnary 10 April 13 April 15 April 17 April: 19 April 21 April 13 April 30 April 25 Jun* 26 Juw 27 Juna 28 Juna 29 Juna 560 480 820 500 105 675 660 655 640 650 105 224 780 960 840 940 540 MM W Varlabla S. m. BV BE NU SB SB SB SB SSB SB BSB VSV V 0.5 0.4 0.16 0.15 1.4 0.82 0.58 0.61 0.80 1.60 3.9 5.3 0.05 0.07 0.10 0.16 0.05 Source Bar**?, G. , And V. G. Stainhauar. 1174. Atnospharlc Transport of Eolychloroblphanyla to tha North Atlantic. Afoaoharlc twlrownnt 8s 77Z-7SZ. ". Prtday ttann 23, 1M4 Part 111 Environmental Protection Agency 40 CFR Part 701 ' *lyehiorlnat*d Blphanyla (PCS*); Manufacture, Procaaainfl, DMribuOon In Commcre* and Ua* Prohibition*; Uaa In Electrical Transformers; Advanced Nollo* ol Propoaad Rutemaklnfl I. HONS 017239 i * 11070 Fdtl KagUtw / Vol . No. M / Friday. Mirch 23,1084 / Prepoted Rul. DNWMMENTM. MOTCCT10N MCNCY 40 cm fm 7*1 IOM* MO 1M4M. MM-71 PTfMapnf, 0*10 Wne ^WTUOmonOi Uaa to Itoslrtoal Transformers / A88N6VJ Environmental PftiKtlon Agency (IPA). ACTION. Advance notice of proposed rulemaking. MaMAAY; EPA Issued a Anal rule which we* published In Iba Federal Reglttsrof August 29.1992 (47 FA 97912) (Hat among ofo* provtafona. authorised the todafalte aaa of certain electrical transformers containing polychlorinated Mphenyle (PCBs) (PCB EJectrteel Uaa Mia). Although EPA had knowledge prior to August 18.1082 of a major Eraralatad Incident to Binghamton. Now York invoking a PCB-Transformer. EPA haUavad that Brat invoking this <A t Malpmant wars rare, laolatad incidents. Thus. EPA did not oonaidar tha riaka ` poaad from Area whan EPA mada Its datarmtoattoo that tha conibioad uaa of alaetrical transformers containing PCBa did not post unreaaonabla risks to pvbHc health or the environment . Meant Information from a May 1999 fire-related Incident In San Francisco. CaMonria Invoking a PCB-Transformer and a Sapttmbtr 1999 flro-ialatod event to Chicago. Unols tovelvtog a PCB* Transformer has brought into aueatton EPA'i oorilor assumption that fire- ralatad events Invoking PCS- Trenaformora ire rare and Idolstad occurrences* Ths purports ef laaetog this Advance Notict of Proposed Rulemaking (ANPS) sre to soHdt data Mtdftc to the riaks poaad hy Area Invoking alaetrical transformers that eontain PCS* and to oticll dote on mochonlnm for mltlgstlng or aNmlnotlng those risks. Dtpsodtog anon the results of EPA's analysts of these data. EPA may propooe further control measures onthaussaf this sgulpmsnt by October 1994. ATtfc Comments on tha Issues reload to this Notts* must be submitted by May 211991 Aoonrttat: Comments should bo submlttid In triplicate to: TSCA PubAe Information Offies |TB-799h Offtcs of Toxic Substances. Environmental Protection Agency. Pm E-108. am M St. BW. Washington. DC 90491 Comments should Include the dediet number OPTS-82035. Comments received to connection with this Notice will be avnHable for reviewing end copying from 100 a m. to 4:00 p.m.. ' Monday through Friday, excluding holidays. In Em. S-107. Environmental Protection Agency, 401M Street 8W.. Washington. DC PON PUNTNM mPOAMATlON CONTACT: eoeri invalidated this portion ef the rule, os well as a number or other provisions, and remanded the rule to EPA for farther action. As a consaqsines of fo October WO decision. EPA undertook a number of rulemaking actions. Tha action refovant lack P. McCartky. Director. TSCA to ths rule which la tha subject of Aasistonca OfAco (T8-799). Office of today's ANFR was published to tha Toxic Substances. Environmental Federal RagMor of August 28,1992 (47 Protection Agency. Km. E-541401M St., TR 97942) (hereafter, FCB Electrical Uaa SW,, Washington. DC 20460. To0 free Mla).ThiiiulaamatidadSttMay3l. (900-124-9066). In Washington. D C: 1979 rule. Ite August 1992 amendment, (894-1404), Outsldo the USA: (Operator among other provMoua. authorised the 802-684-1404). continued aaa of PO-Traneformere igmptot wrowamosr. (electrical transformers containing ' greater thoa BOO parts per mttHua (ppm ^^rtWJaJaf tbs Toxle Substancss KBs) to fsetfities Invoked to the handling of food or food Remo until Control Act (TSCA) jsnuhKy pschJblw October 1,1*6, and. allowed foe use of toe uaa of PCBs after January 1.8971 sM other categories of eon rotors J Tha statute dote, however, sat forth two electrical transformers ceuletotog or exceptions under which EPA may, hy eontamtosted with PCBa far the rule, allow o particular uaa of PCBa to continue. Under section 6(a)(2) ofTSCA. EPA may allow PCBs to bo used to a remainder of their uaefel Ikes. In tie Aaguet 28.1992 decteton. EPA mada a determination that authorise foe aaa ef "totally enclosed manner." A "totally fosse transformers far the ramehMv of endooed manner" Is defined by TSCA to ha "any manner which will ensure that any txpoaure of human beings or their usofallkos denotement an unraasonahle risk to pahfae health or foe anvtronmont for tha fallowing realms: tbe environment to a polychlorinated 1. EPA datormtned that If It dM not biphenyl will ha Insignificant, as - authorise ths use of PCBs to determined by tha Administrator by rule." TSCA also allows EPA to transformers, tha eoate to tha public and United States Industry would be hiAiees authorise tha use of PCBs In a manner of dollsrs, primarily as a result of foe other than a totally snofaead aumnfr If tha Agency Ando that the uaa "will not t an unreaaonabla risk oftofury to or tha environment" . disruption of electrical service. EPA oelenuiiatd that foe resulting reduction In risk would not outweigh theta substantia) coats. EPA promulgated a rule, which was 2. EPA determined that foe tospactien published to tha Federal Register of May and maintenance programs regufrod 91.1S79 (44 FR 91814) to Implement under tha rule reasonably reduced tha sections 9() (2) and (91 of TSCA. IMs exposure risks aaaodatod srtfo foe uaa rule la Bated to the Code of Federal Regulations under 00 CFR Part 701. The of PCBs in PCB Transformers, and foe servicing cOodHteas psavsntsd farther rule, among other provisions, designated PCB contamination of transformers. all Intact, nonleeldng eapodtors, . 9. EPA datarmbiad foot rttoatmef electromagnets, and transformers, other PCBs to the environment and ixposan than railroad transformers, se "totally to bumans and biological ergantom* enclosed," thus permitting their uaa from mineral all treaeforewra are without specific euthorisaUoos or minimal. EPA estimated that those conditions. The Environmental Defense transformers contain fata than B19 Fuad (EOF) petitioned the UA Court of percent of all tha PCBs used in Appeals for tits District of Columbia . transformers and relearn less than one- Clrotit to review a number of provisions half of a percent of theta PCBa on on of Dio rule. Including tha portion of the annual basis. rale that designated all intact and 4. EPA determined that foe easts nonleaking capacitors, electromagnets, associated with other risk reduction sod transformers "totally enclosed." {Environmental Defense Fluid, bte. v. measures such as accelerated pknasst reducing the PCB concentration In the Environmental Protection Agency. 996 . dielectric fluid, or providing PAd 1297). ' containment for transformers ware net On October 96,199a tha court, among reasonable whan compared to foe other things, decided that there was potential reduction to reloom of PCBs Insufficient evidence in tha record to support the Agency's deesifkmtfon of achieved. . In evaluating the risks posed by the transformers, capacitors, and continued use of alaetrical transformers electromsgnets ts totally enclosed. Tha containing PCBs. EPA had constdared . MGNS 017240 Fadatal Kagistor / Vol.`48. No. M / Friday, March O, lax / Properrd Raia. 1M71 Ba |niiw raralUng froia I--kj --d pdydilortMlod dlbrruofuroM lo Iho ptfa af FCBcaaUMiig dMacbfc (laid dactwork of Ika ballBag M ranaHWHu tha yriadpal rani* of rataaaa of PCBa la tha tmireaBaal for Tha Son Fraodoco taddact. orxl u ovoo aora rocoo) BdBnt to Ba Fbol That. ok hawavar. aa hMhcalian Bat Iraahnahriag tnaafanaara oho cooU ba mpsMWt hr Ba roloooo of PCBoFOrouaplo.ooFobnMnrl.lMl. I *o Highaataa MM Oflloo MIA* bBfwin, Now York, o PCS* Tnoofonaorwot hmolvod la a Rro lo *0 bmonol of Iho batkfag MniiMlM cm|IiM liter tbi bi, tedtentedlmdtetfbetkmofPCBe. pilpuldovlncliil dtlimirfiaana H Notloool Booh BHHHg lo Chicago. Baida bliiliolo 1M1. hooo pmoplil m lo coutdw nooowrloi Ha nrltor pnltfM n iiwpicted n^WHEJ MoVl mMHMV*--M. --MO-1 nai-l bioolobu (noofonwra At) contain PCBa. ~ Thta Advance Notice afPrapoatd ftelemakbig |ANFH) lo tbo Agency'. Ural atop In formally imnbw Iho pobllc baallb and anatamantal riaka paced by mimwN mvMNmM mIM Am tetertar if dw budding. Broa faYoMn| alactilcal Haoalocaora containing PCBa. IfWA doterwina. that The MWlMttoB of PC3> |Md aacpoctad tio riaka paced by Brea bnrohdnf MiteiniH)a) ttaaaghoit Am Ifr traoaforaiara that oontaio PCBa an ctetp WWm occarrad ala two ratted wfBdcafly large. wku wigkad agataat *MblteiiMllilkat ria Am length af tha banaflla of tbla aqatyMwit and Ika *i bdhfe* and opend Into Am coata af oonttoi rtiarai. Ibu PA will tenhmr k III birniwl At ptopeee anaawoa by Octobor IfM la teteiteMV.IPAbilimdtel rodoco or aOwOnH tboaa riaka- Am teething teifiwiH ttei cenlate ' Thoprapoooof ddaANnt. Am. la la VMOMteMv^mi Mmimli --H,B-B(-tQaV-inQ`ten`dw---m-M- o-R--t-Me!.M--T--V-h-AuM.*MI r FnaonlcartaAaaaUaWatiiaiaattwu aha riaka yooad by Aaa AaahAtg KBadriaotanaa riaka tepebUc health or Aa aorbootaaot. KFA M not directly miMfr te pabic hootfe nd turtmiwM) riaka pond hw An* related aeonta. BPA ateodM not mknte te ml if Implementing rick wdilteiiMii te mitigate tei rlaka pMd hg Am Imohdng tb^o ogaipi^voiA edfcfl data in flra --ter aiaet: (1) Tbe riaka pud te bomm boilfe end Am iBvten--l te te iwl W i Imnlitid irrhtinl Imoirtag in iterlrtril tranefaimar nuftehg PCBa: (!) fee pwvwMvy vi inwiw ran oeenrHag that Inoahra olaotiflaal tranafonnoTt that ooatabt PCBa. and fedora Aal aay hteraua Ala yrobabtUty; (1| Ao roacHona and . Iranafanam. ariadyally. Ao blab ooata of rfua ay hDcwhi| Aoaa tncifcatr. flail aaala ratkMa Aa bonahta uaartataf wHh Aa ooriUnoad ooa if Aaaa troncfarMcee. Mai praandgattoa of Aa 1MX tala. Tnncfcraer Am ray eccar mi maeoUyjhoe pnvMHQf expected* nd Ant rOTrinitenwar An toirdi m not nUritted vcWp te tranaforawn b---.-J oil ^ ARAe-a--y-aaa^w MMl te fei Om Market Win ccraylm tel--Awlioi. dlUvnlMlCV Trancforamr u Involvtd In i vraoky tnmternyr vnh An. Mmltorlni wnlited lAir Un Bn tedlcilid tin pnmn rf POi ind eelychtoHnstRd dtemhiM ffCOVaj In not from fete An. AAAmfA m nail kowlnc fei Inntemr mi tented ixtirlor to fei tedldteiltMlt vnmted eondulte from fei vmm te Am brnmnrt and ontakte Ir teteli note draw lha conlanlnated niBki fete Am bnOdtaf and iltewid ter Am dtelfeillun of dm PCli and farmtten if PCDft and ^iMterteited . dfemndtoHn (W!I)Di) In Art ralated n---a-o-ab--m- anvaraI ni a-bm- m* m-n . tranafarwnrv eanttentegyCAa; |4) fea coata and Mtn if dm eoal tecnrrad by Am owmi of i tetmtewmr te*ratead te a Ararateted arant md (1) Am IdanABciMin cf aradibte opttem far mltteiUnir lABinitfnf Am rteka poaad by Iteaa tenlvtet atectrical tranafonmra contatainc POa aa waO aa the coate and banaAla caaodtad wkl> Avon option. . ff BPAta not pvovldad wife adaqMte ' data, aapodotty In Am araaa of Am riaka poaad In Am event of a Arc, Am probability of fetea flm octwfln|. and Am coata aaaodated with damp fottewtef fem teddanta. BPA wfll make tta rafiilatory jadpnanta band upon dm data act forth In fete docranent Tnaaa date Indicate Amt PCA- Tranaformar Am pon ratetlrate high riaka. occur wife ankaown fracocncy and can roach In ralatfraty hfoli ctecn* p coata. * . A priniry aamca of tefanaalaa an tha canan af and drnmilw"' aurroondtamAm teaotetef I contadnlat PCBa an data an thraa VCA-Tranrfannar Amte Ataghantoo. Haw Vatic Aao Ptanciaa. California: and Chicago. OAnate. In ardor to aadnataad batter fee riaka paaad by tha.aaa of feta iqotonant in Am event af a flu. BPA hae ctamted aach af than teddanta. and oamporadfet order te dctemtai who! fedora tecraaaad tha itehl pond ham fee tea. and what footer*. If any. aodacad Am rick* pmontad ter Am An. BPA mime fete Am iteki pmd hy a Bn involving PCB-Traaafenncr m ratatadm Amitej^afdteparatearf tantechamkatel Into araaa when pooplo my ha pmont Thoa. BPA enoclB that PCP Tranrforaaar Amin bafldtego ar near boftdtega my pm gnater itehl Amn cMniaaha kite i feat Am gaaatar ^ ^ ^^jfemnte wtfeln haildh^ Am palter fee mmtel for anpocanofh--mimtadmia contaadninta. and Amnfori. Am higher tha riaka. BPA hn nadmd rirtete condaakwa aboat Am tteka poaad hy an the three moat i and we&aooaorchoi U owara aL BPA la iiAriAng itevA tefomaUon aa ether Are related teddanta tevoMag haneforman contaMna PCSa. A navAal Aal af eAmr teaa w^I-knawn and laae waA* raaaarchad Ineidintc feat BPA te man ofappeerataUMI JBA EfA ia volteMng addiAoaal tefamattoa an fem athar teddanta mi todadad on Ada Ad 1. Binghamtom, Ntw York. At Kim on Fabraaiy 11SAI. a Bn accanad te Am awtlchgear idjnrnt te a Kb Ttaniformar In Am baaaomnt mechanical room of Iho feghoorien State Ofltea Budding. Thte haAdteg te an ll-alory offioa tower Amt waa eeaspteted In ItTh Power te Am batfdtag woo auppAod by two tranaforamra whUb contained a coolant flaid canateAngaf AS percent PCB (trade name Ancfar 12S4J and W pamnt adxad trb and tetracblorinaled baatanaa. . Ahboadi Am city An dapcrtnunte rtapondad within mteataa, Amy fed nat niar tha roachanica) room anAI fee power waa dtecoanected te Am HONS 0l72bl 11172 Fade--I Rapbtot / Vol. 49. No. M / Friday, March 23. MM / f>ropoetd Ral-- treneformere approximately 30 mtoat-- after the Art started. Daring this period, tkan mi repealed electrical arcini and report! erf loud oxylootoni occurring tn Ik* nek-toil no*. Sowho i--ri by the hi w-- dlevrtbeted by conreclion dtrough--t ibi building through an ape* vertical ehep that started hi tba mechanical room and tan to tba penthoan. This connate block abaft e--totoad tba ahaat natal duct far tba axbaaat air ban tba man'a ii--acmi -- el the doers. Tba abaft taaa --4 air tfakt. and aUowsd moka to escape tba epeca between the structural ceUtop and tba aaapandad oatlbit on sock Root at tba bedding. Aa a malt, tba anttra tnatda of tba btdldinf ataa eoatad arttk blaek cook Tba yrababto aonrcs of tba aaat was --tbaetton if the materials to tba aaritob year. Tba bait of tba Bra ayparaalty caaaad a ear--tie baebbn to Mieb--a-- aftbatr--afawata. to tba irtoMty of tba lira. photographs tab-- ebortly altar tba lira at-- ' *' iiidogalchid shewed that tba switch ---- ta-- eowptatoly da--oead, bat then w--kkto damage to Ike lydd i--Mdmd -- tba Ito--. 1 ha tba ft-- ana --IBctonl to dame-- abybdy a --actoral at--I baaia dm atu dbactly attar tba earltch year. However, die too apparently did not rprired to --y antwlal Mkar tbaa tba rwttch gear BsvatodWsels efPCDFsta the soot' ware raporlad wttbtn a weak aftor too Ira. Cogmich--live anilyeei at tba root warapananaadbyOr. David Stoldap af dto UJ. Flab and Wtktofe Saratov, CiImUi, Mtottowla by Of, cbrtataybar lappa af dn IMeonky af Uana to Sweden. aad by Dr. Pht O'Keefe af dn New Verb Itato Deportment af H--lib Labetatort-- Tba-- aaelyeoa ripeitad tba pear-- af PCOPc. FCDFa and potycbforteatad blpknylnii (PCSPi)* although tba ana--le band varied koto sample to --nab. Initial --alyaw of hvo root aamplaa by 8mlth af of. (Ref 1) raporlad Dn ptowaee of 2.1 end 3.0 ppto tjjA-totrecUorsdlbeiizo-p-dlpxto |UJ>TCDO) --d MO and 270 ppm 2J7*totoochMcodlbsntoftic-- |Wb TCDF). A more detailed a--lyele af a hato--mtoad niatira of aoot takan Iroaa thfoa--oot lha balldlap and aaad. ta aa--al hodfcw atadtoa c--talnad 7.300 ppm Pda and tba following a--aaatiattona af varla-- bomolopa of PCOto telralt ppm. panla-21 ppm, hemt ppm. hapto`9J ppm. and MtaOtl ppm. Analysis of a ifafh not aampla band 107 ppm total tetra-chlorinated dtbanaofaran. 40 ppat 13.7A-TCDF, 1.0 ppwi total totra-chlorinated dibanaodloidna. --d Lt ppn 24,73- TCDflCoiip--arepaeWcaaalyata of a dtfferatn Btnohamton aoot aampla found *A7J aabatltotad caoatlta--ta to be tba moat predominant caagsntra within each of tba levela af cwortoatton af both TCDFi and PCDOa. Additional a--ipttap data on PCS. PCDF and PCX*) lavala found following tba Btnfbamtoo fira. aa wall -- additional Information -- the rlrramataae-- aurra--dtop thle bidden! ora pro--Wad to tba Varaar report, "bpaaaa Aeeeeement: Pb-- tovalvlnp PCBTianotoemoir (Ref. 1). The Binghamton State Office Bulldta| ramalna cfoeed to aoimal a--. Tba buUdine k-- be-- --tw--ly cleaned by vacaaaatal and waabino to tamova tba loot Analysis of air aamplaa. wlpa aaatpl-- fcoavtoyfataPa.--dladfc niaplee af rprayad-on --atop to--toSon kavo data--atratod that dn ratio of the varlo--tonic eeaadto--to la aot ooootant ftoat one BMtitx to--other. --d tbot dn vaportaaIton aad rtaaparitioo pncmii m ciwtm radaal ndlatrlbattoa of the awtortol within tba haUdlnQ Eatlaiataa of clesn- ap o--to to data an batata-- ttt --d $30 million. . 15aff Fhoncfaco. Cglifonuo. Shortly aftor rfdo am. on May It, 1003. a Rra tartod to tba aatoboa--i--t to--of--r vaalt of tba O-- Marknt Plaaa office balldtap cctaphx at tba earner of Slaoarl and Mtookm Straato to San Francisco. The vault coatatoad Ibr-- tnaafarawra that arete BBod wttb ' Arodor 1042 eootoaI bqald. H--vy black anoka toaaad kan dm rfdowalh prod-- adfacant to tba btdldl-- far aboat three koara antll the high voitafa power to (be to--afanaar w--totanaptod by tba etdlty. Dartat fab tkraa-kear period. Ikara waa conalderabto vibration and load nobee eccurrinp to lha aaak that ware daacrlbad by taportoaa at tba aoana aa "explosions.* No Informati-- fa available -- the atoa af lha transformers. bat It w-- reported that aoly o-- tea-farmer I--kad. and that after tba fire tbara ware 50 to 00 --None of Hqald to Ike vault, with the door aad walla of tba rank --bad arlth black root aad Sqalda drlpplnt from tba vaak celHim. The Ipld ramalnbip ta lha - to--atonaar contained 0.137 ppm totrechlorodlben--far-- (TCDF) and no datactabla tolrachlotodlbsiixop-dloxln (TCDOJ. . 8moka and aoot from the transformer vaalt contambtatad dw adjacent avrttch $aar room (lbroa$h the b-- duct) aad email creel of the adjacent parking ' |arape and workehop artae (througb email crocks ta the commit block--ah wallet Santa of the ktavy --taka taaatop from the atdawalk yattogwaa apparently pulled tola Sto baddtop through atraat lava) -- amkaap faaaora and Into the eandlattaf taw mat lapply air through lha ink haia--I. t mm vat, plan levai and doors tdto--pkgofdta St--art Street ofSca tower. Teeti later Indicated that tba r--tomkuHnn waa dmitad to tba baaaownt. too -- kandkng ayaiani thnapb floor g a-- tba anterior of tba buildbig. The epper doora af tba die--ft Street Tower local---- from v--tUattng fa-- awaatad to a piatbca-- above the gMb do--. All aampha tab-- to the a--k ato--np aw--h altar the toe maacaaad 330 la HOOmlcrofMaiapir cable mo-- PCSo. dapaadtop on dw rata afviaMIcHaa throuph tba aaak. lAaibtoat tavata at 1 raapa ham abaal tol tot weableBMtor.JIWaaHtob peer room ad|a cent to die aaak had-- concaatoatto----hlpk--M rnta--pnaw pr coble Mtir bihn vtMfcMMi wm ftartod. The P-- Fr--rlan Dap--to--w afPubkcHaakkiaatotatodaaaantoa-- at-- haetap a taval af FCtac tatka--to axcaaa of 1 adnipeat paraablc awaar. or nrhee a--tondaattaa ta aaaa-- af 3 aUcrepram FCka pea 1-- aaaara (jnUMtati whniMaliito wMm with a doth waned arObaatona. Akbouph no aaa--ha oalactod ta faa offlc-- on floore 3 Ibiaaph wan tonHial--lad ibraa dm--tavata, tfra dty lap--Had that tba a ayetamnot be apaatad ha--a-- af far pomblHtyaflpiaaiRapr--ataadaa ta dw-- da-- areaa WRto--l Analyaia of the aoot radirtad to dm tranefaitaereaok--dkidtoaab- baaamant adjacent to the wad af dw trmfpnMf vnll ikowd Aft pwMicv of FCBi. TCOfft. and TCDOft. Aaftftt ftm^ft takan d|ftcftttl ! dw vftall howd dw prftftftncft ofAM 99m PCSi, tt.1 ppm total TCOfi |U apm S. S. 7. -TCXn and OJM Wfti TCOO ioosa pgm Uat^TCODk Addhlanrf MmpHng data on POL 9CDF, and PCDD tavata wand aa a mmtl nf Aa tan Franctaco lira artjvaaantad In Aa Varaar rvporl Olat t|> Tba avaRabta raparta an dta analytical wafta froai Ona Marital ttasa do not iptriy At lariyAtal procadvraa nor. In awal caaaa. An datactlon ttwKa of Aa pocadaraa aaad. Howcvar. from a ratapartaan al tvailabl* Information on Aa cantata* af tht iranafornwr and dw anowl af Arid pflfed and ih* lavab af rantamtnanta mianrad. It ta apparent that At HONS 017242 FaAwal RtpMar / Vol. *. No. M / FHdoy, March ailM / Propooad Roloo MOT nmnlM af RCSa to PCDfo ooconod wlM oboM Am oamn offdopey l boA ' MafbeaMoa and San ATnnclocO' lolbaatoo ol Aaaa wiwimit MitMtrktaKGHMd floaMAoa . ' > nUm tMftnfa On iiytmbir a, im 0 hn occomd to boa bor bohnoa i OTMumt aad At wMi got A atrmliin writ owdor Am pUxa on Am mm block m Am Flow NaAoaal Aft lolldtoa Ai Cblnofa. DM. AJAm*b yawor l Iba Am AAtorafc (nda* hr abaat 41 ^Nlii>tapMHni(tlMtaHfcnMn Aar toe to* m extlagutohod MMteatod tof toe mivh> rm m a m viMNiair aaalaa dwt wee ponalbiy eeoeod by - alatlnoa) flfdM. H|idlctR(PClMHaaAMtiN wm . DMM a aw wav at oxneoei av * >, , Aadt Ami Am wall md to tbo MW mHomi Ai mmII boAdlap otporonl M Am AmmAmw aont Tbo nl*boW nadMpooaMdofceoaaltaadlla " okImoW iMm won on i iAAm mi AM wit (rn mtaofm jer IM aoan eaatoetore)deoatttotokeafr wot grito pit Mlranarai pwttoagaare noAnmro) miAm (AAA Ictm*mi ft M> itun oumoMco). Tbo Wtmfonoor ooh u od)ocoM to band a oaaAUtMf oirooom wlAi Am awtfaaa4 a waafl eojeeant Md^i NNfVtfi aaaa af Aaw eroea km beovtfy aaalaariaaiad. TialM Netlene) Bank Poidtaa abed ene-hetf black (tom 4m veok waa aal eeotondoetod. Ahhoagb ana ftbir|lne4fterooanafrtotokautntoB 4m toak Boor af da Flral Nadaul Saak Bonding waa found la i abaai to paa FCBo. naarby Maw d aal abow Mgb bvete.Tba buOdfag tvtcaetod when wake waa aaaa ceoUng frame window Wat bewever. 4m woke waa latar idanttflad oa 4m xkeaal fraat an aoxlHanr dlaaal rftoraterdtotatartadwbanpowar war aaaiaaavaanfnai> ____ Haanalyaaa wart rapofitd lor PCPfa arPCDOa In toe reel. A number of wipe amplaa warn aa8adad In iba Ptoat KeWcwal Bank Bafrdtot and from 4m air aaaal* MbIm naar 4M tranaforawr. bal no PCDFi or FCDOo watt found The Plrwt National Bank Mdtaf waa vaoaaMd allha Maw of 4w Hra aal teoccanMd tba foUowtog day. Cleaning tn touted la tba Mmawroa wdi, m exftmaet ayetem. end the exterior oftbe DoWy rale (2) lb< Vaa HAir mt ml. wall butidlag next lo 4m traalt A Comchaium Band cm Cb* Stvdim Beeedapon VA'e miaetton of tbo etramatoneeenmondbigtiM Binghamton, Haw York; tan FVinciato, Ctflfornte; andCMesgo. BlnaM (Im. tPA boBem 4MI flrta tovofrlnf PC8> Trafleformor present certain riakaof axpaomo effcanmno and 4m ~ anvtroMnant ta tank cantaadsanta aadi aa eukHHaad PCB and cnrttto . oxidation piodacbafFCBatocfadtog KDFi l.TMM(fcffCfraifacMbMM product*famein <wt to earlier rulamahtogt. EPA baa ahaady (1*17) ondy la omIo Snnfoo Dawlojr rad:(0)tboTalh*tW (Mn)and*M Bwloo ariet; (4) Ibo National Cnaow InoHtolo (1MO o. b) Wodtao M roti ood Bie (S) Ibo qm af at (MW pnMaAtn tody In mo; and (A) AM Kami m at (1*71) norirrMofioWllyiaidy la adco (RofJ). laoaaaaaiy. oocoldMa to Ibo Soptoaibn M CAC Hi aoaonaMat put*), mirlaopolr inoioiiibaoo boon ladacod la Mica and Mo at my low doooo of WA7CD0. M odWaon. 1A7ATCDO boo bna Mown M boo wg *QMal lira qhwiIii. TlMoo noam. MfotetHIttMjAMAm conekrfad bat. baaad ^on arattabUr hfewafav paraana anpoaad to K3a can dtwka dtawaRjadi 4wt baaad ooaoAlali 24.7>ATTCQDDhllka%Mboal oa anfrna) data, ftart la a potential for fpradmUoi aflacta and davlop--ntal MJdty aa wot aa oocoptalchy In b--xna aaaeaad to FCBa. AAkoaph 4m HNda of cktoracne era rtvarvIMa. 2PA 1R7ATCDD. M a**aon *M *A7A . TCDO la a Mata *aMA ooRbM*oa tm tfMoala A,, wbkb to oao atAm mow daaa aal aonatdM 4de affacl af aapoeara ibaewalRotA). to PCBa to be MfoMcaal pUf. S). Aom<MAAllnAitB,AA Cintimwfc AmiiimipI Ctomp'i (CAG*i) HA AaMMDMDt m WA TCDO (M. J. iMtad bjr nnh of tmkUjr tMttafhi mAMb lor * nriMy 0(rflKI*.laj-1CDOI*MO(llM MOW Hide rhlMlrih Iiiiimb.TMi aabalaaeaaraa (band to aooi aaaplaa tokm Mowtai Am DmAmitoB widAon ftoncltoo Aonrfmm Ifcoo. IPu oolooo AtV^TCOOmiohnM MkrainMO por Umo omAy far AM moIo fohMa to 9AndcroBOMo nor kAoanjo duMotiy lot tAo robUt. vrMdi woaad ctoaalfy 44i oonpoaad aa apartwde (Rat 4|. (Hm aeale af aorta toxtdty ranpaa froai practically nontoxic to aapaiioxfc;) Oeatha typloaUp occar boat ana weak or nan after ttaetewnl to dhroato and aorta era) UOICDD nriedy atodlai anaoaaral antoaal apadaa 4m HvoTi Ibjnaaai and aplaaa mvo oonototondy boon AM toitW oi|nno. Uonr danoto, Indndint nmntlc HotoaaoffCDK) lAMaMalaqot U.7ATCDD. Ilowonr. b Body dnlmod lo ooaloaOo Mo oaoMMoHio loxtahy ol ICh and *CDAa M raM. RCDFo wanbond Inbo OHM Male Man PCAoffotAMayoiApAM.AMWoolloot lUa oMy IndMaM Am *CW0yndoaad aavon laide oBacIo aa bnaaMloiieaad tbynle haaAoas. M raw M dMM comamns poownrawai dlbanaaftoann AaiHih m rydaocytt a aM---n----i-iIwIIm----- blood attean indtoatod tomato anaada. Following the Bkubaailen too, wtoil lavaarcbtra cen^leled tedcatogtoal MatfeM af tool aaaiplaa to fotoaa ptoa. Baaad on 4Mee atodtoa aatoa * BtodMmton Stoto OOktMMtof (B80M tool. VA bne condadod4mI nmltlpfc fxpwana to tool bnKb Trantfonnar Rm bava 4m patonHal la product toaldly In 4m tkyam. 4m hcmatopoMtic apatam, tba aatvarp wt*til luno boon oboorvod In mlck rota, Mend dud apitkdlal and porribly, to ind lotnoo ptgl foltowti>t 2.3,7>TCDD Hvtr {Itoi ). trootmoaL Atiopb)r ol tbo Ammo tod ft t> worth noting BmI tbyte rtMakp. ptooa boo oloo conotWonAytMon lonad bono marrow daptotton. anddbriniinad ta loboratonr ontoolt. Otbor officti ot body wolgbt mM, al oflben ol a *AfJ'TCDD Iwfiotton tndodo oubchfonlc odmalolnAoa otAm AAOA opfMvuton of reproductive fooctloo In oool hjvo bwo rooMoily donoaoWolod roto and dtotiaboacoi of Am In octIo olodloo bo yiWooo pM. ooM* bOMOtcnoloAeoirotOM ortlb occoikmol PCWo and PCDDo |Rot. fa oAAMom bmiornio^nn ta owidtoyo. rot md Am |ini* of (oMoa *% doaod wAk Mlco (Rot At Wl.l p*m BSOB oool la bo oobcfanolo Tboro on aevorelcoacor bloomy tudj oohfbuad oympMoM cbonBooMIe llode ofIA7.0-TOX3! (1) A Dow of ocolo oxpooon lo AA7A-1CD0 aad CompainroMylXocibaofof. tA7.0-TCOF wUcb tadodo lllliM 1*7A) In aMlo and {mole Sprafoa aioodo dcyofiorotloa. faltv ebomoo la HONS 01?2b3 f 1107# fdrl RtUt. / Vol. 49. No. M I Frid.y. Mich 23. 1904 / Propottd Rule. h>>loqtt md dfmtnlion of temperature. That la. tha fact that law utnMnttuI trkct tpHhoUwB (Ret.tt. PCS is praaant maana only that laaa total Out Mpar italad OwmIm oral LU M PCDF wUI ba formed alnca low Oi 1600 loot hi oOmsIm ll 410 coneantrattooia alone at* not expected to bava any affact on tha reaction rata, (Rat 4), wMek wow daaally Ihii machanlam of reaction, or product yield. oaaiOBaoO aa *ay took (Rtf. 4). Theta alao appear to ba law fedora lUtcmtioii Hformation of extortion mrwtocta from fCffl TH*r It praaant In an ancontrotted Bra aitnation which would canto dm total destruction dtrocl ovMmco of Im bnoaUoo of PCDra and PCOOi from nMtina and of PCBa and PCDFa or which woald praaant nthar noainatlm reertlona tn bonhw oowwtcM aUnlotaa of fCBa redneathayfoldafPCDF* - and dUowrto. Tha dlnd ovMonco Is hat II) Laboratory oxportmonta An uecantroDad fire of oolBdant tamparatwra (about BOO*C) to bam aobMod lo cbaadcol rad odwr motortela containing PCBa can read! in Morahno. and (1) ehaiileal analyoat of dm formation of PCDFa as lerye aa e ^ wlartala ot lha aftaa whara lhaa wan perceataga of tha Waal of PCBa haown lo hrrotv* iranafomtn that originally praaant (n tha material oonllhitd POa- PCOa. TCOFa. and Concentrations would vary with tha RCDOo awn all loaod la loan root yohrma of contained combustion gaae iRaehaaaa horn hath Iho Sbjfhuitm or eanatttoania of material rantalnlnt aad too Fraadaco lhaa. (KOTa and partlcalala combustion ootid* Although PCOOa war* not anatytad for in tha aoot nigh tamparatara Indnaratkm la aaad to lr.w lha Chkaga An.) diapoot of PCB< In rf. PCDFt and Labanlanr alodlaa provtda tha bad PCOOa have abo boon datacted avallabla hmmolloo on lha conaaralon following tha Indnaratlon of PCBa In otL af pan TCOa lo PCOfa. la than alodlaa. tatirmratioa of PCBa roqatree at 1P00*C a aanbar af dtfhvonl PCO coaahaan ; tamparatwra. a tw^eocond raatdanca aad adnlana of oonaanon bon boon time, and aufttdent oxygen Aa hoolad aad Ibo raaaMtaa awlarlala "* awplalnad above, however. laboratory nalyaad hr all FCDFa aad PCODa. experiments Indlcata that the reaction (hna a apadfla PCS compound raada lo tamparatara lor tha formation of FCDFa farm a hadlad aombar of FCDFa. lha la optimised at aroand BOOT. lonwtlaa of TCSFa Involna Commatclal mtxtaraa of PCBa hnrawalacalar aHndaailea af Ihna fragrantly contain mixtures af kinds (f dfotondc embculea. with or chlorobantaarr aa watt aa PCBa. Bven wMmwI pmm n#frn|MDMt of (UoriM "para" PCB may have tew Hew -- tha ramalirtnp phtayl ring* Ttom dm product* obtained lo thePCB concentration# of chtorobonaonaa praaant aa contmainent* Experiments reaction* dm dUtootic molecules. h)^N|N) hjf^NfMI chlwtdli Mid have ahown tha formation at PCPFa and PCODa from pyrdyata of adxtovoa of chlorine, irt formed from on* hydrnpan chlorobtmenae In air. Other chlorlnatad and/er ehforine itM la ortho poiWom oompoanda chlaropbanola on each of dm two phenyl Haft. The ware alao formed. Amoonta of PCDFt opMaM temperature ranpe Im Iho ranpad aa Mph aa tenth# of a percent for mixtoree of trichlorabanaanaa. Tatra* PWC. YhWa of PCDFa are to the and pantaddoro^banma wtixtarw _ partael reaps from 88B*C to MOT. bet drydfkU.lh.^.pmonl.lKXrC foramd amowntt of PCDFa aad PCODa which wrara two ordara of mayiltoda amallar than tha amoonta of thaoa Tha description and characterisation compoonda formed by trtchfocobensane. of Iho chamlcal reactions occurring la a PCDFa and PCCHh run alao ba formed ftrt la which arodora (or any other from the chlorinated paanola observed commercial adxtwroe #f many PCS ' In the pyrolyele of chlorinated bonaanta. compound*) art burned b far mow Tha reaction# to form PCDFa and complex then iho laboratory PCODa art btmolecular and the oxportaoali. However, lb# same axparlmantal concantratlana of reaction# obaarvad la lha laboratory chlorobanxanaa ware bidk ^ha radnead ahoeld alaa oecar In Art oHoattona concentration of cbloroibinuna aa a whan do foaetaata aad raactfon cooftamlnant In commercial earn of PCBa conditfona ar alaaflar lo laboratory would probably not load a ubetantlal reaction condtiiona. Since tha laboratory tocraaaaa In the amoonta of PCDFa and raectba id rtaolta In tha formation of PCDOa formed from bornlnp or boadnp PCDFa bom PCBa la fetramolacwler and the PCBa. The notable exceptions art an allmbmtion, tha affact of lower commercial aiatariab aalnp - conceulroHem of PCBa (aodi aa tboao prowl In minorat all transformers) chtorobanaanaa at a aolvant for coocontratad PCBo. La* aakarab- BPA obowld have a otinfme) affact on tha . baHavaa that lha PCDO lavab (bond fat reaction rata or product yield at a phren tha Btnphemton aoot aamplaa naahod from the oxidation of chiorebeasente. The low level PCDOa found fottowimp tha San Fraadaco lira eowM have bean aaaociatad with tha poeeihle praaanc* of low coocannaMona af ddarobanaenta In tha fluid, from poet aarviclnp operation* Information b not available on tha producto reaultinp from pyrolyslnp ddorobansena in commercial waaa of PCBa, ot dlflarani tamparatara* In tha ranpa axpactad to ba formad In oncontrdladbaralnf. *- With raapact to paiwibb bumtep or heattap af cennnarcial PCB mtotaraa at low concantrattona In mtairal ad. dm ttadi point and ttm paint of dm ad aripM Incraaaa Urn ebanoea of bavtnp a ttro tart and. once an dtt fire start* Mb not unexpected that inch a ttta would provide suitable raaetion condMona for produdap PCOFa and PCDOa (If chlorobanaanaa are proaantl from * commercial PCB* The Baab potato md fba points of bodiedMralott end tllicona oil coaid permit dm baatbf af diaaoNed or dbpaiead PCBa tn temperature# comparable to dm temperature# aaad In pebttahed atadfce of thaaa reaction* The* BPA export# ttmt mineral ott opalpnmnt and other hrpta af aqalpnmat cantandnolad wtth PCBa may abo poet cartafaibka in dm event of a fire from dm panpactlva af dm formation of toxic pyrdyth flaah potaN aad ttro point afatHcono etta (a potential lebatimta Bald far letrofUllnp PCB TVanafovmaaal ndpht reduce dm dmncoa of hevtap a Bm wtmv o1k> provida adtabb raadbn candMIana for prndactnp PCDFa and PCDOU (whan chlorobanaanaa art paaaanfl from coBMParcialmbrturaaef PCBa praaant in dm tranaformaia at lew aaneanboMan* EPA b aolidtlnp taformetien concarmnp me mawinmencn one quantitation of naidaai cUarinamd erooietic hydrocarbon* reaultinp from xpoaera to open flame buminp af commercial formdadono af tionafawmr fluids conteininp PCBa and afoot chlorinetad aromatic hydracaibe-- IPA la alao aoUddnp Informatian on conditions sdaally praaant In transformer locations, etinr than span flame* that can load to the farmatlan of residual chlorlnotad aronmtic hydrocarbon* BPA b aba aaBdtfnn Information an anbadteb Baida and dm chemical radduaa praaant faBaarib^i buminp of thaaa amtarbb S. PoeukticM at ritkpom *GB> Ttungformorptoo. Pram no analyab ot the three Urea b Wnphimtcn. Ban Frandaca. and CMe^* BPAhaa HQNS Fodorol IUglt / Vol. 49. No. M / Friday, March 23, 18S4 / Propottd Rule. 11*75 MaaHBad dx yayaUUom Itml nay ba at budding* that when they occur in iltk hi Bopotal ala Bn taxoMny FCB- aatdaor locations tuck aa atoctrical TvaaaCinaara. Tha lint froxp'an aabatattona. Prom this prattminary aatawia pm.nl In a boddliii or poaallriy analysis, tt atoo appears that ana or tha la aa adjaoanl haUdtnf at tha Man o a primary (actor* that enbihiti to tha Bn. Tha mind you* an Unman and te IMpCOMptnOOMl rtoka posed by An* involving' tranarormara that eoatato PCBa to nopaadB*ta tha tin. Tha third poop latldtop to tha pmanca of mtltottaa on oakokan pno.nl darloa tha ekofte or dwtwwi to tha vidnHy of a axHafalahln* of Uw Bn, .nd tha loxrth transformer that la Involved to a lira, to reap an aarioaa XivoIyW la tha daan- both Binghamton and Ban Francisco, oplobowtoy lha Bn. Tha Baal taro ventilation oaulponnt or ductwork in . boom an oorooaa rotofaln* to tho tha vicinity of the transformer* MMhi| Mowbt* daaanp, and, eigniAcantty contributed to tha |unpi lo tyilpcmt dtoperatoo of PCBa and aavtata mUmiMn. ito. that may have been oxidation products. Including PCDD and FCDP Into the budding. A aaeond factor that appaara to certain risks te parsons pneant to ar tocroaaa tha risks poaadby Area homJ baAdtogs lavohid to Ansa Ilfis* torotvtoa PCB-Tranaformara to tha DA behove* that thaaa Incidents may falter* of protective davtoaa aach aa alee peat rtoka to athar population* and drcalt bracken to Jntempt the flow of la ha aavtroamaat Specifically, electricity Into a tranafcrmar. la both dependtog upon lha location and Btnahamton and flan Ftandaco, than la mooneye! thaaa incidents, EPA bofleves Ant tha dtocharga af arwtnci that aagnti that powor . coooauoa 10 oa provinoo vo bmm ooolonlMtod wxtxr |oood to cotitaio tranafermara far aoma ttoaa altar tha Aon BnolooaMoini PCBa. KOTload hdttaf malfanction. Than to apacolatton PGODo Mo Bio xrrar oyoton cooid pop bat Ada factor oontribotad to tha torloli |M * pint oopoloMo* yoopo formation of additional toxic ayroiyata oo onB. VA lo ipocincony toBcMof prodaeta. by cnattog oxeoaa haat and dolo n tho iMnaoood lo hwxxn. and othar oondittona conductor to tha *o *wxx.nl Bon tho dlochoroo of fannatloo of thaaa oxMatton prodacta. wotor nod to eorttolo thooo fim. EPA A third factor that appaara to tocroaaa loBoHo lnlonn.ilon on othor potontlol tha riaka pcaad by flna toaototog PCB- * popoliBooi dnl noy ho ot iloh lo tho Traoafonnara if fifaman batag anawan IoWBvanI BtnolOf oTBBBnrwhwOTo.lvln* o troufonnr f /totoatfa/for mumoon to PCB$ and that thay an naponding to a An laroltog a POTranaformar. ha both Atonhamtcn and flan Praaetoco. than to ex/dteton eramicte non Ann avMtnca to aaggait that tha Unman ManNartoffar PCSh PCDPa and/or win tolttoHv napendad la tha flna arara PCDOa waa aemptotad altar tha not awan mat ICA-Tranafermara wan February Mflfll ntnghamton An. tha lnvoivad.T1ma. thaaa Anman may not May It. 1M flan Fruncleoo lira, and tha haw foBowad cartaln procaattona that flaptombarlfl. 1M Chlcyo fin.PCS aantomlnatton waa bond to all faraa ml^it ba conaMand to ba appropriate gtoan dm potential riaka paaad to tha toddanta. and PCDFt and PCODa war* count of axttamdahiag aocb a An. For tdanttflad to aoot aaamiaa from both tha axampfa. Ahnad accoonta of tho flan Btoghamtoa and tan Fnndaco Ana (aao Frandaco An tndkato that heavy bladi UaH DA far summary of sampling amok* pound ool of tha andargroond fall). . atdewalk vault hooalng tha PCS* templing data aceamalatad following - Tranafermara. Thaaa aama fUmad lha Ataghanrien An dearly todtcotos Am aocoonta Indicate that napltatery patontia) far expeeen lo PCBa, PCDPa. protection waa net aaad by flraman end PCDOa by Bremen, budding praaant above tha tronafarmar vaak occupants. and others In lha victohy of a during their rotponoo to Am lln. Forthor. PCB*Transformer An. Sampling from tha 1 thooaTilmod oocoonta oko todtooto tho Ban Frandaco fin alaa supports a. pnttneo of aovonl aimifaHy dolermtaetion that POTtonaforwer unprotected dvAUn onloohora In the Araa poaa cartaln riaka of exposure to one durtoa tho oxtlngulahlna of the Bn. PCS* PCDPa. and PCDOa. A nltiM factor that amy bo nlovont KPA aalicHa addfttonal data on PCS. to tho degree of rtah ooaod by flno PCOP. and PCDD level* maaaand Involvfng PCB-TrandbnMfi to Ate typo foflowtog PCB-Transformer Ana. . of building to which tho toenefarmar to I. Actors thot appear to incnam faceted. EPA bellevca that PCA- rkit pared frypm. From EPA'a Tnnaformor Ana to offica buAdlnga and prtflmtoary analysts, II appaara that ahopphm malla may poaa gnator riaka to rCfaTranmormar Araa may poaa Mgk tha pebUc. bacauaa of tha concantratlon risks whao lhay occur naar or inaida of poopla normally praaant fa thaaa typo* of budding*. Firm tovoMng PCA* Tranaformor* at toduotriol facUitiaa may poaa iooMr riaka. boenuao fawor povaooa an gananlly praaant and EPA expacta that tkoao transformers an alien to piacoa that an more open, when any malfancAona weald ba npldfa fafantiffad. EPA aoBdta ramaaaf an dm nlattvf rtoka paaad by tnaafarman faceted to offica hwlliflnga. akapptog malla. hotab and moleleuereee twmfonnan located to todoatrial fadlititf or alaatoteal aobHaHaai Finally. EPA baUovoa Amt Amn la one Ant factor Am! may tocnaee Am riaka poted by PCD^Tranaformar Ana. Thto factor la Am lack of knowledge oa Am port of many persons. Incfedmg Ariwn and poteons occupying these bulldtags obootlho potaaUol ihb yoonl lo Iho QTOnl of > fir, hwohih^ fcowfonmn that eontola FCBo. hi BhakoMao. Boo haadoco, oad CUoaao. KMo Mneloial domofa occanod lo Bio hoBMoio aa a novh of thooo Bno. For Bo Boot port.' dowoio woo BdBj h Boh foio*. In Ihooo eaooo, a coaodooo Bctdow woo ado by ooBortHoa ol Bo ocona la anolyio hr Bo ynoonoo of FCBo ad cortoh) oddaUoo yradKW hdon oBowfan n ooooyoncy. WIB.ol Bio dodolon on Iho part d ooBorlllo. praMnt ot B. OCMH of oBw ilwllir Bno, H lo pooalMa that Booo oBor Port of Bo. .far Bio laaoral loch af knowhdno ahod tho rtoho poood to the evemntl ot f fO-Tnntnno Bit. Boy be tha lack of e coordinated eEart to when Amy occur. Currently. Aten to no EPA requirement that Ana touhtei PCB-Tr*n*formara bo reported to Am Agency. EPA aofldta canunaato on the betmflUof meiatatalnganEPAPCD* ' TruaformorFlnlUpAng|irteaiMM^ for infonntog paepfa of Am heaarde posed by dmaa toddanta. EPA plao aottdta tofarmatton flam knowledgeable parties on Hs analytes af what factors toertasa Am riaka paaad by Ana tovoMng PCBTraaafarmen aa well aa comments oa oAmr facton praaont during Am Btaghaatesn. flan Frandaco. and Cblcagn flna |or oAmr Ana) Amt aaay have tocreased Am rtoka posed by tbeaa Ana. 0. Factor* <Aal appear la kava thcno--dthtrkktmmdkyprm. EPA bollovoo Amt oAmr baton may antol that in contrast to tha facton Itotod above, limit dm riaka posed by PCDTranalbrmar Ana. That to. aMmagh (tea Binghamton and Ban Prandacn Arab an HONS 017245 tin Federal Register / Vol. 49. No. M / Friday, March 23. IBM / Propoeed Rule* co--Ifsrsd to pooo certain ricki, botfi of m. ProbohiBty of Fbee Occmftog these sites are office bufldtags, 13 ere IIwn Incidents M the potential to pooo lSb-mock greater risks. For example, one factor fast tatted the rlofce associated * with the fires to Binghamton tad Son A. 71* Numb*andlocation of Tmnofomott Containing PCBi Fraadeeo mi too tooo of too flrts, Both flroo attuned during periods when these buddfags were, for toe most peri, unoccupied. to contrast, the CtUcefo lire to September Ittt occurred to the Pint National Beak Bntidteg daring s period of htoh occupancy. However, to this Incident. power to the transformer wes V Data contalood m tbo Auguct 2S. IMS mtomabmg record, nratnm n KMd txtnuhrriy by dacMc MiUHn ad odwt IndtuHn to naaarit and dMritwttriMlric power ffidratly. Bom. tniufonmn dMtyntd ior um with PCBimlata btwan do and 70 tatcant Kk aMaia, daatvwd to eet oiler oboet ten mtoetw. In contain oilaaral all dlalacMc Bald an Btaghimion end Sen Francisco, the contamloalad with FOB. bum paat transformers vemstoed energtaod far 10 Mrvtdof aod manafactarinf activitlM. mtoetse end torse hoars, respectively. An aitlnata of tha otaobar of utility RPA Is sotictlne information on other factors thet may hove mitipsted the vishs posed by liras tovolvtot PCBTransformers. C Chon-tfp Grata Following PCB ownad PCB-Tranlfanain waa pf.vloualy provldad to ERA irla ao Ediaoa Electric batituta and UtUMee od SoHd Waata Advtwoy Crap (ESI/ USWAGI aarvay of tka amity tndaaby. Tima dau wan pmaotad io labeler Tttmfonmr faw Iona Io dw ftopeead KB Bktlul Uaa Clvsn toe well-established toxidty of PCB* end the presence of materials toot ere non brake thee PCBs to the soot' * from e lire tovolvtot > KSTtaufareeii owners of fCSHmifeiMfi Involved to PCB-Traasfatmw Bras hove tovestad ep to MO edUton etch to ensere toe sefaty Ruia. paWrirndla tha Man! RegMer of April tt 1SBZ M7 ni ITOB). bt tha AaceettS.Mtt,PCBEIeclricBlUee ' Rala, EPAaaadtfcaaa data, bt combination with axiatinf data troia an atUar ntlatoaklof to oattaaato tha total aambat af FCkTmoafanoan bt aaivlea aod to Mtimala tba diatribaMoa af thm nf poteens retarntot to occupy those hulltap For s faH oneiysie of traoaforawra amcag utility and nao- otiUtv owners. eweseios tehee es pert of the deen-ep In the August IS. 1082 PCB Electrical of the Btaghsmtun Bra, too The Uss Role. EPA sstaneted toot toe utility Btophemfan Stole Offtoe Budding Clean industry owned epprmdmotoly 9R0OD to- up: e Pioprses Report Update. lUT oervice PCB-Traaatonwii. SPA (Ret T\ end "hveetigetion of the CentsmtoeHen Remetoh^ to toe Binghamton Stele Office BnUdtoc Fbttowtag Completion of Pratataary Cleon up. October HIT (Ref. Theee costa, far the dean-up end removal of contaminated materials eontatotof PCBs. PCDFs. end PCDDe found after these toddents eon he factored Into the economic analysts of the benefits of the contained ate of PCBTrsnefarmers. Earlier analyses of the estimated that Ittif of theee transformers ere iocetad to non- subetation locations, such ns to end sround buildings end industrial faculties. The NJOO transformers represent about ooe-thirdofellPGBItenefonaere ta service. VA estimated thet about 9QA00 PCB-Transformsrs ore non-eHUty owned transformers. RPA also estimated tost there ere over ID rnliDm mineral oil transformers to ths electrical utility industry end ebon! five million in sO other applications. These shopping malls. 5 are Industrial facilities, end 5 are hotels or metsli. Over BO percent of the PCB- Transformen hated to tide tatted eurvey ere owned by ettfMte (Ret fa. EPA behevoe that the setlmsHs of the number of ta-eervtee PCB-Ttonefonnere used In toe August 25.1BI2 rule era etiB valid today. Itowsvan in order to value!* folly foe hazards peeed by Brae involving transformers containing PCBs, EPA needs move detailed tafaemnltan on PCB-Transformers. The dnta needed include dele on: (1) The types.of buildtags to width PO-Transfonesrs rawed. (2) toe number of PC*Transformers wed to each hufltag, (3) the ages of the tienetormsn. H) toe sgw of the buUdtags.fi) the location ef toe PCB-Traneformers serving the beddtogs. end (6) toe ownership oftaPCBTransformera. EPA seftrim tofatmntien horn other buOdtog ewwra slmBer ta that provided by Equitable Ufa EPA eleo eoBcfta tafarmetien an dta costs of requiring PCB ft --farmer owners to report ta EPA dm numhmend location* of PO-Ti--tonwii. B faro/b From m fenj ofEPA iUgfone/ Office* lnOctobw IMS, EPA candcrieda telspbem survey of its ragtannl effiew acroes the United ttatae to w etwwpt to obtain additional tafetmetten an the frequency of Use related event* Involving tranefan ` `` PCBa (Ret M). f eurvey. EPA teemed that ta toe parted from February 1991 through fiepismber 1903, there were at leeet 19 foe-rotated involving tra containeid PCBs (fdoie h Binghamton lira, dta Son Franriece Brm and the Chicago flreh EPA ww the term Hra raletad Incident or evmlM bscowe ta many cases it is not deer whether so eetaal benefits of ths conttoeed ese of thsee transformers, completed In rapport of mineral oil transformers may contain relatively lew level PCBs (Iras then MO fir* occurred fa the vtctotty of the transformer. However, tome apneas* to the Aepest SR IMS PCB BlocMcal Use ppm PCBs) as a result of contamination bo a full spectrum ofBra-rotated ownta Rule, did not take into cenelderatloa the from pest servicing activities. thet can occur to the vktattv el a costa of deen-ep to ths event of e PCB- 2. New information on PCB- transfonoer. EPA believes tost mtoer Transfarmer firm Trontformm. In fate September 1901, a arcing with no eppersnl vofottitoeMan of In Unit V of tide Notice. SPA hee presented yroBmlniry wtlmetw of the eosta of ctaarnrp to combinstioo with estimetas of the probability of such an occurrence. end preliminary estimates of ths coats of various control moooureo dsslpaed to mitigate or sUminote toe rtahs posed by PCB-Transformer (tree. major building owner to the United States, the Equitable Ufa Assurance Society of the United States (Equitable Ufa Assurance), approached EPA with Information on PCB-Transformon present In Its butidtags. The savvey conducted by Equitable Ufa Assurance Indicates that of the ever 500 buildings owned by this corporate building owner, PCBs or formation ofoxidation pradeeto is at one end of the spectrum end a Binghamton-ttht event Is at the other end of the spectrum, ft is not deer whether conditions short of a Binghamton or Sen Frandoce ittuotisn can eleo lead to ths voletfosallen of PCBs and ths formation ead/er distribution of toxic oxidettoe prodjeete pproxfmately M sitee ere serviced by of PCBs. EPA solicits dote on whet ether about 277 PCB-Transformer*. Fifteen of * fire-rstaled cendttiew. short of toe MONS 017246 Fadetal Raylett* / Vol *, No. M / Friday. Mirth 23. 19M / Propoaed Rule* 11*77 _. . l darln* Dm Ilk* at)malar M toe-related taddanta per btohaailea er San Fnadece, can alao bad to the velaHkxiUce el TO* and 1.000 PCB-Tranafatmaia pat year and 0 0 Rra-ratalad tocMaato toaolto( FCB- dwfaramtlenaaddltttlbellonofPCPrt. Ttaitofnraiara par toe department par FCDDe. led other toxic anidatioa year. If an* aaaamea that that* at* 100400 Arcrrjto* to dm nauM* of thie FCB-Ttanafetnwta to aetvto* (aa tabphaaa lereay toare wet* two Rre- atimatad by EFA to the Aufeat 2S. 1102 *` to mien I (both In PCI Electrical Uae Rato), then, e-l flra- related loddaota par yaet pet 1.000 teftoalaa I (to NowJafaay, Albany, ttaaafbnaat* would yield an eethnate of Now Taak. and Bhuhtmlnn New Yotk|, between 030 and HOflra-retatod two beedanta to Krplon FV [Hi toddanta naryaar. Van* aaaamaa that Cbarwetoraed Mead. Florida), me hriMriri to Ratoa V (to Chicapo. afl aea eahatatlen FCB-Traaefotaiata (110.40*) era located to or around toetoh *** toddat to lto|lea VI (la ballihapa toan. M toe-tdatod toddanta Ohm* CtototL Teuul. on* torideat to pat year pat MQOatin adbatadon Raaiaa VI (to Kaaaao CHy. Kaaaaa). two tranefonaarr would ytatd an eatbnata of tdhto to laaloa VB (to Danaer. between Ml and OMPd-Tranafarmor Calltidal. tad (oar bcktouti to Ration BCIto Ceitonda) (Ret. 10). ba-talatod toddantapar year to, Tbm. to a two yaer period. without Venae a that hat* la an aay laaanl IFA toachaalaa that averape of le majettoe department piMkW As wptrtM of (hw IwoKIm baaahaaon aaatotohm FOa. fifleaa lariadlcltona pat Itata. and * total of el leaat IM (vtodldlona to dw Udted kaUaato waaa rapartod to IFA ntoonal eBtoee. Pttodad tofaimtHn anaflof dtoae toaldaato la ael noddy aaaUaU*.. v dapettmanl ylalda aneathaato of to toaav ana* amarierlaf toe die between HQ and 1,MO toe minted ytaaaaaaaad dhblbalicQ otFCto and ' FCV-IVanafeimar torldanta pat yaat. Htobrie peasant* ^leee eat eeeet te to additlan. bom data oaUactad to MW# PMB wdwMMk Finland an FCB-Ttanafatnar Brea, the The eaaaaa af theae 11 flra-raiatad Dtracter Canatnl af dm Ftodah katitnta bddeata ate aheael ahmyt kaown. of Occnp*Hanoi Health (FlOlf) ateato toaatleaed be eaney oattomtad Bmt than toey he a* many oa k toey toriadad- (1) l.M( each toddanta to'lh* United State* to baa-beta. (I) awttdtoMr . atomdeae, (a) alacltioal ahotto er H--a aWA. VIMWM--I-t--S----M-J |WjkJa a -A each year. Ilda I* hated aa the aaaneipHon that the Itoananry af Bnrtlalad eaanta to th* United Main aaltoa* aabia handaa. Oae of too ante would be the tame aa that to Finland. ImMhIimicHM by tt of EPAhn contacted dto Mactor General dtoN|taa*w**a*a**to which tehee yaaeeat to the vielnlty af a eaaofonnf of F10H to obtain additional data on tha boriaef hteeettomle*. aaephl toe a* e tank ot (parka freaa aa Information caamdid hen tha aratop toaaahnaar. The (It* Madt baaaa National Fin tactdant Raporttn* Syatani to dto Nhaahaaaatb Ik* traadettoar. (NFBS). a eaamntariiad data Han and. R oooeluoRy aaoaad the taytuta of manned by the Natlanal Fh* AdmlnlanaWen. todtcaln that lhara IFA aaidto addWead data baai riadpaahbparttoaendw year 100P. Theta dot* an nob hoamaer, aaneaadtaa the Bam da daacrihaS abaaaiKPA pacific l* FCB-Ttanafonaai*. EFA la to tM ptocm ! ttcttt to tMf dote booo fori *` tho poreonteto toaidaaH that IFA aiay not be aarara el eapaataBy tohnaadaa aa tha eaaaaa d JICOO O^d CiO b^forntollon Oj^d ^MbaNnWiiHiMaliaiMi. Involved PCB-1 A Rang* afKttfmatm ofth Fngowey ofPCB-TromformorFtno &OkatXfai*taaefHil>*aaaacy CPA boo dovlopod a ronfla of . prtUminoiy Mtlmotea on tho frtqooacy of Ikoroloted toridoate tnvoKing PCS taytaaaatodaaa aad tepiaaaalattaaa at Tronoformoro- tbo lowool oaHmato It A* Caaatd laraleae Ahalnlittatlaa (HA), laatoaal to* department*. and Ml por yoar boood on roporte to CPA. Xfm WtehMt prttontoory otUmoto. UN to NbRaad Fba Adaudatraltoa have SroMMted Inddonte por yoor. te ontvod ytatotd mm yteltadaaiy aatbaatea of itofaand .................... ol by oooumlnt Ibot nt doportmoU Ihrwqhwl tho United States mpondte totohbp FCT-Tttatfaratrt. CFAbaa on ovortfo of 3 PCB-Tronoformor flro> abtotoad the hBearitto tohaatol rotated tocSdonte oocb. por yoor. OthwprttolMTy ooHmotoo toetodc MO lwchfantopor y (mw-- 4 Brt- rrialvd InddtiMpf y--f pflJOOPCBTriiforaMn). 1.130 taridwf par jmr (muidm probability of ftrt In tb United Stetet te mho! to tbo probobfllty of a tin fat PbUaad). and \M toddMrti por y--r (tnini ol tiimtewi lw> rtpwted to dto NTOtS tro PC8- Trotufonotr Atm). . CPA coHdts date on tho wMdto of dw tttanott! provktejd abovo, m wil m dote to npport othor oottMteo of tlte froqo--cy of flro^otetod toddeote PC8a wort ortonoQy oood oo fluid to otectricu bonotennort.____ bocoooo of dM flroMttetent pNpordoo> Trtdliteitotty. KSlteMimm wort ptecod te tecotlono wboto o--o--ofar nroooibly roHteO troptacodteororoondl wboro flro ootety te a coma Obter diolocirte flnidOa oocb m tobtoto) ofli booo ooporlor oteebiool propordoo to PCBo. bot tbob flro notate ~ " oro nol ao pood oo PCBo. TboOxOiy coMldontiooofpboteM ' oat PCB-Tranaformara maul be* . acconpaatad by aa aaalyaia af dto fbn- raotalant nropariln and patantlaf toxicity of canabnaltan peaducta af iubatltala Baida, to arldttten PA meal oTuOtow dm oooqoocy oi m omskh proportteo of tbooo cobctttotec A Sobotfarto TYoimAwow - In Ho Aofoot ltM PCiBocbteal Itao Cote. CPA conchidtd tbto ado ubotltoteo otdol for PCM In h bonoformor locotteno. Tbo MmHm onite ooMDorteo vraflobte teterowflan on tho flro ootety ond oteebteai ofteMp of MboHtvta bonofonnoro. onddteeooooo ovolteblo toformotioo on Ibo tonteby of rabotitoto dtelocbte lloidt toe ` ` Tbort ore tta prworol typooof obotftotoo for F8o in bonofinoton SiHeonoo. blfH-tiiyuten hydrocorbono (HTH), cMorbtotod hydrocorbono. non-PCI ooliowte. floorocorbono. ond Inorol oft. Tbo foflowlnt oinntrteoo doto molbbb to CPA on tho flro oofote. toxteby In Uto tvont of o flro, ond ofocbteol tMcncy of oocb typo of oobobtoto Stod. Then nro oovtral phyolcol/cbowteol proportteo of oobobtoto dtetectrlc Mb tbot oro oood oo o |Mo In doteimininp flro oofoty. Tbooo proportteo oro tbo HONS 017247 1H7I Federal Reflate, / Vol. 48. No. 58 j Friday. March 23. Igg4 / PropoeadRules MMUon laapmtan. tka flask paint, ad <M Bra point. Tka minimtan Ifpowtaw al wkfck a fast karate Into Daawa whan dm atlnHitaa la thermal ta rafartad to aa tha aaMpiltlon tawparataia. Tha tampaiatma at which Iral lamaa appaat Ima a ha radical oarsa aaah aa an arc. spark. at Hama la lalarrid ta aa Ika llaak paint. Tha Bra petali la a allfhtty Mfhar taniparatara at which flaaaa era aaatalnad. Carnally, dm Nktlanal Bactrical Coda require. a adaknam Hn point of !00*C lor anvsuhad electrical tranatoman. Tka praparty of kavtof a lira paint kMar Uun MFC allow. clM.lfic.tloa at Baida lots fiaianabla tranafortaer Mda~ ky Factory Mutaal Raaaarck CorporattonlFMRCV Dartn| tha part fear yaara, FMRC. with Ika aoalatanea al Indarky and aoveRuaaal. kaa daaalopad a pMaaonky lor kuard radoctton. parfarmaa eaperimaiital and tfcaanHcal _______`_k__a_n1dkaaaa lloaaanaead taat raquanoa tar raaapalllea eF laaa flammabla Thaflrstieqeiraaiantof theFMRCia Biat dm fluid have a fin point of at boat MfC-Thta rapaaatara la arifidartp kl|fc la aflord laalatanca ta anall Ipalden acarcaa. each aa matchoa. but la add law aaaa0i ta ka mat ky aevaral alaaaaa at ceaanerdal Balds. tactadtaf meant all. Tka aaal raaulnmant la tkat tka tcaaafaaiaafke located aritkln a dan tkal la a laaat bar dmaa Ika aaaa of Ika cantata aU tka Bald In tka avanl al a epH.Jfceald tka Ikdd kaaaaaa fated, and k la liaamiil tkal It wifi ka. and baaatna tally tnvolrad In flanwa. dda Inaant that tha flamaa will not apaaad sIonc dm fleer. Tha final esqatr.msnl la a a-1 knew afiawakla nta al canncttn kaat . rsieeee. In a aonflanunabla kalldkn arttk naatllaniaiabla eonlanta, Iks risk af extensive fin loaa la mainly to tha Irvchno ItaeK. II tka calHna avat Ika fin la overheated. aaBapaa al Ika root coaid occur. Heal talaaaa ntea kava keen maaearad ky FMBC lea aavatal ftotdo. 1. Silinmm. BlUccatas rafar ta a family f relatively loan liquid onaooalloxana pctvawra aaad aa alactrical Inauladaa. AWtaafik aWcona Mlad tranafoemara kava kaan aaad tinea MFa, In tka laal five years, their see kaa Incnaaad riwamaally. They aaa superior la mmaaal ad and aoo-FCB oakonla In tkarmal atakdlly and, anllka mineral ad. vHd aol daarada la lorn sludge. They alaa have fin pointa abeva ne'e Camkaellaa at elUcaaee. whathaa ky arodadoaad anplaalan or apny mlat tankleik predates flooccolent afflcaara inj glo^in tflfce* gab. Breakdown products during Arcing U the absence of oxygen art silicone dioxide. hytkogsn. im hydrocarbons. Water, carbon dbxMe. and carbon mnoxlde are abo produced In the pmince of oxygen. SUIcooa Qaida in self-extingulshW| whan burned hi a pool since a crust b formed which smothers the flames. 8tUcooe transformer Adds also have some disadvantages. They abaorb moisture from tbs ak very rapidly and extreme cere amt be taken to transfer the fluid wlthoet contact with tha atmeaphara hi order ta maintain prayer electrical properties. Product Ultra(we from one alBcooe fhdd manefectarar roughly estimate* that at 100*C sUiouos flaWa wifl dradata I ar g ttaaaa mart slowly than asharel or mlnatal oil This alowar rata of dradatton may have HnpHcatlana an tha abfltty of tha flald to dlealpots heat tampanturn ftytkvcmrbem (HTH), EPA aaaa the term HTH lo refer to mineral otts with a fire potot highar than MO* C This category af fluids Indadaa high temperature aatara that ere primarily used in raikond tansfermers. The primary advaotagsa af HIM* are high fka point low tnkMra biodagredablHty. and tha long nasaa history compered with other transfonner oils. 11m highar Bra point of HTH flidds mltfgalaa aomawhat tha flra haaard normaDy asaodatad with tha aaa of mineral aU hi Indoor locations. . HTHs are raflnad from |mraflhdntypa base ott. Breakdown products from compute combustion during awing hi the absence of sxygao ate byWogaOt carbon, and bydrocsrbaoo PrwUcts . produced in tha prasanca of oxygen mduda water, earhon dUxlda, and hydrocarbons, Data are not available on uw^-kwt^-^rak. Betar HTHs art used primerfly U ralhond transformers or wham transformers must start up under very cold conditions. Because there cost Is higher then other HTHs end they offer no real advantages U Indoor locations. It la likely that the paraffinic HIHs wifl be the materials of choice for these eats. Tba viscosity of at least soma HTHa decreases mare rapidly than othor transformer fluids under tha action of Increased temperatures associated with overioedlna. Tali property allowe greeter coning daring overload The primary disadvantage associated with the eee of HTHa ta that they have a higher Beet release rata than other. ubetilutes. Thle mean that tba HTHa wffiWn at over twice tha temperatare of silicone fluids, thus, potentinfly causing more damage in on indoor fra. Another disadvantage af HTHs m be increated viscosity compared wtth that of mineral oil* This higher HacaaMp al normal operettas bade eaaaea attahdy higher operating femairetmee andcould poesibly ahortan be ttfe ef be transfomer. 3. ChJonnomikydroauioM. Chlorinated hyihorarhana refer to a roup of chlorinated sUyhetlc hydrocarbons. The priniary chlorinaled hydrocarbon being eoostdeted Car eat as a electrical Insulating flald la parchloroatlylena, Tat primary advantage of parchloroathylena la Ms nonflammability. . Breakdown products from cenmbm combustion during mclng delude hybogea, chloride* enrbamearban monoxide, carbeo dMda. and webi. Data are not available an be predicts of incomplete nombmUan af cUerhmlad aUphattc hydwraihona ' Aton-fOnsdorwh. WanrCl AAaral la a gmtaria tans far a grow af aypthetk. fci lariilanl, ddcrhmmd aromatic hydrocarbons Insulating Bald. The prim ii | a of the aon>PCB a ` ` ` nonflammability compared ta HTHa and a fluids an kaatad dm amna aa PCS> askartls In the National BaekWd Code. As mentioned UUnttl.E2.af dda Notice, howaver. experiments have shown the formation af PCOFb and PCDPa from tha tacwnplsts pyraUNs af mixtures af chUsabaananaala afc. Amounts of PCDPsiungsd as W^loa tenths of a psrosnl fsr mixlmas af (specifically Freon ill) ere heUp loosed for uaa aa a transformer fluid. flPA la soliciting Information an flm Ika safety, electrical efficacy, and toxicity affruan fields U Are situations. a. Mftw/o/ oil MUerol ofl la a laftmd mineral IneuleHnf oil to which afdMns such as oxidation Inhibitor have bean added. It Is aaad U tha vast mofartty af outdoor transformers. I! flra safety were net a csnoidsratlaix mineral od-flfled transformers would probably ha aaad b off appttcnflana. Mineral alb coots boo than FCBa. have better heat transfer psopsrtisn, aw considerably Mflrtsr U wvijfltta and foam noncorrosive products under cendMone of eleclrlcel arcUtt The major dbadvantaga efadnaral afl b Its flammablttty due U a bw Basil point If arcing oecara. the aarnpbb combustion breohdown pradnsti osn hjijingin sultisni altmi bjibruaibiima carbon monexlde. end water. Dote ase not aveflabb on the products af HONS 01724& Mm1 klUfet / Vol. 4B. Mo. M / ftMiy. Mmh . UM / Pray--d lulu MtbHttlR |f MiMVSl oN< rfMMiklM rftuKil nAmlfe.Afehl MnMiiilaMil ImAimn. - AMMbMkVAVA^Hia, AM>CILmfcliUntMl.PA MbjM Ad iAmM hMMMi Mrf _________ ikiitlm, IpictilclBy, PA Imllcklnl fan m A* pmAiett it ! jnWWeiiam IwV^MHVI^pipVI MUdMNlirKlihtoaBiliriMi * itaiwlniiNifiHiM ttodMalti*Yfeaaa Bnldt art aBtoanaa* ' MHNHN IN Bi mi ifiMi imm Ai hIm M Ai ranhtot Hiif Al kmfcnm id A inMIi'illui M |fofd Pi kNNMI pMNNIi OBMT IlMli lOCb M MMAMI ly^iimkuA AmnmAm. hB Blnnl ML my ki MB il III ^BIMfM^nn klf Ml t Mum 1km mi iki sAam ^kiWi nW ky iti <AM imyiMi# AfAliiMi fed ffenffeA Hnw km I kfejui vfemHy Am KhMf mAmmiiMiMi . mtymkfe n i hoImA Am Ail Hm mu*.m. klwi ymmilb^mfe_h^_.kimi. Imnf.Mc^n-niii kfeiMAwiiMkiMi kAn.fki km wm feky feifel. i Awnfei nt mnAiiy An yuml mis ki k kn km wiwtlmJ k A* Dliratm Am InUny ynkbn mM ki mmi ^nnm iHnn in m MfitlUi Mi >ani nbW (iikid and Bn aaaflktom if axpanaton if iMmi Mi It Nfmnl malv than bat afPCBa. la actual practioa. tfwanb tbt eodRcbiH of mpmaidm fe areolar Oiaa (bat lor PCBa, ifctfraotar wfeldHy tldraMtrg--(witrof--)b ExpirimtwttfcnfcMUlfef PCA Haifcnwnhcilhlimiiiiiilih AlfuM B. UR KS BmM1 U lull I krifeim IA JI<wm tondindyinaalMmniiMKlli no4 fracikd It Ail IfeM. fe ifl. Mij> mm tunrfiifrr nlinfikiil PI IIII iIihiii MkiihHiAlitiMMkiad Am/pik ifAkniMAi KriLmj Cations forKB-Trvmfarwmn 1. CbaiMMfe Ifen m two filwife ilAfeR mn Ail PA j_ m-- - ccnfedm) A itaknAif Ai nM- ` ' ilMfewferKA few feswitw few MB Am lln few . . _______ .'MafAifcm Amnm.kfeAmlAMIKI IfecWoal UntahAAimMIK OJ | wr--l M KB TwwfewwfeM |miMAMM|imMilAm AHm-lbrnmiAMniA UMMMIMkMmM Am in mm MIMA WII lyl pm mM In >* cmyiMM Am mn> kimd Htnkt -'fe`totont toB`Ofc tfetoO : ympw--iyaMa<-I amI^i AmMUkrMiiAM IfeMiMMIlAl QtBiimpHhlli.rr|miiM minHIM - AkbMmAAMMmi tttttbephk hStin nit TMI pMMri Mrjrttr. ind tknt dtm*W ttdttttii aBHon'ptt InaUbnL Hmm mHwm not bclortd Mo db AtMor^t mmbI tntlydt caapbM bt tbt Atpd U, Tki Mkn An tMda in Mm ilm Am Aw (item* M feint feMpMitafn. tat All mn npMy it mil fpiAni. AcmJtayfel HTM wimfectmr. Afe yraiwfe i Ai truwfotwri feW nlnBlii i . HIH wttkoM uqr dwillny Al km ocml ImA mymfem. teim Ai kuwfarmn (fe rm kMfer. Tkm Biidi ltt2PCS Atdrica! Utt Rtlt. IfA pttttnii santa*tltdbnnitttf tbt probability of citiibitllc Matt In UdlllLCTbtatptbbtMMaaiantt from MOW pttcaib mmyotr(tbtnt lnekbabpflryttv|won^il ` par yotr (abooi UtO bd ` tpapoarV (AddKlenallablot(lbatl........ . lowar probabOWaa of ealadrapfcte M) art prataniad bi At prdMnary oaol> Trtaafonntte. ttd they ft nWh It PCB.Two if dbtt Bokhara approved by factory Matnil m "lttt Bt--bU trsntfonnar JJekla," and lha Bra point of tb third barer MO* C. At witb ifUconi. dot mot mm tfftcthrantttaodpabaplaladbrbb ANPK (Rat U\) EPA't ttrtaab af rittn wp --ab attndalad witb raiatlwpblB atonb mm dtrbtd from tttltwbt pwddti boa (be Bfaifbeialan and San f _ toddentt. Fertber, to dn innlyab preteoltd btlovr. VA aaeoaoa bn ycttwl to wlwWI to owlnttln KI (Hde ooet b nontaBy aatecbbd wMi MtcntntiiM MidtfNmm> HiwiWi ctaan-opfoBowlwf npnKBfeandbaar It b piiifth mi iMt<ilnc(li in nuf firaa la cataa wbtre bub tbaclerel ctttt in adultin ooneontrattoaa ondar 00 ppm. Hm tod variable* art tint tba mm for tiBcoot fluid*. txotpb HTH flulda faquir* imwal tittinf tnd pottibb Ittltriin Hiwwi aofdtrt tr ptrliednln. ^ Btctutt dw ptrafflik HTHt bvi ` k%h convtetjyt and rtdtont bit rtbttt ratta, tbt owntr't bwnct cnmptny danapt occert la Iba beBdbf bvebed In the lire. EPA b aelkltb* data an d catti ataodabd witb eban-ep ItBnwbp first it tranalannara that do nal contain PCBa. 2. Comporiam efrfmm p attb veroatpAdai pdonO.lbltbwin labb atat t population af StAOIt enba (EPA't atlknoto af tba aambar daon tebtUtton PCB-Trantferintrtl and an atiteataof tqeipietnlttbaf Wyeara, EPA b tobdtinf eowMnti an Em tnformatlon proddad above pertatabif to oUHtbo* axpaHanca witb rvtrofUKno, end die abibty prectlcelly to reduce KB cencenlratlant to Mew N ppm bp and cowparaa pnaaaad caob in daanup cotf avddad E pbata tat wat impbmantad ovtr a Bpaar ptriaA near 110-yaur period, and owr 0II poor period EPA dM not ctntidir haitdlalt phatt out bacteta tavarai pavtant vetreAMng, ' indicatad tbat waarftrtwbn iapaiE| wu bitoflldant to allow for tbb opdta. MOMS 0172^9 MIM.......... Fadaral Rrjtatot / VolW^Ne. W / Friday. Mirth 83, 1984 / Propoaad Baba Far a Ml dMfrtpIkm of Urn onumpdaw oad la A* fowmtap aaalpab, no lor mart dotoMod rrrlprb af phrw out coal) vorow daoa-op esato avoUad. ooa "Fiittmlaaiy budy mi CartIffcrtfownc Analyraa l AHamaMva jtegaiatien* far Indoor PCB Tmufanain, Fabnarp MM" dial. It). Trau i racjiniiiY owimwinwia or ALTtMMTwa oca WaaumnoMa pom PibtaOw or Unm-OaMD tmtim. 1 JtataqffMv. VA haa eamplatod a praWaaqr aaaMoafttaasato af MraMbtPCB-Tnatforam to tadao. FCB caacwlrcttom la balew IOO ppac 1M aalkaalaa dpi ntroDU eealarial camahamHftrpdtotMJbpat Iraaafarmar. apan tha afar of: dm MMhnmr. Tlmaa aattamtoa da tocbdt dm aaala of dlapoaal of PCS canaldaratlea of a laaa afafllebnep or daraltai aa a raaah of dm rrtrattl. Aa aattamta af dm total oaab af nqaMapdmiatrafllbpafaaFCBTriaManairi (UltoP b aanrlaa aoaMkMftMoii tiaoafermer1*) lo bdlow goo ppai b abaal >14 MUoa. IMa aaa ba eomparad la aa aadaiHa el daaa-ap aaab araMad af abaal *tJ bOtaa. Thb rltmab af data op aaala aroldad num mi ramannnMiinNn that eaalab baa Ikaa HO pm PCS* that an brobad b Bcarabtao faiddaala world aal laaaP b tha formaIba af PCDFt or FCDOa b aaflbtaal mmaWtaa b trlppn ma)ac cbaa ap tflocta. PA daaa aal haacr whathar Ihb b a raUd aaaamplba. VA b aaMaMaa data aa tha pobalbl hr tha formar af PCDPa aad PCDDa b PCf Caalambatad PA alao campbtad a praUmbacp aaalpata at lha aaab afntreAttap af PCT-Ttaaafarmara b ndaca dm . caaaaalnllia af PCBr top parent. Aa aahaab of dm total caala of taqabtap ratroMbf af al aaaaabalatba PCS- TVanafenoart loIpwcM PC0v It iboil BA hWtaa. 1PA ta aha aottdtlna data aa dm bramtba af PCDFa and PCDDa tn thh cabpprp af trrarfornwrr. For addNbaal taformrlton on tha aaala at Ibfp and Coat-glftaWvmata Anatpaaa . of AHanmHra Rapulattana for Indoor PCS Ttantfanaarr. Fabnarp taac" (Rat II). 4. finhomdbuptcUont. FoUowhm dw martormar flra ta San Frmncbco. tha owner of tha tranaformat tnvohrrd tn tha fin (Pacific Car aad Kbctrtc Company [TOP)) tnattlabd a Bn hatnd fahbd laapacUoa pravam for PCB-TVuttfonntra. TUa prepram canalatod af tnapacttng al artwork PCBTtaaafemara aa a npalar aad fkaqaant hub. aalap aaw tadmtqaaa aoch aa Infrand aaaaoto to tWtoct potonttol dafacta ("hot rpotr") b dm mnafanaaia aad alaiMaal aqatpmant b lha ana af dm maafctaaan. baddBba.br bmaawd Bn pnbedoa. PC*B batallad aacaatdarp dbaaanaal amBchn al PC^ PA baSataa that aamphdm traaaloramr Bn haaaid bapacUana af PO-Traaaformar lacattona map ba tha taltlai atop ha >ro(raai to cadaca tha Hkatthoodaf Man Una baolvtaa Ihb aqalpmaal and b mWaab ibha aaaacbbd with dmaabaa abavld lhap hbtorp. dm tacadoa af lha traaafcrmar, tha location af aaadlMlaa aaalpaaaat ductwork b dm rlcbltp af lha tnaafatamr. and dm paaaaawa of cambaadbtai b a haaafacmar wall or PA b aohctthw dab on dm affacdoanaaa aad aaab af aaba bhand aaaaan b Idaallly pabaUallp Mtp iqu^mcat. EPAb aloe aohcttbqdata aa dm affoadvaaaaa and aaab af t ttaktlw tvchftoloftMo ud InfanM1 ... Ib> --d cwteoHitiitei location*. KPA la wrfjdHng ooMomt* m tta Hat of lactora la ba oooattarati ta lira lha ability le radaea lha potential far ftraa by oomplatint Ufa kasavti Iwapactiona and biatlfvtiiif appropriate corrtcUvo Maaaaraa. EPA la aotidtinf information an athar ftetew that ifcowld ba tndudad In a PCB-Ttanafonoar flra kaaard knaoaction, and information aa dan coat* ofcoodnctiaf aock Inapactiooa. I. Fir*/mok0 C9*troJ teoAneJbaten PCtiK. In addition tecomplateq fca batard InrparWen. baa committed te taatinf off ad opening* throogb tte network vwha. PtaawnaWy. ala la being dona to radact lb* apraad af moka lo area* a^acanf to Iba trantformar location In Ibt avaol af a Arc. EPA ba* obtained a prollminaip rang* af aattaala* of Iba coat* aaaodatad with Mating off tranaformar location* to radvea tha apraad of contaminated amok*. Tit** aatiatato* ranialrom fUM b 14000 par Oaaafomar bealba (Hoi Uh teaddWeabaloabfaB bcatlaaa throath dm aaa af PA balbvaa that thy aaa ofam datacton aad adrnr aaaaan b warabf ipatam amp ha haaaBcial b atittpatbi dm ibka bom Ikaa baoMap traorfonaara. Farthar. dm aaa afa haa*AaaalUoa or amaha aaaatllaa haSBap apatam ta raatUatba dacb aaMap lha of ilak radaedaa a___________ "PrtUntoarp Stwfp aad CamHhrtfomwaa Aaalyaaa af AhmnaOi a apalatbaa hr hadaar PCS Traoafaramra. Fabamy IfBat 1U PA b aoMtilbsbmtmidaa an avalbbb cmaha aad >11 aortal bdambbaa. Mr aaaBaatba b PCS- thaArahdMp t--Ap--at.t.p afP-C|inS-Tb|a,,info|r-m- w/lw tha haamBb afbalbtlbf a PCb tha EPA EPA brllcfaa toot ipadflcaEp rtqulrii^ dm raperting rf tkaaa Inctdcnte woold locraaao the ganoral level if knowladft abaal bear tbaae teddanm eocw. the drcamotencaa anmandteg tbaaa tnddante and,tea aatera and tonal af rlaka poaad bp timet toddmtin Wfh la aotidUng caamaant aaaodatad with nipditeg each martin* and the benefit* tepaUtebeafcfe mam auch a ajratam. EPA aofidte aammante on the mechanic* afeach a qwtoat tedndtaaeoMMtttaoneanalriaMtiann auch ir (l| Who weald ba mapenaMa for reporting tha ftra W whan tim report meat ba filed, aad (I] what tepoaaf information moat be rapericg 7. fiagiafirolion cf with fin dbpoftewwte PC4X. tea telephone convtraation with EPA. Indlcatad that It ronttealy tafenna fin department* of the locfttiaaafPCfi' Ttenafonnaia te tba nttifip gpaim Repraatntetfvaa of lha teternafiaMl Firefighter* Aeaodatiaa and repreMntattraa of fire dapartemnte I informally Indteatod te EPA teat dm to * thi* practice teetitnted nationwide. EPA batiavaa tikat tha riaha poaad to fireman and hpotandava daring PCB-Tranaformar ftraa canid ha Ifnifkantly wdswd If tiw hWal raapoMa team la aware that tim ten InvolvM a PCfiTV*ajfotm*. and tent there art certain rlaka Mtadated wMh xtingulthteg each a fire. HONS 017250 / m w im aa f moy. mana so. PA k laMaM-- DMM M * - iMUlIt IntpnMklnlK t|MlnMfeiktidMk|4li 'tadepartBMpSadkSaMT ** AttHnlMAmlMiOMMM VWhuMVliMatOMKS- L KM: FGUWac Addi4 to TepUca IH--wa-Hurf--an lathataa fkaaekca m aa a petaalty fcaata by OaaaBber el --7. Am--m n PCM. maiMaMn k null Iceattaae nkWnikiiihikn Mk MM* aad KtlkafenmklikNn ' M*# aee be aapiaaed by taaa I*. IMmmahhiPCklMMiMn M to W PHWlW H kM DHMI |Ml la Me Meeka. PCal la aoevUtlai tttltag |p| WlhdMIMlMR lMAiiklCM>M> Affarida fraer Miff fit Plarida hwkllKII faMaaay (PPIQkae Wm h--M M npMat Hi--PC* , l|lMkM<MNku plilkikiiiklliiihMritw- EalaCeadM ytierity ayrtM feclka" miilih n kpa. bi. pa la nmim< li tfcitMng Mi ^fiifhdlDiMiiMi UMMMtaAmrikiktklkr din k--H>--I kualiim Hm SSiKtfTrLMMM. if dtvohpto^^FoptiM toff tot ttdiffljf WsILWf^W--^WAPWa>j LRRBs|w^Ha |--L--t. nH--MIW--fmj WmvW ImifftoffMff nvto h WMh^itoff W WH it Miki4 fftot ImvIm ffchtdoitd. PA hf -- tor&ff toA-- RCi MdM it on Hi priority iyHi tor to* ftaitvtl if iklff ntopoMiL VA Iff fftfitMtg iddMffOlt toftmOfllMa PA k Mkrilhn kknmlw bale ImiiliiiMikakmmKA knUMMl--nkibiikb Mtkh^ flw totMiM it photo ( toit1 TSkIMihi 1. Mwwtffr. hewibm, turfwmntmnhip of /Cto7>ntonptri. KPA It ttlleHInf tofarwHit m tot typtff ol btldiftgff to (ktalKM each befldt*. Ike apairftfceMi Ihi ifi of Ike IranefotMra*--k dliK>1lMhMMantM MM--MMktMHdMjb MhmiIIm m * faoaSeaafKS IMknn MiMi b dbecdy aanMap h iAMMMMMdMa^ chMakMMbV--BA ptfttaty earned laKakaadraT* oxJdatfea predacta h Dm mu f fee. nlllklmkilAiiMkbiMilki PMiUliaM in wMHlftrmmA mkblimpndmctt. IPAic aakrttkil tafonMOan b Iki pa----IM if *i*ia --MMaL 1FA la aakattka kdonaatiaaaa Ika lala ataMttfckua MMMRI IN OHClOTtn IB O-- dlapenleeafPCBeaadeaddaliee amkctaftaaKPImalHaNi braked la Oiae. 4. Xapeaaairtatfaaaaae ofMJaghcmtan miSen Fntcbao date IPA la aoUdUna eaaaaaati aa lt aaalyaie ad tta Bb--aialaa aad BaaIkaadMa 1 Bra >aa tkapanpectWi at aaahalkn Ika aataaa at Ike me peaad wkau a PO-TYaaafnaiwaa Waaahad la a Bia- ralalad hteMaart. . %.lnfeanatim on OttrUupettibf tiwflrt l* Chicago. IPA la atHteflfaa ad--aaal data aa *e caaaMafnd cbaaaalaaeMaaataaBdkna laalaadiaal-- CMcaaafia.araaallaa kiloaaiaalea aa lha rtafa yoaad frtaa Ikta tocldnfta ttotoiwtonii>tof/fci nfetod jncAfcnte invoMmPCB'f>*imfmntn. KPA It tottcM^M m ttotr PC* Prtocteco. tod GtoctfOk EPA It ttficKtaf dtte on tot toot, dtte. tod toctfito tf tot Inddrnt tot ettfft of tot hddtd tot txteat tnd tvtnnt of IrtM tot loctfion ofttoHItWon ndptwt nUttvi to tot toerton tf tot Art; tot lypt oftquipntnt involvtd to to Inddtofc tot tft of tot #<tu*pnint; tot typo of bvtofinc to wWdi Hit toddtot occtrrtd: tot mmbtr of ptoplt pfftttM to totbufitonftl tot ttoteoftot incktenb tot Him ttepotd bttwttn I iht ftrt Mptrtatnt: tot toM ttqtlitd to dt-tntr^t Hm toMfaur, tot ffffctivtmffa of tot drcttll bftffktr tt t protection dtvlct to tot lnddwts tot potential tor 0-- torwtlon ofwWiffw prodoctff tod) tt PCDF tod PCOOt Uvl of PCBff. PCOFff, PCDOffa nad . Mia urfy^tNtoyifftoto ff IfnMto| ^oK^n^dnp tho fire tot atm afaaqv daaiaap ---aJo.e.InaJ-u--e--a---aoa^aa -ibu *ukiu*hu-* aA MMaanaaAaBaaMaa ktddeai 7. Foclort that atoy incraam/di * rightpoaad by OCM-7 tht mol ofa fir* mhtwd tar>dka< PA la aoUdffiia tnloaa*akM aa ladaaa. aack m Ika lalhaa alaralaallaa dwlaaa* aka heaflaa el iMWallaa aa--aaaak daa brpa al buDd-- M aahlak a ka eaaaai ale. Ihal any lacaaaM Dm alaka paaad la kuaww aaddia aaakaaaaaal feaai Bna laaala-- PCT-lkaaafcaaiaia. ka addMaa*BPAIaaeMllaf i * on ladera Ikala ' a Exp __ rmpm.WKk riaka dial ia laaall ki otiMmlntffffQ tt fiftta ^ wffttr mjt vtffito tmm tot tppKeallt* tl peaalhlyadMra `' ntMi okaaoapa flra Ooalaadaalad a . aaarar ayaleaH (ball aaaAaay aad alaaai aaa ayalaau) aad ay aaa ag dkaadj lo avko water. CoakaakaabM af aawaaa. IraalaMat aaka aka^paa aad aurfaea aralaraavraealL "- inlonoatloo aad data aa d at PCBa and otbar tenia a thraaik aadi taataa* htdadtapMaa of dlatHkatioa and eai *" actual er aalldpatad a Wacla In watar. aladM* ayetenH and btota; adi nd aandaalat dak la drialdai walar ar--aaHaaa( tnilMmMiltd Ittto fftok It vtotff EPAItffoHcMMtta toilMliipmtfft.i>tdtptvHMNto tHHUtt. tnd ttotff ptrtttt to tot tcctricy of EPA*t nttttwIdttttoMtot of Iht frtqntngr tf fint^ttod toddMlt Involving PCtomnffiMnitfftaIPA It ttoo lnttrtfftedtodttetndwtot^ttncytf toft Hm vffttt tot uttftot trtnfffoi ` `` C FonnoUon cfMtwtfion PtotoffM l TtoiMctoffpffdKPAtef foihwfng KB-TmmtfbramtJkm. IPAto ffolldtlnt tefomtHtn on tot toptt Md Itvtlff ofoxMtHon/piittytof Incomplvte comboMltn pffodneto toll trt foand fdlowtog fin ntotol tecldtnte Involving PCBTiwfni--. HONS 017251 1MM Podocml Badatec / Vol . No, M / Friday. March a IBM / Propoaad lulat t lit roecl/taa and mtchanimt of rooctiont invotvad fa tAo formation of raacttanprodacta. VA toMVdUni Information on tha raacdaaa nd awckanltaw d inlw Inaelted la the formtdta d atddallaa/pyrolyala/ Itciiaaltlt combuttlon predaclt h PCS-Tran.format (lm. I. Thapetotulalfor tha formation of nwclioa product* following firm kmtringPCB-CotUomlnoUd Tromformtrt. KFA la aobcltbM data on tha totanttalfortht tarnation ot toxic raactloafiodvdi from lint tarohdnf PCACoatiWlntltd Tranafomtra. D. Coda mi Noiur* ofCotta Auodotod WMOwm-Up PAIaaoUcMailafotaMtloaootha aaata hearted by owner. ( PCB- Dwtawn knolead Is Iro^alatad kaddeata. Tfceoa caota hehadt dw tnlt d tnalytit dw totit of dttn-tp and MtwdaMnMid wuriali, dM M d lawoalta Iliad tap daataiad parthe. tad dM ceele d repiectnd dM dfiptd mt aad/or traadoraMt(e) Mberia(lfcatMidant.lPAkialee aelcMai dale M Hm tin d Ifct area nltftd. dM It it!11--tlidag iflw * diflMpiiidiltlifnpliMMjf IrfwiiiiwwWwdiMHyiWMy wm ipint iM why oto-- ip iW MNMri Of BMMOy md. .. C Cot* andPtmfilt ofAfalotery 1. Panafit* ofPCM* 1PA It toticHkM apecHle hfanaaHoa raartralad whether MnilmifliiMliirtiWvibMi redeeod attar Dm paddO yean dw to PCI eeafe, whether lkioaoao hat Made iMIcimI tapoel (mdiMkWlki whether tart ooagt hat roodted fa any OMCWIiMv OOVtog of homos Mfc. Ifthtf/fWa trmformon. IPA k aolWthdlnlotinolloaoa the lankily d aahatltahdlolectrkReldt totheenaat dlkt I. AttroflBing SPA It aoldthf htdnaalloa oa dM Bn aalhty. tbeMed efficacy tad loxicky (la Dm mat d t (Irt-rtltladlBcldtal)dPOTrttifonatn dial kata btta rebelled with aonPCB Hatd. IPA It alee tohctthu ottaptnu oa tka PIPCa Environmental he. atady d toktdhle tratufoneera and dielectric Ihride. 4. Mbnfifftoghlgh ri*k tronrformon. MPA It aoUdUnf Information oa what conatltvtea a Mjh ritk PCB-Trenefonaar baa Im aerapacdte of hatarda yoaad la Dm tvaal d a Irt-rtlaltd laddont. aad baartanaer. IPA la eaUeltttti khaMtaa aalka eeete oaeaolalod with tnaynHag al PCB-Trtntforwtt laaadaaa to determine wWch PCB- TltatfotMtii would peat higher ritha In tka event d PCB-Trantfnara that Bay ba canridand la ke h%h rich bandsman. ' 1. PCt-7>wiwf<rmm phuo* out coot*. IPA la aokddai hlometloa aa dM eoalt to Inaaftmar awaatt d laqnlfkii tha phtto eat of ell PO-Ttaetfemtara over a-. 10-, or lt-yeer periods. IPA la alto talakkn tiemonls aa tka Potman Have, end Bartlett Ptedminafy Study and Coet-lffarttvanaet Analyses d - Allomatlvo Btmtlalloae far Indoor PCB- TnailnrMtit (Rat II). A Miooo out eoit* ofUgh rki PCMTronoforwmo. IPA la eolklttng ewaart d raqalrtaa tka thaaooat d PCB-TYtndorMtTt that nl within the k^hriaktatadoriaattaa.' T. Fir* hanard taaparti'nn program*. MPA la toddtiag htotaittloa oa what lactoft thonld aa hriadtd h a PCB- Traatfnnatr Ira kaaatd laapactloo. and an tka tfFacUrtnaaa d hMywctioBo and tabaaqaaat eanacdaa aMaaarat h iadada| the prabakllMp d haa aad add(atlii( tka riakt peaad when Bna do accar. IPA fa tlto tolkltlna hfennatlon on tka coata attodattd wttt caapladnf tfcaaa kMQtttliait md Ika caatt MWCtlHj wrtl WtFWOTf NMm taJI---^- H^MIi . A AvaOabJbtyandofinctlvOBMi of party datactioadavtcaa andunoka controltachnalepiaa. MPA la aalalthf hdonwllea aa d dhcdveaaae d auly dataedaa dtaleaa h radadai Ika rlaka ralalad taddaeta. IPA la aba toUelthM IdowMtltn aa tha ardhkaty dtanJia central lecknelodlee ta radaca Ika tptaad d Ika toatandnated tawka beat flraa InaaMai PCB TTanafaiaart. IPA la telcllkn data an ha affteMraatia d tfMM itckMloflM hi Iht rtirt W mi TnMfoem9rfiT9nfpcrtiii$nt9m. BPA to toHdttoa InfonMtloa on on eecto ud btMflto offtoitftalfnf oo SPA PCto> Tronoformor fin riportiiif oyttos. 1& JUfitintim ofPCB-Tromfonnn withfin dnartmmtjuritdkUcat or N^jPAffA1iNM|ditooalto cooto tad bonoftto of mMoftaf PCB* IVanoformor Itooo with loeol Bn dtoportmonte off with ngtonol olBooo of thoBPA. 11. WHtim iftof ora ptao/Af ooff FCB* Tnmtfonmn. EPA to ooftcMaf MonBottoafrooi oH otUHloo ftMtovo auto tko dictoloa to photo ot PCStVindfoniui. BPA to toUmlid la obtalatot Infenaotlon oa tho rattoaolo for taotltvtinf ditto pboto-ol pregranw. in iota. om. mux- CaaaMattaoHtoMkUL_________ aakMlttad by da Cktakal MtadkaMwo AtaacMIon aad dM Mata OattMtl'IAapanaittl). WBUPACtirtnanU Atn ~TlM CmMipiMr AjataaotM Cfauat Htfc tMtiaai iiaaHas- ~ THrUinptiiiuiulAataaAMdUAl.T) (1.4J..Trtrtl|iii)ti nm| Ptapltati arid (Sdvaa) Um-TtatiklttadBtata > daa floor (StaMahM u mm. It) Catena tad Dm* |Mtl) Tar . NMtaoCt,hi,mMI ffl Olthi t, MtrOa. uTtoOirfa "CwfOiduTohto (IMphtoOiiil pho^odOftoMnaoliloa* Towltilo0 lad Appltodlhowooto^p, 4f ivtt - m uwa. om no.-no^imo% oi m TW 111! it1i Uh hi iinli dll! of dM IMUd SMM. UN loMiM gAtHtoMMoUMiaaion WmtfT (OmhtrlWtoh (101UWPA om MX "dll--y off HipliailPolotatCtoHoortMuPfcoir Amommbi offK*i to too AtonapitoM? TaMaMtodMIAaflMI 114] Bmk. HhmtoMI TtMlMd >VCM IdtotM mrjr- lOI|rlM a UMa---n-.Mk.--M----M----V--ta aIOyMMOb (1ft) Bottr. Htat BaMiMPioaoitoaof PotychlortMMd DtotaottoMaopCSPI froMllM tffPCIO- (MB (10) BMW. Hmm RaMt Tiwlad PotoiMuiloHid Pto--otmwm (pCDBi frtulMpywIntotfhtoiidiilftCi -- bta it Mowaaai dociMBoato whiihc forlhtor _ ooauntnU aa my odat 4 ohoold ho Indodod DoomommoH conllmit lo bt addod lo Iho tocord 00 MONS 017252 -*gU^**/ Vol- No. / Friday, Match 23. IBM / Propped Rulet IMP PWeprlata, hdadtaf hferaaHon abmritod III raapoaoa M UUi rate. . M National Hrt Incidant Reporting SjralaiB foe 10*2" (November to, 1983). . A Aaefcat JUbamUaf Rooorrib _ (3) USPA OPTS, U). Tokphone fllOSckl raiamaUai noon) foe, ^MiiImIiI *>tn|rl Mi| btaeataetaM* Piacooataa. DMrOmlloa la Ccaaaerca aad Um PrAMtioa Rale' MUhM Ik *t Man* Rotator of May n. wra lor ni tiiiaj ' Commonlcatlooe baterean Daniea Kaabaar. PA and Can Gkod. Ventura Coantp Fir* Protoctloa Dietrlct. Traaaaacy of PCS-Traaefomoi Pfot(Aufaai a. tat]). (t) USPA OPTS. ERD, Telephone 0) Official raiamakiaf record fom C--aIcaMaaa boiaaaan Danlaa Mphmrk (PCSak OlMaai aad Marking Final RofaloMaa" aftAH la tap radorafRM.toTof ntmn i7, ura (u n root. M gfctaliaMakto record fom TaVM*mtod ateW.,1. <rea,t raiMai.PAaadMasHakaaa.MMIo Cao lad Electric. "Manmtloa on PCSTlaanonaor Pka la Boa Pnaciaco* (Parotator 1. toot). - (!) United Statea Department of Many. Canter hr Pka Raaoarch. . Mamrikttoro. PtecMolao. DtoMbaUoa, aad Uaa la Ctaaed aedOaakOltad Way lliaafatlaili flawin' Paoalapaial ofHammiblllly Criteria hr Traaebrmar DMooktc PUA* (March uao). PabSebed In tee federal Regletoeef M PaeMIe Cat aad Bookie Coomoay. Oatakartt Mat (7 P* tooio). tr>*.HMTySotaydarioa. USPA RaHoa IX. -PCS Tmaafarmer Pin to San ed taaMoyle (PCS.): Haadtoo" Dana MISgj). Hocaaaina,DtoMbe rn PaeMIe Coo aad Bocklc Company. W temmarw aaardtUUeaaaPPrreeehihibWHoIonaec; Uaa tettor to Mayor Dlanao rotootoln. "Hoa BaaWaal frylaar pabltohed la < Win ll WiMiIii of Aegon . UM k Raaiaaa PCHMilkaoW Dana n UM). (wminat). M USPA OPTS. BEDl Record of A Mparl fWaninte . Stealing between PA aad Dote (I)USSPA OfH KO, Tatoeharia frtj--liiMtai biliina Dnilii MakMKlTA aai Mar CDIaaa. GSA. *sS5 'Sslfosj^r.*'`TtogatatyaadNeteroafPCa HUm.OnknTaMaa roarmeaUmiaa between Daniea Kaakaar. PA aad David ladlcalt Waiaail Pka ArbnMetratloa. "Date ki WaatfcrmtrPkee" (SeptemberSRWW). (S) CMmteaiRosatatlaa Reporter. Artfda aa PCS-Tranaformar niaa, "UA Caa Rapact 1.1U Ttaaafarmm Pkaa Sack Tear. Phmteh SateaUM ToRa NUHT (StptemMr a UM). Ik) taaam Raateaaa. Dkactor Cmtrml iattltato of OocapaMoaal ' Haaltfc. Latter to Ooa day-PA Taoldaneo of KATraaefonaer rkaa" (November >3.1101). (11) U8PA cn& RED, Racord of Maoliat between lob WaoMa ol Veraar ad Dealae Kaabaar, PA. "PCSTreneformer Fkaa beat" (aaaab of September M, MM). (12) USPA OPTS. EEXk Tahaboao CooammicaUoo between Lenketoaaba. EPA and Slava Farrow. USPA Kenton Vln. "PCteTranohrmaa Pkeoarto Rotated hddeate" (October It. MM). (Ml Mar. R A (1071). "fonaattoo of PohrAloriaoted ntaonrofaroao IPCOFa) and DMtonan y dteateo (PCOOa) (roai tha Pyroiytea ofOMon>bMaaa~ CMiaotpbt.aNtea.tlMM ^ ^ Tart Ttama. Tlartda September a Mtq. (Ill USPA Office of Water MphMaatmtd Steadatda CHteria mid Steadmde DhMaa. "Ambteal Water QtwIMy CHterto tar SAT* Ttkarbnlmdlbtaao p dtaata- (Fatraary Ud ofSahtacla la M CFR Part PM _ Marardrm moterlala. I abtSas. Wbrcbtarlaated blpb railteRtatrM no rwavdkMptaf DmiiiMitttiM. wmm*i HONS 017253 1/ J V. CHEMICAL REGULATION REPORTER Transportation Committee. Both committees have jurisdic tion over the tuporfaud. Breaux said that the liability provisions in the superfund "should be interpreted narrowly" to cover only third party damages (or economic loss, not for medical injuries. Breaux said that he agreed with the Administration s proposal not to award third party damages to victims of abandoned hazard ous waste sites because such claims would drain the super fund. According to attorney Duane Miller, the salt is the first one filed by an Occidental employee against the company itself. Worker s compensation laws prohibit a worker from suing his or her employer for work-related Injuries er illnesses. But the attorneys for Arnett said that recent evidence, which indicates Occidental knew DBCP was in tile drinking water supply of the plant, but did nothing about K, provides cause for action against the firm for intentional and willful Poe Not A Ponotty Regarding industry assertions that the fee assessed against the petroleum and chemical industries to finance Ute sujperfund it unfair and is a "penalty" for past disposal prac tices, Breaux said that he does not regard the fee as a penalty, but rather as a fee on a product. He said that in dustry can add the fee onto the cost of its products, ul timately pasting the added coat on to the consumer. In addition, Breaux said he did not agree with Industry assertions that the liability concept in the mperfond is an ex post facto denial of due process. Injury. A high rate of sterility among workers st the Lathrop plant was first discovered in September 1977 and resulted in the issuance of an emergency temporary standard by the Oc cupational Safety and Health Administration (Current Report. September 16, 1977, p. MS). Arnett charged in lUs suit that bis DBCP exposure t his sterility, which was reversed when the plant < manufacturing the pesticide. The complaint was filed as an amendment to i suit against several chemical companies and i which alleged the defendants failed to peMtefec their research on the harmful effects of DBCP. Utigeti?"* II Spokesmen for Occidental CuCiVuvai >Aid Ik; hud not yet been informed of the suit, and therefor* had no c US. SUPSEME COURT TO HEAR BENZINE ARGUMENTS OCTOBER 10 The U.S. Supreme Court will hear oral arguments October . Hazardous Btfbstaneuo II on the validity of the Occupational Safety and Health Ad ministration's standard governing worker exposure lo Tbs arguments before the Court will come more than a yuur oflsr the U.S. Court of Appeals for the Fifth Circuit struck down Hit standard on the ground that OSHA failed to how that the standard's benefits bear a "reasonable rtlailimihin" to its costs. 03HA and the AFL-CIO, both of which are seeking to have the appeals court decision overruled, attacked the concept of balancing costs against benefits In setting an exposure level for toxic substances. Oil producers and users who successfully challenged the standard in the Fifth Circuit Court accused OSHA of ex aggerating the appeals court ruling. The producers and users Insist that the court did not require OSHA to conduct an elaborate coat-benefit analysis but only that it consider a "rough but educated estimate" of benefits expected from reducing the permissible exposure level from 19 parts per million to one ppm. The Court scheduled one and v half hours for argument of the \ CHLORINATEO AROMATIC COMPOUNDS SOURC COF DIOXINS, FURANS IN COMBUSTION PROOUCTS Highly toxic polychlorinated dkntins and (vm, Hand to combustion products from municipal and todmfertol to> cinerators, come primarily from burning of certain chlorinated aromatic compounds, according to EUropian researchers. This finding was reported by Chrtstaffer Rappe, of the University of Umea. Sweden, and Hans-RndeN Suaer, ef the 0 Swiss Federal Research Station, Waedenswfl, ffwttssrtoad. during the American Chemical Society mastiag bsM to Washington, D C.. September 9-14. The researchers identified chlorinated polychlorinated biphenyls (PCBa), cMoriitelod _ . ethers, and chlorinated benzenes as the major precuroarsef the toxic dioxins and furana. Their findings draw attention to the possible eavkooms* tal Hazard from polychlorinated dibewanfureas. Tho taraaa are similar in chemical structure and toxic effects to toe dioxins, but art somewhat less toxic and have received Ism attention from environmentalists and the pabHe. However, Rappe told Chemical Regulation Reporter he considers the furans to be more worrisome than,the dtoataa. He said the dioxins found In combustion products eenstot litigation largely of the less toxic members of the dtoxto fentity. He most toxic furan isomers, however, are major c "* ` OCCIDENTAL EMPLOYEE CLAIMS ol the lurans found in fly ash and flue gas, Rappe i DBCP CAUSED CHILD'S DEFORMITIES Rappe said one study indicates that 1.9.7.6-* ' An employee of the California plant which manufactured the prolicide dibromocbloropropone (DBCP) filed suit against the company charging that bis exposure to the chmkat caused his child's deformities. The action, filed August U by attorneys for Frank Arnett, an employee of Occidental Chemical Company, Lathrop, Calif., charged Occidental with carelessly, negligently, and dibenzoforan (TCDF) is about one-fifth as toxic as I3.7.Metrach)orodtbeii20'p-dioxin (TCDO). toe mast toxic of the dioxins. __ Rappe and Buser recommended that the berntog of PCBa and of chlorinated phenols, benzenes, and dtoheayt etitors he carefully controlled by monitoring chlorinated dtontoa and furans in fly ash and flue gases. recklessly" (ailing to prevent employees' contact with sen* DBCP, allowing Arnett lo become seriously Injured. The researchers said burning of commercial PCBa was The suit asks more than H million in punitive damages and found lo produce o variety of chlorinated furans, with ytsMs 61 milhea in compensatory damages. of between 3 and 36 percent. They said the moat toxic fans. P-14-79 CtwmfcW Refutation Reporter OMSTSr^^WSSOSS MOWS 0lVi54 CURRENT REPORT TCDf, was s main constituent of the forana prodecod from PCBs. Rappo said the pattern of Isomers termed from burning KBs shswod s close match srith the pattern found In fly ash staples. He concluded that uncontrolled bontlnp of materials containing KBs may be an Important source of heaardoee lurans In the cneiroament. Tbs researchers also said bunlaf wood shavings bn- pupated with chlorophenoh produced significant qwan- WtH at dtanins. They said their results sanest that chlorophsneli are Important precursors to dioxina fowid In ftyaeh. TWsfladtag may have serious implications lor the future status at pentacMorophenol, a common stood preservative which Is currently being reviewed by the Environmental fretactlsn Agency for possible regulatory restrictions (Comet Report, May II, p. 330). . The idealists also said chlorinated furana are produced from combustion of any of the various chlorinated diphenyl ethers. In addition, they said, tome of the ethers also yield varying amounts of dlosins. Including TCDD. They said chlorinated bensenea stem found to yield both dlmlm and furaas when burned, but at lower yields than the PCBs sad diphenyl ethers. Wai4 NmwhIbh Rappe and taar reported experiments with a variety of Rm retardant chemicals. They said a number of the chsmlcsll tested yielded dtonlns or lurans. One flame retar dant, hesabromohlphenyl. yielded 3 to I percent of the mast Isulc furaa Isomer. They recommended that halogenated phenols, biphenyls, and Rphsnyl ethers should not be used as flame retardants. la a related development. David L Stalling, at (he U.S. Pish and Wildlife Sendee's National Flthtriea Research Lahoralety, reported the discovery of chlorinated dibentofurant In froth water fish la the central end northeustecn Untied Stales. Ipluting at an ACS press conference September IP, Stall ing said the forans have been detected at levels of about one port per bUHon la carp, catfish, coho salmon, and lake trout from Lake Michigan. Staling misled the finding of furaas in fish to Rappe and uasr s discovery that furaas are created by ccenhutlion of KBs. He said the farane are as much as lid times as Idle as Traosfermsr Ores, in locomotive or In electrical generaUea seslpment. could cause the conversion of PCBs to the highly Ionic forans. Stalling sold. Use of PCBs In hydraulic systsins also could cause the conversion, he added, as csuM low temperature Incineration of PCB-contaminated in dustrial wastes by municipal inciaeratloo plants He cautioned that careful analysis and investigation should he dsne before any heating or incineration of KBs is per* Stalling said furaa levels In fish taken from the Hudson River were lower than the levels found In fish from the other vterwsye. He said much of the KB found in the Hudson, which Is heUeved to contain more KBs than any other UK. BUI waterway, came from original production of the chemical rather than from its use in industrial pipepause. Stalling sold the level of furaas in manufactured PCBs Is less than one part per million. PChe and DtojUn Initial Interpretation of the new data showed that there It little relationship between KBs and dioxin formation emu. Ingsafd. Dioxin, for example, was found la the only body of watar where no furan contamination of fish was found. Staling said. The data presented by Stalling was found by testing If fish samples collected at five sites between IP7* and 1P7S He said U to so more sites will be tested for furaas In the earn ing year. He and co-workers also hope to Identify which of 13$ furaa Isomers are present In waterways and whether they are harmful to aquatic life. Stallings said. He said that, for the time being, people can protect themselves against consumption of farms by IsIMwMg ad visories against consumption of fish taken from waters con taminated by KBs. NrOlwlM From CnI-FM Punt Flam The amount of dioxin In particulate enUauiaas (ram coatfired power plants "Is so small as to escape datacUan wMh the finest scientific equipment available. US. isssifihsis said at a September 13 ACS press conference. Breads Kimble, of the Department of Energy's Radiobiology Laboratory, and Michael L. Groan, dfreeSsref the Midwest Center for Mass Spectrometry, at the Uutveeslty of Nebraska, described thslr analysis ef fly ash pusHeim collected from the stack of "a typical power plant burning low-sulfur, high-ash cool." They said they found no dioxin si the lowest level ef detec tion. corresponding to one mUlioath of s grim of TCDD from the burning of 300 tans of cool. They contrasted their findings with results reported by the Dow Chemical Company. Dow researchers found iRuslus In emissions from a wide variety of common csmbusUau sources, including fossil-fueled power phmu (August 31. p. 003). Kimble and Gross suggested that Dow's csndaslsas cannot be applied Is all fossil-fueled power plants. Donald Townsend of Dow, who was also present at the press conference, said the power plant tested by Dow had burned primarily fuel oil. with a small amount of coal. He said uow had found dioxins all over Uur KUIwusL Tv imind said dioxins. Including TCDD. were even found In a U.S. Bureau of Standards standardised sample of urban par ticulate matter. Gross said he would not want to extrapolate Ms findings to aU power plants, Including those not burning western caul. Bueer said the European researchers had ant atudfed emissions from coal-burning power plants, since coal is sot uood to generate electricity In Swltscrtaad, SteHHty tintied by nssssrshsr So PCho Functional sterility significantly correlates with die level of KBs found la human males, according to Ralph C. Dougherty, a Florida State University (FSU) research chemist. He said 33 percent of the males he tested were faarHausHy sterile because their seminal fluids contained law numbers of sperm. The lowest sperm densities were found in mm with the highest levels of PCBs in their bodies. Daugherty said at a September 10 ACS session. 3-1S-T0 Coovitpht * tSTO by The bureau of Notional Affairs. Inc. etes-rsrsiTseoeie HONS 017*55 M2 Stain 1974. Uwrt has bm a greater than 100 parent Inertaaa in tea Mnbtr at mates with tew sperm dmtila, In nesting functional sterility, Dougherty said. Ills rasaarctl shows that PCB eoataniinatioa accounts for shoe! 24 psrctnt of the shift toward lower sperm counts, he aaM. addin* that he beltevea other taste suhotances eventual ly will be Implicated ia the decline. Dougherty said his study of 1 S3 men at FSU showed that 23 percent were fuactienally sterile because they had sperm densities of leas than 30 minion per milliliter. la a 1020 study, only about 7 percent of the men tested were functionally sterile, while, in 1071, about 10 percent were, Dougherty's statistics showed. Dougherty said several identified toxic substances were found in the seminal plasma of his volunteers, but that only PCBs correlated with low sperm densities. Among the labotaucse found, but not tied by Dougherty to sperm density, were pentachloropbsnol, hevnchiorobenssne, and various metabolites of DDT. He said seme other chemicals found correlated with the low sperm densKfea. but that he and bis cowurkers were un able In Identify the substances None of them, however, seemed to have the significant coriviutMW which PCB had, Dougherty said. ' Psfduty DosUntse Dougherty said median sperm density has declined from SO million per milliliter In 1333. to 99 millioa per milliliter In 1974, and to SO million per milliliter In 197b. Tbs moat common sperm density found in volunteers, however, Uaatrales the sleep decline ia the fertility rate, Daugherty aaM. Plotting the sperm densities on a graph shows that the largest amnber of men tat the UM study had sperm densities of lit milllsa per milliliter, according to Dougherty. Is 1(74, the largest number of men had a density of 44 million per mOigtar, while in the IS7S study, the most com mon dsarity had fallen to IS million per milliliter, Dougher ty said. The researcher said he believes college students may have lower then normal sperm densities because of such factors as strata and sexual activity. He added, however, that the lower densities found in his study could not be accounted for by the makeup of the study sroun alone. To eaUdate kit study, he has recruitad a number ef workers in an electrical plant Beeearn these worked have been expsesd to PCBe an u tegular hash In their jobs, their sperm eeaaia Shield confirm hit fludiagt with cottage indents, ha said. PCUu OsgruRng HuaUh Dueghbrty snM there In "s strong presumption" ihal PCBs are 'TupoasMe tor dtgradtog Um henilh parametsrs of peoute in the Untied Tinir " Further study Win Rum. he said, that PCBu and an of the poiychieriaattd areuattc* art toe dangerous lo ha oaad or CHEMICAL REGULATION REPORTER For that reason, evaluation of sperm cuuwt and sendsal plasma could provide a method cf correlating Impeded cal division with the amounts of toxic substances la the dsear, he said. Those substances which seem to be lowering sperm exeat should be considered too hazardous for use sad should be banned, he said. PCS* in Orggt The contamination of the Great Lakes by PCBs nmy con tinue to increase In spite of the EPA ben an further produc tion or use of the chemicals, researchers leM ACI September 11. The researchers said the atmosphere Is (he major soaset of PCBs presently entering the lake, and thtrefere. (be con tamination cannot be prevented by rhmnatlng nualrtoil and industrial discharges of PCBs IMe dte lakes. Thotnas J Murphy, of DePoul University, fibrin. ssM levels of PCBs found in Greet Lakes fish hove dochntd only slightly since the early 1170s, despite pent rsduedsn In PCB use. He contrasted this wtth eartter eipsrtencs wdh DDT. He said DDT levels In flah declined ragidfy after dm pesticide was banned. Present concentrations of PCBs in many hah earned gw Food and Drug Administration limit of two parti pm million. Murphy sold (dime 2*. p. 471). FDA recently stsjod the new two ppm action level tAugoat 31, p. lag). Murphy ssM known poUudon tram mssMpaL hhdrisl inl'Tihilinr nr-- 1- rrt mm In sirsmltsnkisismnt PCB levels in the Great Lakes. He ssM he and eteor researchers set out to determine whether fsllsut Item me sS- moepherc could be an important mures el PCB cantmstansUon. They measured rates ranging tram II In 71 grama pm square kilometer per year at various paints in Labs Michigan and Lake Haim Alooming ao averago rate at M grams per square kilometer. Morphy oataL the esalrihsltea of PCBs from the atmosphere would be tbool 3.3SU panada per year in etch of the two lakes. This is greater Man dte conuibotiou from oil other known source*, k* said. Murphy said the PCBs in the atmosphsn prahahly causa from such sources as municipal IndacnNra and sutpmu lion from landfills, from PCBs discarded In BM pant and from PCBs used in paints and as priservSilvas. Lak* geoertef S. 1. Eisenreich of the University ef Mteuuta reparted research on PCB contaminatioo of Lak* Supettee. He aaM atmospheric deposition from rate, parade*. tad PCB super account for over M percent ef the total FCBo priwafty entering the lake. . Elooarcich estimated that Id thoooand 33 teuuad poonds of PCBs enter Lak* Superior ouch year, wMte only 3.200 to 3.500 pounds are removed by outflow and oodb mentation. Consequently. II thousand to 21 Ihcumodpounds apparently accumulate lo the lake each year, hu aaM. HunWaanea te Center (tody Doaghcrty said hit study hu major significance for detecting hontnlooe autwtancil end for carcinogen detectionII II takes sight cell divioteu to crule a sperm, a towered spgrm cennt shows that something la Inhibiting eell division. Doughtily said. Mart substances Uut slow coll division art found I* bo earrtaogsnlc or molsgsoic. hn said. Eisenreich said he believes the atmospheric caatomtantion of Lake Superior hu oat yet reeched Its peak. anheaM PCB production has been dropping since 1940. Ho said PCBcoutoininf materiair and product* such u ateetricul aqalpnwnt are being disposed of continuously. Ho said thore la a substantial time Ug between the disposal of PCBs and thaw appearance to the Great Lakes. Eiaenreick said ike importance of atmospheric depoteCtea u o source of PCB cenlaminaUo* is dsmsulratsd by (ho n-M-70 swa.mv7wtMJt HONS 017256 CURRENT REPORT mMH of PCBi in mull lakes on Islands isolated from nqp source o4 direct PCB contamination. He said Bahcaught la ike island laktshad PCB levelsas much a* IM dmes higher than Iboa* caught in the Great Labes. Ha attrlbatad Iha higher contandnattou lewis in Uw Maad M to Urn shallowness a< Iha island lakes, which Makes lhaae man sensitive to atmospheric coatanUnatioa. tisarslch saM Iha Greet Lahaa have tow sedimentation rotas. PCBa which settle eat at the lake water remain close to the aartece at the bottom where they ere aaaUabte to bettonefeedtag saarine life, he said. He estimated that it woald intake sheet yam tor PCBs to be boried la sediments so deeply thet they cannot reenter the lake. Ilka presence at bacteria In drinking water Increases its ahHRy to carry pesticides and PCBa bp ap to lag percent, accetdtog to Jabs Deck, a research chemist with NUS CorparaUan, Plttskargh. Pa.. WMto Mm findings mean bacteria la drinking water may pass a greater health hasard than originally Unaght. they alto amen that bacteria could ha need to remora haaardous sahetaaces from ambient water systems, the rtsearchet said. Deck said his research thaws that the presence ot bacteria in walartocriaaaa the nmoants at pesticides and PCBs that too water can held. The chemicals seem to attach themselves is the cell mem- The Inmllcations at the study are that pesticides. PCBs. and SQesmjp ether toxic substances could be removed from drtafchg and ambient water supplies by pasting bacteria canted pialaa through the water, Pack said The researcher said he found that bacteria form a major made of transport lor PCBs and pesticides in water so- WNhsat Uw bacteria, the PCBa and psatlcldaa tend to set tle set sf water or tend to be adsorbed. Hack said Bacteria, along with the attached haaardous sahetaaces, land to remain saapeadad In the water and are difficult to Biker eat. Deck said Be said that he found destruction of the bacteria cell had MUs effect an Ra ability to hold the haaardous sahetaaces. The chsmlcakl tested, aldrfa and PCBa, seem to attach to For that reason, chlorination or other means at steriliaalloa do "net necessarily ehmiaatc" the potential hazard that Duck said that filtering the water may remove some of the kactarto and csaaagaeatly the haaardeaa substances, bat Mat mere tasting needs to be done before a definite Judg ment esa he made an the efficiency at filtering. Be said further work will be done to determine the exact masked by which Uw bacteria carry the hazardous sub stances and to find eat the feasibility of suing bacterta-laden plates or membranes to remove hazardous substances from He said his study has significance because treated drinking water cantatas between ISO and one million microorganisms per mMHHer. lhaae mteromganlama. which arc resistant to aanaal treatment processes, serve as convenient carriers tor hoisidano substances, he said. litigation COURT PARTIALLY BARM CLAIM AOAINMT ALLIED CHEMICAL IN KEPOMt SUIT A former officer and director of a Virginia firm which manufactured the pesticide kepone wee partially honed to his attempt to collect damages (or emptianal distress sad defamation from Allied Chemical Company/ which con tracted to buy the pesticide.- The U S. District Court lor the Easters District sf VkgMa, in William p. Moon v. Allied Chemical Corporation, The Travrlrn Indemnity Company, and Hooker Chemicals t Plattic Corporation, dtSsrwdned that Moore was barred In the emotional distress ettom but could proceed in his defamation salt to recover damages. Moore's former company, Ufa Science Products, pro duced kepone purchased by Allied. At Issue was whltoer Moore had an opportunity to litigate Urn matter tutor daring Occupational Safety and Health Review --------------proceedings following an Inspection of Mm Life Science Prefects. Hopewell, Vs., plant August 11 to II. im - Allied contended that admissions in MM former gu-- prohibited Moore from alleging that he wai unaware at too ruO dangers of kepone and thereby parsMag Ms ctotoM against Allied. Moore contended Oat Allied knew sf the devastating physiological effects which kspsns could haspso Ms workers, but Hat the firm dellberatoiy faded to wan Mm of these dangers, and that, coneeguantly. ho auftand severe emotional distress. In determining Mat Moore was estopped on Mm smsllsnal distress count, the court adopted AlHed's argsmenL However, as to the defamation claim, the court found that the facts and Issues determined In Uw 08AHRC prsriidtogs were not substantively the same. Writing for the court. Judge Calvttt Clarke. Jr., said that the truth of Allied's statements and their defamatory nature were matters to be determined ot trial. Perilcidos ROHM HAAM AMUR CPA TO CANCEL REGISTRATIONS OP VACOR RODENTICIDE The Rohm E Haas Company vohmlorUy rsqeesfcd tool MM Euvitvtuueotal Fidtection Agency cancel V.?,,-eyictretiene of Its rat and mouse pesticides caotabdag the active In gredient Vacor (N l-pyridylmcthyi N-p nitrcphsnylmso). Uw agency announced September IS. The company said It stopped sale of toe redeutfcldeo worldwide and has begun a recall of Ac products, sresrdtog to the agency. EPA was already in toe process sf tsklswtog MM registrations of Vacor because of concerns stpissosd by MM California Department of Food and AyUsttara. wteeb bmmad the rodentidde for home use March 1. the agency said Vacor has been toe cause of several human deaths to teeth Korea, moet classified as suicides, EPA said Callfseala reported tune adult poisoning cases, two of which resulted in death, the agency said. California was else canetrued toot the packaging of Vacor products appeared to be attractive to children, according to EPA. The products involved were soM to raeeumsrs under MM name "Vacor Rat Kilter'' and "Vacor Rat and Manes Kilter," and to pest control operators as "DLP-7B7 Haase Mouse Killer" and "DLP 707," the agency saM. b-ia-Tb Copyright * 1070 by The Bureau of National Affairs. Inc. sitarsr7suooM HONS 017257 ChM09pitcro Ho. 5 Pl> 231 - 23^* L97t* P*r,jiuon Press. Printed in Great Britain. A0AWSIS 07 POLYCHLORINATED DIBEKOPURAHS IN YTJSHO OIL 0S1HG HIGH RSSOLOTlOlt CAS CIBWHATOGRAPHY - PUSS SPECTHOKBTHT ChristoTter Rapp* and Indore Cart Department of Organic Chealstry, University of Gael 3 - 901 67 UaeA, Sweden and Hans Rudolf 3ua*r and Hana-Paul Soashardt 8wl Federal Research Station CH - MQ VUcurell* 3wlts*rUnd (Received in UK 7 A?rU 1377; accepted for publication X5 April 1977) Introduction Polychlorinated biphenyls (PCBe) are induetrlal cheulcsls now knot's t? ii widely distributed In the eirrlrooaent. The ccaoerclal product* are couples air.tssea :f at 1*-j; 60 different substance*. The toxle effect and the bloaocuaulatlon of t.-.e discrete PC6leoaers vary reaarfcably. 1.2 In 1970 7o identified polychlorinated dibensofnraaa (PCDfe) at toxic laparltiee !n Suropoaa PCBe at the ppa Ual^ end the net has also been reported for Aatrleaa end Japanese PCBe.^'^ Doing ycked-coluan GC/HS, Bowes jt. el. found that the aoat abundant KDT* ted th* .ate ntMtlon tlw aa 2,J,7,C-lotr-COT and 2,3,4.7.*-Plta-ar.* tn 19(0 nova than 1200 persons In South-Vest Japan were intoxicated by nnnsaali^ a nn--ainlal rice oil ooot--Lnated with 1000 ppa of a Japanese PCB (Kanechlor).* lap^aia et al. analysed the rloe oil (Tusho oil) and found 5 ppn of FCBfe. Conee<|ueatly, the fCW concentration in the Yuatao oil was about 250 tines hi(tor than In ordinary Tans nhl tit 211 HONS 017258 2J2 ">. *5 preparations. flageyana ajt jl. also four.d totra- and penta-CDFs to bo eost abundant, but they alto found Mall woounto of the tri- and hexachloro isoatera.^ Recently, Bevea %K ml. have reported that they found three isouere of both the tetrs-CDF and pent*-CDF, the dominating tetre-COT had the mm retention tine on a packed coluan aa 2,3,7,8-tetra- or.7 The torio effects of the PCDFe are very elnllar to thoee reported for the polychlorin ,ated dlbensodloxins (PCBOe), in both eaeee the 2*378-tetrachloro coapound being the Boot toxlo isoaer. 1 2*.8 Like PCODe* both PCSPe and certain KB leonere have been found to lncreaee eytochroM P-490 activity and a nunber of drug aefc*bolialng eiuyuee. 2 ' 9 Xa t2Ua paper* ve report on the analyala of "Yueho oil CH using glees capillary col\n 00 1r combination vith different naa epeetroeetrlo technique!. ' Experimental the elean-up of the Tuehe ell (l. jg) eeo peiToreed essentially as Otc-.r::.: eluding alkaline saponification and chroaMtogrsphy on silica gel.* Pinal chriui:?!?.'.;:* tai carried out on an elaalna-aioxocoluen using 10 al portions of 7% end 50 sethyless chloride In n-hoxane.1 the PCtf fraction was carefully evaporated and the residue rt- dlaaelvad in 100 piX of n-tetradecane. Sialloxily, a solution of synthetic 2*3*7*8-tetrsCOf uaa prepared in n-tetradscane at a concentration of about L ng/ul. Allquota of 2 pi of aaaple vara analysed on Of-101 and 0f-17 glass capillary coluane (22 a x 0.3d aa IP) using w lwthaaal aplltleaa lnjeotlon technique as previously described.1* The oolwu uare coupled via a fuaed pietism capillary* leading directly into the ion-source of a ftiml^a 1019 b GC-W (eleotlon lapact source at 70 of). The ooluans veto operated at 197*0 (0f-10l) ant 207C (0f-17) uith a heliua oarrier gas preeeure of 0.8 - 0.8 eta. A vaporiser taapsratnra of 270*0 uaa used, the interface use at 250C. Maaa apealflo dataction (aaea fragaentography) of PCOPa vea carried out by aeni taring aelaoular lone at mfa 270 (trl-CSV), a/a 304 (Utra-CDP), u/e 336 (penta-CSP) and /* 372 (baza-dr). At a further stage complete BI aaea spectra were recorded using e PimUgan 4000 OC-HB equipped with a dill data eystea. HONS 017239 0 9 ? TO SNOW t? ? i i \ r\ yjt N HONS 0 1 7 2 6 1 Xi"" 2 ' * ft~ntocr3 (OV-17 itlni'.' oo|>UJai> o.lia, ,,t 2O70) of Tiuho oil tOovli^ .lotion of PCV. (/. 270 ~ tri-, / JIM - totru-, / - |i.nt3~ and n/o 372 ftaxa-CDF). . 5 835 ftaaulta and Discussion Th mii frafMntograaa using OT-lOland OT-17 colums ara trivn in Fig. 1 and a. The OV-101 la a non-polar coluan with a good grouping affact according to tha mbar of ehlorlna atoas. Tha OY-17 la a tani-polar coluan, with aera apraading of tha positional laoaara. Consaquwntlp, OT-17 appaars to bo battar for an optlaal aoparatlon of tha lacaarie pCDTa. 7ig. 1 and 2 alao allow us to aaka an astlaation of tha nuabar of tri-, tatra-, pantaand ha*a-CDT praaant In tha Tuaho oil (auspactad isoaara, Tabla l). In tha cast of tha aoat abundant laoaara, tha dlaorata PCDFa could ba ldantifiad bp running cosplata SI aasa apactra. All tha apactra war# la agraanant with publlahad data* axpactad ion cl;^taring and najor fragaantntlon (H*-COClf H*-CCC1-C12). Tabla 1 Nuabar of PCXFa In Tuaho Oil Cl. 3 '4 Cl,5 Suapaetcd laoaara ldantifiad laoaara 66 9 2441 Idantieal rataatlon tinaa wara found for tha aajor tatxa-CW paak and an aathantio tanplt of tha 2,5,7,B-tatra-Cir (501 aae on 0V-101 and 557 aao on OV-17), Bp alapla eon* parison of paak halghta tha aotlaat# waa aada that 2, j, 7,8-tatra-CPF aacunts to at it Jo of tha total tatra-CWa. ' 0r inraatigatlen aging high raaolutlon GC strongly aupporta tha aaawption that 2 Ji7,8-tatra-CDF la 00a of tha aain FCDTa In Tuaho oil, an aoowptlon ao far onlp baaad on aaparatlons ualng packad colunna. Optlaal aoparatlon using high raaolutlon gas chro matography ia raquixad whoa It lo iaportant to aaparata batwaan a larga naabag of pooltional laoaara. MONS 017262 23* Wo. 5 Actaiowlcdgaanta The author* or* Ludabted bo Dr. Toahlto Maanda, Fukuoka, Japan for th c^ncro-ij gift of tha Tuaho oil and to Dr. J.0. McKinney, Rotearch Triangla Park, USA for the 2, J,7,5tatra -CDf seapla. Referenced 1. J.D. KeKiimay, V. Chao, B,D. Gupta, J.A. Moot* and J.H. GolAatein, Toxicol. App^. Fhanicol.. 6$ (1976). 2, J.A. GoIdatain, J.B. McKinney, G.W. Luelar, P. Blckaan, R. Bargaan and J.A. ^oore, Tonicol. Aool. Bumcol.. J6, 81 (1976). J. J.C. Tea, J.H. town, B.l. van dar Kaaa, K.C. tan Boavar da Brat* and B.3, ie to., W. Coonol. Toxicol. J, 625 (1970). 4* J.A.G. loaoh Md I.H. ?o*eranti, Dull. Environ. Contea. toxlcol.. 1^. 553 r ,,*;*). ). G.V. Bovoa, M.J. rtulrlhlll, B.H.f. Siaoneit, A.L. Purlin#-- and Jt.W. Upton. 756. 305 (1975). 6. 7. Vomrapo, R. Xurstoono, T. Ruuds. Boll. Koolron. Contu. Toxicol.. 15 J (1976). 7. G.V. hm, R.4. RolTihlll, 8.R.T. Slaooolt, 4.1. Burlin&a. uid R.V. Rltobroo^i, F.fr prownUd . Workshop on TCEB, Rllan, Itply. Oct. 25-24 (1976). 8. >.I. KbCbomU, J.A. Hovro, J.K. ffioopon and R.V. Hprrlo, Toxicol. Appl. PhoTMOOl.. H, 146 (1976). 9. 4. tolMd pnd 1. Glow, Rol. Phoruocol.. 2, 736 (1973). 10. R.R. hM, J. Chropotopr.. 107. 295 (1975). 11. 1.1. loom, Innl- Chu.. ji, 1553 (1976). HONS QllZbl DRILL, FRIESS, HAYS, LOOMIS & SHAFFER, INC. Consultants in Toxicology 1901 N. Fort Myer Drive -- Suite 204 -- Arlington. VA 22209 HONS 017264 Potential Health Effects In the Human Prom Expoeura to Polychlorinated Biphenyls (PCBs) and Related Impurities January 25. 1902 HONS 0122*5 Victor A. Drill, M.D., Ph.D. ir L. Fries*, Ph.D. Harry W H*y, PJ Ted K. Loomis, H.D., Ph.D. HONS 017266 TABLE OF CONTENTS Executive Summary ................................................................................ I. Introduction .............................................................................. II. Yuaho Episode ........................................................................... III. Body Burdens, Metabolismand Kinetics.............. IV. General Toxicity .................................................................... V. Skin and Other CutaneousTissues ................................... VI. Liver Effects ........................................................................... VII. Gastric Lesions ....................................................................... VIII. Carclnogeneslsi Experimental and Clinical .......... IX. Reproductive Effects ........................................................... X. Mutagenesis .....................................................................'.......... XI. Other Health Effects ........................................................... XII. Epidemiology .............................................................................. XIII. References .................................................................................. XIV. Glossary of Terms .................................................................. 1 $ 25 31 53 si S3 95 99 117 131 137 159 203 223 MQNS 017267 - 1EXECUTIVE SUMMARY The present study on the potantial health effects in human populations from axposura to cosuiarcial polychlocinatad biphanyl (PCB) mixtures undar occupational or othar environmental conditions was conducted by a tea* of specialists in tha medical, toxicological and epidemiological sciences designated as tha Category I taaa. Draft material for tha study report was reviewed by a second group of specialists designated as the Category II team, and other scientists, leading to comaents 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 teat 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 U.S. during the past decades, with the most Intensive integrated exposures having occurred in manufacturing operations that were terminated in this country in 1977. HONS 017268 -2- Yusho Disease Separate consideration was devoted to the Yusho aplsoda recognizing tha apaeial charactar of tha human exposures to high concantrationa of mixturaa of PCBa and thair tharmal dagradation producta, polychlorinatad dibanzofurana (PCDFa) and polychlorinatad quaterphenyls (PCOa). Savaral conclusions raachad by tha Catagory I taam ara of importancai (a) it ia lmpoaaibla to atipulata whathar any of tha haalth affaeta obaarvad ia cauaally ralatad to PCB axpoaura. ainea tha othar haloganatad compounds ara also biologi cally active; (b) tha doaaga pattarna axpariancad by Yusho patianta and IKS* industrial workers (PCB-axpoaad) ara not at all comparable; tha lattar group axpariancad low leval, long tisia pariod axpoauraa prisiarily via inhalation and skin contact, with only minimal oral ingestion* (c) tha aiailar haalth affaeta saan in Yusho patianta from tha Japanasa and Taiwanese episodes of axpoaura to contami nated cooking oils point to tha same type of toxic mixtures resulting from thenaal heat axehangar action in the two avantsr (d) because of points (a)-(c) above, and tha fact that at least tha PCDFa in tha Yusho oils ara potentially more toxic than tha PCBa on tha basis of animal data, it is not possible to extrapo late tha Yusho axparianca to prediction of acuta and sub-chronic effects of commercial PCB mixturaa in tha human; (a) finally, with respect to predictions of huauui carcinogenesis from the Yusho type of axpoaura tha data are so incomplete that conclu sions regarding any types and amounts of excess cancers attributtable to those axpoauraa have to await further definitive study. HONS 017269 -3- Kxiv Burdena, Metabollem, and Klnatica Son* general obeervatione derive from conaidar- tlon of the data on tha storage, dlatrlbution, metabolism and exeretion of commercial PC* mixtures (with aaaoclatad inpuritiaa such aa tha PCDFs) In mammalian ayatama. Tha dynaaiea of tha pathways by Which thaaa processes occur in taat animal nodala hava baan explored intanaivaly and hava baan fairly wall workad out. Tha variability of PC* affacta with dpaciaa of taat animal nodal haa baan invaatigatad for a numbar of important offacta, and aoma ganaral atructura va. activity ruloa hava anargad from thaaa atudiaa. Thara thua axlata a conceptual fraaowork, but not axparimantal data, for daacribing auch phononona in humana. Further, inportant data on tha biochemical intoractlona of Pda, PCDPa and netabolitea with tiaauaa hava baan obtainad that boar diroetly on intarpratation of toxic offacta in thaaa tiaauaa. Oanaral Toxicity Prom acuta, aubchronic and chronic atudiaa of PC* af facta in taat animal nodala, a ganaral auaaaary of hoalth affacta oneountorad includaat (a) a low ordar of acuta toxicity; (b) akin laaionaj (c) affacta on liver tiaauo that ara ganarally ravaraibla at lowor doeaa but that trand toward irravaraibility with incraaaad dosing; (d) affacta on tha gaatrlc mucoaai (a) affacta on tha manatrual cycle and on reproduction; HONS 4 (f) porphyriat (9) effecte on the kidney; and (h) mlaeallanaoua changaa including hematologic altarationa, thymic atrophy and lymphatic changaa. Thara ia a conaidarabla ranga of apaciaa auacaptibility to biological activity of tha PCBa, with ona rapraaantativa compariaon of ordar of decreaaing activity baing mink, monkay, rat. It ia concluded that thara ia no baaia for determining which apaciaa moat accurataly eervea aa a modal for prediction of ganaral aubchronie/chronic toxicity in man; rather, the judgamnt of tha moat auitabla aurrogata for man muat be made indepen dently for aach major health effect. Finally, it ia noted that although thara ia aoata aimilarity between acuta health affect phenoaMM produced by PCS axpoeure in the monkey and human Yuaho diaaaaa, it would be incorrect to equate Yuaho diaaaaa with PCB intoxication bacauaa of the much more complex mixture of ceapounde encountered in Yuaho oil than in a commercial PCB mixture. Skin and Other Cutaneoua Tlaauaa Coauaarcial PCBa are capable of producing akin laaiona in tha monkey modal and in expoaed humane. Chronic adminietration of PCBa to the monkey prodjicea chloracne. In hmaana occu pationally expoaed to PCBa akin diaordera Including chloracne have occaaionally been obeerved. Theae akin diaordera have been ehown to be reveraible in aone of the animal and human atudiea. HONS 017271 5 liver Eff*ct PCB mixture* art capable of generating important effacta on liver tiaeue in animal model*. Theae affects include (a) incraaae in liver weight*; (b) histopathologic change* in liver including enlarged hepatocytas, depoeition of fat droplets in tlsaue, and tisaue naerosia and cell death; (c) enlargement of the liver; (d) the occurrence of adenoflbrosis, a benign lesion; and (e) an increase in proliferative lesions of the liver, including increases in hyperplastic foci and nodular hyperplasia. These increases in proliferative lesion* appear to increase in severity with increasing degree of chlorination of the PCB mixture, as seen in the greater potency of Aroclor 12C0 over Aroclor 1254. The effects on liver tissue are gen erally reversible at lower doses but trend toward irreversibility with increased dosing. However, in contrast with the positive findings of PCB effects on liver tissue in animal models, no significant effects on liver function tests have been observed from clinical data on human populations exposed to PCBa in the occupational setting. Further, there has been no epidemiological finding of liver disease in U.B. occupationally-exposed personnel. Also, as noted in the Yusho discussion about persons exposed to contami nated cooking oil with a PCB content of 1000 ppm, there was no finding of liver disease in the categories of either jaundice or hepatocellular Injury. HONS 017271 6- Gastric lesions When tasted in monkeys and rodents, PCBs show species specificity with respect to a toxic effect on the gastric epithelium, or stomach lining. In the monkey, with Aroclor 1242, there is a mucous conversion of the gastric epithelium that can best be described as a dysplastic growth pattern. This growth pattern does not constitute a neoplastic transformation. In rodents, PCBs do not evoke this effect on the gastric mucosa. In humans occupationally exposed to PCBs there are no clinical findings to date of gastric lesions, and no evidence of stoamcb cancer due to this exposure. Carcinogenesisi Experimental and Clinical A eiseable volume of animal experimental work has been directed toward chronic studies in several species: the mouse, the rat and the dog. There are seme areas of intsrpretation that are still under debate by the investigators concerned, but in the opinion of the Category I team the following represents conclusions that can be drawn from presently available data: (a) the evidence on carcinogenicity is negative for gastrointes tinal carcinesw and bladder carcinoma in rats and hepatocellular carcinoma in the dog: (b) some studies have reported an increase in hepatocellular carcinoma in mice and rats exposed to commer cial PCBs chronically, whereas other studies have afforded nega tive results. HONS 017273 -7- With respect to tha poaslbillty of cancer linked to exposure of humane to PCBs, epidemiological atudlea show to date essentially negative results for hepatocellular carcinoma, gastro intestinal carcinoma and all other forms of cancer. There is a Single preliminary study that purports to show an Increase in melanoma (skin cancer) in occupationally exposed people, but the full data display and analysis have not been made for this study. In contrast, in two larger and more detailed studies, this finding has not been confirmedt no excess incidence of melanoma in exposed personnel has been observed. Retrospective mortality studies of PCB-exposed human populations have not demonstrated a consistent relationship between extent of exposure and the development of any par ticular type of cancer. The human studies in hepatocellular carcinoma are not comprehensive, but to the extent that they have been developed the results do not confirm tha projection of a risk for livsr cancer based on the animal studies. Some findings of increases In lymphatic and hematopoietic malignancies were below the level of statistical significance, and were refuted by observations of changes in the opposite direction in other epidemiological studies. Bven findings of statistically signi ficant differences between exposed and control populations with respect to the incidence of rectal cancer 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 Hortality Ratio (SHk) may vary widely in different HONS 0172 74 -8- studies, and that undue emphasis ahould not ba placed on the SMR found in one study unleaa it haa been confirmed by aimilar findings in repeat or parallel atudiea. Reproductive Effects Experimental work with commercial PCB mixturee and animal aodelg haa been directed to the reproductive proceaa itaelf. to teratogenesis in the offspring, and to possible fetotoxicity. In most test species PCBs produce deleterious effects on reproduction at high dosages. In the female monkey at relatively high dosages, difficulties are encountered in con ception, in implantation of the fertilised ovum, and in carrying the fetus to term. Similarly dosed, the male monkey does not transmit these difficulties to the reproductive process. In the human, exposed occupationally or otherwise to PCBs, there is in general no evidence for adverse effects on the reproductive process, although there are little data from which to draw con clusions. In the very special case of Yusho exposure to high levels of pcbs and other polychlorinated hydrocarbons, the new born in significant proportion were pigmented, small, and showed a retarded rate of growth. However, this pigmentation disap peared and the infants caught up with control population Infants in total growth. The potential for PCB-induced eeratogenesis, or produc tion of defects in the embryo or fetus, has been investigated in several species of test animals. Most animal teats have yielded negative results when pcbs were administered to pregnant females during the critical periods for organogenesis. HONS 017275 *> -9- ' Several possible exceptions to thia statement might ba noted. In mica, a mingle congener, 3,4,3' ,4'-tetrachlorobiphenyi, in duced a behavioral defect ('waltzing syndrome") that may be related to an anatomical defect in the inner ear. PCBa in mice nay produce aome delay in implantation, in rata, no groaa teratological changea were obaerved, but aome alterationa in thyroid atructure or function produced by PCB adminiatration might fall under the definition of terata. in doga and in awine, no teratological effecta were noted at lower PCB doses; however at the hlgheat doaea of PCB in the feed, at which the dan auffara marked reduction in food conaumption and ia therefore nutritionally deficient, there are doae-related teratological effecta in the offapring. In monkeye doaed with PCBa, there are no doae-related abnornalitiee in the offapring, but they are emaller in else. Baaed on thoae obaervationa, it la the Cate gory I team's concluaion that commercial PCBa preaent no appreci able riak of teratogenicity in offapring of human females exposed under occupational conditions. In teat aninala, l.e. rata, doga and rabbits, PCBa are fetotoxlc when administered at relatively high doses to the pregnant female. In the human, the only reported epidemiological evidence for fetotoxiclty in exposed populations stems from the unique Yusho event, in which causation may not be linked to PCBa. HONS 017276 - 10 - Mutaoanasls investigations of possible mutaganssis from acuta or chronic exposures to coauaarclal PCIs hava ahown negative rasulta in a aarias of in vitro and in vivo taat systems. laolatad bactarial taat ayataiaa (Aaaa taat) and human lymphocytes in cul- tura ahovad no avidanea for PCI-induced mutation or tranaforaation. Nith in vivo ayatoma in intact animalat (a) cytogenetic taata for altarations of call atructuraa or for induction of chromosome abnormalitiaa yialdad nagativa raaulta; and (b) both tha nouaa micronuclaua taat and tha dominant lathal taat damonatratad nagativa raaulta. Incubation of human lymphocytaa in culture with PCls cauaad an alteration in glucose transport through tha call aembranes. ' There is no significant avidanea that PCIs are mutagenic in test systems, and no reports of such activity in huiaan populations. It is quite unlikely that comaercial PCI mixtures would exert mutagenic activity in humans. This conclu sion is consistent with tha lack of excess cancer incidence observed in PCI-expoeed human populations. Other Health Effects This grouping includes anxyse induction, immuno- ecmpatanca and porphyria. PCIs induce mixed function oxidases (MPO) in tha liver of test animals. Tha important issue is whether or not this process includes tha specific induction of cytochrome P-441 as a general property of the PCIs, with tha added iiaplieation that soma oxidase system is being induced that HONS 017277 - XI could be Involved In chemical carcinogenesis. Several conclu sions were reached with respect to this issuet (a) the pre dominant effect of coauaercial PCBs is cytochrome p-430 induction, not P-448i (b) commercial PCBs in the U.S. can contain up to about 2 ppm of PCDFsr and (c) the PCOPs can induce cytochrome P-448. From these observations in animal model systems and our judgment, it is concluded that under conditions of U.S. occu pational exposure to PCBs, none of the MPO inducing actions of the commercial mixtures will be of toxicological significance over the lifetime of a PCB-exposed person. With respect to potential PCB effects on immunoccmpetence in test animal systama, some observations are pertinent to the assessment of probable hasard in the human, it has been ob served in chicks that if the PCB dosages are high enough, atrophy of the splenic pulp and necrosis of the lymphoid system can be demonstrated. Similar indicators of change in immunocompetence can also be produced in ducklings, nice, and monkeys as a conse quence of severe change in nutritional status. High doses of PCBs leading to marked reduction of food intake and utilisation can lead to such changes in nutritional status. These considera tions lead to two general conclusions relative to the FCB-exposed humansi (a) as projected from animal studies, if the PCB dosage is high enough to lead to general toxicity in the human (e.g., decreased food intake, fall in body weight, fall in weight gain). HONS 017278 12 immunosuppression nay ba demonstrable aaeondacy to malnutrition; and (b) at lover doaa lavala, there la no likelihood ot signifi cant lnnunoauppraaaion. Porphyria, or dapoaition of porphyrin-derived plgaanta in livar and urina, haa baan obaarvad in experimental aniaala aueh aa tha rat and rabbit doaad with PCBa. Tha affact haa a dalayad onaat, and aapacially in tha rat, saans to taka placa by mechanisms diffarant fron thoaa anployad by known ehanieal porphyrla-producara in tha hunan. It ia eoncludad that, aaida fro* tha uniqua caaa of yuaho diaaasa, no avidanea haa accroad for tha occurranea of porphyria in populations axpoaad to PCBa even undar high laval occupational exposure conditlona. Epidemiology Thia aactlon (xxi) of tha atudy praaanta a aaparata, indapandant assessment of tha racordad apidanlological litaratura and data baaaa on huaan exposures to connarcial PCBa, and on tha aignificanea of tha haalth affacta attrlbutad to thaaa axpoauraa. Suauaary pointa in thia aaaaaanant includa tha following: (a) mortality data, basad on vary Mall nuabars of daatba, do not confirm a carcinogenic affact of PCBa in man: (b) data on huaan akin lesiona in relation to PCB axpoauraa have shown variability in incidence of thia affact with geographical locus and with In creasing blood level indicators of exposure; (e) data from studies of livar eniyats and livar function suggest changes in one or mors entymes related to PCB exposure that are not associated HONS 017279 - 13 with liver disaasa and that occur at Xavals balow thoaa at which chloracna occura; (d) thara it frequently a positive cor relation between PCB level* and triglycarida level* in blood: and (a) epidemiological data on reproductive effect*, hematology and iMunology in human* exposed to PCB* do not suggest abnor malities in these system* or processes. Human Occupational Exposure Levels Of the various effects noted in animal tost systsias, only dermatological effects, including some chloraene, have been clearly demonstrated in human populations st the dosage levels associated with occupational exposures. Table 10 summarises the nature and intensity of some exposures that have occurred to per sonnel involved occupationally with PCBs and the biological indices that have accoaipenied these exposures, measured as PCB content in blood and adipose tissue. Since ths risk to human health from even high level occu pational exposures has been shown by the studies available to be low, it may be concluded that much lower human exposure levels do not present significant risks. MOMS 017280 JodneUi (1954) wagaam (1972) Plant * m icpponcn (1972) itaaira 3* ladtein 0973) (1976) (1979) __ alff _____ COWn aith X o (1901) mog* (1901) aK) (1901a) anmaKL ocamasm. txsoaim or wow-- to hob* (dpeltnr punt win ml-- oUmwio nsfdT~ PCB Oagntridai in Air . Benga_______ mV 5300-6000 Doom! ' Contact noted? PCB liwl in Plan Parts par billion** Ho. airtecg* Hw Range PCB Lewi in Adipoar- Tiaaue Parte par million** Ha. 8i4. Mean tangt A (FCB Mfg.) B D B r SO- 200 100- 500 500- 700 200-1700 99 370 60- 920 < 1000 12 - 13 320-2220 M 34 U> expos. 70- 410 150 ttad. * 410- 600 62 Hi 600-1100 43 As Abovm 24- 393 170-1260 H.O.- 264 Yoa 26 14 " " 440 110-1900 820 320-2100 -w 400 TT.-1200 L- 73 B- 41 L-171 H- 25 L-266 H- 82 Ir- 83 2-1412 H- 19 1-60 3 360 160-635 -> L-24 2-271 m K- 6 .2-19 L-502 210-3330 - 44 20-150 L-237 34-2400 H- 51 10- 250 fc`8 fc*H8 iff I tetm ith (198lb) utility tocher rnnafonaar rapeir gratia) mu l KB Concentration In Air , mnge inj/ia (cont-uad) IQ Laval in Denaal Blood Flnaaa Contact Part* par billion** Hotad? Ho. BirincS1 Kan 37- 215 14 b- 23 B- 24 *>m 5- 52 7- 74 8 L- 16 *- 7 1- 52 4- 19 4 L~ 36 23- 59 H- 10 7- 17 13 Ir 24 12- 35 H- 6 1- 18 3- 82 7 Yas 15 Ir 11 R- 6 IP Si' B- 31 1- 30 4- 10 47 11-140 ` 10 Ir 22 12- 48 B- 26 7-250 13 Ir 23 13- 52 B- 8 5- 25 a L- 19 12- 42 H- 6 3- 11 KB Laval i.. Mipoao Tiaauc Parts per Million** tb. Sub.* P-- hnia HONS 0 1 7 2 8 2 ooni (19(1) *** mm xontia capair) awnwiwj oonkrali 48-275 Yea 48 12 377 88-1319 200 41-470 Vaa n----------------- ISA" TJP3I5------------ ST "5.5-inMl.t------- is 14.2 10- 30 5 1.4 1.0- 1.1 Nota: KB pi*-- analyaaa as* manssad in pacta par billion (including mam ng/U), tdiila artipna* tissue analyaaa ana agrasmt in part* par illicn. *1'" KB* flnar Isaplogn) and *H" KB* (hitter hcnologa) ara defined aa species having, mpactiwlr, Tartar and longer 5M cduxsetographic retention tiaauaa than tha COT aetaholibe p,pl -a. V BOb includv 2-KDa thsou0> 4-KB*. plua ease S-KBai "IT KB* include S-KBs Md higher, plus aoaaa 4-PCBa. , i 19 I. INTRODUCTION A. Origin* and Methodology of the Study In August, 1981, ths firm of consultants In toxicology. Drill, Frlsss, Hays, Loomis and Shaffer, Inc., Arlington, Virginia (DFHLS) entered Into a contract with the Edison Electric Institute (EEI) and the National Electrical Manufacturers' Association (NEMA) whereby DFHLS agreed to exaiaine the toxicological and epidemiological literature on polychlorinated biphenyls (PCBs) and provide EEI and NEMA with DFHLS' independent, professional opinion on the luuaan health effects of PCBs at varying dosages or exposure levels. To this end, the principal scientific studies and data compilations available on toxicological and epidemiological effects of PCBs, as ecauaereial mixtures and as purified single congeners, have been reviewed by a team of scientists designated as the Category I team. Members of the Category I team are Drs. V.A. Drill, S.L. Fries*, H.M. Hays, T.A. Looses, and C.B. Shaffer from DFHLS. Additionally, Dr. G. Matanoskl 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 their human health affects, leading to an Independent assessment and evalu ation of the probability, causality and reality of these effects. Category I team review of the animal and human data resulted in draft material on the relationships between PCB exposure and specific health effects in test animals and in HONS 017283 20 exposed human populations. Further, vhare human data were lacking or Incomplete, the Category I team members developed specific projections or opinions as to the probability of occurrence of certain health effects in exposed humans, based on the existing animal/human data bases. Health effect areas scrutinised in cluded) general toxicity; effects on skin and other cutaneous tissues; effects on liver; effects on gastric tissues; carcino genesis (experimental and clinical observations); reproductive effects including fetotoxiclty and teratogenicity; mutagenesis; Yusho disease and occurrence of cancer; and other health effects including ensyme induction, chanqes in lnmunocompetence, and porphyria. Dr. Hatanoskl'a treatment of epidemiological obser vations constituted an independent section of the draft report. Draft sections front the Category 1 team were then reviewed for content, conclusions and opinions by the members of a scientific team of pharmacologists and toxicologists designated as the Category II team: Dr. P.G. Standaert (Georgetown Univer sity ), Dr. A. Alvares (Uniformed Services University of the Health Sciences), Dr. J.A. Thomas (West Virginia University) and Dr. P.E. Enterline (University of Pittsburgh). Dr. Enterline was the prime reviewer of the epidemiological contribution made by Dr. Matanoaki. Comments and critique from Category II team members, singly and as a group, were then transmitted to the Category I team for consideration, leading to revisions and amplifications that HONS 017284 - 21 are In place In the final draft of this study. Consents and suggestions from scientists representing the sponsors of this study, EEI and NEMA, are also considered. In the final version of the study, to the extent possible, a section on susaary and opinion is appended to each discussion of a potential human health effect attributable to PCS exposure. The prlMry responsibility for each of these sections is assumed by the Category I team, even though the con tent nay have benefitted from useful contributions by Category II personnel. B. Commercial PCB Mixtures Polychlorinated biphenyls (PCBs) are members of a class of non-polar chlorinated hydrocarbons based on the biphenyl nucleue, in which multiple chlorine atoms are substituted on 32 ry HONS 017285 - 22 - either or both the primed and unprimed aromatic rings. Csrtaln individual mambara of the PCB family have been praparad in a ralativaly pure state, with substitution of ring positions by chlorine ranging from dichloro isomers (symbolized as 2 - CB) up to the nonochloro (9 - CB) and decachloro (10 - CB) derivatives. Coauaercially, PCBs were marketed in the united States under the trade name of Aroclors. They were also manufactured abroad under the tradenames "Phenoclor* and `pyralene* (Prance), *Clophen* (Germany), and Kanachlor (japan). They are comprised of mixtures of chlorinated biphenyls. The last two digits of the U.S. commercial name denote the percentage of chlorine in each mixture, e.g., Aroclor 1242 contains 429 by weight of Cl corresponding to an average of approximately three chlorines per biphenyl molecule. Likewise, Aroclor 1254, Clophen A50 and Kanachlor 500 all contain 54% chlorine corresponding to five chlorine atoms per molecule on the average. Commercially useful mixtures of PCBs have been widely distributed over the world in the past few decades, usually in applications that have precluded excessive exposures of user populations. However, because of the great chemical stability of theae polychlorinated molecules, their persistence in the enviromsent after accidental release can be lengthy leading to possible exposures of people and biota in the biosphere. The results of these exposures, as well as those of personnel occu pationally exposed to PCBs in the course of chemical synthesis HONS 017286 23 and Manufacturing operations, ara of great importance from the atandpolnt of potentially harmful health effecta that might occur on an acute or chronic baais. C. PCS Impurltlet Commercial PCB mixtures are truly complex, containing variable numbers and amounts of congeners within a given family of compounds, and traces of impurities, all of which are poten tially toxic to humans and animals. Impurities that have been Identified in PCBa as manufactured are polychlorinated derivatives of napthalene (PCNs), terphenyls (PCTs), methylblphenyls, and dlbeniofurans (PCDPs). The occurrence of PCDFs is particularly noteworthy in view of the higher toxicity for certain congeners, relative to PCBs. It is important to note that there are theoretically 135 possible PCDP congeners, s few of which are believed to be highly toxic. Mhlle reviewing PCB toxicological or epidemioloqical data, a number of factors related to the actual material involved must be considered. The PCDP content of commercial PCBs varies> for Aroclors the reported range is 0-2 ppm of total PCDr congeners. Por Buropean and Japanese PCBs, the reported range for PCDP con tent is 5-20 ppm. The impurity levels can also be affected by exposure to high temperatures and oxygen. For example, Aroclor 1254 is converted to 2-3% PCDFs at 550-600 degrees C. These same conditions result in the fonaatlon of polychlorinated guaterphenyls (PCOs). HONS 01728 7 - 25 - II. Yusho Episode In 1968 a mass outbreak of food poisoning occurred in Japan, following ingestion of a cooking oil contaminated with PCBs and other compounds, that aroused worldwide concern over the potential human health effects 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 States so that data from the Yueho 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 ss PCDFs and PCQs (see Kuratsune et al., 1976; and Hayabuchi et al., 1979). The rice oil that caused the disease was found to contain about 1000 ppm of PCBs, S ppm of PCDFs, 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. Hayabuchi reanalysad the intake data for the yusho patient, and calculated that the average intake for the mean latent period was PCB 466 mg, PCDF 2.5 mg and PCQ 439 mg; the smallest Intake by a patient was estimated to be 111, 0.6 and 105 mg respectively. PCB concentrations in the tissues of Yusho patients were much lower than those of asymptomatic individuals with body HONS 017288 - 26 burdens of PCBs resulting from occupational exposure. Further, PCB fractiona of blood, tiaauea, and breaat milk of Yusho patients yielded gas chromatographic patterns shoving a larger amount of late-eluting peaks than do PCB fractions of tissues of individuals subject to other types of PCB exposure (Koda and Masuda, 1975). These patterns have never been observed in individuals (human or animal) exposed to PCBs in other situations. They are unique to Yusho disease. Also, PCDFs have been found in tissues of Yusho patients. Further evidence for the uniqueness of the syndrome in humans exposed to the Yusho oil is furnished in two recent studies. Hayabuchi et ml. (1981) in follow-up studies on these patients five or more years sfter the poisoning found significant positive correlations for the years 1973-1976 between blood concentrations of PCBs and the total amount of rice oil consumed, but not with the dosage of rice oil consumed per unit of body weight per day. Kashimoto et al. (1981) found that Yusho is quite different from ordinary PCB toxicity in the sense that, even 12 years after the first outbreak, PCQs have been found in the patients' blood and both PCQe and PCDFs have been found in their tissues and organs. It is obvious from this brief review that Yusho cannot be considered a model to reflect the possible effects of the PCB exposure in man. Although much can be learned from the Yusho HONS 017289 27 incident, It would be misleading to attempt to interprat the obaarvatlona on Yuaho patlanta aa valid signs and symptoms of overexposure to PCBa or to attempt to quantify tha posaibla affacta of PCB axpoaura baaad on Yuaho diaaaaa. A. Yuaho Diaaaaa Yuaho diaaaaa la charactarixad by the inqeation of a xiixture of chlorinated hydrocarbona containing PCBa in large amounts over a relatively abort period of time (latent period froai atart of lngaation to onaat of tha diaaaaa averaged 71 daye). In contrast, tha etudlea of PCB axpoaura in workera in tha unltad Stataa have bean concerned with tha poaalbla affecta of chronic axpoaura to snail aaounta of PCBa through inhalation or akin contact. Tha principal aigna of Yuaho diaaaaa are akin conditiona auch aa acnafora eruptions, pigaantation of tha akin and nails, and hyparsacration of tha Meiboaian glands. Chloracna and hyper secretion of the Meiboaian glands are believed now to be caused pradoainantly by PCDFs. Hyperpigmentation of the akin la observed rarely, if ever, in huaan populations with heavy occupational exposure to primarily PCBa. Tha actions of PCDFs appear to differ in several ways froa those of tha PCBs. Kuratsune at al. (1976) showed, for axaapla, that the liver appears to concentrate PCDFs selectively relative to PCBa. It was also found that relative to PCBa, the concentration of PCDFs was about 250 tines higher in the rice oil than in unused Kanechlor-400. Additionally, the PCDFs appear to HONS 017290 M 28 ba highly toxic, at laaat in tha rabbit; a aingla oral done of 0.5-1 ag/kg of tha trl- and tatra- chlorodibensofurana causad avara and oftan lathal nacrosla in tha rabbit (Hofnann, 1958; Bauar at al., 1961) B. Yuaho Diaaaaa and Llvar Function In view of tha affaet of PCBa on tha llvar of tha rat and tha highly toxic action of PCDFa on tha livar of tha rabbit, it waa anticipatad that tha Yuaho patiant would hava aavara livar damage, but auch haa not baan found. In thair raviaw of Yuaho diaaaaa, Ruratauna at al. (1972) liat "tha aubjactiva ayaptoaia of Yuaho aa atatad by 189 patlanta*; 11% raport jaundica. Data to confirm tha patlanta' 'aubjactiva ayaptoaia* ara not provided, nor ia tha praaanca of thia "ayaptoe' confiraad by othar atataaanta of clinical findinga. Prof. Uraba (Chiaf of tha Study Croup) did not liat jaundica aa a aign or ayaptoa of Yuaho diaaaaa and tha diagnoatic crltaria adoptad in 1972 do not make rafaranca to jaundica or tha naed for a llvar function taat in thaaa patlanta (aaa Ruratauna t al., 1976). Tha following two papara on Yuaho diaaaaa and livar function ara in japanaaa and tha briaf aummary givan below ia taken from tha report of Ruratauna at al. (1976). Okuaiara and Rataukl (1969) i They examined 24 patlanta aoon after tha onaet of tha diaaaaa HONS 017291 - 29 (i) Thar* war* no objective signs of liver disorders; (ii) No patient* were jaundiced and only three had palpable livers (in one patient examinetion* of a liver biopsy showed marked hypertrophy of the smooth endoplasmic reticulum). Okumara (1972) t Liver function tests were performed in 38 Yusho patient* with various subjective symptoms. (1) hn increase in lactic dehydrogenase (LDH-5) and in thymol turbidity titer was observed in some of the severe cases, 'but no definite evidence for liver disorders was obtained.* In a follow-up study of 121 Yusho patients the seen serum bilirubin was 0.48 *q/100 ml compared with 0.87 mg/100 ml in control patients (Hlrayama et al., 1974). The difference was statistically significant and. the authors suggest that there may be accelerated bilirubin disposal from the blood. It may be concluded that the Japanese findings do not provide evidence for the development of hepatocellular Injury or jaundice in patients with Yusho disease. C. Yusho Disease and Carcinogenicity Drab* and co-workers (1979) report that SI of 737 Yusho patients in the Pukuoka district had died and they list the cause of death for 31 of the patients. There were 11 deaths (35.4*) from neoplasms which they state is substantially higher than the 21.1* rate that is 'the mortality rate from neoplasms in the HONS 017292 30 iim prefecture this yeer.* A further analysis is not provided. The following malignant neoplasms were listed as the cause of death for the 11 patients with cancer. Anatomical Site Mo. of Cases Stomach Cancer 2 Stomach Cancer a Liver Cancer Liver Cancer a Liver Cirrhosis Lung Cancer Lung Tumor 2* 2* 1 Breast Cancer 1 Malignant Lymphoma _2 TOTALl 11 "Autopsied Information on age and other relevant epidemiological data are not given, and even a tentative conclusion regarding Yusho disease and any malignancy oust await further analysis. MONS 017293 31 III. Body Burden*. Metabolism, and Kinetics A. Introduction The degree of chlorination ( 2 to 10 atone of Cl per PCB nolecule) and the posltiona of the chlorine aubatltuents on the biphenyl rings both exert a profound Influence on how mamnalian systems handle any given PCB nolecule. The degree and position of chlorination play a major role In determining the pathways for metabolism and elimination of the parent molecules and their metabolites by animal models and the human. These structural factors also bear on lipid solubility of the molecules, and therefore influence to some extent the kinetics of PCB tissue distribution and storage. The following sections deal with the present state of knowlege on these PCB handling mechanisms em ployed by animal models and the human, recognising that there is a strong linkage In the dynamic processes beginning with exposure and ending In excretion. These topics will be treated in three groupings! (1) distribution and storage of PCB metabolites in tissues! (2) metabolism and excretion; and (3) kinetics or the dynamics of PCB turnover in animal models and the human. Presently, some generalisations esMrge with regard to PCB struc ture vs. reactivity relationships and mechanisms for handling PCBs in test animal systems that make reasonable extrapolation to potential events in the human organism possible, even when direct evidence for actions of a given compound or PCB mixture in human populations is not available. HONS 017294 32 Additional attention has been directed to available information on the actions of PCDFs in animal models and the human, and to a variety of biochemical effects recorded for PCBs and their metabolites in mammalian systems. PCDFs may be con taminants of some commercially used PCBs. Although 10-20 ppm of these contaminants have been found in PCBS manufactured in Burope and Japan, only trace amounts on the order of one or two ug of total PCDF congeners per g of PCB have been reported in the American manufactured mixture Aroclor 1254 (Bowes et si., 1975). B. PCB Distribution and Storage in Tissues A considerable body of literature exists on studies of the time dependence of the distribution, movement and storage of __ PCBs and their metabolites in the tissues of experimental animal models and of humans, following exposures to chlorinated biphenyls as pure compounds or mixtures. In test animal models using unlsbeled or radiolabeled (1/2 C or 1/2 H) PCBs, controlled exposures were generally by the oral route (stomach tube, or in the feed) or by Intravenous injection, followed by study of the changing distribution of the agent and its metabolites in the circulating blood, in tissues, in bile fluid and in excreta as a function of elapsed time after dosing. In the human, exposures with resulting body burdens of PCBs were generally of the subchronic type stemming either from massive poisoning events, as in the Yusho events, from chronic occupational exposures in air and via skin contact, and via PCB contaminants in air, water, food and surface contacts in the ambient. Humans may also have been HONS 017295 33 exposed to PCBs occupationally in the chemical manufacturing process, in tha manufacture of capacitors and in the manufacture and repair of transformers. Until, recently, several microscope immersion oils contained 30-401 PCBa as Aroclor 1254, causing potential exposures of students, pathologists, microscopiats, etci the degree of exposure is low and the penetration through skin from these products may not be as extensive as in large scale manufacturing processes. In human studies, PCB distribution and storage in readily obtained tissues was generally followed epidemlologieally in exposed populations by monitoring levala in blood, soaetiMS in mothar's milk as a function of time and soaetimas by measuring PCBs in adipose and other tissue samples obtained clinically and post mortem. Animal Model Results The picture of distribution and storage of PCBs and their metabolites in tissues over time has been developed most completely from controlled dose experiments in animal models. Generally, rats and nice were the animals of choice for this work (Burse at al., 1974) Geyer et al., 1980; Gulney et al 1978; Nattews and Anderson, 1975; Morales and Matthews, 1979; Albro and Fishbeln, 1972; Burse et al., 1976), but the dog, as well as the monkey, has also been used (Hsu et al., 1975a; Hilling et al., 1979; Sipes et al., 1980). The dynamics of tissue distribution vary with different isoswrs and congeners, and depend in large measure on whether or not the specific PCB MQNS 017296 34 nolacular structure allows rapid metabolism and eacration of polar laetabolltea via bile, facaa and urine (Milling at al., 1979; Safa at al., 19751 Sipas at al., 1980; Matthews at aK, 1978; Guiney at al., 1978; Gusalian, 1979) or slower metabolism with retention of parent compounds and metabolites in tissues. As will be discussed in the following section, metabolic trans formation in the liver is particularly facile for those PCSa with lower chlorine content ( 2 - CB through 4 - CO, i.a. 2-4 chlorines per PCB molecule) and with adjacent ring carbon atoaia unsubstituted by chlorine atoms (Matthews and Tuey, 1980; Sundstrom at al., 1976; Mato at al., 1980; Jensen and Sundstrom at al., 1974b; Ghiasuddin et al., 1976; Matthews et al., 1978). For many PCB molecules in which metabolic transformation and excretion is not excessively rapid, the dynamic distribution of parent compounds and metabolites in tissues following dosing has been studied carefully (Mlsutani et al., 1980; Safe et al., 1978; Sipes et al., 1980). The following generalisations appear valid in animal models for structures ranging from l-CB to 6-CB and higher. First, the PCBs are readily absorbed from the gut following oral administration and appear rapidly in the blood stream (Albro and Flshbein, 1972; Berlin et al., 1975; Chen and Matthews, 1974). Within minutes to hours, the materials largely clear from the blood and accumulate In the liver and in muscle tissue (Berlin et al., 1975; Burse et al^, 1974; Chen and Matthews, 1974). However, traces of PCBs have been found in the HONS 017297 35 blood of humans, probably by redistribution from other tissues, years after exposure. The liver is the primary locus for meta bolism of the PCBs, especially for reactive species, leading to lxtures of parent molecules and metabolites that then either translocate to other tissues or are excreted by both bile/gut, lumen/feces and urinary pathways. As translocation from liver and muscle occurs in the rodent model and other species over time periods ranging from hours to many days, the ultimate depots for major amounts of the non-polar PCBs and their polar metabolites appear to be adipose tissue and skin (Berlin et al., 1975> Hansen, 1979; Guiney et al., 1978; Burse et al., 1974). The general distribution pathway in rodents may therefore be characterised as 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. When the PCB structure is such as to permit ready metabolism to polar hydroxy, dlhydroxy or diol derivatives, the metabolic process may be closely linked in time with excretion of the metabolites (Jensen and Sundstrom, 1974; Lay et al., 1979; Matthews and Tuey, 1980; Matthews et al., 1978; Matthews and Anderson, 1975). Animal studies on urinary and fecal ex cretion of PCBs (Guselian, 1979; Matthews and Anderson, 1975; Berlin et al., 1975; Lay et al., 1979; Chen et al., 1976; Van Miller et al., 1975), and rates of elimination of PCBs from liver into bile and then into gut/feces, ahow that the larger MOMS 0172^8 36 proportion of excretion in rodents i* by fecal elimination (Rato at al., I960) Lay et al., 1979) Chen et al., 1976) Van Miller et al.. 1975; Chen and Matthews. 1974) of polar metabolites, mostly glucuronides, eliminated via the bile. The dynamics of distribution and elimination of PCBs in two monkey species have been studied (Hsu, et al., 1975ai Sipes et al., I960) Hsu et al., 1975b), and are found to follow a similarly complex pathway, but with wider tissue distribution ultlmstely than that seen in the rat. In our opinion, this difference nay relate in part to the ability to analyse more tissues in larger animals. Nlth fat tissues present in only small proportions in the infant Rhesus monkey, the ultimate depots included bone Mrrow and the adrenal glands, in addition to skin (Hsu et al., 1975a). Long-term studies involving chronic administration of PCBS at low dosage levels to animal models for significant fractions of their lifetimes, with determinations of total bur dens and tissue distributions achieved over tine periods of one to two years of ingestion, are lacking. Human Body Burden Results from Epidemiological Studies Experimental data on body burdena and tissue distribu tions of PCBs in humans as a result of precisely-measured in takes are not available. However, there are several population sectora for which exposures to PCBs can be at least roughly estimated, and from which tissue samples (blood, subcutaneous and other fatty tiaaue, etc.) have been taken to obtain indices of HONS 017299 37 - body burden. These sectors includet (1) humans occupationally exposed to PCBs during years in which they were employed in manufacturing processes (Karppanen et al., 1972; Hasegawa et al., 1972; Kltamura et al., 1973; Ouw et al., 1976; Fiachbein et al., 1979; Wolff at al., 1981; Maroni et al., 1981a, b; Smith et al., 1981a, b; Chase jt jl., 1981); (2) humans accidentally poisoned by PCBs ingested in contaminated foods, as in the Yusho experience in 1968 and in corresponding ingestions of contaminated rice oil in Taiwan (Chen, 1980; EPA summary, 1980); and (3) humane living in areaa in which PCBs have somehow entered the food chain or water supply in measurable amounts, leading to long term, low-level body burdens in adults that may also be present in the human milk supply for transmission to Infants (Ruaiphrey, 197S, 1980; Kuwabara et al., 1979a; Kuwabara et al., 1979b; Has and Davies, 1979; Watanabe et al., 1980). An additional source of exposure that is more difficult to characterise quantitatively sterna from the exposure of families to contaminated clothing of PCB workers. Survey work has been done in all of these popula tion sectors worldwide. The results are sketchy, but tentative qualitative generalisations can be drawn. Blood or plasma levels of PCBs are most resdily followed in potentially exposed population data using highly sensitive analytical techniques such as gas chromatography and mass spectrometry. For occupationally exposed people (NIOSH, 1977; Smith et al., 1980a) values ranging from 10 ppb up to a maximum of 3330 ppb have been observed, with the additional HONS 017300 38 qualitative finding froa Japan*** references that the half-life for disappearance of PCB* from blood following cessation of exposure ranges from 3 to 30 months. PCB blood levels were higher with increased duration of exposure. For Yusho victims in Japan, with blood samples taken 5-7 years following exposure to PCBs, in the 1973-1975 time frame (NIOSH, 1977) values in the range 3-33 ppb were observed. Enhancement factors over control group levels (mean, 3 ppb) as great as 10 were calculated, but the observed blood levels were still much lower than levels found in Japanese capacitor workers. It is of Interest to note the observation of Huaiphrey (1975) on the very slow clearance of PCBs from the tissues of humans exposed by eating fish. In general populations, blood plasma or serum levels of PCBs in the range 5-29 ppb have been found (NIOSH, summary p. 30. A current and well documented study of body burdens of PCBs in persons employed for many years in capacitor manufactur ing (Nolff et al., 1981) is of special value froa the standpoint of its correlations of tissue concentrations with extent of exposures. With highly chlorinated PCBs (H-PC8s), plasma concen trations of 1-54S ppb in exposed personnel correlated with total accumulated exposure time. For the less highly chlorinated PCBs (L-PCBa), plasma levels in the range 6-2530 ppb correlated better with specific tasks of individuals working with these 2-CB to 4-CB molecules. Also observed in this study was a correlation of levels in plasma with levels in adipose tissue for each claas HONS 017301 39 of PCBe, with H-pcbs and L-PCBs taken aa separate elaaaaa, and an ovarall adlpoae/plasma partition coefficient of 190. The levels of PCBs and metabolites in subcutaneous fat in humans have also been surveyed in general populations (NIOSH, 1977), in groups such as Yusho patients with high exposures, and in some occupationally exposed individuals. For the general population, levels in fat range from less than 1 ppm to greater than 3 ppm. For Yusho individuals, elevated fat PCB levels in the range 13-75 ppm have been observed, corresponding to peak enhance ment factors ss high as 30 over the population at large. It should also be noted that the spectrum of compounds in human tissues is not necessarily Identical with the spectrum in the mixture to which a given population was exposed (Kuwabara et al., 1971a). Ranges of adipose tissue PCB levels in occupationally exposed individuals have been reported as 160-635 ppm (Karppanen et al., 1972), 1-13.6 ppm (Chase et al., 1981), and 2-271 ppm (Nolff et al., 1981). Special surveys have been made of PCB levels in the milk of lactating human mothers (Mes and Davies, 1979* Natanabe et al., 19801 NIOSH summary) and of levels in human embryonic and fetal tissues resulting from in utero transfer from Yusho females (NIOSH, 1977). Human milk samples with values of PCBs In the ranqe 0.008-0.1 ppm have been observed. Clearly, con centrations in milk are higher than those in blood primarily because milk is rich in fat. Organs from the embryonic and fetal tissue displayed PCB levels in the range 0.002-0.750 ppm HONS 017302 - 40 - for whole tissues, with fat derived from these organs yielding levels In the range 0.06-1.14 ppm. C. PCB Metabolism and Excretion Animal experiments involving exposure by feeding, in tubation or injection of purified PCB isomers in test animal models have yielded some important generalixations on the mechanisms employed by mammalian species to metabolize PCBs to more polar derivatives, and to excrete both parent compounds and metabolites. Beginning with ready absorption from the gut and transfer to circulating blood, or with direct injection into the bloodstream, a given PCB molecule ultimately reaches the liver where major metabolic actions are initiated. The processes of metabolism and excretion as a result of these actions are complex and dependent on the swlecular structure of the PCB. General features of these processes include the following pointsi (1) Variable aaeunts of PCB metabolites are excreted via the feces after delivery to the gut lumen via the bile flow pathway. Unchanged PCBs can occur and be discharged in milk. Relatively lesser esnunts are excreted as polar metabolites in urine than in feces in most animal models (Kato et al., 19*0; Lay et al., 1979) Chen et al., 1976; Van Hiller et al., 1975) Chen and Hatthews, 1974). (2) Hetabolites are formed in patterns that differ quantitatively or qualitatively among mammalian species. They are generally formed by oxidative processes that are thought HONS 017303 41 to involve an arena oxide formation that results in monohydroxylatlon, dihydroxylation, hydroxylation and methylation, or dlol formation accompanied by partial reduction of an aromatic ring (Berlin et al., 1975> Lay et al., 1979i Lucier et al., 1978> Milling et al., 1979 Sundstrom et al., 1976> Gardner et al., 1973> Chen et al., 1976 Matthews et al., 1978> Van Miller et al., 1975 Hsu et al., 1975at Hsu et al., 1975b Burse et al., 1978). Evidence also exists for dechlorination of a PCB in the process of metabolism (Rato et al., 1980; Hutxinger et al., 1974b). For some PCB structures, the process of oxidative metabolisa may be closely followed by excretion via the llver-bilefeces pathway (Chen and Matthews, 1974). (3) Compounds with lower levels of chlorination (2 CB to 3 or 4 - CB) generally undergo metabolism more readily, and faster than the store highly chlorinated PCBs. The more highly chlorinated PCBs may persist in tissues for years because they are not metabolised. Indeed, 10 - CB is virtually inert. (4) In the case of metabolism by oxidative pathways, ths 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 unsubstituted by chlorine atoms. In the absence of unsubstituted vicinal positions, direct hydroxylation can occur in the ring, but with greater difficulty (Geyer et al., 1980; Matthews and Tuey, 1980). HONS 017304 42 The importance of vicinal unsubstituted positions on PCB rings in facilitating oxidative metabolism in the liver is explained by a mechanism that involves an arene oxide interme diate (Daly et: al., 1972). When either or both of the vicinal positions contain chlorine, reaction rates will be lower, but the mechanism is not entirely ruled out. Additional molecular rearrangements, including the so-called NIH (National Institutes of Health) shift of a ring substituent (Daly t 1,, 1972), may be involved. Less is known about mechanisms of direct ensymatlc hydroxylation that do not proceed through an arene oxide inter mediate. Arene Oxide (5) Hydroxylated metabolites of the PCBs and their conjugates will generally display different orders of toxicity than those shown by the parent molecules. (6) A general point of interest with respect to PCB metabolites lies in the observation that they are usually more polar than their parent compounds. Conjugation of the hydroxy and dihydroxy metabolites as glucuronides or sulfates can occur, leading to polar conjugates that can readily be excreted. The polar character of metabolites, in contrast with the non-polar HOMS 017305 43 characteristics of the starting PCBa, can lead to differing dis tribution, storage and excretion patterns for the two classes of chemical 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. PCB Kinetics Profiles of the dynamic growth and decay of PCB/ meta bolite concentrations in each key tissue can be drawn from controlled toxicological experiments. The distribution of e given PCB and its metabolites in the blood, tissues and excreta of test animals is followed as a function of time after administration. Tissues are viewed as body compartments into which materials are delivered from the arterial blood supply, in which some metabolic processes may 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 compartments, with postulated equilibration of any given chemical in a compartment with its venous blood flow, constitutes an appropriate modeling system for correlating PCB distribution, storage, metabolism and excretion kinetics in an animal over time. This multi-compartment model has been employed by Matthews and co-workers and others (Anderson et al., 1977; Bungay et al., 1979; Tuey and Matthews, 1977; Luts et al., 1977), to sort out the kinetics of specific PCB isomers in rodent models. The PCB administration can be either direct HONS 017306 44 injection of PCB into the blood circulation, or it* absorp tion into blood fron the gut after feeding or intubation of the compound. Excretory pathways are via the liver/blle/gut route or the blood/kidney/urinary elimination system. The success of a model equation system in fitting analytical data for a given PCB and predicting the shape of its concentration vs. time curve for each organ or compartment de pends in large measure on several factors, including! (1) the assignment of suitable values for distribution coefficients of PCB compounds in each compartment; (2) the differential blood flow to various organs; and (3) the clearance from organa and the body. This fitting process has now been carried out for a number of PCBs for which kinetic data are available (Anderson at el., 1977; Chakraborty, 1978). The goodness of fit of the model to each set of PCB kinetic data available attests to the validity of the assumption that materials partition at equi librium between blood and tissue according to purely physical properties involving solubility parameters of the chemicals. E. Miscellaneous Biochemical Effects of PCBs Studies of the actions of PCBa in animal models and humans exposed to these chemical agents accidentally or in the occupational setting have revealed a variety of biochemical effects on mammalian organisms. Some, such as alteration of drug metabolism by virtue of PCB induction of microsomal mixed function oxidases (MPO), are treated elsewhere in this document. HONS 017307 45 - Other facta appaar to ba unralatad to MFO actions, and have baan datacted In tha coarse of acute or chronic toxicological expariaanta with laboratory animal models or epidemiological surveys of exposed human populations. In an animal study (Bastoasky at al., 1975) aimed at probing tha previous evidence on reduced serum bilirubin levels in Yusho patients, it was found that Aroclor 1254-treated rats showed increased liver microsomal protein, as expected, but with no significant elevation in liver bilirubin UDP-glueuronyl trans ferase activity that could have accounted for reduced serum levels. Other studies (Grote at al., 1975; Lake at al,, 1979) have shown enhanced levels of this transferase activity. At present therefore, the mechanism underlying the hypobllirublnemia in Yusho patients remains speculative. From epidemiological studies of Yusho patients (Strik, 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 therefore 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 PCBa in certain sensitive human populations, e.g., fetuses, neo nates, ensyM deficient adults, etc., is related to the ability to excrete the toxic phenolic metabolites rapidly and efficiently. MOMS 017308 4 - 46 - Sine* common roue* of excretion involves preliminary conjuga tion of the phenolic hydroxyl groups with glucuronic acid in the body, or eulfat* conjugation, it has been pointed out (Calabrese, 1977b) that human groups that are biochemically deficient in the ability to conjugate could be predisposed to accumulate PCBs and metabolites because of this deficiency. A more serious con sequence of altered livar capability would be a reduced capacity to deal with arena oxide intermediates effectively. An interesting biochemical defect in human lymphocytes has been studied (La* and Park, 1980) that can be attributed to direct action of PCBs on these whit* blood cells. Por both human lymphocytes and monocytes, it has been found that incubation of the cells with Aroclor 1254 in culture medium causes a de crease in their ability to take up glucose from the medium. A non-metabolisabl* analog of glucose, 2-deoxyglucose, was used to detect the biochemical defect, which was attributed to PCB expo sure but which may well be nor* general for any organic chem ical that concentrates in the fat of the cell wall, it may entail direct action of PCBs on an active transport process in cell membranes. In this regard, liver glucos*-6-phosphatas* has been found to be inhibited in rats fed various Aroclor mixtures (bitterest at al., 1972). The processes by which PCB pretreatment influences rates of protein and nucleic acid (RNA) synthesis and turnover in rat liver tissues have been Investigated systematically MONS 017309 47 - (Narbonne, 1979a, b, c, a), using radiolabeled aubatrates. It it clear that liver tieeue, in vivo and in vitro, reaponde to PCB treatment (Phenochlor DPO by increasing the protein ayntheaia in liver microsomal fractlona in a process that is both age and sex dependent. Concomitant increases in liver fat are also seen in vivo, as well as changes in levels of RNA synthesis in various liver fractions and increases in liver weights. Prom the turnover experiments in rats, it la also observed that micro somal membrane protein metabolism la enhanced by ingestion of Phenochlor DP8. Some further biochemical effects of PCB exposures on the human are seen in workers occupationally exposed to these chemicals for extended periods of time (Smith et al., 1978). The findings, as yet unexplained in terms of requisite dosages or underlying mechanisms, are that: (1) the circulating tri glyceride levels in blood plasma are elevated for exposed workers over controls, but are still within normal levels) and (2) the circulating levels of high density lipoprotein are lowered in exposed groups of workers. Another biochemical effect seen in PCB-treated rats is worthy of note, since it relates to an impairment of excretion of an important drug and its metabolites (Schmoldt et al., 1979). In the Wiatar rat pretrested with Aroclor 1248, the drug digitoxin and its metabolltee were blocked to a significant degree from excretion via the bile. The results suggest that the HONS 017310 - 48 - blockage 1* due t leeet in part to a PCB-induced impairment of tha cleavage- of ona of tha sugars from digitoxin. Finally, tha action of PCBa leading to induction of aixed function oxidaaaa (MFOs) in tha liver, with elevation of asaociatad cytochromes P-450 or P-448, has potential consequences. These are discussed elsewhere (section XI). F. Sosa Observations on Polychlorinated Dlbemofurans The PCDFs are of special interest since they are known to be highly toxic in their own right, and the degree to which, as contaminants, they add to the potencies of PCB mixtures in production of adverse health effects in anisal models and humans has not been fully evaluated. Howev.er, toxicological studies in animals with PCDFs containing 1-4 or sore Cl atoms per molecule (Norlta and Olahi, 1977j Goldstein et al., 197ti Veerkamp et al., 1981) have shown that the PCDFs are qualitatively quite similar to their structural PCB analogs with respect to properties of tissue distribution, metabolism and excretion, in the mouse, the heavily chlorinated isomers localise in liver, spleen and fat (Morlta and Oishl, 1977), with a half-life for clearance from the body of about two weeks. In the rat, metabolism occurs by oxidative pathways leading to mono- and dihydroxylated derivatives (Veerkamp at aK, 1981), with a wide variation in ring position by the hydroxy function among the lower chlorinated PCDFs. The octachloro derivative yields no metabolic products in tissues or HONS 017311 49 excreta (Veerkamp it *1., 1981). In the chick (Goldstein et al., 1978). the 2,3,7,8-tetrachlorodibenzofuran (TCDF) has been shown to be relatively poor In enzyme induction. However, Goldstein et al. (1978, 1979a) have shown that 2,3,7,8-TCDF is a potent Inducer of cytochrome P-4S0 and aryl hydrocarbon hydroxylase. Some important data on pCDF metabolism and excretion in the human were obtained (Rappe et al., 1979) by analysis of liver tissue from two deceased patients in the Yusho disease 9roup in Japan. From the differences in PCDF structural rela tionships in the contaminated rice oil and in the PCDF fractions Isolated from the livers. Inferences could be drawn with respect to PCDF structure (all containing 4-6 chlorine atoms per molecule) retained by the liver vs. those that had disappeared from liver by processes of metaboliast/elimination. In striking parallelism with PCS disposition in SMsuaalian tissues, it was found that none of the PCDFs retained in liver had two vicinal unsubstituted (by Cl) positions in either aromatic ring. Apparently, all such molecules had been sufficiently susceptible to oxidative metab olism to be hydroxylated and excreted from liver in the bile. The above observations are not to be taken as allinclusive with respect to the body of information that must be developed in the toxicology of the PCDFs. This class of com pounds, even at low contaminant levels, is an important contrib utor to the total spectrum of toxic effects from comswrcial PCB mixtures. HONS 017312 50 G. Summary and Opinion Some general reflections and opinions can raaaonably b drawn from the previous discussion regarding the uae of animalderived biochemical and kinetic information to predict certain events and hatards in human PCB intoxications. (1) Pathways of absorption, distribution, metabolism and excretion have been explored fairly extensively in animal models. From the species variability seen, coupled with limited observations in the human, educated guesses and predictions can be made on the occurrence of certain toxic effects and proceases in the human. (2) Mathematical analyses of kinetic data from animal modeling experiments lead to some generalizations (Luts et al., 1977) that could apply to PCB turnover kinetics in the humani (1) kinetic rate conetants for metaboliam of PCBs by the liver decrease as the degree of chlorination increases; (2) rate con stants for biliary clearance of PCB metabolites from the liver are nearly tha same for all PCBs; (3) urinary clearance rates for PCBs decrease as tha degree of chlorination of the parent molecules increases; and, (4) for each PCB, the value of the distribution coefficient between fat and blood is greater than that in any other major tissue, Indicating that the fat compart ment of all tissues may constitute the major PCB depot. (3) Kinetic models derived from animal data may be use ful for prediction of time courses of action in the human once HONS 017313 - 51 - additional data on mataboliam and clearance rates for Individual PCBa in human tissues are obtained. (4) Some general PCS atructure vs. activity relation ships have emerged from animal studies, particularly rodents, that can have useful predictive power for the human. (5) There is some relevance of the features of the absorption/distrlbutlon/metabollsm/clearance processes discussed in this section to the toxicology of PCBs in animals and humans. Por examples (a) The possibility that an arena oxide intermedi ate can occur in PCB metabolism has special significance in terms of potential reactions with protein, RNA or DMA to cause tissue damage or damage to a cell's nuclear functions. (b) The retention of PCBs in adipose or other tissue can hava 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.j., chloracne, could stem from the physical presence of unreacted material in the cells along with oils and/or sebaceous materials of the skin. HONS 017314 53 - IV. General Toxicity A. General Considerations Any attempt to undertaka a systematic evaluation of the toxicity of PCBs is confounded by a number and variety of factors that complicate the interpretation of the findings and Unit their generalisation. Therefore, these factors should be recog nised at the outset of consideration of the available body of toxicological literature. The more important of these factors are listed as follows: (a) The multiplicity of commercial products of both D.8. and foreign manufacture; (b) The multiplicity of isomeric forms of PCBs in commercial products; (c) Qualitative and quantitative differences in meta bolism of different lsoswrs within the sane species; (d) Qualitative and quantitative differences in meta bolism of the same isomer between species; (e) Differences in rates of metabolism of different isomers within the same species; (f) Differences in rates of metabolism of the same isomer between species; (g) Differences in the biological half-lives of different isoamrs within the same species; (h) Differences in the biological half-life of the earns laomer between species; HONS 017315 54 (i) The presence in commercial product* of impurities of auch greater toxicity than that of PCBa; (]) Th# variability batwaan commercial products of tha same type U.e., same degree of chlorination) in tha concentration of impurities of auch greater toxicity than that of PCBa; (k) Tha variability between commercial products of the different types U.e., different degrees of chlorination) in the concentrations of impurities of much greater toxicity than that of PCBsj and (l) Differences between species in susceptibility to the toxic action of (1) individual isomers and their metabolites, and (ii) the impurities that may be present in commercial products. The preceding factors nay underlie the conclusion reached by the Panel of Hazardous Trace Substances (1972) that "(t)here is no consistent relationship between toxicity and degree of chlorination which is valid for different species and different routes of exposure. To this might be added the obser vation that there is often no consistent relationship between the results of Investigations on products of the sane degree of chlorination from different manufacturers. These observations constitute caveats that should be borne in nlnd as individual toxicological experiments and results are evaluated. B. impurities in Commercial Products The work of Vos and his associates (Vos and Koeman, 1970; Vos at al., 1970; Vos and Beams, 1971) led to a recognition HONS 017316 - 55 - of the significant rols played by traces of impurities in com mercial PCBs in Influencing the apparent toxicity of the latter. In studies involving three commercial PCBs of the same degree of chlorination, these investigators found marked differences in toxicity that were traced to the presence, in two of the products, of smell amounts of chlorinated dlbenzofurans (PCDFs) and chlo rinated naphthalenes. The PCDFs are related closely, both struc turally and toxlcologically, to the chlorinated dibenzodioxlns. The 2,3,7,8-tetrachlorodibenxo-p-dloxin isomer is an extremely potent toxicant in mammals, especially for the fetus. The chlo rinated naphthalenes are less toxic than the chlorinated dioxins, but nevertheless cause chloracne and other symptoms in man similar to those produced by PCDFs. The extent of the contribution made by contaminants to the toxicity of commercial pcbs is uncertain, but the consensus is that it is substantial. There seems little doubt that the skin lesions. Including chloracne, are caused by PCDFs. The Panel on Hazardous Trace Substances (1972) states that the PCDPs "are probably the chief if not exclusive cause of chloracne in man," Fishbein (1974), in his review of the toxicity of chlo rinated biphenyls, observes that "(l]iver damage and skin lesions are believed to be caused primarily by chlorinated dibenzofuran contaminants and to a minor extent by PCB itself." Furthermore, since the chlorinated dibenzodioxlns exhibit pronounced embryotoxicity, it is not unreasonable to expect that the PCDFs share this property and, hence, are largely responsible for the fetal HONS 017317 56 deaths and resorptions that have been observed experimentally with commercial PCBs. An appreciation of the role played by contaminants in the toxicity of commercial PCBs is important for two reasons. First, it may explain discrepancies between the results of studies of apparently similar coausercial products. Second, it points up the difficulty of attempting to use PCB tissue levels to correlate the results of laboratory studies with observations of occupationally or environmentally exposed populations. For example, some animal populations in the environment appear to be unaffected by PCB tissue levels that are equal to or greater than those associated with adverse effects on comparable species in the laboratory. C. General Toxicology 1. Acute Toxicity The Aroclors of the PCB class have a low order of acute toxicity. The acute oral LOSOs for rats range from 1-10 g/kg. The 1,050s by single application to the skin of rabbits are approximately 1-3 g/kg. Oral and dermal u>50 data have been summarised by Pishbein (1974), Kimbrough et al. (1978), and the Panel on Hasardous Trace Substances (1972). 2. subchronic and Chronic Toxicity (a) General Subchronic and chronic toxicity are grouped together for purposes of this discussion since the effects of chronic HONS 017318 57 - exposure to PCBs are essentially extensions of those observed from repeated exposures of shorter duration. There are nuaerous published studies in which commer cial PCBs (Xrodors) have been administered by various routes for varying periods of time to most common mammalian species of laboratory animals. Out of this mass of observations, one may identify two principal classes of biological effects of these substances. These classes are (a) alterations in the liver, and (b) skin lesions. (b) Alterations in the Liver Enlargement of the liver, both in absolute terms and as a percentage of body weight, has been observed consistently in most species consequent to repeated exposure to PCBs, although it is more pronounced in rodents than in others. This phenomenon has been reported for mice (Kimbrough and Under, 1974), rats (Bruckner et al., 1973, 1974a, b), guinea pigs (Vos and Van Drlel-Grootenhuls, 1972), rabbits (Roller and Zinkl, 1973), dogs (Calandra, 197C), and monkeys (Allen et al., 1973). Early enlargement of the liver is primarily the result of an increase in the site of the hepatocyte associated with an increase in the amount of the smooth endoplasmic reticulum (SER). These develop ments are associated also with increased entymatic activity of the liver (Bruckner et al., 1973). A detailed discussion of the effects of PCBs on liver in test animal systems is given in section VI. HONS 017319 58 (c) Skin Lesions Cutaneous effects from repeated exposure to commercial PCBa can be elicited by leading to monkeys or skin application to rabbits, although the results are somewhat more draaatlc in the former. The results of these animal studies are discussed in section V. (d) Miscellaneous Effects Hyperplasia and dysplasia of the gastric aucosa have been observed in monkeys fed a diet containing 300 ppa of Aroclor 1248 for three Months (Allen and Norback, 1973). Gastrointestinal lesions do not appear to occur in rodents, except at very large single doses by mouth (Kimbrough, 1979). A dietary concentration of 2.5 ppm of Aroclor 1240 produced alterations in the menstrual cycles of adult, female rhesus monkeys (Allen at al., 1979). Menses vers prolonged, and there was an increase in menstrual bleeding. Hepatic porphyria has been demonstrated in mice after feeding Aroclor 1254 (Kimbrough and Linder, 1974). in rats after feeding Aroclors 1254 or 1280 (Kimbrough, et al., 1972), and in rabbits after repeated skin application of Aroclor 1260 (Vos and earns, 1971). Urinary excretion of coproporphyrin was Increased in rats fad Aroclor 1242 (Bruckner et al., 1974), and both urinary and fecal excretion of porphyrins was increased in rabbits re ceiving repeated akin applications of Aroclor 1260 (Vos and Beams, 1971). Other effects reported for one species or another include structural changes in the kidney (Vos and Beeas, 1971) Bruckner et al., 1974a, b) hematologic alterations (Bruckner et HONS 017320 59 - si., 1974a, b) and thymic atrophy together with a reduction in tha number ot germinal centers in the spleen and lymph nodes (Vos and Mama, 1971). 0. Summary and opinion Voluminoua literature eatabllahes that commercial PCBa are capable of producing a variety of biological effecta when administered in large quantitiea to experimental animals. The majority of theae effects can be grouped into two categories, nasMly, those involving the skin and thoae involving the liver. A number of miscellaneous effects that have been observed in one species or another can be considered secondary to the action of the substances on the liver. In general, theae effects are only elicited by relatively high dosages of the PCBs, reflecting the low order of acute toxicity of the u.S. commercial mixtures. There is a considerable range of species susceptibility to the biological activity of PCBs as measured by the site of the dosage, the duration of the exposure, and the severity of the effect. Mink appear to be the most susceptible, monkeys soauwhat less so, and rodents the most resistant. There is no basis for a judgment as to which species most accurately serves as a model for man. A comparison of the observations on humans in the Yusho incident with those on monkeys fed relatively small amounts of PCBa has led some investigators to conclude that the latter species is an appropriate surrogate for man. Although there are some similarities between Yusho disease and the findings in monkeys, they are not sufficient to justify such a conclusion. HONS 017321 60 There Is evidence throughout the literature that soae of the biological effects observed experimentally with commercial PCB mixtures are caused not by PCBs themselves but by other chlorinated aromatic compounds present as impurities, such as the pCDFs The significance of this finding is that PCB levels resulting from occupational or environmental exposures cannot be interpreted in the same way as those observed in experimental animals. A broader implication of this circumstance is that the results of laboratory studies are not necessarily predictive of what may be expected from incidental exposures since the nature of the exposure may have differed in the two Instances. As is always the case in experimental toxicology, the validity of test results as predictors of hasard to nan must await confirmation or denial by observations of exposed human populations. Fortunately, the reports of actual injury to man from PCB exposure are few, although extensive epidemiological surveys have been conducted and others are in progress. An evaluation of the epidemiology of exposure to PCBs is the subject of section xil of this report. Still other sections of the re port deal with specific potential health effects in greater detail. HONS 017322 ! Stily Ha. Subjects Ibugno ot si. .99 1972 KitSOMTO Ot ll .13 1971 Ouw t Si. , 1974 7 IIOSH 1977 7 Flscbboli ot el J21 1979 Tibia I IIhIimIciI SM1i if Emw and Llw Function Avnraga Oom wb SCOT SGPT or elevettoo with Ion GGTP AX UM (litrubto Tot. 370 N.T. N.T. N.T. N.T. lot. 020 lot. >500 Tot. 90.4 Lo 124 Ml 48 hepstic flection tests unreel N.l. N.T. N.T. N.T. N.T. N.T. More. Nora. N.T. Nora. N.T. NonS. Oeported S above oorael 2.25 7.25 1.95 1.25 2.55 05 Asker ot si., 1900 09 Sludge Tot. users IB uortors 19 worker fsa. 22 Cooeuntty HI Correlettons with PC8 17.4 (10.) 75.1 (24.5) None None None None None 33.4 (14.8) efter correction elcokel 24.4 (12.8) lbroot ot si., 80 19BI Liver sboons. 10 Liver * oono. 41 to 215 Ml 300 Tot. 524 Lo 92 Ml lot. m174 7 1 505 elev. Nora. 7 Positive sssoctstlen abnorasl liver findings and PCNs None Nora. Notts cholioeotorooo 8SP sbnornsl In 57 percent * No cossMrlson group. No correction confounding vsrisbles ; i Analyzed with noo-drlnfcers No other vsrisble controlIn II1-PC8 used In tnelysts Hepstonegsly 805 Slgniflcsntly higher PCBs In liver esses Hi 210 study to. Subjects TABLE I (continued) Btadlee of Enr-- ud Uwr Funotloa (continued) tonfi tost Correlation or elevation with tost pph sax sen OSIP NC UM lillrubla totes Chase at si.. 120 '1981 Tat. 39.44 Erased (18-312) Pas. toaa toaa toa- T 12.0 abased (18-27) Corrected for tea tot other risk factor as alcohol. Saith at *1., 244 1981a to 09-802 af/M tout (spares ppb) HI Pas. NM toaa toaa Pas. toaa toaa toaa toaa toae Correlation Include , corrections Saith at al., 47 Pub.La 11-36 H/al toae toaa 1981b HI 6-24 Haas toae 46 Prlv. La 19-23 e/al Pat. toaa HI 6-31 toaa toae toae toaa toaa toaa toae toae toae toaa Nate toaa toaa toae toaa toaa toae toaa toanalysls Saith at al.. 1 A 2 abase Saith at al., 1981c 224 Lo HI 47 Pub.Le HI 46 Prlv. La HI toae toaa Pet. toaa Note toaa Pas. toaa Pat. toaa toae tone toaa toaa toae toaa toaa toae toae toaa toaa toaa toaa toaa Pas. toaa toaa toaa toae toaa toaa toae toae toae toae toae Analysis each PCB Independent of other Kretss at al., 4S8 17.2 adcroo./L N.T. toae tot. N.T. N.T. Nona (3.2-187.9) 1 j 1 1 I l *n o I KK>* - 181 - Ouw et *1. tested the liver function of capacitor workers through the use of biochemical markers and found the overall test data for the group to be normal (Ouw ejt al., 1978). The BSP liver function test was conducted only on individuals with blood PCBs above SOO ppb; four out of seven workers were above normal levels, but it is not clear whether these values were above the range of error of the test or whether there were other factors that might have influenced the results. It is indicated that the blood PCB level and the BSP test do not correlate. NIOSH (1977) evaluated the liver function of seven of eight workers exposed to PCBs in the manufacture of electrical equipment. The levels of SCOT, SGPT, alkaline phosphatase, and total bilirubin were normal in a group of seven workers with s mean PCB level of 98 ppb. Fischbein et al. (1979) examined a group of 321 work ers from two capacitor manufacturing plants. The workers had mean levels of L-PCBa of 124 ppb and H-PCBs of 48 ppb. A small proportion of the workers had abnormalities in the biochemical tests. Two percent had abnormally high levels of SGOT, 7t high levels of SGPT, 2% high levels of GCTP, It high levels of alksline phosphatase and 3t high levels of LDH. However, there were no abnormally high levels of bilirubin. The results of this study have not been corrected for important confounding variables such HONS 017423 182 age, alcohol intake and other diseases currently or in the past (e.j. hepatitis) that may influence these findings. There is no unexposed group for comparison. The investigators have not presented data correlating increasing enzyme 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 chotomized by two levels of SGOT, less than 50 and greater than SO l.u. and two levels of both lower and higher homologues of PCBs. These data indicated significant differences between the proportion of individuals with high and normal SCOT levels for H-PCBs greater than 75 ppb compared to lower levels and for L-PCBs greater than 200 ppb compared to lower levels. It is not clear whether these PCB levels were selected after examining the data, in which case the conclusions would be questionable. The 16 individuals involved in a PCB spill (NIOSH, 1980) had normal liver function tests 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 test procedures. Choles terol levels were normal. This group had very low blood PCB levels of 6.4 ppb as a mean value, a level lower than that of non-exposed groups. Baker et a_l. (1980) studied PCB levels in users of PCB-contaminated sludge as a fertilizer compared to workers in HONS 019*2'* 183 a PCB-uSing facility, their families and non-sludge users in the community. The PCB level varied from 17.4 to 75.1 ppb in the four groups with the lowest level being found in the sludge users. There were no signs of changing levels of SCOT, SGPT, alkaline phosphatase, LDH or bilirubin in relation to blood PCBs in drinkers and non-drinkers of alcohol. The GGTP level correlated with PCB level in the total population but, when alcohol consumers were removed, the correlation disappeared. Haroni et al. (1981) studied liver abnormalities in 80 workers from a capacitor manufacturing and testing plant. Sixteen workers (20t) had asymptomatic liver abnormalities. Over 80% of these had enlarged livers. Among this group the most frequent enzyme elevations were the gamma glutamyl trans peptidase (GGTP) in half the cases, the transaminases in 44% and the ornithin-carbamoyl-transferase (SOCT) in 38% of cases with enlarged livers. The mean L-PCB level was significantly higher in workers with abnormal liver findings compared to con trols (215 to 92 ppb), mean H-PCB level was significantly higher (308 to 176 ppb) and total mean PCB level was significantly higher (524 to 296 ppb). The levels of PCBs in these workers are high compared to values from many of the exposures recently reported. It is interesting that the authors report that al though there is an association between liver disease and PCBs there was no such association for chloracne, but the number of cases was smaller for the latter parameter. HONS 017425 184 Chase t a_l. (1981) examined the serum PCB levels and the biochemical markers of liver and lipid activity in 120 main tenance workers who had had varying exposures to PCBs in their work. Plasma PCBs were correlated with SCOT and, after adjusting for age, the correlation between these two variables is still significant. There is no significant correlation between plas ma PCBs and GGTP or SGPT. If this correlation is correct it has occurred with levels of PCBs in the blood of exposed wor kers (33.4 ppb) that are lower than those found in other studies relating subclinical changes in liver function with PCBs (NIOSH, 1977). However, without corrections for other potentially con founding variables such as alcohol intake and the history of other diseases such as hepatitis, it is difficult to assess the finding. Recently, NIOSH has completed three studies repre senting cross-sectional medical surveys in two groups, individ uals working in capacitor manufacturing (Smith et a_l., 1981a) and individuals working in maintenance and repair of electrical transformers (Smith et al., 1981b). The third study combined the data from each study in an overall analysis. In the capacitor manufacturing qroup there were 224 participants for whom L-PCBs and H-PCBs were determined, as well as biochemical studies. Several simple correlations were cal culated and, for all those that were significant, multiple regression equations were developed using all other predictor HONS 017426 185 variable* tor which information was available. This included drug intake, smoking history, other biochemical markers, age, sex and others. Serum H-PCB was significantly correlated with SCOT and GGTP. 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 PCB levels being 8 to 50 times the level found in the community. Smith et al. (1981b) have reported in the survey in formation on 93 individuals who were about equally distributed between a municipal electric eystem and a privately-owned elec tric utility company. The level* of H-PCBs and L-PCBs are simi lar in the two facilities. There were very few enzyme tests related to liver function that were significantly correlated with PCB levels. The only significant correlation was a positive relationship between L-PCBs 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-PCB and GGTP. The positive correlation between L-PCB and SGOT still remained after corrections for the private utility company. Combining the data for all sites it is HONS Q17M1 186 noted that log SCOT and log GGTP demonstrate both significant and homogeneous trends in relation to log L-PCB level. Only log SGOT is related 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 PCBs. Because of the many changes in relationship, it is difficult to indicate precisely the association between spe cific liver enzymes and specific hcmologues of PCBs. It does appear that in these studies one or more enzyme levels within normal ranges may be related to one or more types of PCBs in the blood. In order to identify the enzyme system that is induced by the various chlorinated farms of biphenyls, Alvares et al. (1977) tested the induction of liver cytochrome P-450 and P-448 by Aroclor 1016 in rats and in workers occupationally exposed to the agent, in rats, the lower chlorinated PCB elicited a barbi turate type of effect on the oxidative enzyme system inducing cytochraxe P-450, ethylmorphine-U-demethylase, and microsomal pro tein. Unlike Aroclor 1254, which induces both P-450 and P-448, the rats with Aroclor 1016 showed little effect on benzo<a)pyrene HONS 017428 187 hydroxylase activity, which suggests little induction of P-448 by the chemical. The tests in exposed workers were conducted by determining the half-life of the antipyrine whose metabolism is stimulated by the barbiturate class of inducing substances. The workers had a significantly shorter metabolic half-life of the drug than the controls suggesting that the Aroclor 1016 had induced cytochrome P-4 SO. In a study of 458 community residents in a town that had high levels of PCBs in fish, Kreiss et al. (1981) found a correlation between PCBs as measured against Aroclor 1260 and GGTP. There were no correlations with other liver enzymes. Corrections were made for several other variables such-as age, sex, fish and alcohol consumption, and obesity. In summary, the data from the studies of liver en zymes and function suggest that the populations exposed to PCBs usually do not have clinical liver disease, although in one study there was asymptomatic hepatomegaly (see Table 8). Few of the early studies allow us to separate the various homologues of PCBs in order to correlate enzyme response to level of chlorina tion of PCBs. Recent studies suggest that SCOT and/or GCTP are the most sensitive markers of change in the liver enzyme sys tems related to PCB exposure. In the studies that included extensive testing of all enzyme systems as well as characteri zation of the PCBs, the data have inconsistencies that do not allow us to judge clearly the level or the specific type of HONS 0W*29 188 - PCB that ts related to increased levels of specific liver en zymes. Many of the studies have not corrected for other con founding variables such as alcohol consumption. The data are suggestive that there are changes in one or more liver enzysies related to PCB exposure that are not associated with disease and may occur at levels below those at which chloracne occur. D. Lipid Metabolism The long-term studies of patients with Tusho disease have revealed several other abnormalities, among which were elevated blood triglycerides (Urabe et al., 1979). In recent reports of individuals exposed to PCBs, assessment of lipid metabolism has indicated some abnormalities, but in general no clinical manifestations of these abnormalities such as increased risks of cardiovascular disease have been noted. Some of these studies are summarized in Table 9. | HONS 017430 I I I * Study Hater Sabjacts Hesegawa et il. . 1972 Her* t al., 1973 119 Mwf9i Ddm PP<> Tat. 3703 Tat. 7-300 TfaU 9 Hold Studies Correlation or alavatlaa of lipids Triglycerides Cholesterol M-'hol. L-Chol. It..- LOL- Oacr. Oacr. H.T. Oacr. lacr. N.T. H.T. H.T. NoUS OMaaraer et *1 .. 37 Tot. 4 M.T. Horae 1 H.T. H.T. 1973 flschbetn et il ..321 1979 to 124 HI 49 Reported at t abova nonee1 10.5* 17.9* No coapartson with | control. No correction 1 for confounding variables Haker at al., 1990 99 sludge users 19 workers 19 worker faa. 22 casualty Tot. 17.4 75.1 33.6 24.4 Ml (10.1 (26.5 (14.9 (12.9 fos. Coopered for ll-PCB onl) Hone sl. nag. H.T. Analysed only on non- (MS) alcohol drinkers He other variables controlled. Saltk at > 224 1991a to 50-502 ao/al Nag. HI 22-51 Ns. Mom Hone Moae -Corrected for other Pas. Hone Haoa variables i HONS 017431 o 2 in I i II o I Kj - 193 Hasegawa e al. (1972) had noted changes in lipid metabolism of Yusho patients as manifested by decreases in the blood levels of cholesterol, triglycerides, phospholipids and beta-lipoproteins. Other studies such as that of Hara et al. (1973) on Yusho patients had noted elevated triglycerides in SSI of subjects who had blood fobs 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 more mg/100 ml were found in 17.81 of workers and triglyceride levels of 200 or more mg/100 ml were reported in 10.51 of the popula tion. The total lipids were elevated (above 1 g/100 ml) in 3.41 of the papulation. These metabolic parameters, however, are influenced by age, personal habits, and the presence of other diseases; it is therefore essential that the data be compared 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 wars not made, no conclusions can be drawn from these observations. In the study of Baker et al,. (1980) in which PCBccntaminated sludge users were compared to exposed workers, their families and community controls, there was a highly significant HONS 017433 L. 194 positive correlation of plasma triglycerides and serum H-PCB. This correlation was strengthened when alcohol consumers were removed. There was a negative correlation of HDC. cholesterol with H-PCBs that was not statistically significant. The investi gators suggested that the mean level of serum PC8 in fasting subjects with hypertriglyceridemia was only 2S.0 ppb which is lower than the levels at which this abnormality was noted in previous studies (50-200 ppb, NIOSH document). It is not clear, however, whether the other studies with higher levels have used total PCBs, whereas this study used only H-PCBs in the correla tion analyses. The H-PCBs constitute 35 to 594 of the total mean PCBs in the groups. Personal characteristics may influence triglyceride levels, and many factors were apparently considered I by these investigators including age, sex and drinking habits. These lipid abnormalities may be occurring at the lower PCB limits, or even below those limits reported previously. Chase et al. (1981) in their study of maintenance workers exposed to PCBs found that levels of plasma PCBs were significantly correlated with triglycerides but not with choles terol. Adjusting for age or length of employment does not change the significance of this correlation. The triglycerides sre not significantly correlated with fat PCB levels. As mentioned pre viously the levels of plasma PCBs in this group of workers is low (33.4 ppb). MOHS 012434 195 Smith et _1. (1981a), in the study of 224 workers frost a capacitor manufacturing plant, found that serum PCBs were correlated with measures of lipid metabolism. Corrections were made for 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 clinical dis ease in relation to the elevated lipids. It was noted that several of the lipid measurements were correlated with GGTP level. As the authors suggested, this may indicate that PCBs induce hepatic microsomal enzymes, as has been found in labo ratory animals and man, and these in turn may 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 PCB levels that conflicted with data from the 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 MOMS 017435 196 one facility even though the levels of the biphenyls in the blood were similar in the two populations. High density lipo proteins were negatively correlated with H-PCBs in only one establishment. In this case, the other facility also demon strated a similar negative relationship but the level of the correlation was much lower. Smith et al. (1981c) have combined the data from these two studies and corrected the results for only age, sex and study site. Under these circumstances there were less con flicting data in the correlations. Only one significant corre lation with L-PCB was noted and that was a positive correlation with cholesterol at the private utility. Both cholesterol and log triglyceride were associated with H-PCBs at the equipment manufacturing site. Triglycerides and H-PCB were positively correlated and HDL-cholesterol and H-PCB negatively correlated at the municipal utility site. Combining the data from all study sites indicated that log triglyceride was significantly associated with both L-PCB and H-PCB but the trend for all sites was homogeneous only with L-PCB. Log HDL-cholesterol was significantly and negatively associated with H-PCBs and this trend was consistent across all sites. There was no significant relationship of PCBs with total cholesterol. Kreiss et^ al. (1981) have studied a community where high levels of PCBs and DDT were founds in fish. Among the 498 participants, there was a positive correlation between cholesterol HONS 017936 197 and PCBs measured as Aroclor 1260. There was no additional contribution by serum triglyceride or HDL-cholesterol to the prediction ol 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 homologues of PCBs and occurs in some cases with blood levels of H-PCB at 25 ppb or below. The data associating HDLcholesterol and H-PCBs are not as often significantly correlated, but when they are, the relationship is negative. Lower levels of HDL-cholesterol 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 the specific lipid changes observed would suggest that there may be a confounding variable that has been ignored and that is influencing these relationships. A positive correlation of blood lipids with plasma PCB levels could in part be a consequence of the ten dency of PCBs to distribute equally among all lipid pools in the oody. E. Reproductive Effects Very few papers have addressed the problems of human reproductive effects related to PCB ingestion. The early paper MOHS 017437 198 by Kuratsune (1972) on the Yueho patients had indicated that out of 11 women patients and two of the wives of patients who were exposed at any time during pregnancy, there were 10 live born and two stillborn infants and three of the live born were small for their age. The authors do not provide comparison figures on reproductive outcomes for that area of Japan so that it is impossible to assess the meaning of these figures. It is clear, however, that for all babies whose records were reviewed, skin staining and eye discharge were usually present. Kreiss et al. (1981) simply indicated that there was no association of miscarriage, still birth or infant death rate independent of age effects in a study of a community with high PCB levels. In gen eral, the data on reproductive effects from exposure to PCBs are k limited. F. Hematology and Immunology Host of the studies of hematological effects have found no abnormalities and these observations have been made in simple statements. The studies of Kitanura et al. (1973), Buxqarner et al. (1973), Karppanen and Kolho (1973), Fischbein et al. (1979), Baker et al^. (1980), and Naroni et al. (19B1) have not revealed any abnormalities of hemoglobin or leukocytes. Ouw et al. (1976) reported several protein and globulin tests on exposed workers that were higher or lower than the reported normal. However, the overall levels of globulins were not different in two groups of workers with high and low exposures. In the initial abstract HONS 017938 199 relating to the Baker et al. (1980) study, the authors reported increesed hematocrit and hemoglobin In relation to PCB levels controlled for 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 hematocrit 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- o tlons 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-hydroxysteroids. G. Other Factors Kreiss et al. (1981) in the study of a PCB-exposed 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 017439 - 200 correlation between diastolic blood pressure and h-pcb but this disappeared when corrected for age. Other investigators have not found this relationship, so the difference may be associated with an unrecognized interrelated variable or a chance association related to the multiplicity of factors that have been e'xamined. Marshaw et al. suggested that workers in a capacitor manufacturing plant (population of Fischbein et al.) had de creased vital capacity and restrictive impairment of lung func tion in the absence of signs of radiographic change (Marshaw et al., 1979). They have compared the FVC to that of other worker populations in previous hazardous exposure studies as well as to a non-smoking normal population. The reported percent abnor mality of PCB workers is 14% compared to 5.6% cited for non smoking populations. The comparisons do not indicate that they have been controlled for smoking habits and sex. Host studies have reported no clinical disease in PCBexposed populations with the exception of Vusho disease and chloracne (Karppanen e al,.> Humphrey, Smith et al.; Chase et al.,; Kreiss et al^.). Some have reported symptoms that are difficult to evaluate since most are subjective and could be related to worker bias. Fischbein at al. suggested that neurological symp toms were increased but there is no similar group with which to compare workers and thus make this assessment. Smith et al. MQNS 017440 201 (1981) in the study of the combined work sites found that cough ing at work and irritated eyes were related to both L-PCB and H-PCB. Loss of appetite and peripheral 'tingling' were associated only with L-PCB. History of skin rash was associated only with H-PCB. Many of these differences were not observed when individual work site data were analyzed separately. The lack of a difference in each site may result because jobs were included as a confounder variable. Most studies have not even reported any symptoms or history of disease (Baker et al. and Kreiss et al.) In all studies reviewed there was little evidence of clinical disease with the exception of chloracne and this condi tion seemed to be most frequent under specific conditions of exposure. The other common but not consistent findings were abnormalities of lipid metabolism, especially blood triglyceride levels, and abnormalities of liver enzymes, especially SCOT and CGTP, which were related to levels of PCBs. The lipid and liver changes appeared to occur at lower levels than the skin manifes tations and were not associated with clinical disease or symptoms. HONS 017441 -203- XIII REFERENCES ALLEN, J.R. and ABRAHANSON, L.J. (1979). Responses of rats exposed to polychlorinated biphenyls for fifty-two weeks, ll compositional and ensyaatic changes in tha livar. Arch. Environ. Contaa. Toxicol. 8, 191-200. ALLEI.. J.R., AURAHAnSON, L.J. and NORBACK, D.H. (1973). Biological affacts of polychlorinatad biphenyls and triphanyls on the subhunan primate.. Environ. Res. 4. 344-3S4. ABRAHAHSON, L.J. and ALLEN, J.R. (1973). The biological response of infant nonhunan priaatas to a polychlorinated biphenyl. Environ. Health Perepect.. Experimental Issue No. 4, 81-8?. 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LEVINSKAS, G.J. (1981). Toxicity of Aroclor products 1242, 1254 and 1260 to the liver of albino rats. Unpublished. Report dated Oct. 14, 1981. LINDER, R.E., GAINES, T.B. and KIMBROUGH, R.D. (1974). The effect of polychlorinated biphenyls on rat reproduction. Fd. Coamet. Tox icol. 12, 63-67. LXTTEREST, C.L. et al. (1972). Effect of polychlorinated biphenyls on hepatic microsoawl enxyxMS in the rat. Toxicol. Appl. Pharmacol. 23, 112-122. LOOSE, K.L., PITTMAN, K.A. et al. (1977). Polychlorinated biphenyl and hexachlorobensene induce? Kumoral immunosuppression. J. Reticulo- endothel. Soc. 22. 253-271. ~ LOOSE, L.D., SILKWORTH, J.B. et al. (1978). Impaired host resis tance to endotoxin' and malaria in polychlorinated biphenyl and hexa chlorobensene treated mice. Infect. Irnmun. 20, 30-35. MONS 017*53 -215- LUCIER, C.W. et al. (1978a). Structural requirements for the accumu lation of chlorinated biphenyl metabolites in the fetal cat intestine. Drug Metab. Dlsp. 6, 548-549. LUCIER, C.W. et al. (1978b). Transplacental toxicology of the poly chlorinated an? polybrominated biphenyls. 17th Hanford Bioloqy Symposium-Developmental Toxicology of Energy-Related Pollutants. LUTZ, R.J. et al. (1977). A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. Drug Metab. Disp. 5, 386. ----- ~ McCONNELL. E.E. and MOORE. J.A. (1979>. Toxicopathology character istics of the halogenated aromatics. Health Effects of the Halogensted Aromatic Hydrocarbons (W.j. Nicholson and~3.X7~Hoore, eds.), pp. 156-150 New Vork Academy of Sciences, NY. MCMAHON, R.E., CLINE, J.C. and THOMPSON, C.Z. (1979). Essay of 855 test chemicals in ten tester strains using a new modification of the Ames test for bacterial mutagens. Cancer Res. 39, 682-693. MARKS, T.A., KIMMEL, G.L. and STAPLES, R.E. (1981). Influence of symmetrical polychlorinated biphenyl isomers on embryo and fetal development in mice. I. Teratogenicity of 3,3',4,4',5,5'-hexachloroblphenyl. Toxicol. Appl. Pharmacol. 61/ 269-276. MARONI, M., COLOMBI, A., CANTONI, S., FERI0L1, E. and FOA, V. (1981a) Occupational exposure to polychlorinated biphenyls in electricsl workers. I. Environmental and blood polychlorinated biphenyls concentrations. Brit. J. Ind. Med. 38, 49-54. MARONI, M., COLOMBI, A., CANTONI, S., FERIOLI, E., and FOA, V. (1981b Occupational exposure to polychlorinated biphenyls in electricsl work ers. II. Health effects. Brit. J. Ind. Med. 38, 55-60. MASUDA, Y., KAGAWA, R. and KUROKI, H. (1978). Transfer of poly chlorinated biphenyls from mothers to fetuses and infants. Fd. Cosmet. Toxicol. 1. 543-546. MASUDA et al. (1979). Transfer of various polychlorinated biphenyls to the Zetuses and offspring of mice. Fd. Cosmet. Toxicol. 17, 623 627. MATTHEWS, H.B. and ANDERSON, M.W. (1975). Effect of chlorination on the distribution and excretion of polychlorinated biphenyls. Metab. Dlsp. 3. 371-380. MATTHEWS, H.B. and TUEY, D.B. (1980). The effect of chlorine posi tion on the distribution and excretion of four hexachlorobiphenyl isomers. Toxicol. Appl. Pharmacol. 53. 377-388. HONS 017454 -216- MATTHEWS, H.B. et al. (1978). Metabolism and biochemical toxicity of PCBs and pbbs. "Environ. Health Persgect. 24, 147-155. MAYERS, M.R., SILBERBERG, M.G. (1938). Skin conditions resulting from exposure to certain chlorinated hydrocarbons. j. ind. Hyq. Toxicol. 20, 244-258. ~ ----- MEIGS, J.W. and ALBOM, J.J. (1954). Chloracne from an unusual expo sure to Aroclor. J. Am. Med. Assoc. 154, 1417-1418. MES, J. and DAVIES, D.J. (1979). Presence of polynchlorinated biphenyls and organochlorine pesticide residues and the absence of polychlorinated terphenyls in Canadian human milk samples. Bull. Environ. Contain. Toxicol 21, 381-387. MILLING, A. et al. (1979). Comparative metabolism of 2,2'-dichlorobiphenyl-14C in mice, rata, and rhesus monkeys after single oral application. Chemosphere 1, 15-19. MXZUTANI, T. et al. (1980). Comparative study on accumulation and elimination o?~hexachlorobiphenyls and decachloroblphenyl in mice. Bull. Environ. Contam. Toxicol. 25, 181-187. MORALES, N.M. and MATTHEWS, H.B. (1979). In vivo binding of 2,3,6,2',3*,61-hexachlorobiphenyl to mouse liver macromolecules. Chem. Biol, Xnterac. 27, 99-110. * ' MOR1TA, M. and 01SH1, S. (1977). Clearance and tissue distribution of polychlorinated dibenzofurans in mice. Bull. Environ. Contam. Toxicol. 18, 61-66. . MURPHY, M. et al. (1979). Potentiation of fluroxene toxicity with polychlorinate3~biphenyls. Toxicol. Appl. Pharmacol. 48, 87. NARBONNE, J.F. (1979a). Effects of age and sex on liver response to Phenoclor DP6, a polychlorinated biphenyl, in the rat. Bull. Environ. Contam. Toxicol. 22. 49-54. NARBONNE, J.F. (1979b). Effect of polychlorinated biphenyls on in vitro amino acid incorporated into liver proteins. Bull. Environ. Contam. Toxicol. 21, 322-327. - NARBONNE, J.F. (1979c). Effect of polychlorinated biphenyls on in vivo protein and RNA synthesis in rat liver. Bull. Environ. Contam. Toxicol. 23, 36-43. NARBONNE, J.F. (1979e). Turnover of liver proteins in Phenoclor DP6-treated rats. Toxicol. Appl. Pharmacol. 47, 245-252. HONS 012455 -217- NARBONNE, J.F. (1980) Time course of induction of microsomal onzymes following dietary administration of a polychlorinated biphen yl. Toxicol. Appl. Pharmacol. 56, 1-7. NATIONAL CANCER INSTITUTE. (1978). Bioassay of Aroclor 1256 for possible carcinogencity, No. 38, NEW. NIOSH. (1977). Criteria for a Recommended Standard .... Occupational Exposure to Polychlorinated Biphenyls (PCBs). PB 276849, NIOSH77-225. NIOSH. (1977a). Industrial hygiene survey of Aerovox Industries, Inc., New Bedford, Hass. (Nov. 29, 1977). NIOSH. (1977b). Industrial hygiene survey of Westinghouae Electric Corp., Bloomington, Ind. (Dec. 1, 1977). NIOSH. (1977c). Health hazard evaluation determination report number 76-S2-386, Westinghouse Electric Corp., Bloomington, Ind. (April, 1977). NIOSH. (1980). Hazard evaluation and technical assistance report. TA 79-58. OERBERG, J. (1978). Effect of pure chlorobiphenyls on the repro ductive capacity in female mice. Acta Pharma. Toxicol 42, 323 327. OISHI, S. and HIRAGA, K. (1980). Effect of polychlorinated biphenyl, dibenzofuran and dibenzo-p-dloxin on the susceptibility of male mice to endotoxin. J. Environ. Science Health 15, 77-85. OISHI, S. et a_l. (1978). Comparative toxicity of polychlorinated biphenyls and dibenzofurans in rats. Toxicol. Appl. Pharmacol. 43, 13-22. OUW, H.X., SIMPSON, G.R. and SIKALI, D.S. (1976). The use and health effects of Aroclor 1242, a polychlorinated biphenyl in the electrical industry. Arch. Environ. Health H, 189-194. PANEL ON HAZARDOUS SUBSTANCES. (1972). Polychlorinated biphenyls: environmental impact. Environ. Res. 5, 249. PARKINSON, A. et al. (1980). Polychlorinated biphenyls as inducers of hepatic microsomal enzymes: Structure-activity rules. Chem. Biol. Interac. 30, 271-285. PUCCINELLI, V. (1954). On chloracne. (ted. d. Lavoro. 45, 131. HONS 017456 -218- RAPPE, C. et al. (1979). Identification of polychlorinated dibenzo- furana (PCEFs) retained in patients with Yusho. Chemosphere 4, 259-266. " REUBER, M.D. (1968). Histogenesis of cholangiofibrosis and welldifferentiated cholangiocarcinoma in Syrian hamsters given 2-aceta- midofluorene or 2-diacetamidofluorene. Gann 59, 239. RYAN, O.E. et al. (1979). Separation and characterization of highly purified forms of liver microsomal cytochrome P-450 from rats treated with polychlorinated biphenyls, phenobarbital, and 2-methylchloanthrene. J. Biol. Chea. 254, 1365-1374. SAFE, S. (1980). Aafeient water quality criteria for poly chlorinated biphenyls. EPA 440/5-80-068, p. C-60, U.S. Environmen tal Protection Agency, Washington, D.C. SAFE, S. et al. (1975). The mechanism of ehlorobiphenyl metabolism. J. Aqrlc.~Td~Chea. 23, 851-853. SCHMOLDT, A. et al. (1979). Impaired biliary excretion of digitoxin and its metabolites after treatment with polychlorinated biphenyls. Toxicol. Appl. Pharmacol. 47, 483-491. SCHOENY, R.S., SMITH, C.C. and LOPER, J.C. (1979). Non-mutageni- * | city for Salmonella of the chlorinated hydrocarbons Aroclor 1254, * 1,2,4-trlcblorobensene, Nirex, and Kepone. Mutation Res. 68, 125-132 SCHWARTZ L. (1936). Dermatitis from synthetic resins and waxes. Am. J. Public Health 26, 586-592. SHIMADA, T. and SATO, R. (1980). Covalent binding of polychlori nated biphenyls to rat liver microsomes. Toxicol. Appl. Pharmacol. 55, 490-500. SHIOTA, K (1976b). Embryotoxic effects of polychlorinated biphen yls (Kanechlors 300 and 500) in rats. Okajiiaae Fol. Anat. jpn. 53, 93-104. SIPES, I.C. jt (1. (1980). 4,4'-dichlorobiphenyl Distribution, metabolism, and excretion in the dog and the monkey. Toxicol. Appl. Pharmacol. 55, 554-563. SMITH, A.B., SCHLOEMER, J., LOWRY, L.K., SMALLWOOD, A.W., LIGO, R.N.. TANAKA, S., STRINGER, W., JONES, M. and GLUECK, C.J. (1981a). Cross-sectional medical survey of a group of workers occupationally exposed to polychlorinated biphenyls (PCBs) at an electrical equip ment manufacturing plant. Draft report prepared by National Insti tute for Occupational Safety and Health, Division of Surveillance, Hazard Evaluations and Field Studies, Cincinnati, OH, and Lipid Re search Center, University of Cincinnati Medical Center, Cincinnati, OH. (51 pages, 12 tables, 4 figures.) HONS 017457 -219- SMITH, A.B., SCHLOEMER, J., LOWRY, L.K., SMALLWOOD, A.W., LICO, R.N., TANAKA, S., STRINGER, W., JONES, M., HERVIN, R., and GLUECK, C.J. (1981b). Cross-sectional medical survey of two groups of workers occupationally exposed to polychlorinated biphenyls (PCBs) in the maintenance, repair, and overhaul of electrical transformers. Draft report prepared by National Institute for Occupational Safety and Health, Division of Surveillance, Hazard Evaluations and Field Stud ies, Cincinnati, OH, and Lipid Research Center, University of Cincin nati nedical Center, Cincinnati, OH. (36 pages, 14 tables.) SMITH, A.B., SCHLOEMER, J., LOWRY, L.K., SMALLWOOD, A.W., LICO, R.N., TANAKA, S., STRINGER, W., JONES, M. , HERVIN, R., and CLUECK, C.J. (1981c). Metabolic and health consequences of occupational exposure to polychlorinated biphenyls (PCBs). Draft report prepared by National Institute for Occupational Safety and Health, Division of Surveillance, Hazard Evaluations and Field Studies, Cincinnati, OH, and Lipid Research Center, University of Cincinnati Medical Center, Cincinnati, OH. (58 pages, including 8 tables.) SMITH, A.B. et al. (1978). Lipid lipoprotein alterationi Occupa tional exposure~To polychlorinated biphenyl. Clin. Res. 26, S49A. SMITH, D.M. (1968). The effect of the time of estrogen injection on implantation in ovariectooized pregnant mice. J. Endo., 41, 11-15. ~ SQUIRE, R.A. and LEVITT, M.H. (1975). Classification of specific hepatocellular lesions. Cancer Res. 35, 3214-3223. STEWART, H.L. and SNELL, K.C. (1957). The histopathology of exper imental tumors of the liver of the rati A critical review of the histopathogenesis. Acta Unlo Internatlonalls Contra Canerum 13, 770. STREET, J.C. and SHARMA, R.P. (1975). Alteration of induced cellular and humoral immune response by pesticides and chemicals of environ mental concern! Quantitative studies of immunosuppression by DDT, Aroclor 1254, carbaryl, carbofuran, and methylparathion, Toxicol. Appl. Pharmacol. 32, 587-602. STRIK, J.J.T.W.A. (1979). Porphyrins in urine as an indication of exposure to chlorinated hydrocarbons. N.Y. Acad. Sciences. SUNDSTROM, G. et al. (1976). The metabolism of chlorobiphenyls A review. ChemospKere 5, 267-298. TAYLOR, J.S. (1979). Environmental chloracne: Update and overview. Ann. N.Y. Acad. Sciences 320, 295-307. THOflAS, P.T. and HINDSDILL, R.D. (1978). Effect of polychlor inated biphenyls on the imsune responses of rhesus monkeys and mice. Toxicol. Appl. Pharmacol. 44. 51. HONS 017458 -220- TILSON, H.A., OAVIS, G.J., McLACHLAN, J.A. and LUCIER, G.W. (1979). Tha effects of polychlorinated biphenyls given prenatally on the neurobehavioral development of mice. Environ. Res. 16, 466-474. TOERUEK, P. (1973). Effect of PCB on the developing mouse. Chemosphere 2, 173. TOROK, P. (1976). Delayed pregnancy in NMRI mice treated with PCB 2,2,-dichlorobiphenyl. Bull. Environ. Contam. Toxicol. 16, 33-36. TUEY, D.B. and MATTHEWS, H.B. (1977). Pharmacokinetics of 3,3',5,5'tetrachlorobiphenyl in the male rat. Drug. Metab. Dlsp. 5, 444. URABE, H., KADA, H. and ASABI, M. (1979). Present state of Yusho patients. Ann. N.Y. Acad. Sciences 320, 273-276. VAN MILDER, J.P. et al. (1975). Distribution and metabolism of 3H-2,5,2',S'-tetrachlorobiphenyl in rats. Proc. Soc Exp. Biol. Med. 148, 682. VEERKAMP, W. et al. (1981). The metabolism of some chlorinated dibenxofurans~Ey rats. Chemosphere 10(4), 397-403. VILLENEOVE, D.C., GRANT, D.L., KHERA, K., CLEGG, D.J., BAER. H., PHILLIPS, W.E.J. (1971a). The fetotoxicity of a polychlorinated biphenyl mixture (Aroclor 1254) in the rabbit and in the rat. Environ. Physiol. 1, 67-71. VOS, J.G. (1972). Toxicology of PCBs for mammals and for birds. Environ. Health Perspect. 1, 105-117. VOS, J.G. and KOEMAN, J.H. (1970). Comparative toxicologic study with polychlorinated biphenyls in chickens with special reference to porphyria, edeaM formation, liver necrosis, and tissue residues. Toxicol. Appl. Pharmacol. ,17, 656-668. VOS, J.G. and BEEMS, R.B. (1971). Dermal toxicity studies of tech nical polychlorinated biphenyls and fractions thereof in rabbits. Toxicol. Appl. Pharmacol. 19, 617-633. VOS, J.G. and VAN DR1EL-GROOTENHUIS, L. (1972). PCB-induced suppres sion of the humoral and cell-mediated immunity in guinea pigs. Sci. Total Environ. 1, 289-302. VOS, J.G. and NOTENBOOfl-RAM, E. (1972). Comparative toxicity study of 2,4,5,2' ,4*,5'-hexachlorobiphenyl and a polychlorinated biphenyl mixture in rabbits. Toxicol. Appl. Pharmacol. 23, 563. HONS 017459 -221- VOS, J.C., KOEftAN, .7.11. . VAN DER HAAS, II. L., TEN NOEVER DC RRAI1W, M.C. and Ut VIJS, R.ll. ( 1970). Ident i icat ion and toxicological evaluation of chlorinated dihenzofuran and chlorinated naphthalene in two commercial polychlorinated biphenyls, Fd. Cosmet. Toxicol. 8, 625-633. -- ------------- - ---------------- WATANABE, 1. et^ al. (1980). Distribution differences between poly chlorinated terpKenyls and polychlorinated biphenyls in human tissues. Bull. Environ. Contam. Toxicol. 25. 810-815. WICKIZER, T.M. et al. (1981). Polychlorinated biphenyl contamina tion of nursing mothers' milk in (lichigan. Am. J. Public Health 71. 132-137. ~ ~ ----------------------- WOLFF, M.S., FISCHBEIN, A., THORNTON, J., RICE, L., LIUS, R. and SEL1KOFF, l.C. (1981). Body burden of polychlorinated biphenyls among persons employed in capacitor manufacturing. Submitted for publication to Int. Arch, Occup. Environ. Hlth. Presented in part at the XIX International Congress on Occupational Health, Dubrovnik, Sept., 1978. UYNDHA11, C., DEVENISH, J. and SAFE, S. (1976). The in vitro nctar- olism, macromolecular binding, and bacterial mutagenicity of 4-chlorobiphanyl, a model PCB substrate. Res. Commun. Chem. Pathol. Pharmacol. 15, 563-570. YAKUSHIJJI, T. et al. (1978). Long-term studies of the excretion of polychlorinated~Eiphenyls through the mother's milk of an occu pationally exposed worker. Arch. Environ. Contam. Toxicol. 7, 493-504. ~ YAMASHITA, F. (1977). Clinical features of polychlorobiphenyls (PCB)-induced fetopathy. Pediatrician 6, 20-27. YOSHIHARA, S. et al. (1979). Toxicological assessment of highly chlorinated bipKenyl congeners retained in the Yusho patients. Chemosphere 8, 531-538. HONS 017460 XIV. dowry of Term or Abbreviations AK BSP GGTP H-PCBs L-PCBs LDH PCBa PCDFs PCNa PCQe PCTa SOOT 6GPT SOCT Yuaho ro Fla, Fib alkaline phosphatase bromsulfonphthalein liver function test gamma glutamyl transpeptidase PCBa with high degrees of chlorination PCBa with lower degrees of chlorination lactic dehydrogenase polychlorinated biphenyls polychlorinated dlbenzofurans polychlorinated naphthalenes polychlorinated quaterphenyls polychlorinated terphenyls serum glutamic oxalic transaminase serum glutamic pyruvic transaminase serum ornithine carbamoyl transferase the diaease.noted in Japan following human ingestion of cooking oil contaminated with PCBa, PCDFs and FCOs parental tast animals litters derived from first generation animals at their first (a) and second (b) matings HONS 017461 61 V. Skin and Other Cutaneoua Tiaauee Epithelial and follicular hyparplaaia and hyper- karatoala hava baan raportad to occur following tha application of PCBa on tha akin of rabbita (Voe and Beeaa, 1971). Skin laalona hava also baan obaarvad in rata and guinaa pigs from tha application of PCBa. Rapeated application of Aroclor 1260 to tha akin of rabbita cauaad thickaning of tha akin aa a raault of hyparplaaia and hyparkaratoaia of tha epitheliua (Voa and Baaaa, 1971). Cutanaoua affacta hava baan alicitad in mala rhaaua aonkeya fad a diat containing 300 ppai Aroclor 1248. Nlthln ona aonth tha aniaala loat conaidarabla hair fro* tha haad, nack and back (Allan at al., 1973. 1975). Siailar affacta hava baan obaarvad in faaala rhaaua aonkeya-^ed a diet containing 25 ppa Aroclor 1248 for two aontha (Allan at al., 1974). Within aix waaka tha aniaala began to lose hair and developed obvioua aigna of adaaa of tha 11pa and eyalida. Saall puatulaa involving hair folliclea appeared about tha aouth, chtaka and neck. Abrahaa and Allan (1973) ahowad that tha infant aonkey waa able to tolerate doaea of PCBa that produce extreae aorbidlty in adult aonkeya. They euggeated that there aay be variationa in abaorp- tlon, diatrlbutlon, aetaboliaa, atorage and excretion in adult and Infant aonkeya that aay account for thaaa dlffarencaa. Follicular hyparkaratoaia la an laportant feature of tha occupational dlaeaae known aa acne, which ia characteriaad by tha appearance of papulea, coaedonea and cyata. induatrlal HONS 017323 62 dermatosis of the acneform type has been observed among workers exposed to chlorinated hydrocarbons (Jones and klden, 1936> Mayors and Silverberg, 1938; Maronl et il., 1981). Seven cases of chloracne of the face and head have been reported among 14 chemical operators exposed from 5-19 months intermittently to low concentrations of chlorinated biphenyls (Meigs and Albom, 1954). Fuccinelli (1954) and Hofman at al. (1962) report ehloracne in several capacitor workers, whereas Smith et al. (1981) noted that none of the capacitor workers examined in this recent survey were found to have acneform lesions suggestive of chloracne. The acneform eruptions that occur in the skin of both monkeys and rabbits may be caused by a squamous metaplastic change in the epithelium lining the sebaceous glands, which result in a change in the character of the secretion from normal oily to keratinaceous. This condition frequently results in plugging and rupture of the glands with consequent inflammatory reactions (acne). The question of whether a similar condition can occur in man from exposure to pcbs will be dealt with in another section of this report. It has been suggested that the cutaneous eruptions that occur in both animals and man from exposure to commercial preparations of PCBs may be due to certain impurities. Chemical analysis of the pcbs that contaminated the rice oil that caused the Yusho disease in Japan showed high levels of polychlorinated dibenxofurans (Kuratsune, 1976). HONS 017324 <3 VI. Effect of PCBs on Liver A. Experlmental Data 1. Liver Wight The administration of PCBs may Induce an increase in liver weight (Table 1). The effect is more prominent at the higher dose levels; the lower doses of PCBs do not increase liver weight. The detailed data of Kimbrough et al. (1972) are not Included in the table. They found that Aroclor 1260, administered with the diet in doses of 500 and 1000 ppm for eight months, significantly Increased liver weight in male and female rats) doses of 20 and 100 ppm were effective only In male rats. Aroclor 1254 increases liver weight in both male and female rats at doses of 20, 100 and 500 ppm. Although the data in Table 1 illustrate the effect obtained in subchronic and chronic studies, it should be noted that liver weight may also be increased in acute toxicity studies. PCB congeners (penta-, hexa-, and heptachlorobiphenyls) given in a high single dose of 50 mg/kg, can increase liver weight in the rat; in most but not all tests, liver triglycerides, cholesterol and phospholipids were Increased (Yoshihara et al., 1979). in the monkey a single oral dose of 1.5 g or 3.0 g/kg of Aroclor 1254 produced slight enlargement of the liver in 4 days (Allen, Norback and Hsu, 1974). The increase in liver weight is correlated with hepatic cell hypertrophy and an increase in smooth endoplasmic reticulum HONS 017325 (S Table 1 Effect of 90s on Liver Weight and Moroholoev Wsight Changss +*incr*M 0-no chsngs Stadia* in Mica Major Histolog leal findings Hiabrough ( Lindsr, 1974, Aroclor 1254 Stadias la Rats Pleomorphism, naerosis Sannatt, at al., 9CS, 45% "cl _ 300 ag 250 mg 4 days to 100 Aay + Colls swollaa, hyalins gran9olas Xsplia^ar at al. 100 ppm 19 Booths + Arr-lor 1254, 12S0 10 ppm 1 IV- Aroclor 1242 100, 10, 1 ppm IS months It aoaths It aoaths' 0 0 0 Idttarast at al., 1972 Aroclor 1242, 1241 1254, 1240 500 ag 50 ag S ag 0.5 ag 4 waaks 4 weeks 4 waaks 4 waaks + + 0 0 Allan a Abrghaasoa, 1973, . Aroclor 1241, 1254, 1242 0.1 la. diat raekaor at al., tl973)_ v100 ag/k traxy 2nd Aroclor 1242 day n - isr at al. ')l*74 25 ppm 5 ppm 4 waaks 3 waaks 2,4,4 months f Fat droplets, areas of necrosis + Sodaaophille vacnolatica 0 HONS No change with BCE stain, increa lTiWpiad*a4with Sodaa 017326 carrnrozD - 67 Table 1 CgOHTIWPgP) Effect of Kk on Liver weieht and Morpboloer Suras st al., Areelor 1242, 1016 st al., l Areelor 12CO bexachlorobiphenyl KoUtr 4 Sinkl, 1973 Areelor 1254 Areelor 1242 Aroelor 1221 Allan at al.. 1973 Axodor 1241 Areelor 5460 Weight Changes +increase 0no change Stadias in Rats (Continued) Major Histolc ical findings 100 ppe up to 10 Months in Rabbits ! m 0 Enlarged hepatoeytes, waceolatad cytoplasm ehanetsrlieO as mild changes 120 deraal 4 weeks 5 x week + Hydropic degae oration, noexos 300 ag once/wk a. a 14 weeks 99 99 99 Stadias in the Monkey 300 ppe 5000 ppa 90.days >a a + Enlarged bepato cytas, necrosis + Enlarged bepato cytea, seen necrosis 0 Mo histological change + Enlarged bepatocytas, no naero + a MOWS 0X7327 Table 1A Liver Lesions in Albino Rats Treated with Aroclors for 2 Years (Data from Levinskas, 1981) Diet level, ppm Control 0 Ho. animals examined Vacuolar change Focal necrosis Focal lymphoid infiltration Focal hypertrophy hepatocytes Nodular hyperplasia Ductal hyperplasia Hepatoma Cholangiohepatoma Hepatocellular carcinoma 23 1 1 1 0 1 5 0 0 0 Aroclor 1242 1 10 100 32 29 78 11 00 23 i1 33 00 00 00 16 9 0 0 8 8 3 3 1 0 Aroclor 12S4 1 10 100 30 26 79 31 20 34 03 63 00 00 00 26 13 1 1 14 14 14 4 2 0 *The results of this study were presented in a summarized form (T/) by Calandra (1975) and were later reanalysed and tabulated by Levinskas (1981). Aroclor 1260 1 10 100 26 25 57 43 01 3 13 07 67 01 00 00 25 9 6 0 9 6 12 7 4 0 - 71 - In the rat, rabbit and nonkey (voa at al., 1972; Allan and Abrahaason, 1973; Bruckner at al., 1974a; Allan, Norback and Bsu, 1974; Allan, Carstana and Baraotti, 1974). Ecobichon and Coaaau (1974a, b) found that tha affaet of PCBa adainiatered intraperitonaally on liver weight and on hepatic ensyaea aaaoclatad with hepatic endoplaaaic ratlculua waa related to tha poaltion of the chlorine aubatitution on tha biphenyl nuclaua. However, all of the congenera and laoaera adalniatared at a doae of 50 ag/kg intraperitoneally for three daya produced an increaae in aaooth endoplaaaic, lipid dropleta and alcrobodlea, although the quanti tative reaponae varied (Hanaell and Ecobichon, 1974). 2. general Hlatolooy The adainlatration of PCBa to eiperiaental aniaala will produce hlatopethologlcal changaa in tha livar. Tha aaln effacta obtained are the production of enlarged hepatocyfea, fat dropleta and alight degree of necroaia; the occurrence of thaae changaa depend particularly on the doae of the PCB and to aoee extent on the particular Aroclor (Tablet 1 and 1A). Necroaia aeeaa to be ore aevere in the rabbit than in the rat. In general, the Morphological changaa obaerved in the liver of PCB-treated aniaala arc alailar to thoae found after treataent with other chlorinated hydrocarbona. In a detailed atudy, Kiabrough at al. (1972) found that Aroclor 1240 (20, 100, 500 and 1000 ppa) and Aroclor 1254 (20, 100 and 500 ppa), given in the diet of rata for eight nontha, produced HONS 017329 72 enlarged liver cells and cytoplasmic inclusions. At the higher doses, there was evidence of lipid accumulation, which was asso ciated with a foamy cytoplasm, and pigment accumulation in the Kupffer cells. The pigsMnt gave a positive Prussian-blue reaction, indicating the presence of hemosiderin. Studies of rats four to six months after exposure to different doses of Arodors 1014 and 1242 indicated that the morphological changes are reversible and disappear gradually after dosing is stopped; the hepatocytes were still larger than controls, but the frequency of vacuolated cytoplasm or inclusions within the cytoplasm had decreased (Burse et al., 1974). Aroclor 1254 was evaluated by the National Cancer institute (1978). rlscher rats receiving 25 ppm in the diet for eight weeks had enlarged livers, but without evidence of histo logical abnormality. The administrations of doses of 25, 50 and 100 ppm for 104-105 weeks did not increase the frequency of liver lesions such as congestion, InflaxMtion, necrosis or anglectasls. 3. Adenofibrosis Adenofibrosis (synonymsi bile duct proliferation, bile duct adenomatosis, cholanglofibrosis, fibroadenoma) has been ob served in some rats receiving PCBs. Adenofibrosis is generally regarded aa a benign lesion. In their review of experimental tuanrs, Stewart and Snell (1957) stated that there is no con vincing evidence that adenofibrosis is a precancerous lesion. HONS 017330 - 73 It should be noted, however, that Reubar (1968), studying 2acetamidofluorene and 2-diacetamidofluorene, suggested that adenofIbrosis Is a precancerous lesion for the development of cholanglocarcinoma. (1) Studies In mice. Kimbrough and Linder (1974) observed foci of adenofibrosis in the liver of some mice with 300 ppm of Aroclor 1254 in the diet for 11 months. Ito et al. (1974) comment that they did not observe cholanglofibrosis in mice receiving Kanechlor. (il) Studies in rats. Kimbrough et al. (1972) observed adenofIbrosis in rats treated with Aroclor 1260 and 1254) the effect was observed at the higher dose levels and particularly in animals receiving Aroclor 1254. When the feeding of 500 ppm of Aroclor 1254 was discontinued and the animals studied up to 10 additional months, the fat and liver content of PCS remained high and the adenofibrosis persisted (Kimbrough et al., 1973). In a latar paper involving treatment with Aroclor 1260 at 100 ppm for 21 months, mention is only made that a few rats showed areas of adenofibrosis, indicating a low degree of response, but data are not tabulated (Kimbrough et al., 1975). In further studies by the same group adenoflbrosls was not ob served in rats fed Aroclor 1016 or 1242 (100 ppm) for up to 10 months (Burse et al., 1974). In a study with three Aroclors, administration of 100 ppm in the diet for 24 months produced a low incidence of HONS 017331 74 cholangiohepatcwui (Table 1A), but concentrations of 1 ppm or 10 ppm were without affect (Calandra, 1976; Levinskas, 1981). Treatment did not significantly affect ductal hyperplasia. The study of the National Cancer institute (1978) did not observe adenofibrosis in rats receiving Aroclor 1254 at doses of 25, 50 and 100 ppm for 104-105 weeks. In studies with various Kanechlors, Ito et al. (1974) administered Kenechlor 500, 400 and 300 in the diet at concentrationa of 1000, 500 and 100 ppm. At the concentration of 1000 ppm of the Kanechlors, the Incidence of cholsngiofibrosis ranged from 13 to 304 in the ratsi cholsngiofibrosis did not occur at levels of 500 or 100 ppm. Kimura et al. (1975) also reported cholsngiofibrosis in rats treated with Kanechlor 400. 4. Hyperplastic foci and Nodular Hyperplasia in the Liver___________________________________ Hyperplastic foci or hyperplastic areas represent minimal changes in the hepatocytea. Such foci or areas of hy perplastic changes are uncoauaon in untreated young rats, but increase with age. The hyperplastic areas or foci nay coexist with nodular hyperplasia and/or hepatocellular carcinoma. The significance of hyperplastic foci is that they nay be part of a spectrum capable of progressing to a nodule (Squire and Levitt, 1975). The hyperplastic nodule (nodular hyperplasia, neoplastic nodule, hepatoma) is generally as large or larger than the area of several lobules, and the lesion is sometimes elevatad above MQNS 017332 - 75 the aurfaea of tha liver. The laaion ia frequently referred to as a neoplaatlc nodule and some coneIdar it to be a manifestation of a carcinogenic process, the earlier atagea of which nay be represented by tha hyperplastic foci discussed above. The use of these tanas in the literature is confusing, as some who use the word 'hyperplastic nodule* regard the lesion to be part of the neoplastic process whereas others consider it to be unrelated to neoplasia. Some investigators use the terms adenoma or hepetoaui to designate the lesion, implying that it is a benign neoplasm. Despite the differing terminology, it may be considered that the hyperplastic foci and nodular hyperplasia (neoplastic nodules) occurring in the liver are benign lesions rather than carcinomas. However, such nodules may be part of a eeguence of neoplastic changes that eventually progress on to hepatocellular carclnoaMS. Although the data on hyperplastic foci and nodular hyperplasia are discussed in this section and hepatocarcinogenesls are discussed in section VIII, the experimental data on the inci dence of benign and malignant lesions are given in the same table so that the overell biological effect of the treatment can be observed as a unit. (i) Studies in mice. Ito et al. (1973) observed nodular hyperplasia in mice only at the highest dose level of Kanechlor 500. (Nagasaki et al., 1973, reported the sama data.) Whereas Kanechlor 500 produced nodular hyperplasia at 500 ppm, lesser doses were not active and Kanechlor 400 or Kanechlor 300 HONS 017333 - 76 - was inactive at all doses studied (Table 2). There was sene evi dence that the administration of Kanechlor S00 increased the nodular hyperplastic response induced by cfcor p isomers of benzene hesachloride. Kimbrough and Under (1974) observed adenofibrosis and hepatomas in 9 of 24 mice fed Aroclor 1254 (300 ppm in the diet) for 11 months* in animals fed Aroclor for only sis months followed by a five month recovery there was no adenofibrosis and the inci dence of hepatoma was only 1/24 mice. (ii) Studies in rats. Keplinger at al. (1971) did not observe hepatic lesions in rats receiving different Aroclors for It monthsj however, re-evaluation of the slides indicated a significant increase of nodular hyperplasia in the treated animals (see National Cancer institute, 197S). Ito et al. (1974) observed nodular hyperplasia in rats receiving 100, S00 or 1000 ppm of Xanechlor 500; a lesser effect was observed with Kanechlor 400 and there was no significant effect of Kanechlor 300. Kimbrough et al. (1975) reported a significant Increase in the Incidence of hyperplastic foci or areas and neoplastic nod ules in female rats given 100 ppm of Aroclor 1260 mixed with the diet for 21 months (Table 3). In another study, the dietary administration of 100 ppm of Aroclor 1242, 1254 and 1260 for 24 months increased the incidence of nodular hyperplasia (Table 1A)> a lesser effect was obtained with 10 ppm, and 1 ppm did not produce HONS 017334 -77- TABLE 2 Incidanca of Livar Lasions in Mala Mica Traatad with PCBa for 24 Haaks (Data of Ito at al, 1973) Xaaaehlor 500 Kanschlor 400 Xanaehlor 300 Controls ppa in dlat Incldanca Modular Byparplasia Bapatocallular CarciaeM 500 250 100 500 250 100 500 250 100 - 7/12 0 0 0/12 0 0 0/12 0 0 0/S 5/12 o o 0/12 0 0 0/12 0 0 0/5 ) HONS 017335 -79- TABU 3 Xncidanca of Liver Lesions in Famala Rats Traatad with Aroclor 1260 (Data from Kimbrough at al., 1975) Lasion Myparplastic foci or araaa isoplastic Nodules Hepatocellular Carcinoma Incidanca Controls Experimental 29/173 0/173 1/173 182/114 144/184 26/184 ) HONS 017336 -81- TABLE 4 Incidence of Liver lesions in Msls and Fssisls Rats Trsstsd with Aroclor 1242, 1254 snd 1260 100 ppm in Diet for 24 months (Data from Cslsndra, 1975) Nodular hyperplasia Hepatomas Hepatocellular carcinoma 1242* 8/20 2/20 0/20 Aroclor 1254** 13/27 4/27 0/27 1260 7/27 5/27 0/27 *10 males and 10 females **13 males and 14 females ') HONS 017337 -83- TABLE 5 Incidence of Liver Lesions in Mala and Female Rata Traatad with Aroclox 1254 . (Data from Rational Canear Institute, 1978) Number of animele nacropaiad Hyparplaatic foci or areaa Adenoma, NOS+ Hepatocellular carcinoma* ** ___________ Males tow Mid High Doia Poaa Doaa 24 24 24 . females_______ tw Mid High Poaa Doaa Doaa 24 22 24 58 00 01 12 1 2 9 17 0 12 0o 0 * Hyperplastic foci, hepatocellular adenomas or carcinomas ware not diagnosed in the controls. + Not otherwise specified ** As defined in report OV^58 RONS 85 a positive raaponaa (Calandra, 1976; Levinskae, 1981). all thraa Aroclora produced an Increased number of hepatomas at the high dose (Teble 4). There was no evidence of metastasis or invasiveness, and the lesions were regarded by the pathologists as benign tumors. The results of a bioassay of Aroclor 1254 for carcino genicity, using doses of 25, 50 and 100 ppm in the diet, are summarised in Table 5 (National Cancer Institute, 1978). Their use of tens is confusing, for although they use the words 'nodular hyperplasia* in their table, they state in the text that 'the areas of nodular hyperplasia appeared to be microscopically similar to what is currently termed 'focal areas of cellular alteration." Thus, we have used the term 'hyperplastic foci or areas* in Table 5 to describe their results. It is evident from the data in Table 5 that the hyperplastic foci were present in a dose-related frequency. Although the incidence of the hyper plastic foci did not differ significantly from the controls, this incidence appeared to be related to treatment. The biological significance of the Increase in 'focal areas of cellular altera tion* is not dear as relatively few adenomas were found. Both the above studies (Kimbrough et al., 1975 National Cancer Institute, 1978) demonstrate an Increase in proliferative lesions of the liver> the effect is greater with Aroclor 1280 than with Aroclor 1254. (ill) Studies in dogs. Hepatic nodular hyperplasia did not occur in the dogs receiving dietary levels of 1, 10 or 100 HONS 017339 86 ppm of Aroclor 1242, 1254 or 1260, respectively, for two years (Calandra, 1976). Each treatment group consisted of eight dogs (four female and four male). 5. Summary and Comment The administration of high doses of PCBs to animals 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, are readily induced by high doses of PCBs, but are absent when lower doses of PCBs are given. The 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 hsve been reported to be increased in some studies, but other evaluations have not confirmed these effects. The effects of PCBs on the occurrence of nodular hyperplasia, neo plastic nodules, hepateaws, or adenofibrosls is highly variable; some studies have reported a positive effect whereas others failed to show an effect of treatsMnt. Again the change in histological response or in frequency of benign hepatic tumors is related to both the dose of PCB administered and the degree of chlorination of the PCB. HONS 017340 87 Data on hepatocellular carcinoma in PCB-treated animala ara discussed In auction VIII. B. Clinical Data 1. Liver Function in PCB-exposed Workers Baaed on results In animala, it was expected that if PCBs produced a significant degree of injury in man, it would be to the liver. Such haa not been the caae, aa the clinical etudlea auamarlzed below have provided little evidence for the occurrence of hepatic dyafunctlona in PCB-exposed worker* even though the blood level of FOB may be relatively high. (i) Ouw et al. (1976) atudied liver functions in 34 workers exposed to Aroclor 1242 for one month up to 23 years; 31 ware exposed for more than one year and 16 for five or more years. Scattered individual abnormal test results were obtained: serum bilirubin was normal and in all 34 subjects, alkaline phosphatase was elevated in 1 of 34 subjects and serum transaminase (SGPT) V was increasad in five tests. There was no relationship of the results to the blood level of FCB and the mean of each hepatic function test for the whole group was within normal limits. BSP V The abbreviations used in this section are as follows: SOOT * serum glutamic oxaloacetic transaminase SGPT serum glutamic pyruvic transaminase SGGT serum gamma glutamyltranspeptidase LOG serum lactic dehydrogenase AST * aspartate aminotransferase ALT serum alanine aminotransferase SOCT serum ornlthln-carbamoyltransferase BSP bromsulfonphthaleln HONS 0173*1 88 tests wers also parformed on seven workers with relatively high blood PCB; four of the seven tests were slightly above the normal limit of 5t but, as the authors state, since other conditions such as fever may increase BSP retention, these results by them selves could not be taken as proof of hepatic damage. The BSP test results did not show a significant correlation with blood PCB levels or the length of exposure (5 to 23 years) to PCB. (ii) Flschbeln et al. (1979) studied liver func tion testa in 321 workers exposed to PCBs in an electrical manu facturing plant for less than five years to more than 2S years. The percent of tests that gave an abnormal test result was SOOT 2.2%, SOFT 7.2%, LM 2.5%, alkaline phosphatase 1.2%, and serum s bilirubin 5.3%, and indicated a 'very low prevalence of abnormal liver findings.* There was no comment or analysis to state that a certain number of the subjects showed a pattern of abnormal liver function tests indicative of hepatic dysfunction. These data can be taken to represent a series of random test results that might be expected in a population of 321 individuals ranging in age from less than 30 years to over 70 years. Control subjects or non-expoeed workers were not Included for comparison. There was perhaps soaw indication of a relationship of SGOT levels to plasma levels of PCBs, but the two exposure categories of PCB levels are too broad and require a finer analysis. (ill) Baker et al. (1960) studied liver function in 148 individuals with various degrees of exposure to PCBs; the MOHS 0l73%2 89 Man PCS Mrua Xavala for the four teat groups varied from 17.4 ppb to 75.1 ppb. There was no change in liver function tests (BOOT, SOFT, LOT, alkaline phosphatase or serum bilirubin) in relation to PCB blood levels in either drinkers or nondrinkers of alcohol. Serua GGTP (gaaaa glutaayl transpeptidase) correlated with serua PCB, but a correlation did not exist when alcohol drinkers were reooved froa the analysis. (iv) Maronl et al. <1981a, b) studied liver function in 80 workers exposed to PCBs for an average of 12 years and reported that 1C individuals had an abnormal liver finding as judged by clinical examination or by laboratory tests. Inspection of the data shows relatively few instances of abnormal liver function tests. The most frequently altered laboratory tests were as follows 1 8 of 80 subjects with increase of SGGT activity 7 of 80 subjects with increased serua aaino transferase activity (AST or ALT) 6 of 80 subjects with Increase of SOCT activity. It is evident froa their data that many of the changes are slight, and as test rssults froa control subjects were not Included, we do not know what the norasl test variations nay be for 80 control subjects of a similar age. Further, examination of the data for the 14 subjects with clinical hepatomegaly shows only one subject with an abnormal test in three types of tests (SGGT, AST/ ALT and SOCT)1 only two of the subjects gave a positive response in two of HONS 017343 - 90 the test typesi eight subjects had an abnormality in only one test; these subjects had noreal test results. Serum bilirubin and alkaline phosphatase activity were within the normal range in all subjects. Based on the above review, it is evident that only one of the 80 subjects showed a pattern of test results indicative of abnormal livar function; the other test results reflect only random variations from normal. Maroni at al. also reportad that the mean level of blood PCBa in tha 18 workers with abnormal liver findings was sig nificantly higher than that of 64 workers without abnormal liver findings, but the ranges for the two groups show considerable overlapping and tha two subjects with the highest blood PCS . levels had normal liver function tests. The only control we can use to evaluate the suggested relationship between PCS blood level and liver function are the 10 subjects with chloracne; these 10 individuals had normal liver test results despite the fact that their mean blood PCB concentration was high and not significantly different from the mean blood PCB level found in the 16 workers discussed above. Thus, it cannot be said that this study demon strates a relationship between a high blood PCB level and abnormal liver function tests, attesting further to the randomness of the liver function test results in the study. (v) Smith et al. (1981a, b, c) evaluated liver function testa in PCB-expoaed employees from an electrical manufacturing plant, a municipal electric utility company and a privately-owned HONS 017394 - 91 - electric utility company. The data on SCOT and GGPT arc difficult to avaluata aa tha rasults of tha measurements ara not given, and tharafora may ba aasuaad to ba within normal population levels; rather, tha author* sought corralationa between the log of SG07 and GGTP with tha log of tha lower aerum PCBa and tha log of high aarum PCBa. Calculations include almple corralationa, aeparate ragraaalona with tha confounder* aa predictora, and squarad par tial corralation, plus othar computations to aaa if aaaociations existed. Their tables 6, 7 and 8 summerlie many of their calcu lations, and data for transaminases from table 7 are summarised below. Correlation With Serum log L-PCB Serum log H-PCB Electric equipment Company log SCOT log GGTP Municipal electric utility company log SCOT log GGPT Privately-owned utility company log SCOT log GGTP NS Sig NS NS Sig NS Sig Sig NS NS NS NS Slg - statistically significant HS not significant L-PCB lower chlorinated biphenyls H-PCB - higher chlorinated biphenyls HONS 017345 - 92 - Correlation* (aasociationa) war* found at the equipment company but the data cannot be examined to determine if the calculated value has any madical elqnificance. Correlations at the publicly-owned utility company were not significant. At the privately-owned utility company, the only positive finding was a positive association of SOOT with serum L-PCB. it is not clear what the change in this one test result means as the serum L-PCBe were not significantly different between the exposed and nonexposed groups. The test results for total bilirubin, alkaline phosphaatase and lactic dehydrogenase are not discussed, and it is prasusMd that these measurements of liver function were not 2. Liver Disease in PCB-Exposed Workers Medical examination of PCB-exposed workers has not shown the presence of liver disease. In the study of Pischbein at al. (1979), physical examination of 326 individual* (age less than 30 to over 70 years) revealed 4 individuals with abnormal liver site, two of whom had a history of heavy alcohol Intake; one of the four had a slight elevation of one liver function test (SOOT of SS). In another study of 148 individuals with varying degrees of PCB exposure, there was no evidence of liver disease as determined by medical history and physical examinations (Baker et al., 1980). Smith et al. (1981) did not find evidence for live- MONS 017346 93 disease in their subject*, thr* being no signifleant finding* on physical examination of worker* at an electrical equipment manu facturing plant who were heavily exposed to PCBs, or worker* at a municipal utility company or a private utility company who were less heavily exposed. Deaths from cirrhosis of tha liver ware not increased by exposure to PCS (Brown and Jones, 1981); six deaths were observed (three of tha six consumed alcohol regularly) versus S.C expected. 3. Summery and Opinion The review of clinical data demonstrates that exposure to PCBs doss not significantly affect liver function tests. Liver function remains normal in Individuals with measurable, and freq uently high levels of serum PCB. Also, exposure to PCBs does not result in the production of clinically detectable liver disease. The induction of ensyme systems in the liver and the biological significance of this process, as mediated by PCBs, are discussed in section XX. MONS 017347 - 95 - VII. Gastric Lesions The oral administration of PCBa to nonhuman primates hat been shown by Allen and co-workers to induce hypertrophy and hyperplasia of the gastric aucoaa. Mucosal cysts nay be present within the epithelium of the stomach, but in the mucosal lining and the subaucosa, there may be edema of the submucoaa of the stomach. In addition, there is frequently invasion of the under lying auooea by isolated glandular elements of the mucosal epithelium. General effects of this nature have been produced in the monkey by: 1) A single oral dose of 1.5 g or 3 g of Aroclor 1248 (Allen, Norback and Hsu, 1974). il) Aroclor 1248, 300 ppm and Aroclor 5400 (a polychlorinated trlphenyl), 5000 ppm in the diet for 90 days (Allen, Abrahamson and Norback, 1973: Allen and Norback, 1973). ill) Aroclor 1248, 25 ppm in the diet for 2 months (Allen, Carstens and Barsotti, 1974). iv) Aroclor 1248, 100 ppm in the diet for 2-3 months (Allen, 1975). v) Aroclor 1248, 2.5 ppm and 5.0 ppm in the diet for up to one year (Barsotti and Allen, 1975). (Gastric changes were not listed for these doses in Allen's review.) HONS 017348 - 96 - wi) The hyperplastic gastritis may persist for over one year following discontinuance of PCB exposure (Allen, 1975). A mixture of low chlorinated biphenyl (Clophen A-30) was not observed to produce gastric lesions in the monkey (latropoulos et al., 1977). The findings of Allen et al. were recently confined and extended by Becker et al. (1979). Their study Involved six monkeys, one untreated and one each receiving a diet containing 3, 30, or 300 ag/kg of PCB (Aroclor 1242); two aonkeys received a diet containing 10 ag/kg. Monthly biopsies taken froa the greater curvature of the stoatach showed a draaatic decrease in the nuaber of parietal cells with a concoaitant increase in the * number of aucous neck cells. The syaogenic (chief) cells were also reduced in nuaber. This was followed in all treated aniaals by a aucous conversion of the gastric eplthellua, with downgrowth of the gastric glands into the subaucosa and the eventual foraation of cysts. It is noteworthy that the lesions were confined to the stoaach; no changes were found in other regions of the gastrointestinal tract. The gastric Changes can be described as a dysplastlc growth pattern, but there is no neoplastic transforaation (Allen and Morback, 1973). However, the authors speculate that they are 'suggestive* of an eventual neoplastic transformation. Analysis of the results obtained in the aonkey indicates that the PCB-Induced morphologic changes in the gastric aucoea HONS 017349 - 97 may ba specific to this apaciaa and not predictive of possible ffsets in man. (1) Even within the monkey a specificity of action is present, as the lesion induced by PCBs is found only along the greater curvature of the stomach; neither the cardiac nor pyloric portions were affected (Becker et si., 1979). Ill) Hypertrophy and hyperplasia of the gastric mucosa have not been reported in the rodent (Allen and Abrahamson, 1973), rabbit (Vos, 1972) or in other species (Vos and Koerman, 1970). Clinical findings to date have not suggested or Indicated that exposure to PCBs Increases the occurrence of cancer of the stomach in the human (see also section vin, relating to carcinogenicity). ' HONS 017350 99 - VIII. Carcinogenesis; Experimental and Clinical A. . Experimeat*1 Studlea All authors do not use the words tunorigenesis and neoplasia to Indicate the sane type of response. Tunorigenesis is a general tern that refers to both benign growths and nallgnant growths) compounds nay affect the occurrence of benign tumors without inducing cancer. Neoplasia naans siaply a new growth. The tern 'neoplasia* can refer to a benign or malignant growth. Oftentimes authors may combine data relative to benign and malignant growths so that when the terms tunorigenesis or neoplasia are used, they must be carefully defined. 1. Hepatocellular Carcinoma (I) Studies in mice. Ito et al. (1973) ob served hepatocellular carcinomas in mice only in the high dose group given xanechlor 500; lower doses of xanechlor 300 or the other Kanechlors did not produce a carcinogenic response (Table 2). The administration of 300 ppm of Aroclor 1254 in the diet for 11 months did not Induce hepatocellular carcinomas in nice (Kimbrough t Linder, 1974). (II) Studies in tats. The administration of Xanechlor 400 for 400 days did not induce hepatocellular carcinoma (Kinura t Baba, 1973), but the period of treatment nay have been too brief to detect a carcinogenic effect, in a further study Kinura et al. (1976) administered xanechlor to rats for sis months but due to body weight changes a variable dosage schedule was employed. Following the cessation of treatment, the rats were HONS 017351 100 - (d on a normal dint for 270-410 days; autopsy, after a total experimental period of 4S0-S90 days, did not reveal hepatocellular carcinoma in any of 12 rats, Ito efe al. (1974) treated rata with different doses of Kanechlor 500, 400, and 300 for periods up to 52 weeks; hepato cellular carcinomas were not observed, but the duration of treat ment was probably too short to rule out the possibility of a poaltive response. The three major atudlea pertaining to PCBs and hepatic carcinoma in the rat are those of Kimbrough et al. (1975), Calandra (1975) and the National Cancer Institute (1978). Kimbrough and co-workers, using the Sherman strain of rat, found that 100 ppm of Aroclor 1260 in the diet for 21 months produced a significant increase in the incidence of hepatocellular carcinoma in female rata (Section VI, Table 3). Male rata were not atudied. The administration of three different Aroclora at a dose of 100 ppm to rats for 24 months (Table 4) did not induce hepato cellular carcinoma (Calandra, 1975). The author states that this negative finding waa based on evaluation of the liver sec tions by 3 pathologists, who read the slides independently and separately. He atatea further that Profesaor p. Pour re-evaluated the Kimbrough slides and did not agree with the reported findings (see also section VI, Table 1A). The results of the National Cancer Institute (1978) bioassay of Aroclor 1254 for possible carcinogenicity are shown in section VI, Table 5. Fischer 344 rats were used and the PCB HONS 017352 - 101 lxtur* was administered at three dose levels (25. 50 and 100 ppn) In the diet for 104-105 weeks. The effect of the treataent on body weight and Mortality at the higher doae level* demonstrated that maximum tolerated doae* were uaed, thus providing a satis factory test of carcinogenic potential. A sufficient number of rats of both sexas was available for meaningful statistical analyses of the incidence of late-developing tumors. Treatment was associated with only three hepatocellular carcinomas in male rats, which was not significantly different from the controls, and it was concluded that Aroclor 1254 was not carcinogenic in the bloaasay. (ill) Studies in dogs. Hepatocellular carcinoma did not occur in dogs (four male and four female per group) receiving 1, 10 or 100 ppm of Aroclor 1242, 1254, and 1200, respectively, in their diets for two years (Calandra, 1975). (iv) Discussion. Data from the mouse provide only limited and restricted evidence for a carcinogenic affect of the Japanese compound Kanechlor 500 (Table 2). Studies on the rat give conflicting results on hepatic carcincsM. (Section VI deals with the benign hepatic proliferative lesions found in the treated rats, which may or say not indicate carcinogenic potential.) Kimbrough at al. (1975) reported an increase of hepatocellular carcinomas in female rats receiving Aroclor 1260, whereas the studies of Calandra (1975) and the National Cancer Institute (1978) did not observe a significant increase in hepatocellular carcinomas in rats receiving different Aroclors. Whether the HONS 017353 - 102 divergent raaulta ara ralatad to tha different atralna of rats that were used, represent differences In the effect of the two Aroclors, or ara due to other factors is not known, it is obvious, however, that in view of tha differing results obtained it is not possible to extrapolate or project possible effects in stan. Hepatocellular carcinomas did not develop in dogs treated with Aroclor for two years. 2. Bladder Cancer Kiebrough (1972) observed bladder cancers in two rats fad 100 ppe of Aroclor 1260 for eight Months. In a later study with 200 rats receiving 100 ppm of Aroclor 1260 for 21 Months the only bladder tuaor observed (a transitional cell pepllloaa) was in a control aniaal, and it was concluded that 'the occurrence of the bladder tunor in the previous experlnent was apparently un related to the ingestion of Aroclor 1260* (Kinbrough et al., 197S). This type of variation deaonstrates the unreliability of attaching significance to saall changes in tuaor incidence in a given ex pertaent, particularly when the incidence does not show a statistically significant difference froa a control group. Benign or Malignant bladder tuaors did not occur in rats treated with Aroclors 1256 (25, 50 and 100 ppa) for 106-105 weeks (National Cancer Institute, 1978). The above studies do not deaonstrate that adalnistration of Aroclor 1256 or Aroclor 1260 induces bladder cancer in the rat. HONS 017356 - 103 - 3. Stomach. Intetlnl Tract Cancer Treatment of female rat* with Aroclor 1260 (100 ppm In diet) for 21 month* did not indue* tumor* In the gastrointestinal tract (Kimbrough et 1., 1975). Treatment of rat* with Aroclor 1254 (25, 50 and 100 ppm In the diet) for 104-105 week* did not Induce gastrointestinal carcinoma* (National Cancer Institute, 1978). Tumors occurred in random manner a* illustrated in Table 6. 4. Carcinogen**!* - other Organ* Studies with PCBs in relation to cancer of the liver, gastrointestinal tract, and urinary bladder have been discussed separately above. In the studies with PCB* other organ* have been evaluated in detail without finding any effect of chronic administration of Aroclor* on the incidence of benign or malignant neoplasms. The following appraisals refer to tumors of these other organs. Kimbrough et ml. (1975) found that the chronic administration of Aroclor 1260 to rats did not affect the incidence of benign tumors or carcinomas of the thyroid gland, adrenal gland, uterus, lung and other organa. Frequently investigators look only for increases in tumor incidence, when in fact decrease* are often obtained. It 1* worth noting that mammary adenocarcinoma occurred in 5/173 control animal* verau* an incidence of 1/184 in treated animals. If the incidence had been reversed, some authors may have commented or suggested that PCBs may increase the occurrence of mammary cancer, but such would not have been HONS 017355 -iUS- Tabla 6 Xncidanca of Gastrointestinal Carcinomas in Rats Traatad with Aroclor 1254 - (Data from National Cancar Instituta, 1978) Nwbar of Carclnomaa Malas Control Low Dosa Nad. Dosa Rich Dosa Stomach, adanocarc incma Jejunum, carcinoaw Cacum, adenocarcinoma raaalas 0 0 0 0 0 0 10 01 10 Stomach, adanocarcinosM 0 1 10 HONS 017356 - 107 the case M the number of mammary adenocarcinomas in control groups can vary significantly from study to study, if the incidence of spontaneous tumors can vary, then the number of malignancies in the treated 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 tuiaors which was 5/149 in controls versus 0/163 in the treated animals. In the National Cancer Institute (1979) study, the chronic administrations of Aroclor 1254 was without affect on the developatent of benign or malignant neoplasms in the various body organs of the rat (the liver, gastrointestinal tract and urinary bladder were discussed separately above). In the study, 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 , wers found in 13% of control malas and 17% of control fesMlss. A statistically significant dose-related 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 the control group were not statisti cally significant, so that an affect in males could not be clearly related to the administration of Aroclor 1254. Adding the few lymphomas to the leukemias for the analysis did not change the HONS 017357 108 - conclusion. Kimbrough at al. (197$) also aid not find a sig nificant affact of Aroclor 1260 on leukenla incidence (1/173 in controls vs. 0/184 in treated animals). It may be concluded from these studies that the chronic oral administration of high doses of Aroclors 1260 or 1254 does not induce benign or malignant tumors of the thyroid gland, adrenal gland, uterus, lung, hematopoletio system, pituitary gland, thymus, kidney and other organs in rats. 5. Summary and Opinion Animal studies do not provide convincing evidence that PCBs induce liver cancer. Of the major studies in the rat, one has been judged positive and 2 have been negative, hepatic car cinoma was not produced in the dog. Chronic administration of Aroclors in the rat did not induce bladder cancer, gastro intestinal carcinomas or cancer of the thyroid gland, pituitary gland, adrenal gland, uterus, lung, hematopoietic system or other organs. B. Clinical Studies The studies of Brovn and Jones (1981) and Bertaxzl and co-vorkers (1981) have evaluated the relationship between ex posure to PCBs and the subsequent development of cancer. Both analyses are retrospective mortality studies of workers to deter mine the cause of the death and, for malignancies, the specific type of cancer causing the death) the deaths are designated as "observed cases." The person-years of exposure of the vorkere to - HONS 017358 109 PCB war* determined and combined into calandar tiaa parioda and flva-yaar age groups to calculata from mortality atatiatica the number of "expected* deatha. The number of observed versus expected deaths was then compared. Background data relative to these studies are suauaarized briefly, as follows: (i) Brown and Jones (1981). The authors analysed Id known deaths occurring aaong 2,567 workers exposed to PCBs for 39,016 person-years. Exposure to PCBs ranged from three months to over 20 years. The type of PCBs used at the plants were Aroclor 1254, 1242, and 1016. (ii) Bertaxxl at al. (1981). The authors analysed 27 deaths occurring in 1,310 workers exposed to PCBs for 20,565 person-years, determining "observed* versus "expected" rates for malignancies. Mortality was studied for a 25-year period (1954-1978). Exposure up to 1964 was mainly to Aroclor 1254 and Pyraline 1476i starting in 1965 mixtures with 42% chlorine were used (mainly Pyraline 3010 and 3011). (iii) Bahn at al. (1976, 1977). These authors report 2 cases of Mlignant melanoma in 31 men exposed to Aroclor 1254. It is not clear from their studies if they are discussing morbidity or mortality^ Brown and Jones (1981) interpret the report as mortality. Pertinent data on the mortality from malignancies are aumawrised in Table 7 and are discussed below. HONS 017359 1X0 All Malignancies. Brown and Jonas reported 39 ob served cases of cancer versus 43.8 expected cases, whereas Bertazzi et al. found a statistically significant increase in alas, but not In feMle workers (Table 7). There was no In crease in the risk of aortality front all aalignancles with length of exposure or with the nuaber of years of eaployaent (Brown and Jones, 1981), Bectua. The only statistically significant difference observed in the study of Brown and Jones was for rectal cancer in feaales froa plant 2 (Table 7). There was no significant finding for feaales in Plant 1, aales in Plant 1 or 2, or for the coabined data for aales and feaales. The Incidence of rectal cancer showed e slight, but statistically Insignificant, increase with Increase in latency; no direct relationship with increased length of exposure is apparent. Bertazzi at al. (1981) did not report a case of rectal cancer in PCB exposed individuals. Stoaach, Pancreas. The studies did not deaonstrate an increased risk for stoaach or pancreatic cancer (Table 7). Hepatocellular Carclnosa. Three cases of liver cancer were observed in the study of Brown and Jones (1981), but the difference froa the control rate was not reported to be statisti cally significant (Table 7). Bertaszi and co-workers did not aention observing any case of hepatic cancer. Exaainatlon of the data for latency effect or for length of exposure to PCBs did not show any relationship to developaent of liver cancer (Brown and Jones, 1981). MONS 017360 Table 7 Deaths From Specific Types of Csncsr Comparison of Observed Deaths in PCB Workers With Expected Deaths Humber of Cases Reference 1 2 2 Malignancy All Sex M,F K P Observed 39 8 6 Expect 43.79 3.32 2.33 SHR 89 241 258 1 Rectum M 1 0.S1 1 F(plant 1) 0 0.1S F(plant 2) 3 0.50 1 K,F 4 1.19 336 1 Stomach M,F 1 1.66 60 1 Pancreas M,F 1 1.90 53 2 Digestive Organs (stomach, pancreas, biiiary tract) M F 3 0.8S 340 0" 1 Hepatie Carcinoma h,f 1 Lymphatic t Hematopoietic 2 2m M,F M F 3 1.07 280 2 4.34 :) 46 2 0.46 435 2 0.45 444 3 Helenom M 1 M,F 2 M.F i 0.04 0 -" - 0 - - Statistical Significance NS P-0.04 its NS NS K0.05 NS NS NS NS NS NS NS NS NS P-0.001 NS NS Ref 1, ? * 2, S 3, SMR, SS, Brown and Jones, 1981 Bsrtasxi at al., 1981 Bahn at al., 197S, 1977 Standardised mortality ratio (observed deaths/expected deaths x 100) Not significant HONS 017361 - 1X3 - Lymphatic and Hematopoietic Cancer. Th two studies how diametrically opposite rlak valuta, although nelthtr la tatiatlcally. aignifleant (Table 7). Melanoma. Bahn et al. (1976, 1977) reported two caaea of malignant melanoma occurring among 31 men who had been expoaed to Aroclor 1254. Baaed on the Third National Cancer Survey incidence ratea, Bahn et al. calculate for a person-year analysis that only 0.04 malignant melanomas would be expected, the difference being statistically significant (PaO.OOl). The extensive studies of Brown and Jones and of Bertassi et al. fail to confirm the Increased risk of mortality for malignant melanoma reported by Bahn and co-workers (Table 7), raising doubts about the significance of the Bahn studies. Even an association with the low P value of 0.001 has not been con firmed . Summary. The clinical evaluation of PCBs relative to cancer is currently based on a limited amount of data, and any conclusion regarding their effects must be regarded as tentative. Nevertheless, some detailed analyses are available and conclusions based on them, as listed below, are of some significance. 1. Retrospective mortality studies have not demon strated a consistent relationship between exposure to PCBs and the development of a particular type of cancer. 2. The clinical findings on hepatocellular carcinoma are of great interest as some experimental studies report an HONS 017362 114 Increase in liver cancer in rodents receiving PCBs. Although Brown end Jones (1981) observed three cases versus 1.07 expected cates, the difference Is not statistically significant. Their analysis of PCB exposure and risk of Mortality fro* liver cancer is also noteworthy since it did not demonstrate an effect of latency (number of years fro* date first employed) or a relationship to increased duration of employment in jobs involving PCB exposure. These latter observations are, how ever, based on small numbers. Bertaxsl et al. (1981) 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 humans based on the animal studies. 3. The SMB (Standard Mortality Ratio) may vary widely in different studies, and emphasis should not be placed on an Increase in the SMB found in one study unless a significant change in SMB can be confirmed in several repeat studies. For example. Brown and Jones found the SMR for lymphatic and hematopoietic malignancy to be decreased while Bertasxl et al. reported an increase, although neither result was statistically significant (Table 7). 4. Brown and Jones observed a statistically signi ficant Increase in SMR for rectal cancer in women at one plant, but not in a different plant, and no significant effect in male workers at either plant was observed. Bertasxi et al. MOMS 017363 1X5 did not report any ractal cancer (Table 7). Overall, therefore, a convincing demon*tratIon of rectal cancer as a result of extended exposure to PCBs has not been made. HONS 0173*4 - 117 - IX. --productive Effects A. --production NuMtoui report* h*w appeared In the literature on the effects of polychlorinated biphenyls on reproduction in anlMls. Gellsrt 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 effect on the reproductive function of the offspring as judged by (a) normal estrus cycles, <b) normal appearance of ovaries and uteri, airi (c) fertility of males. Feeding 550 ppm of Aroclor 1254 for 67 days to Sherman rats resulted In fewer litters, smaller litter else and 100% mortality by day three of the Fla pups. At 100 ppm survival of both FI, and Fib offspring was reduced. The pups were smaller than controls but appeared normal at weaning. Aroclor 1260 fed at a dietary level of 500 ppm (35.4 mg/kg) for 67 days prior to mating markedly reduced litter sire and survival-to-weaning in the FI, and Fib generation. Dietary levels of 5 ppm Aroclor 1254 and 100 ppm Aroclor 1260 had no effect on reproduction in rats exposed through two generations (Linder et al., 1974). A dietary concentration of 2.5 ppm of Aroclor 1246 produced alteration in the menstrual cycle of adult female rhesus monkeys. Menses were prolonged and --nstrual bleeding was increased (Allen et al., 1979). Keplinger et al. (1971) fed rata and dogs Aroclor 1242, 1254 and 1260 at doaes of 1.0, 10.6 and 100 ppm. No adverse HONS 017365 118 - effect on reproduction was observed In rata given 1.0 and 10 ppa Aroclor 1242, but there was a decrease in survival of pups at 100 ppm of Aroclor 1242, 1254 and 1260 as well as a decrease in mating indices. The effect of PCBs on reproduction in beagle dogs and swine has been studied by Earl et al. (1974). Aroclor 1254 interfered significantly with reproduction in dogs at doses above 2.5 mg/kg/day while in swine 10.0 mg/kg/day lowered ferti lity and survivability of neonates. The reproductive effects in dogs are questionable because of unexplained changes in the repro duction pattern aang controls. B. Teratogenicity 1. Introduction Teratogenicity is that property of an agent whereby it is capable of inducing congenital defects in the developing embryo. Such agents that are chemical substances are known as 'teratogens' and the defects they Induce are known as 'terata*. Although teratogenicity is considered generally to involve only anatomical defects, some authorities regard functional or bio chemical changes as manifestations of teratogenicity. A distinction must be made between teratogenicity and fetotoxlclty, l.e., toxicity to the fetus. The finding of dead or resorbing fetuses in the uterus of an experimental animal is not evidence of a teratogenic action of the test substsnce. Similarly, a smaller sise of the newborn la indicative of fetotoxlcity rather than teratogenicity. HONS 017366 119 A substance may appear to be teratogenic if it pro duces severe toxic effects on the pregnant female. Maternal disease and malnutrition affect the number and quality of the offspring. Defects in the offspring that are secondary to toxic effects of the substance on the mother are not considered tarata. Teratogens produce their harmful effects during the period of formation of cells, tissues, and organs. Hence, once development of the fetus has been completed, a teratogenic event can no longer occur. Chemical substances administered to the mother can be transmitted, together with their metabolites, via the milk to the suckling young, and may produce toxic effects in the latter. However, such effects are not Indications of teratogenicity. Conventional tests for the detection of teratogenicity involve administration of the test substance to pregnant females at repeated intervals throughout the period of organogenesis, e.g., days $ through 15 of the gestation in the rat. The treated females are sacrificed on the day prior to parturition, and the fetuses removed from the uterus surgically for examination. Alternatively, the test substance may be administered over rela tively long periods of time, and the animals allowed to breed normally as in the usual one- to three-generation reproduction studies. The appearance of malformed offspring among the succeeding generations would be evidence of teratogenicity. In order for a chemical substance to which the mother is exposed to exert a direct action on the conceptus, it or one HONS 01736? 120 - or ora of It* metabolites must be able to cross the placental barrier. Transplacental passage of PCBs has been demonstrated In several animal species (Allen et al., 1980; Curley et al., 1973) Couvilllon et al.. 1974; Grant et al., 1971). and is known to occur in the human (Funatsu et al., 1972). 2. Klee PCBs were not teratogenic in mice at dosages up to 500 mg/kg given on days 1 through 6 or days 7 through 11 of gesta tion (Toeruk, 1973). However, a recent study (Narks et al., 1981) with the hexachlorocongener 3,3',4,4*5,5*-hexachloroblphenyl in mice at dosages in the range of 0.1-16 mg/kg/day during days $ through 15 of gestation produced a significant increase in fetal malformation, a significant decrease in average fetal weight, and an increase in the percentage resorptions. Torok (1976) reported that oral administration of 375 mg/kg or 750 mg/kg of 2,2'-dichlorobiphenyl to mice on days one through three of gestation resulted In prolongation of the Interval between breeding and parturition. He attributed this observation to delayed Implantation. Although the treated animals had fewer litters and lesser mean litter sites, there was no indication of teratogenicity. Some mice exposed to 3,4,3'4'-tetrachlorobiphenyl were reported to exhibit a "waltzing syndrome* (Davis et al., 1979; Tilson et al., 1979). The dosage was 32 mg/k? administered by gavage to the mothers on days 10 through 16 of gestation. The HONS 0173b 121 syndrome consisted of Increased motor activity, hyperreflexia, and apisodaa of haad bobbing and rotational movements that ware present up to at least eight months of age. Not all expoaed alee were affected similarly, but even those that did not exhibit the syndrome showed diminished performance in various neurobehavioral tests. Tilson et al. (1979) refer to these observations as the `behavioral teratology* of 4-CB. 3. Rats There are a plethora of studies in which the reproduc tive effects of feeding various Aroclors to rats have been in vestigated (Calandra, 1976; Gellert and Wilson, 1979; Keplinger et al., 1971; Keplinger il., 1972; Linder et al., 1974; Ville- neuve et al., 1971a). Collectively, these studies reported feto- toxicity as the dosage was increased, but no teratogenicity was demonstrated. It may be useful to note the order of magnitude of the dosages involved. Villeneuve et al. (1971a) found no effect from the administration of dosages of up to 100 mg/kg per day orally to pregnant females from the sixth through the fifteenth day of gestation. Ultrastructural lesions in thyroid follicular cells and a reduction in serum thyroid hormones have been reported in neonatal and weanling rats whose mothers had been fed a diet containing 50 ppm or 500 ppm of Aroclor 1254 throughout the period of gestation (Collins and Capen, 1980). The authors suggest that alterations in thyroid structure and function in the fetus or neonate nay be related to subsequent disturbances in growth or development. HONS 017369 122 Poq In the study conducted by Earl et si. (1974), pregnant bitches were given dosages ot 0.2S, 1.0, or 5.0 mg/Kg of Aroclor 1254 from the day of breeding to the day on which they were necropsied. At 5.0 mg/kg, there was an increase in the percentage of resorptions, a decrease in the number of live pups per litter at birth, and a reduction in the percentage of those surviving to two weeks. The terata observed consisted of enlarged fontanelles, cleft palates, and superfluous phalanges. This dosage was said to limit diet consumption severely. The authors state that one litter of the controls "may have had a genetic defect that caused an unusually high incidence of terata." 5. Swine Earl et al. (1974) included miniature swine (Hormel strain) in the investigation described immediately above. Pregnant sows were given dally oral dosagea of 1 mg/kg, 10 mg/kg, or 30 mg/kg of Aroclor 1254. Dosing began 21 days before breed ing and was continued until the day of necropsy. The authors concluded that dose-related effects were seen at all treatment levels as evidenced by decreases in the number of pregnancies, number of live pigs farrowed per litter, and percentage of live offspring after two weeks of age. Syndactyly and cleft palates were observed in the young of sows receiving 10 mg/kg, and patent fontanelles and cleft palates in the offspring of those receiving 30 mg/kg. As in the case of the dogs, the higher dosages caused a marked reduction in food consumption. HONS 017370 123 - 6. Monkey In a study reported by Allen et al. (1974), six adult, female rheme monkeys were fed a diet containing 25 ppm of Aroclor 1248 for two months. During this period, all animals developed characteristic signs of toxicity, although they main tained a regular menstrual cycle. One animal died. At the beginning of the fifth month, or three months after discontinu ance of exposure to the test substance, an attempt was made to breed the survivors. Three animals appeared to conceive, but only one succeeded in carrying her feeus to term. Although this infant was well developed, its body weight was considerably lower than that of the average rhesus infant. Examination of the tissues showed no gross or microscopic lesions. In a second study by the Wisconsin group (Barsotti at al., 1976) involving 18 adult, female rhesus monkeys, nine were fed a diet containing 2.5 ppm, and nine were fed a diet containing 5 ppm of Aroclor 1248. After seven months on these diets, the eight surviving animals from the 2.5 ppm group and eight from the 5 ppm group were mated with control males. All animals in the 2.5 ppa group became pregnant, but three of these resorbed their embryos; the remaining five gay birth to live infants. In the 5 ppm group six animals became 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 017371 124 hyperpigmentation, their general appearance, hemograms, and oaseoua development aa evaluated radiographically were normal. The adult, female rheaua monkeys that were the original subjects In the study discussed above were fed the diets contain ing 2.S ppm or 5 ppm of Aroclor 1248 for six months prior to breeding, throughout gestation, and for three months after delivery for a total of about 18 months (Allen et si., 1980). Only 16 females were bred, inasmuch as one had died and another was dropped from the study for some reason not explained. About one year after discontinuance of the Aroclor-containlng diets, the animals were bred again to control males. All of the seven survivors in the 5 ppm group conceived, but only four gave birth to live infants. In the 2.5 ppm group, one animal had an abor tion and the remaining seven had uncomplicated deliveries. Apart from their somewhat smaller sixe compared to the young of the control animals, the infants appeared normal. Analyses of adipose tissue from two stillborn infants of mothers in the 5 ppm group showed the presence of PCBs, but histological evalu ation of adipose and other tissues showned no abnormalities. 7. Clinical Data Funatsu et al. (1972) studied in detail four babies born to mothers who had ingested rice oil contaminated with a heat-exchange fluid containing PCBs, PCDFs and PCQs. The mothers were among the population exposed in the *Yusho* episode. Three of the four babies exhibited some evidence of intrauterine mal nutrition or retardation of growth, and all four had dark brown HONS 017372 - 125 pigmentation of the skin that was most pronounced at the geni talia, axillae, and near the fingernails. The same pigmentation was noted on the lips, gums, and palate. While one or more of the infants displayed other clinical signs, no neurological or cardiovascular abnormalities, nor any malformations were observed. The pigmentation of the skin and mucous membranes disappeared within two to five months of age in all cases. 8. Summary and Opinion (a) In a variety of tests, commercial PCB mixtures (Aroclors) showed no teratogenic activity in mice, rats, rabbits, and monkeys. (b) Earl et 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 a 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 maternal 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 (1980) on ultrastructural alterations in the thyroid glands of perinatal HONS 017373 126 rata whose mother* were exposed to Aroclor 1254 are indicative of functional changes rather than of teratogenicity. (d) The occurrence of a "waltzing syndrome" in mice exposed prenatally to 3.4.3', 4'-tetrachlorobiphenyl might rep resent a true teratogenic effect (Davis et al., 1979). This phenomenon usually results from a structural or functional defect of the middle ear. The dosage used to produce the syndrome is relatively high. While the exposed aniswls were not uniformly affected insofar as the overt signs are concerned, Tilson et al. (1979) presented evidence to show a wider pre valence of more subtle neuro-behavioral effects. It is not known whether this condition could be induced by a commercial PCI mixture. (e) The scientific literature presently supports the conclusion that PCBs present no appreciable risk of teratogeni city for humans, in our opinion, in view of the essentially negative test results in four test species and the questionable positive findings in the dog and in swine. C. Petotoxicity Rabbits given 1.0 mg/kg of Aroclor 1254 dally for 20 days of gestation had no effect on the developing fetus but doses of 12.5 to 50 mg/kg were fetotoxic. Rats appear to be more resistant than rabbits, as doses up to 100 mg/kg do not cause fetal deaths or malformations (villeneuve et al., 1971a). Embryotoxic effects of Kanechlor 300 and 500 were produced in HONS 017374 127 Sprague-Dawley JCL rats when fed at levels of S00 ppm In the diet throughout gestation (Shiota, 1976b). Diets containing 5.0 ppm of Aroclor 1248 were fetotoxic to rhesus monkeys. Fetuses and neonates of mothers with Yusho disease have developed some of the characteristic signs of disease as a result of transfer of PCBs to the fetus and infant through the placenta and breast feeding (Yamashita, 1977; Hatsuda, et al., 1978; Yakushijji et al., 1978). Studies in mice on the transfer of PCBs to fetuses and offspring Indicate that the amount transferred depends upon the chemical structure of the individual compounds and the position of the chlorine stasis within the chemical structure (Hatsuda et al., 1978, 1979). ' Aroclora 1242 and 1254 are potent inducers of hepatic microsomal ensymes. A single intraperitoneal injection of 100 mg/kg of Aroclor 1242 to rats increased liver weight, total microsomal activity, as measured by hydroxylation of acetani lide and N-demethylation of aminopyrene, and hepatic cytochrome P-450 (Bruckner et al., 1973). The breakdown of endogenous sub stances such as progesterone, estradiol and testosterone has been shown to be Increased in animals pretreated with chlori nated biphenyls (Orberg, 1978). It is possible that alterations in the metabolism of the endogenous substances by PCBs may upset the normal balance that is essential for implantation of the fertilized ova in the uterus (Smith, 1968). Feeding a PCB mixture containing 60% chlorine significantly increased the uterine weight of guinea pigs (Vos, 1972). HONS 017375 128 Yamaahita (1977) studied tha clinical features of PCB, PCDF and PCQ Induced fetopathy in four babiea born from mothers poisoned by contaminated rice oil* There was intrauterine re tardation of growth, dark brown pigmentation on the skin and mucous membranes, edematous face and exopthalmus. in eome cases the retardation persisted for many months but the infants eventu ally gained their weight for the age group. Although over 100 nursing mothers residing in Michigan during 1977-1978 had residues of PCBa in breast milk ranging froai 1.0 ppm to over 3 ppm, there have been no reports of serious adverse effects on reproduction or infant mortality (Nlckiser, 1981). Suimaary and Opinion 1. It is apparent from studiee on humans and animals that certain classes of polychlorinated biphenyls are more toxic than others and that the degree of chlorination is one of the determinant factors in their toxicity. But, as stated previouely under cutaneous toxicity, the presence of contami nants may be responsible for the adverse effects on reproduction. Oishi et al. (1978, 1980) compared the activities of PCBa and dibensofurans in rats and found that dibentofurans markedly depressed body weight, decreased weights of the thymus, ventral prostrate and seminal vesicles and reduced hemoglobin and hemato crit values, while PCBa had little or no effect. HONS 017376 - 129 2. On the question of fetotoxicity in PCB-exposed females> positive results are seen in certain test animals (rats, doqs, rabbits') when the pCBe are administered at relatively high doses (greater than 10 mg/kg) to pregnant animals, in the human, the only reported evidence for fetotoxicity in exposed popula tions stems from the unique yusho event, in which causation may not be linked to PCBs. No such reports have been made on other exposed human populations, suggesting the absence of this effect in the human under occupational exposure conditions. HONS 017377 131 A. General X. Mutagenesis The term 'mutagenesis* refers to any process that Induces a permanent change (mutation) in the genetic composition of a cell, thereby causing that cell to differ in a consistent way from its parent. If a mutation occurs in a germ cell, the offspring resulting from the union of that cell with another will have an altered genetic composition that will persist in the germ line unless the alteration is lethal. Mutations occur spontaneously through unknown mechanisms, but they also may be caused by radiation or chemical substances (mutagens). Nhile in a strict sense the term 'mutation* applies only to changes in the DMA at the molecular level, it is considered broadly to include alterations in the number and structure of chromoaosMS. Mutagenicity is the property of an agent, chemical or physical, to induce nutations. Chemical substances may be tested, for mutagenicity by a variety of methods, among which are those that employ (a) bacterial test systems, (b) cytogenetic analysis in vivo, (c) cytogenetic analysis in vitro and (d) dominant lethality in a rodent. B. Bacterial Test Systems The 'Ames test* is the most popular test of mutagenesis employing a bacterial test system. It is a so-called 'backward* nutation system that uses a series of mutant strains of salmonella typhlnurlun that have lost the ability to synthesize the amino HONS 017378 132 - eld histidine. Hence, they can grow only if exogenous histidine is supplied. A nutation has occurred if, after exposure to the chemical substance, the organisms regain the ability to grow in the absence of histidine. ' Aroclors 1221, 1254, and 1260 showed little mutagenic activity in the Ames test (Wyndham et al., 1976) with indications that Aroclors with lower chlorine contents are weakly positive in the Salmonella test systems. However, these results must be discounted since they could not be replicated (McMahon et al., 1979; Safe, 1980). As a general finding, Heddle and Bruce (1977), McMahon et al. (1979), Schoeny et al. (1979), and Safe (1980) were unable to find evidence of mutagenicity of PCBs 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. Bone marrow and the seminiferous tubules are generally the most frequently used tissues for this purpose. It is customary to inject the animals with colchicine several hours before sacri fice in order to promote the accumulation of cells in the metaphsse stage of division. In this stage, the chromosome can be examined more readily for abnormalities. In two investigations, PCBs were judged not to have produced chromosomal abnormalities. Dikshith et al. (1975) HONS 017379 133 examined seminiferous tubules of rats at different intervals after daily dosaqes of 50 mg/kg of Aroclor 1254. Green et al. (1975a) examined both bone marrow and spermatogonlal cells of rats after either a single dose of 5000 mg/kg of Aroclor 1242, or four dally doses of 500 mg/kg. in all cases, it was concluded that no significant chromoaomal damage had occurred. The mlcronucleua test is a test for agents that tend to break chromosomes (clastogens). A micronucleus is a fragment of chromatin that has broken away from a chromosome during cell division and has failed to be included in either of the daughter nuclei. The phenomenon can be observed best in newly formed erythrocytes since these stain differently from the mature erythrocytes in that they exhibit polychromesia for a period of 24 hours or so. Furthermore, the nucleus has been extruded at the laat maturation division so that the micronuclei, which remain behind, are readily visible in an otherwise chromatinfree cell. Micronuclei occur in a small fraction of normal red cells, but their incidence is increased by the action of clastogens. The test is carried out by administering the agent to the test animal, and examining the polychromatic erythrocytes in bone marrow smears after some interval of time has been allowed for micronuclei to form. Haddle and Bruce (1977) reported Aroclor 1254 as nega tive in a micronucleus test. MOMS 017380 134 D. Cytogenetic Analysis In Vitro Hooplngarner et al. (1972) activated cultured human lymphocytes with phytohemagglutinin and treated them with 100 ppm of Aroclor 1254 at various stages of a division cycle. The cells then were examined for chromosomal aberrations for the different stage treatments. Aroclor 1254 had no apparent effect on chromo somal integrity as measured by cytological evidence. E. Dominant Lethality in Rodents A dominant lethal mutation is one that occurs in a germ cell. While it does not impair the function of that cell, it kills the fertilised ovum or the developing embryo. Nice and rats are the preferred experimental species. In its simplest form, the test consists of treating males with the suspected mutagen, mating them with normal females, and counting the number of viable offspring. The test could be used to detect dominant lethal muta tions in females, but it would be difficult to rule out adverse effects on the embryo that might be secondary to non-genetic effects on the mother. Green et al. (1975b) concluded that Aroclors 1242 and 1254 were not mutagenic since they failed to induce dominant lethal mutations in rats. In similar studies reported both by Kepllnger et al. (1972) and Calandra (1976), Aroclors 1242, 1254, and 12(0 were administered to male, albino mice in a single intraperltoneal dosage of either 500 mgAg or 1000 mgAg- Subsequent matings of these animals to control females showed no effect of HONS 017301 135 treatment on the nuaber of implantation or resorption sites, number of viable eabryos, or preiaplantation loss. r. -Summary and Opinion There is no evidence from in vivo test systems that any eosuserciai PCB mixture is mutagenic. The same observation holds true for the bulk of the investigations employing in vitro techniques. In our opinion, therefore, it is quite unlikely that the PCBs as a class evoke mutagenic activity in the huaan, either acutely or chronically. Since chemical mutagenesis and carcinogenesis often correlate for a given active cheaical, this opinion is reinforced by the essentially negative findings on carcinogenesis in populations occupationally exposed to PCBs (sections VIII and XII). HONS 01738* 137 XI. Other Health Effects A. Ensyme Induction 1. Introduction Host chemical* that are allowed to enter the body are converted by the body to a variety of different chemical entities. In this manner, food becomes transformed into energy. Chemicals, other than food or those that are naturally present in the body, that are introduced into the body are generally called `xenoblotics," and they also are frequently converted by the body to deri vatives of the original compounds. The conversion processes are regulated by the eraymatic systems generally termed blotransformatlon systems. Although there are a multitude of xenobiotic sub stances to which humans are exposed, there are only a few different ensyme systems Involved. The body basically biotransforms chemi cals by oxidising, reducing, hydrolysing or combining (conjugating) the agent with other chemicals. Although each of these systems is Important, of particular Interest here are those systems that result in conversion of the original compound to the oxidised derivatives. It is not uncommon for the body to react to some xeno biotic compounds that it normally biotransforms by increasing its ability to perform the biotransformation function by producing an Increase in the amount of enxymes available. This process, which is called `induction* of the ensyme system, effectively makes the body more capable of biotransforming not only the com pound that initiated the induction but also all other compounds HONS 017383 138 that are oxidised by the sane enzymatic system. In this manner It is feasible for a given xenobiotlc aqent to induce a biotrans formation system that affects the ability of the body to biotrans form not only the original compound but also a large number of other xenobiotics as well as some naturally existing chemicals within the body. Shortly, it will be shown that the pcbs in general have been described as being effective, that is, potent Inducers of major oxidative biotransformation systems in experi mental animals and in the human. Via induction of enzymes, the concentration of various normally occurring chemicals may be altered. The scientific evidence associated with these subjects will be evaluated in terms of the available current literature. The major oxidative biotransformation system in the ' body, as far as xenobiotics are concerned, is present in greatest activity in the liver and is present in lesser activity in most other tissues. In experimentsl studies, the liver generally serves as a monitor of drug or chemical effect on the oxidizing enzymes. The enzymes are located in the 'microsomal* fraction of the liver cells. This is a fraction of the cell that can be obtained by proper ultracentrifugation techniques. The biotrans formation system of interest is known as the 'microsoawl mixed function oxidase system (MFO)' Functionally this system operates to incorporate oxygen into the xenobiotic agent via a series of enzymatic actions. The system does this by making an 'active* oxygen atom available via a hemeprotein enzyme. This hemeprotein is in fact a family of proteins collectively identified as HONS 017384 139 - "cytochrome P-450." The ability of the enzyme to operate as an oxidative system is dependent on the existence of several naturally occurring substances and. in particular, on the existence and quantity of available cytochrome p-450 in the microsomal fraction of the liver. Microsomal P-450 can be measured directly or indirectly usinq various substrates. Direct measurement of P-450 is based on measurement of the protein system from which these enzymes obtained their name, that is, when the enzymes are reduced and combined with carbon monoxide they exhibit, in a spectrophoto meter, maximal absorption of light energy at the wavelengths of 450 nanometers, hence the naaw cytochrome P-450 system. The P-450 system can also be measured in terms of its activity on specific substrates such as ethylmorphine and antipyrine. induction of this system is measured in terms of an Increase in P-450 and/or its activity (based on units of protein per sample of mlcrosomes). Investigations of enzyme induction have separated the P-450 enzymes into two groups, identified as p-450 and p-448 groups, on the basis that various components of the p-450 group of enzymes are "induced* to different degrees by different xenoblotlc agents. The P-450 enzymes are ehoae that are mainly induced by the barbiturates, whereas the P-448 enzymes are mainly induced by 3-methylcholanthrene and show maximal absorption at 448 nanometers. The literature includes studies that suggest that the p-448 enzymes as well as the P-450 enzymes are Induced HONS 017385 140 by certain PCBa although there appears to be some species snd tissue specificity in their inductive properties. investigations of the effects of PCBs on cytochroae P-450s have centered on two areas of interest. One Involved the induction mechanism via the use of either a commercially available sample of a single PCB congener (such as 2,4,5,2',4*,5'-hexachlorobiphenyl) that was synthetically prepared and could be tagged with a radioactive atom to facilitate analytical work. Generally, a group of experimental animals (rats) was administered the PCB. Samples were then obtained at various levels. Livers were then examined directly for the quantity of cytochrome p-450 or indi rectly for P-450 and P-448 activity via its enxymatlc action on various substrates. The liver My also be examined histologically ' and for evidence of the state of protein synthesis. Induction of the P-450 enxymes in the human is estimated by measuring the plasma elimination rate (plasM half life) of antipyrlne in controls as compared to exposed subjects. Antipyrlne is a drug that is completely absorbed when given orally and completely metabolised by the liver P-450 microsomal system. The second area of Interest concerned the ability of the liver microsomal system to biotransform PCB. Of particular interest was the nature of the intermediate and final products of the biotransformation process. This subject is important in understanding the toxicology of the PCBs because of the following hypotheses: HQNS 01J386 1*1 - (a) Certain PCBs induce the microsomal mixed funtion oxidation systems thereby influencing not only their own metabolism but also the metabolism and time course of action of available endogenous hormones as well as other xenoblotlcs (Including drugs) administered to humans. - (b) Certain pCBs or contaminants of commercial preparations of PCBs may lead to the formation of intermediate epoxide type derivatives, and these derivatives can covalently bind to macromolecules in the liver thereby leading to hepatic toxicity, 2. Induction of Liver Enxymes various studies have reported on the effect of short term exposure of rats to mixtures of chlorinated biphenyls. One such study by Bcobicbon et al. (1974) used the Aroclors identified as Aroclor 1016, 1221, 1242, and 1254, and another study by a French investigator, Marbonne (1980), used s French preparation known as Phenoclor DP6. In both studies the sample material consisted of a mixture of congeners of the chlorinated biphenyls. These studies showed that when rats were administered 10 ppm of the PCBs in their diet for only one day, the livers from the animals showed Induction of P-450, aniline hydroxylase, and aminopyrine-N-demethylase. The induction of these enxymes was maximum in about five days. If the rats were given 10 ppm of the PCBs in the. diet for 8 consecutive days, induction occurred in three to five days and to a lesser extent over the remaining HONS 017387 142 8 day interval. In the Ecoblchon study, lntraperitoneal injection of the Aroclors in doses of SO mg/kg was made for three consecutive days. Animals were sacrificed 96 hours later. Nixed function oxi dative enzymes were found to be induced in the liver. The greatest induction was seen with the more highly chlorinated Aroclors. The conjugation ensyme induction occurred rapidly on exposure to the Aroclors, and particularly to those Aroclors that are more highly chlorinated. The PCBs used in these studies were commercisl grade. In order to better understand which of the P-450 cytochromes are induced by the PCBs, Ryan et al. (1979) treated groups of rats with Aroclor 1254, phenobarbital or 3-methylcholanthrene. The livers were used to prepare three different P-450 fractions on the basis of differing molecular weights and they identified the three fractions as P-450a, P-450fc and F-450e. All three of the P-450s were obtained from the PCB treated animals. P-4S0a and P-450b were obtained from the phenobarbital treated rata and P-450a and P-450e were isolated from the 3-methylcholanthrene treated rats. (P-450c is probably equivalent to P-448). There fore, this study showed that the Aroclor induced at least three identified cytochromes including the type induced by phenoberbltal and the type induced by 3-methylcholanthrene. in 1980 Parkinson et al. investigated the validity of the concepts that were current at that time regarding the structureactivity relationship between specific PCB congeners and hepatic HONS 017388 143 - enzyme Induction. The study was designed to yield the structure vs. activity data. Basically, they conducted experiments in rats using 8 synthetic PCB congeners plus phenobarbital and methylcholanthrene as enzyme inducers. They concluded that in order for a PCB to induce a methylcholanthrene-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. Nhether PCBs 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 phenoaMnon of induction does not seem to be specifically very harmful to the animals. Allen and Abrahamson (1979) fed rats diets containing 100 ppb of Aroclor 1248, 1254, and 1260 for 13, 26 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 were no greater in those animals that received the diet for a year than in those that received the diet for 13 weeks. Alvares et al. (1973) published results from experi ments that involved treatment of rats with Aroclor 1254. Intraperitoneal administration of 25 mg/kg/day for 6 days HONS 017389 144 - produced a tripling of cytochrome P-448 content of the livere and a 10-fold increaee in the enzyme activity involving benzo(a)pyrene hydroxylation (which ie a typical 3-methylcholanthrene type of induction), aa well as an increase in ethylmorphine-Ndemethylation (a typical phenobarbital type of induction). They therefore concluded that Aroclor 1254 induced a mixture of both P-448 and P-450. In 1977, Alvares and Kappas described some additional work that showed the ability of Aroclor 1254 to cross the placental barrier of the rat, to be transmitted to the neonatal rat through the mother's milk, and to cause increases in biotransfonaation enzymes in the fetus and newborn. Goldstein et al. (1978, 1979) attempted to resolve the question of whether pure PCB congeners had enzyme Inducing properties that were different from those produced by ccsusercial preparations of the single congeners or the PCB coaunercial mix tures (such as Aroclor 1254). These authors synthesized a 'pure" sample of 2,4,5,2',4',5'-hexachlorobiphenyl and showed that it had different enzyme induction properties than did the same commercially obtainable, specially prepared, congener that was reported to be *99% pure*. The difference in the induction capability of the two preparations was primarily in regard to the Induction of P-448 cytochromes in which the synthetically pure Isomer, at doses of 250 mg/kg administered to female rats, induced aryl hydrocarbon hydroxylase (AHHi a P-448 enzyme system) only 5-fold i whereas the commercial isomer at a dose of SOmgAg produced a 30-fold increase of AHH. Also, a GC-HS analysis HONS 017390 145 of the two preparations of hexachlorobiphenyl showed that the commercial preparation contained 4 contaminants that were not present in the pure congener. Two of these contaminants were identified as a tri and a tetra chlorodibenzofuran (TCDF). TCDF was then shown to be a potent inducer of AHH and cyto chrome P-448. The ED (effective dose, 50% of test animals) for TCDF re: enzyme induction was found to be 0.5 micrograms/kg for three days. Therefore, the conclusion was that even a 991 pure congener that was coauaercially obtainable can contain sufficient dlbenzofuran to alter the enzyme induction action. In one report, Alvares et al. (1977) had studied alterations in drug metabolism in both rats and humans. in the rat study Aroclor 1016 elicited a barbiturate type of induction of hepatic enzymes. That Aroclor did not induce cytochrome P-448; however: Aroclor 1254 did induce cytochrome P-448. The human study involved 5 workers in a capacitor manufacturing plant who handled primarily Aroclor 1016. These exposed workers showed a low half-life (10.8 hrs) of antipyrlne as compared to control non-exposed subjects (who showed a half-life of 15.6 hrs). The volume 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, enzyme induction occurs in the human in response to occupational exposure to Aroclor 1016 and the induction HONS 017391 146 as measured by anfclpyrine metabolism is a P-450 type of induction. In 1975 Bickers et al. reported on the effects on liver enzymes associated with topical administration of immer sion oils (as used in microscopy). These immersion oils were known to contain approximately 30t PCBs. One to ten microllters of the oils were applied daily for six days to the shaved backs of rats and the animals were sacrificed on the 7th day. The authors found that both skin and liver enzymes were induced. In a second experiment 10 microliters of the oil was topically administered on one occasion only, and the animals were sacri ficed at various intervals following application of the oil. P-450 and liver monooxygenases were induced (Including benzoa-pyrene hydroxylase, a P-448 enzyme system) showing maximal effect in 2 days with a slow return to normal by 28 days. In this study there must have been very large differences between individuals in the control group because their data show very large differences between groups with only a 95 significance. The immersion oils currently marketed in the USA do not contain PCBs. 3. Metabolites of PCBs Shimada and Sato (1980) studied the reactive metabo lites of PCB metabolism. Their work involved the use of isotopelabeled PCB congeners. This work suggests that PCB epoxides may be the activated forms that covalently bind the macromole cules in the liver cells. A hexaehlorobiphenyl congener HONS 017392 147 (2,4,5,2',4',5'-hexachlorobiphenyl) that has no adjacent unchloriated atons in the biphenyl ring and that cannot be converted to the epoxide wa* found not to be covalently bound althouqh accunulation of this PCB in the liver was found to occur. Other PCBs show covalent binding that is principally with microsomal proteins rather than the ribosomal RNAj a conclusion based on the finding that various proteases would solubilize the radioactivity of the labeled atom. Treatment of the animals with phenobarbital produced livers that showed good covalent binding to the PCB, but treatment of the animals with nethylcholanthrene produced livers with poor PCB binding capability. The authors concluded that PCB epoxides were formed by the monooxygenase system and these epoxides were responsible for the binding of the compound to microsomal proteins. Their conclusions are based on indirect findings. 4. Interactions Based on the Induction of Enzymes by PCBs One report (llurphy et al., 1979) described studies that the 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 enzymes. Their method of measuring 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 comparod to P-448. They found that Aroclor 1254 in rats mainly induced cytochrome P-448 whereas Aroclor 1260 induced mainly MONS 017393 148 - cytochrente P-450. The authors then Indicated that both Aroclors caused animals, to show increased lethality on subsequent admini stration of flurosene. We have difficulty interpreting this article. We do not believe that the conclusions are supported by the data that are given. In one case involving Aroclor 1280 the data are not given in the table and in the other case the data obtained following administration of flurosene do not appear to be different from the control data. 5. Enzymes Other than Cytochromes Affected by PCBa Two additional reports deal with an action of the Aroclors on ATPase activity. One of these reports (Lee and Park, 1979) used cultured human lymphocytes and showed a dose-response relation for Aroclor 1254 and inhibition of mitochondrial respira tion. Frc this effect they indicated that there may be a decrease in adenosine triphosphate (ATP) concentration. We can see no way to evaluate what this report means since the concentrations of the Aroclor used are not correlated with concentrations that might be involved in Intact biological systems. The other report (LaRocca and Carlson, 1979) indicated that the Aroclors produced in vitro inhibition of rat magnesium ATPase activity at a concentration of 30 parts per million. A weak correlation was found between increas ing inhibition and increasing chlorination. A strong correlation was found between PCB-induced inhibition of the ATPases and de creasing aqueous solubility. We don't know what these results signify other than that they seem seem to be incidental findings -- many other chlorinated hydrocarbons do the same thing. HONS 017394 149 6. Summary and Opinion The available data from experimental atudiea on animala and man Indicate that the commercially available preparatione of the PCBs (Aroclors) aa well as some highly purified PCB congeners act to induce some of the hepatic enzymes. Considerable effort has been devoted to determine which of the microsomal enzymes are induced by the Aroclors. There are some data that indicate that the predominant induction occurs for the P-450 type of cytochromes (identified as a phenobarbital-type of induction). When experi ments are conducted with the 'more pure* congeners there is very little evidence for induction of any enzyme systems other than the P-450 cytochromes. In general, induction is greatest with the most highly chlorinated derivatives, but the least chlorinated deriv atives also induce the P-450 cytochromes. The subject of whether the 'pure* congeners of the PCBa have less action on the cytochrome systems than the comawrclal materials may be only of academic Interest, since the preparations that are available to industry and the public are the cosaaercial preparations such as the Aroclors. It should be recognized that authors tend to describe effects due to PCBs whereas they are usually refsrring to effects of Aroclors (such as Aroclor 1254), which are mixtures of PCBs plus various trace contaminants. The commercially available preparations of the PCBs are capable of inducing certain hepatic enzymes in the rat and there is one report suggesting that occupational exposure to HONS 017395 150 - commercial PCBs may induce an hepatic enzyme. There are no data suggesting that the overall health of the animals or man is in fluenced as a consequence of PCB-induced microsomal enzymes. Although it is suggested by some people that changing the meta bolic transformation capability is inherently detrimental to the animal, there is no real evidence to support such an hypothesis. When enzymes are induced and they are then involved in the bio activation of xenobiotic agents, such enzyme Induction could be harmful depending on the dosage sequence and the inherent toxi cologic properties of any specific agent. On the other hand. If the enzymes that are induced are involved in bioinactivation of xenobiotic compounds, then induction may be beneficial to the animal again depending on the dosage sequence and Inherent toxi cologic properties of any specific agent. There is no good ex perimental or clinical evidence that PCBs may act through their enzyme induction capability to affect 'hormone* levels and result in harmful effects on the body. B. PCB Effects on Immunocompetence A few reports appeared prior to 1970 that suggested indirectly that PCBs may influence immunocompetence. In 1970, Vos and Koeman showed that when chicks were fed 400 ppm PCB for 60 days they showed atrophy of the splenic pulp and lymphoid necrosis. (Chicks at higher doses all died during the test.) The chicks also showed porphyria and liver necrosis. In 1971, Vos and Beams reported that commercial PCB samples applied to HONS 017396 151 the akin of rabbits daily five tines weekly for 38 weeks (27 applications each containing 188 rag PCB) produced histologic atrophy of the cortex of the thymus and a reduction in the number of germinal centers in the spleen. At this time the animals showed marked chloracne of the skin, increased fecal coproporphyrin and protoporphyrin as well as liver and kidney damage. The authors stated that these effects were strong in dicators of an immunosuppressive action of the PCBs. In 1977, Loose and co-workers fed Aroclor 1242 to mice for six weeks. The animals were then immunogenically stimulated with sheep red blood cells as an antigen and the antibody response was measured. The method of measuring anti body activity involved plaque-cell estimation in the spleen and the measurement of the plasma immunaproteins. Positive findings were obtained as compared to controls and the authors particularly remarked about the reduced IgA levels found in the PCB-treated animals. It was also noted that clinically subtasic levels of Aroclar 1242 were profoundly immunoeuppressive. These authors also cite the work of Roller and Thigpen (immunosuppres sion by a PCB to pseudorabies virus in rabbits), Vos and van Drlel-Grootenhuis (immunoaupression by PCB in guinea pigs) and Friend and Trainer (increased mortality in ducklings that had been previously exposed to Aroclar 1254 and then inoculated with duck hepatitis virus). HONS 017397 152 In 1973, Loose and co-workers studied the effects of PCBs on host resistance systems. Mice that were fed diets con taining 167 ppm Aroclor 1242 for three weeks and for six weeks exhibited increased sensitivity to salmonella endotoxin and a decreased survival time to inoculation with malaria. Thus they concluded that host resistance was impaired by prior treat ment with PCBs. Also in 1978, Thomas and Hindsdill reported on studies in which they fed monkeys 2.S to 5.0 ppm PCB (Aroclor 1248). After six months the monkeys developed chi oracne, alopecia and facial edema. After 11 months control and treated monkeys were tested with antigens (sheep red blood cells and tetanus toxoid). The only positive finding was in the 5.0 ppm monkeys who showed significantly lower antisheep red cell antibodies as compared to controls. No effect was obtained regarding the antibody response to tetanus toxoid. These authors also fed mice up to 1000 ppm of the PCB for three to five weeks without evidence of overt toxicity, but these animals did show a higher mortality when challenged with the pathogen salmonella typhimurium as compared to the controls. In 1980, Oishi and Hiraga reported on their studies in which they had given mice PCBs (commercial product) by oral intu bation once weekly for four weeks. Other groups of mice were fed CDF (chlorinated dibenxofuran) or CDD (chlorinated dibenzo-p-dioxin). Only the groups of animals that had received 10 or 100 HONS 017398 153 micrograma/kg CDF showed decreased thymus weights, kll groups were 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 PCB pretreated animals did not show increased susceptibility to endotoxin. In the same year (1980) Imanishi et al. showed that mice fed PCBs for 21 days at 100, 200, or 400 micrograms/gm ware significantly more susceptible to herpes simplex virus and electromella virus than were animals fed a KB-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-Chcnq disease, that was related to the consumption of rice-bran oil contaminated with KBs, KDFs 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 15 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 Igfl immune globulin but not IgC. 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. (IONS 017399 154 Environmental chemical effects on immunocompetence have been extensively reviewed by Faith, Luster and Vos (1980). A number of studies cited by them found PCBs to be immuno suppressive in various species (from ducklings and chicks to mice and monkeys), in some cases 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 6.5 mg/kg/day) of Aroclor 1254 to rabbits, showed no significant effect on humoral or cell 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 (.5 mg/kg/day) for four to eight weeks the animals showed significant increase in liver weight. The Faith, Luster and Vos review lists several general factors (nutritional status, hormonal levels and amounts of imraunoregulatory proteins such as alpha-fetoprotein) that influence immune function. Therefore those studies in which immune function was studied following exposure to levels of the PCBs that resulted in overt toxicity are meaningless from an immunotoxicologic viewpoint, in contrast, immunosuppression at dosage levels that do not produce general toxicity would be significant. Summary and Opinion The overall conclusion that can be reached in regard to the studies on the effects of PCBs on immunocompetence is: HONS 017400 155 (1) with exposure conditions that lead to general toxicity, iausunosuppression nay be denonstrable, but it may be indirectly induced; (2) with experimental conditions wherein only subclinical toxicity is observed, such as hepatocyte hypertrophy, there is the possibility that immunosuppression is also produced; and (3) under still lower PCB exposure conditions it is impossible that immuno suppression is involved. Perhaps the best study to estimate a no effect dose for exposure to PCBs would be the Thomas and Hindsdill (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 isuaune system in animal models or the human. C. Porphyria The administration of PCBs to rats 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 sucn 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 increased by Aroclor 1260 HONS 017401 156 and by hexachlorobiphenyl, but the difference was statistically significant only for coproporphyrin (Vos et al., 1972b). Bruckner et al. (1974) observed an increased excretion of urinary copropor phyrin in rats given Aroclor 1242, 5 or 25 ppm for two, four, and six months. Goldstein et al. (1974) emphasized the delayed onset of the PCB-induced porphyria; rats fed 100 ppm of Aroclor 1254 became porphyric after two or seven months of treatment. Although the excretion of coproporphyrin and other porphyrins was increased, the largest elevation was in the uroporphyrin fraction. There was also a marked accumulation of uroporphyrin in the liver. The studies of Goldstein et aK suggest that PCBs may effect uropor phyrin formation or utilization. The induction of delta-aminolev linic synthetase (ALA synthetase, a rate-limiting enzyme in heme synthesis) does not appear to be the mechanism by which porphyria is induced by PCB, as it is fOr many porphyrogenic chemicals. In their studies the increase in ALA synthetase activity was probably secondary to the porphyria. Also, Aroclor acts to increase liver cytochrome P-450 rather than to decrease it. Hexachlorobenzene is known to induce a delayed type of hepatic porphyria similar to that produced by Aroclor 1254. However, the two responses apparently differ significantly as Goldstein et aK reported that the rats fed PCBs did not exhibit the nervous or cutaneous signs associated with hexachlorobenzene poisoning. HONS 01?*02 157 (ii) Clinical Studies. Some of the Yusho patienta ingesting rice oil contaminated with PCBs reported pigmentation of the akin and nails, but there were no studies to evaluate a possible relationship of the reported symptoms to any change in porphyrin metabolism (Kuratsune, 1972). Smith et al. (1981 a.b.c) determined urinary coproporphyrin, uroporphyrin and porphobilinogen in PCB-exposed workers) they did not find a correlation between the urinary porphyrins and the serum level of the lower chlorinated PCBs or the higher chlorinated PCBs. The subjects did not have any recognizable dysfunction and there was no clinically apparent illness with high levels of PCB exposure or with high serum PCB. Other investigations evaluating the health effects of PCB exposure have not reported cases of porphyrin-related disease or cases of porphyria cutanea tarda (Fischbein et al. 1979) Haroni et al. 1981). The observation that PCBs increase ALA synthetase in animals raises the possibility that PCBs can cause an attack of porphyria in patients suffering from acute, intermittent porphyria. However, a case of this type has not been reported in the medical literature. As noted above in studies on the rat, the action of PCBs appears to differ from that of other porphyric agents. HONS 017A03 159 - XII. Epidemiology Although case reports of toxic effects, especially skin lesions related to exposure to chlorinated organic chemicals, have been recorded almost from the beginning of their use (Jones and Alden, 1936), few epidemiological studies appeared until the accidental exposure of a large Japanese population to PCBs, PCDFs 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 must be remembered that there were problems in these studies in assessing the effects because some of the environmental exposures may have involved PCBs that had been altered by processing at high temperatures (Brown, J.F., Jr. et al., 1981). The numbers of individuals exposed occupationally arc relatively small, although some may represent the heaviest and most protracted exposures of any reported, and their added burden of PCBs from the workplace must 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 011604 160 A. Mortality Studies In 1968, an unknown number of persona in the western part of Japan ingested rice oil containing Kanechlor 400 that was contaminated with polychlorinated dibenzofurans (PCDFs) in amounts 250 times more than the usual levels in Japanese PCBs (IARC, 1978) and more than 1000 times the usual levels in u.S. Aroclors. By 1977, 1665 cases of "Yusho" had been recognized based on symptoms of ocular disturbances, skin lesions, primarily subjective neurological symptoms and blood PCB levels (Urabe, 1979). Fifty-one deaths have occurred in these patients and the causes have been reported to include liver cancers and lymphcsMs. However, there have been no reports on the numbers of expected deaths by specific causes based on the usual death rates in simi lar Japanese populations. The distribution of causes may simply represent the usual distribution of deaths found in the age groups characteristic of Yusho patients, and so it is impossible to assess the mortality patterns of these cases at the present time. Bertazzi et al. (1981) have reported a study of 1,310 workers, predominantly woaen, who, beginning in 1946, initially were exposed to Aroclor 1254 and Pyralene 1476 and subsequently were exposed to mixtures with 42% chlorine content. Mortality data were collected on all individuals with six months or more of employment over a 25-year period ending in 1978. The total number of deaths (27) was small but there was an excess of mortality in HONS 017405 161 female workers compared to the general population, which Is un usual 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 (1981) (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 Bertazzi et al. study deserves further attention. A retrospective cohort mortality study of 2,S67 workers in two electrical capacitor manufacturing plants that had used PCBs 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 were 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 was that of the subset of rectal cancers in females in plant 2. The standardized mortality ratios (SMBs) 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 017406 162 as a proxy measure of dose, it is difficult to suggest that the agent is possibly causative for the disease. Although this study has devoted strict attention to details such as the completeness of identification of workers and ascertainment of outcome it has not verified the diagnosis of cases nor investigated the presence of confounding variables. Rectal cancers are often misclassified by location in the intes tinal tract. The classification 'liver cancers* may Include cancers of the gall bladder and biliary system as well as meta static lesions to the liver from cancers at other sites. There fore when one has an excess of liver cancers, verification of specific site within the liver system as well as identification of primary liver lesions is extremely important, especially since che number of deaths from this cause is small. The investigators have not verified the diagnosis of either liver or rectal cancers Since alcohol is considered a frequent etiological agent for cirrhosis of the liver and possibly for liver cancer, some infor mation on consumption would be relevant as a confounding variable No data on possible confounding variables have been reported in the paper. The mortality data from the occupational qroups and the yusho patients are based on very small numbers of deaths and at present do not confirm a carcinogenic effect in man. The obser vation of excess liver cancer deaths in workers occupationally exposed to PCBs is of major interest since the liver was a target HONS 017*07 163 it* for changes in animals and since man has demonstrated evi dence of subclinical alterations in liver 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 relationship of cancers to dose of PCBs. B. Morbidity or Incidence Data Skin Skin lesions have been reported in association with exposure to chlorinated aromatic compounds since the early 1900's (Jones and Alden, 1936). Taylor has emphasized that acneform eruptions are more frequent with the chloronaphthalenes and the dibenzofurans 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 say 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* coaMdones HONS 017408 1(4 sometimes distributed in unusual areas of the body and often associated with cystic areas and yellow pus (Jones and Alden, 1936). Taylor noted that the cystic swelling and hypersecretion of the meibomian glands are important characteristics of the chloracnegenic effect of PCBs compared to other similar chemicals. These were the typical lesions reported by Meigs et al. in 7 of 14 workers exposed to a PCB vapor leak from a heat exchanger in a plant in Connecticut (Meigs et al., 1954). The exposure to vapors was intermittent but of extended duration. Liver function tests were normal in most of these workers and no PCB levels in individuals were obtained, although an air sample prior to the 3 onset of skin disease was 100 ug per m , 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 the skin and nails in 10% of patients. These frequencies were increased subsequently to in clude about 70 to 85% 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 (Kuratsune, 1972). Pigmentation of the skin and eye discharges also occurred in newborns of affected mothers. Ho comparison groups have been included in these studies of Yusho patients. Where the lesions are pathognomic of PCB-related disease this may not be necessary HONS 017409 165 but when the lesions are more general, comparison qroups are essential. There were histopathological changes in five patients autopsied that seem to be associated with contaminated rice oil ingestion. These changes included hyperkeratosis of hair follicles and increased melanin pigment in the basal layer of the epidermis (IARC, 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 PCBs, PCDPs 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 PCB exposure similar to levels in occupational settings. Hara et al. in two separate papers (1974, 1975) 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 (tiara e_t al., 1974; Hara et al., 1975). Discontinuance of the exposure not only decreased the overall PCB level to 75% 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 017A10 166 the correlation of the blood PCB and skin lesions although there are data in this paper on the half-life of PCBs in relation to duration of exposure. Hasegawa has reviewed the health of workers in five plants whose industrial process included exposure to Kanechlor (Haaagawa et al^ , 1972) . The industries included capacitor manufacture) PCB manufacture) and biphenyl recovery. The vapor 3 concentrations ranged from 13 to 965 ug/m . Skin lesions were reported to be unrelated to blood PCBs but generally related to direct skin contact. The average blood PCB level was 370 ppb. The principal dermal findings included brown chromodermatosis of the dorsal joints of hands, fingers and nail beds and acne. There were no further descriptions of the latter lesions so that the presence of chloracne could not be confirmed, but the brown skin discoloration certainly is typical of the Japanese worker reports. Kitamura et al^ described 13 workers fraa an electrical capacitor manufacturing plant (Kitamura et al^., 1973). The lesions in 10 of the workers described in this group are even more vague. They did not include the typical coloration of nails; chloracne was not directly diagnosed; and the follicular lesicns did not occur at points of contact with PCBs. Frcm the description of the study it is not clear that the author's conclusions that the skin lesions were due to PCBs was justified without further in formation on the usual frequency of similar types of skin lesions in normal populations or a description of typical chloracne. The blood PCB level in this group was 820 ppb average. HONS 017611 167 Inoue et al. studied the health of workers who were exposed to Kanechlor 500 in a thread-glossing factory (Inoue et al., 1975). The frequency of skin lesions was low. The blood PCBs were over 50 ppb in 7 out of 54 individuals studied. One person had representative chloracne with blood PCBs of 190-210 ppb. Ouw t al. described one case of chloracne among 34 workers exposed to Aroclor 1242 in capacitor manufacture (Ouw et al., 1976). The average blood pcb was 400 ppb. in addition five workers complained of eczematous rash but there was no de scription of lesions. Seven out of 15 process workers and 6 out of 19 impregnation room workers complained of burning and irritation of the eyes, face and skin. It is difficult to recon cile these complaints with level of exposure since it should have been higher in the latter group of workers than the former. How ever, Aroclor concentrations in air as high as 2220 ug/m were measured. The investigators Indicated that the `dermatological complaints* occur more often among 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 HOMS 017412 168 health of eight workers and found no symptoms or physical signs of chloracne (NIOSH, 1977). There were several subjects who reported skin rashes but not those typical of PCB exposure. The mean PCB level in blood was 98 ppb with the highest value being 286 ppb. Another health hazard evaluation was done after an ac cidental spill of PCBs (NIOSH, 1980). In this situation there were no signs of chloracne. However, the mean blood PCB level of exposed workers was only 6.4 ppb; this was below the mean for unexposed workers. Humphrey studied the PCB level of indi viduals on the basis of fish consumption (Humphrey, 1975). He found that the PCB level was correlated with fish consumption with mean blood levels ranging from 46 ppb to 82 ppb and a maximum individual level of 166 ppb. There were no skin lesions or other health problems associated with PCBs. A medical and biochemical survey was made of 120 male workers exposed to PCBs in the maintenance of railroad cars and locomotives (Chase et al., 1981). Among the exposed group of 86 workers the 'medical histories 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 was there a description of the lesions. It would be of interest to confirm these cases as true chloracne since the current mean plasma PCB level in the exposed group is only 33.4 ppb (range 10-312 ppb), a very low level of PCBs to be associated with chloracne. HONS 017413 169 Fischbein et a_l. (1979) completed a medical survey of capacitor manufacturing workers who were self-selected for physi cal and bio-chemical examinations. A high proportion (49-SSt) of both male and female workers complained of skin disorders with 11% giving a history of acne beginning after the onset of expo sure. 'Dermatologic findings'' were present on physical examina tion in 38 to 41% of female and male workers, respectively. However, these lesions included "erythema, swelling, dryness, and thickening," which would not be lesions characteristic of PC8 exposure. Five percent of the study population had acneform 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 PCB homologues in plasma were 124 ppb and of higher PCBs, 48 ppb. The authors report that the skin findings were correlated with plasma H-PCBs. 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 1S% of workers had eye abnormalities including "injected conjunctiva and palpebral hyperpigmentation and edema." 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. HONS 017<,l<* 170 Haroni et al. (1981) recently reported on two groups 0[ workers who were exposed to PCBs in the manufacture of capacitors. One group (A) had been exposed to both 54% and 42t chlorinated biphenyls. Although the levels of the trichlorinated chemical were similar in current employees in the two plants (128 ppb (A) and 137 ppb (B)), the levels of pentachlorinated agent differed (249 ppb (A) and 88 ppb (B)). It is of interest that 10 cases 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 employees who had worked in a high power capacitor impregnation area of plant A where levels of pentachlorinated biphenyls were high. Their mean blood PCS was 450 ppb. a value not different from that of the five un affected workers but certainly higher than the overall levels in the two plants, naroni et al. also noted two cases of bleeding hemangiomas, but 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 patient had bleeding from the tongue and a cavernous hemangioma was discovered as well as chronic myelocytic leukemia. Case reports 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 et al. examined sludge users, workers in a ca pacitor plant, workers' families and community non-sludge users HONS 017415 171 (Baker e al. 1980). Since the eludge contained PCBa , it was felt that its use as fertiliter night seriously affect the PCB level in the blood. The level of Arocior 1242 ranged from 7.2 to 48.6 ppb and for Arocior 12S4 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 PCB values were above 200 ppb. Smith e^t a. examined workers involved in the maintenance, repair and overhaul of electrical transformers and measured levels of PCBs by job (Smith et 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 017416 172 Smith et al. repotted on the physical findings and symptoms in 197 workers who manufactured electrical equipment. The serum levels of L-PCBs in the workers varied by job, with the geometric means ranging from 89 to S02 ppb, the highest levels (2400 to 3330 ppb) being found in the department where capacitors were processed, finished, and tested, and in a department that had assigned work throughout the plant. The geometric mean level of H-PCBs ranged from 22 to 51 ppb, with the highest values (150 to 250 ppb) in these departments. This plant had always used 42t chlorinated biphenyls, both Aroclor 1242 and 1016. Although there were some symptoms of skin and eye lesions (darkening of skin and nails, skin rash, and irri tated eyes) that appeared to be different between the groups with L-PCB 200 ppb greater than or equal to 200 ppb compared to those with lower values, these differences disappeared when the comparisons were corrected for age and job. Thus one can conclude that symptoms were primarily related to age and job with the latter association being either real or biased. The symptoms were not related to the body burden of PCBs indepen dent of job. No evidence of skin lesions suggestive of chloracne was found on physical examination, in spite of some extraordi narily high PCB blood levels. In a preliminary report, Bahn (1976) indicated the incidence of cancer in 64 employees exposed to Aroclor 1254 in a research and development laboratory and 65 refinery workers HONS 173 with a similar exposure frcm the same area. The investigator reported a significant excess in the incidence of melanoma of the skin as well as pancreatic cancer based on expected cancer rates from the Third National Cancer Survey. In a subsequent letter to the New England Journal of Medicine, Bahn et al. have reported only on the excess of melanoma (Bahn et al., 1976). When Lawrence criticized the study on the basis of the fact that individuals could have been exposed to multiple chemicals in the laboratory environment (Lawrence, 1977), Bahn and col leagues suggested that the reason for emphasizing the melancaia risk was the biological plausibility of such an association whereas an excess risk of pancreatic cancers could have indi cated an association with multiple chemicals (Bahn et al^ , 1977). The investigators themselves have discussed several of the flaws of this study. Information on true exposure is limited and perhaps more importantly one-fourth of the exposed workers had to be omitted. The author has also suggested that she underestimated the death ratio by including individuals during their early years of employment when there had not been a sufficiently long latency from the time of first exposure of PCB to the expected time of cancer development. There are other problems with this study related to the identification of cases in the exposed population and the comparability of case ascertainment in the Third National Cancer Survey data. Apparently the investigators identified casea MONS 017418 174 without attempting to validate the accuracy of diagnosis. Pancreatic cancer is very difficult to recognize and diagnose. The diagnoses of the two cases need to be validated from hospi tal records in order to make them comparable to data from the survey. Skin cancers such as melanomas may be diagnosed in doctors' offices. Thus, the lesions could be missed in the cancer survey data where records were obtained primarily from hospitals but identified in populations with routine medical care. It would be necessary to validate the cases in this study through the use of hospital and pathology records and then to compare these eases to a comparable group of employed individuals who have had active medical surveillance by physi cians. In sumsiary. the data on skin lesions in relation to PCB exposures have indicated a remarkable consistency. Individ uals who have a body burden indicated by a blood level of 200 or more ppb PCBs have an increased risk of chloracne. There is little evidence of risk below this level and those studies that do suggest a risk at lower levels usually do not have a compari son group or they have not collected the data in a manner such that bias might be avoided. The data also suggest that typical skin lesions may occur more frequently in workers exposed to PCBs that have been heated and to PCBs that have 54% or more chlorination. Since the akin lesions occur more frequently after heating, it is possible that chloracne is actually due HONS 017*19 175 to some alteration or contamination of the PCBs with more acnegenic materials such as dibenzofurans, as found in the Yusho incident. Symptoms of chloracne are reported frequently among those who use Kanechlor; this could be related to level of exposure or its high 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 summarized in Table 8. The early study of Meigs et a_l. involving a PCB leak from a heat exchanger indicated that there were no abnormalities in seven workers with chloracne except for some transient changes in liver function tests in one worker (neigs et al., 1954). These changes could not be definitely attributed to PCBs. The study of Hasegawa et al. of 99 workers in six indus trial plants in Japan indicated that increases could occur in enzymes such as SCOT, SGPT and decreases in blood cholinesterase (Hasegawa al., 1972). The authors regarded the changes in liver function as mild and not clinically significant. Kitamura et al. (1973) indicated that in the 13 capacitor workers the hepatic function tests were normal. HONS 017420